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10,782	PROVERA® (medroxyprogesterone acetate tablets, USP) WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia.) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders.) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.) Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS, Malignant Neoplasm, Breast Cancer.) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION PROVERA® tablets contain medroxyprogesterone acetate, which is a derivative of progesterone. It is a white to off-white, odorless crystalline powder, stable in air, melting between 200 and 210°C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, structural formula Each PROVERA tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate and the following inactive ingredients: calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, and talc. The 2.5 mg tablet contains FD&C Yellow No. 6. CLINICAL PHARMACOLOGY Medroxyprogesterone acetate (MPA) administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered MPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. Pharmacokinetics The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight PROVERA 2.5 mg tablets or a single administration of two PROVERA 10 mg tablets under fasting conditions. In another study, the steady- state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one PROVERA 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of PROVERA tablets were highly variable and are summarized in Table 1. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA) Tablet Strength C max (ng/mL) T max (h) Auc 0-(∞) (ng·h/mL) t 1/2 (h) Vd/f (L) CL/f (mL/min) Single Dose 2 × 10 mg 8 × 2.5 mg 1.01 (0.599) 0.805 (0.413) 2.65 (1.41) 2.22 (1.39) 6.95 (3.39) 5.62 (2.79) 12.1 (3.49) 11.6 (2.81) 78024 (47220) 62748 (40146) 64110 (42662) 74123 (35126) Multiple Dose 10 mg * 0.71 (0.35) 2.83 (1.83) 6.01 (3.16) 16.6 (15.0) 40564 (38256) 41963 (38402) Following Day 7 dose A. Absorption: No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration. Administration of PROVERA with food increases the bioavailability of MPA. A 10 mg dose of PROVERA, taken immediately before or after a meal, increased MPA Cmax (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food. B. Distribution: MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin. C. Metabolism: Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. D. Excretion: Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. E. Specific Populations Hepatic Insufficiency MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal Insufficiency The effect of renal impairment on the pharmacokinetics of PROVERA has not been studied. F. Drug Interactions Medroxyprogesterone acetate (MPA) is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted. Inducers and/or inhibitors of CYP3A4 may affect the metabolism of MPA. CLINICAL STUDIES Effects on the Endometrium In a 3-year, double-blind, placebo-controlled study of 356 nonhysterectomized, postmenopausal women between 45 and 64 years of age randomized to receive placebo (n=119), 0.625 mg conjugated estrogen only (n=119), or 0.625 mg conjugated estrogen plus cyclic PROVERA (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg PROVERA plus 0.625 mg conjugated estrogens compared to the group receiving 0.625 mg conjugated estrogens only. See Table 2. Table 2. Number (%) of Endometrial Biopsy Changes Since Baseline After 3 Years of Treatment Histological Results Placebo (n=119) CEE † (n=119) PROVERA ‡ + CEE (n=118) Normal/No hyperplasia (%) 116 (97) 45 (38) 112 (95) Simple (cystic) hyperplasia (%) 1 (1) 33 (28) 4 (3) Complex (adenomatous) hyperplasia (%) 1 (1) 27 (22) 2 (2) Atypia (%) 0 14 (12) 0 Adenocarcinoma (%) 1 (1) 0 0 Includes most extreme abnormal result † CEE = conjugated equine estrogens 0.625 mg/day ‡ PROVERA = medroxyprogesterone acetate tablets 10 mg/day for 12 days In a second 1-year study, 832 postmenopausal women between 45 and 65 years of age were treated with daily 0.625 mg conjugated estrogen (days 1-28), plus either 5 mg cyclic PROVERA or 10 mg cyclic PROVERA (days 15-28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic PROVERA (days 15 28) plus daily conjugated estrogens showed a significantly lower rate of hyperplasia as compared to the conjugated estrogens only group. See Table 3. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3. Number (%) of Women with Endometrial Hyperplasia at 1 Year CEE MPA † + CEE * (n=283) MPA 5 mg (n=277) MPA 10 mg (n=272) Cystic hyperplasia (%) 55 (19) 3 (1) 0 Adenomatous hyperplasia without atypia 2 (1) 0 0 * CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. † Cyclic medroxyprogesterone acetate on days 15 to 28 Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women- years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4 : RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS a,b Event Relative Risk CE/MPA vs placebo (95%nCI c) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.23 (0.99-1.53) 1.28 (1.00-1.63) 1.10 (0.70-1.75) 41 31 8 34 25 8 All strokes 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09-1.90) 26 18 Deep vein thrombosisd 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancere 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancerd 0.81 (0.48-1.36) 6 7 Cervical cancerd 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47–0.96) 11 16 Vertebral fracturesd 0.65 (0.46-0.92) 11 17 Lower arm/wrist fracturesd 0.71 (0.59-0.85) 44 62 Total fracturesd 0.76 (0.69-0.83) 152 199 Overall mortalityf 1.00 (0.83-1.19) 52 52 Global Indexg 1.13 (1.02-1.25) 184 165 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in “global index”. e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g 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, colorectal cancer, hip fracture, or death due to other causes. Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a nonsignificant trend toward reduced risk in overall mortality [hazard ration (HR) 0.69 (95 percent CI, 0.44 1.07)]. Women's Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were aged 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 33 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use). INDICATIONS AND USAGE PROVERA tablets are indicated for the treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. They are also indicated for use in the prevention of endome trial hyperplasia in nonhysterectomized postmenopausal women who are receiving daily oral conjugated estrogens 0.625 mg tablets. CONTRAINDICATIONS PROVERA is contraindicated in women with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of breast cancer. 3. Known or suspected estrogen- or progesterone-dependent neoplasia. 4. Active DVT, PE, or a history of these conditions 5. Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions. 6. Known anaphylactic reaction or angioedema to PROVERA. 7. Known liver impairment or disease. 8. Known or suspected pregnancy. WARNINGS See BOXED WARNINGS. 1. Cardiovascular Disorders. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda a. Stroke In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). (See CLINICAL STUDIES.) The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. b. Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women- years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus 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 plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) 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 plus MPA group and the placebo group in HERS, HERS II, and overall. c. Venous Thromboembolism In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women- years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See CLINICAL STUDIES.) Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens plus progestins 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. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Malignant Neoplasms a. Breast Cancer The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus 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 versus 25 cases per 10,000 women-years, for CE plus 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 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) 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. (See CLINICAL STUDIES.) Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, or routes of administration. 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 healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. b. Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times 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 Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen plus progestin therapy 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 genital 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. c. Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. 3. Probable Dementia In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.) 4. Visual Abnormalities Discontinue estrogen plus progestin therapy 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, estrogen plus progestin therapy should be permanently discontinued. PRECAUTIONS A. General Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 an increased risk of breast cancer. 2. Unexpected abnormal vaginal bleeding In cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated. 3. Elevated blood pressure Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy. 4. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. 5. Hepatic Impairment and/or past history of cholestatic jaundice Estrogens plus progestins may be poorly metabolized in women with impaired liver function. For women 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. 6. Fluid Retention Progestins may cause some degree of fluid retention. Women who have conditions which might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogen plus progestin are prescribed. 7. Hypocalcemia Estrogen plus progestin therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 8. Exacerbation of other conditions Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda B. Patient Information Physicians are advised to discuss the Patient Information leaflet with women for whom they prescribe PROVERA. There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1000 male births. The risk may be increased with exposure to PROVERA. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of PROVERA has not been established. Inform the patient of the importance of reporting exposure to PROVERA in early pregnancy. C. Drug-Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy: 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) levels leading to increased circulating total thyroid hormone levels 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. Women on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda D. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity: Long-term intramuscular administration of medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate to rats and mice. Long-term continuous administration of estrogen plus progestin therapy has shown an increased risk of breast cancer and ovarian cancer. (See WARNINGS and PRECAUTIONS.) Genotoxicity: Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Fertility: Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment. E. Pregnancy Pregnancy Category X: PROVERA should not be used during pregnancy. (See CONTRAINDICATIONS.) There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to PROVERA during the first trimester of pregnancy. However, a clear association between these conditions with use of PROVERA has not been established. F. Nursing Mothers PROVERA should not be used during lactation. Detectable amounts of progestin have been identified in the breast milk of nursing mothers receiving progestins. G. Pediatric Use PROVERA tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population. H. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing PROVERA alone to determine whether those over 65 years of age differ from younger subjects in their response to PROVERA alone. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See CLINICAL STUDIES.) Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen- alone or estrogen plus progestin when compared to placebo. (See WARNINGS, Probable Dementia.) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia.) ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS, and PRECAUTIONS. 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 practice. The following adverse reactions have been reported in women taking PROVERA tablets, without concomitant estrogens treatment: 1. Genitourinary system Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions. 2. Breasts Breast tenderness, mastodynia or galactorrhea has been reported. 3. Cardiovascular Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported. 4. Gastrointestinal Nausea, cholestatic jaundice. 5. Skin Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported. 6. Eyes Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7. Central nervous system Mental depression, insomnia, somnolence, dizziness, headache, nervousness. 8. Miscellaneous Hypersensitivity reactions (for example, anaphylaxis and anaphylactoid reactions, angioedema), rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance. The following adverse reactions have been reported with estrogen plus progestin therapy. 1. Genitourinary system Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrheal/pelvic pain; 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 gallbladder disease; pancreatitis; enlargement of hepatic hemangiomas. 5. Skin Chloasma or melasma that 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; arthalgias; leg cramps; changes in libido; urticaria, angioedema, Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides. OVERDOSAGE Overdosage of estrogen plus progestin therapy may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of CE plus MPA together with institution of appropriate symptomatic care. DOSAGE AND ADMINISTRATION Secondary Amenorrhea PROVERA tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of PROVERA daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing PROVERA therapy. Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of PROVERA may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of PROVERA daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with PROVERA. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with PROVERA. Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens When estrogen is prescribed for a postmenopausal woman with a uterus, a 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 for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3 to 6 month intervals) to determine if treatment is still necessary (see 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. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PROVERA tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle. Patients should be started at the lowest dose. The lowest effective dose of PROVERA has not been determined. HOW SUPPLIED PROVERA Tablets are available in the following strengths and package sizes: 2.5 mg (scored, round, orange) Bottles of 30 NDC 0009-0064-06 Bottles of 100 NDC 0009-0064-04 5 mg (scored, hexagonal, white) Bottles of 100 NDC 0009-0286-03 10 mg (scored, round, white) Bottles of 100 NDC 0009-0050-02 Bottles of 500 NDC 0009-0050-11 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. “Keep out of reach of children” Rx only company logo LAB-0144- 5.2 Revised May 2015 Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION PROVERA (pro-VE-rah) (medroxyprogesterone acetate tablets, USP) Read this Patient Information before you start taking PROVERA and read what you get each time you refill your PROVERA prescription. There may be new information. This information 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 PROVERA (a progestin hormone)? ● Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). ● Using estrogens with progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. ● Using estrogens with progestins may increase your chance of getting dementia, based on a study of women age 65 years or older. ● You and your healthcare provider should talk regularly about whether you still need treatment with PROVERA. What is PROVERA? PROVERA is a medicine that contains medroxyprogesterone acetate, a progestin hormone. What is PROVERA used for? PROVERA is used to: • Treat menstrual periods that have stopped or to treat abnormal uterine bleeding. Women with a uterus who are not pregnant, who stop having regular menstrual periods or who begin to have irregular menstrual periods may have a drop in their progesterone level. Talk with your healthcare provider about whether PROVERA is right for you. • Reduce your chances of getting cancer of the uterus (womb). In postmenopausal women with a uterus who use estrogens, taking progestin in combination with estrogen will reduce your chance of getting cancer of the uterus (womb). Who should not take PROVERA? Do not start taking PROVERA if you: • have unusual vaginal bleeding Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • currently have or have had certain cancers Estrogen plus progestin may increase your chance of getting certain types of cancers, including cancer of the breast. If you have or have had cancer, talk with your healthcare provider about whether you should use PROVERA. • had a stroke or heart attack • currently have or have had blood clots • currently have or have had liver problems • are allergic to PROVERA or any of its ingredients See the list of ingredients in PROVERA at the end of this leaflet. • think you may be pregnant PROVERA is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use PROVERA if the test is positive and talk to your healthcare provider. There may be an increased risk of minor birth defects in children whose mothers take PROVERA during the first 4 months of pregnancy. PROVERA should not be used as a test for pregnancy. What should I tell my healthcare provider before taking PROVERA? Before you take PROVERA, tell your healthcare provider if you: • have any other medical problems Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis (severe pelvic pain), lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium in your blood. • are going to have surgery or will be on bed rest Your healthcare provider will let you know if you need to stop taking PROVERA. ● are breast feeding The hormone in PROVERA can pass into your breast milk. Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PROVERA works. PROVERA may also affect how other medicines work. How should I take PROVERA? Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. The lowest effective dose of PROVERA has not been determined. You Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether you still need treatment with PROVERA. 1. Absence of menstrual period: PROVERA may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. 2. Abnormal Uterine Bleeding: PROVERA may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. 3. Overgrowth of the lining of the uterus: When used in combination with oral conjugated estrogens in postmenopausal women with a uterus, PROVERA may be given in doses ranging from 5 or 10 mg daily for 12 to 14 straight days per month. What are the possible side effects of PROVERA? The following side effects have been reported with the use of PROVERA alone: • breast tenderness • breast milk secretion • breakthrough bleeding • spotting (minor vaginal bleeding) • irregular periods • amenorrhea (absence of menstrual periods) • vaginal secretions • headaches • nervousness • dizziness • depression • insomnia, sleepiness, fatigue • premenstrual syndrome-like symptoms • thrombophlebitis (inflamed veins) • blood clot • itching, hives, skin rash • acne • hair loss, hair growth • abdominal discomfort • nausea • bloating • fever • increase in weight • swelling • changes in vision and sensitivity to contact lenses Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call your healthcare provider right away if you get hives, problems breathing, swelling of the face, mouth, tongue or neck. The following side effects have been reported with the use of PROVERA with an estrogen. Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include: • heart attack • stroke • blood clots • dementia • breast cancer • cancer of the uterus • cancer of the ovary • high blood pressure • high blood sugar • gallbladder disease • liver problems • changes in your thyroid hormone levels • enlargements of benign tumors (“fibroids”) Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: • new breast lumps • unusual vaginal bleeding • changes in vision and speech • sudden new severe headaches • severe pains in your chest or legs with or without shortness of breath, weakness and fatigue • memory loss or confusion Less serious, but common side effects include: • headache • breast pain • irregular vaginal bleeding or spotting • stomach or abdominal cramps, bloating • nausea and vomiting • hair loss • fluid retention • vaginal yeast infection Reference ID: 3749814 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 PROVERA with or without estrogen. For more information, ask your healthcare provider or pharmacist for advice about side effects. Tell your healthcare provider if you have side effect that bothers you or does not go away. You may report side effects to Pfizer at 1-800-438-1985 or FDA at 1-800 FDA-1088. What can I do to lower my chances of a serious side effect with PROVERA? • Talk with your healthcare provider regularly about whether you should continue taking PROVERA. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb). • See your healthcare provider right away if you get vaginal bleeding while taking PROVERA. • Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare 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 a higher chance of getting heart disease. Ask your healthcare provider for ways to lower your chance of getting heart disease. General information about safe and effective use of PROVERA • Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. • Do not take PROVERA for conditions for which it was not prescribed. • Do not give PROVERA to other people, even if they have the same symptoms you have. It may harm them. Keep PROVERA out of the reach of children. This leaflet provides a summary of the most important information about PROVERA. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about PROVERA that is written for health professionals. You can get more information by calling the toll-free number, 1-800-438-1985. What are the ingredients in PROVERA? Each PROVERA tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate. Inactive ingredients: calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, talc. The 2.5 mg tablet contains FD&C Yellow No. 6. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com Rx only company logo LAB-0365-6.1 Revised May 2015 Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.784049	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011839s079s080lbl.pdf', 'application_number': 11839, 'submission_type': 'SUPPL ', 'submission_number': 79}
10,784	SOLU-MEDROL® (methylprednisolone sodium succinate for injection, USP) The formulations containing benzyl alcohol should not be used in neonates. For Intravenous or Intramuscular Administration DESCRIPTION SOLU-MEDROL Sterile Powder is an anti-inflammatory glucocorticoid, which contains methylprednisolone sodium succinate as the active ingredient. Methylprednisolone sodium succinate, USP, is the sodium succinate ester of methylprednisolone, and it occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol; it is insoluble in chloroform and is very slightly soluble in acetone. The chemical name for methylprednisolone sodium succinate is pregna-1,4-diene-3,20 dione,21-(3-carboxy-1-oxopropoxy)-11,17-dihydroxy-6-methyl-monosodium salt, (6α, 11β), and the molecular weight is 496.53. The structural formula is represented below: structural formula Methylprednisolone sodium succinate is soluble in water; it may be administered in a small volume of diluent and is well suited for intravenous use in situations where high blood levels of methylprednisolone are required rapidly. SOLU-MEDROL is available in preservative and preservative-free formulations: Preservative-free Formulations 40 mg Act-O-Vial System (Single-Use Vial)—Each mL (when mixed) contains methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.46 mg dibasic sodium phosphate dried; and 25 mg lactose hydrous. 125 mg Act-O-Vial System (Single-Use Vial)—Each 2 mL (when mixed) contains methylprednisolone sodium succinate equivalent to 125 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; and 17.4 mg dibasic sodium phosphate dried. Reference ID: 3032293 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 500 mg Act-O-Vial System (Single-Use Vial)—Each 4 mL (when mixed) contains methylprednisolone sodium succinate equivalent to 500 mg methylprednisolone; also 6.4 mg monobasic sodium phosphate anhydrous; and 69.6 mg dibasic sodium phosphate dried. 1 gram Act-O-Vial System (Single-Use Vial)—Each 8 mL (when mixed) contains methylprednisolone sodium succinate equivalent to 1 gram methylprednisolone; also 12.8 mg monobasic sodium phosphate anhydrous; and 139.2 mg dibasic sodium phosphate dried. Formulations preserved with Benzyl Alcohol 40 mg Act-O-Vial System (Single-Use Vial)—Each mL (when mixed) contains methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.46 mg dibasic sodium phosphate dried; 25 mg lactose hydrous; 8.8 mg benzyl alcohol added as preservative. 125 mg Act-O-Vial System (Single-Use Vial)—Each 2 mL (when mixed) contains methylprednisolone sodium succinate equivalent to 125 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.4 mg dibasic sodium phosphate dried; 17.6 mg benzyl alcohol added as preservative. 500 mg Act-O-Vial System (Single-Use Vial)—Each 4 mL (when mixed) contains methylprednisolone sodium succinate equivalent to 500 mg methylprednisolone; also 6.4 mg monobasic sodium phosphate anhydrous; 69.6 mg dibasic sodium phosphate dried; 33.7 mg benzyl alcohol added as preservative. 1 gram Act-O-Vial System (Single-Use Vial)—Each 8 mL (when mixed) contains methylprednisolone sodium succinate equivalent to 1 gram methylprednisolone; also 12.8 mg monobasic sodium phosphate anhydrous; 139.2 mg dibasic sodium phosphate dried; 66.8 mg benzyl alcohol added as preservative. 500 mg Vial—Each 8 mL (when mixed as directed) contains methylprednisolone sodium succinate equivalent to 500 mg methylprednisolone; also 6.4 mg monobasic sodium phosphate anhydrous; 69.6 mg dibasic sodium phosphate dried. This package does not contain diluent. Recommended diluent (Bacteriostatic water) contains benzyl alcohol as a preservative. 1 gram Vial—Each 16 mL (when mixed as directed) contains methylprednisolone sodium succinate equivalent to 1 gram methylprednisolone; also 12.8 mg monobasic sodium phosphate anhydrous; 139.2 mg dibasic sodium phosphate dried. This package does not contain diluent. Recommended diluent (Bacteriostatic water) contains benzyl alcohol as a preservative. 2 gram Vial with Diluent—Each 30.6 mL (when mixed as directed) contains methylprednisolone sodium succinate equivalent to 2 grams methylprednisolone; also 25.6 mg monobasic sodium phosphate anhydrous; 278 mg dibasic sodium phosphate dried; 273 mg benzyl alcohol added as preservative. The packaged diluent (Bacteriostatic Water for Injection) contains benzyl alcohol as a preservative. IMPORTANT — Use only the accompanying diluent Reference ID: 3032293 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda or Bacteriostatic Water For Injection with Benzyl Alcohol when reconstituting SOLU-MEDROL. Use within 48 hours after mixing. When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8 and the tonicities are, for the 40 mg per mL solution, 0.50 osmolar; for the 125 mg per 2 mL solution, 0.40 osmolar; for the 1 gram per 8 mL solution, 0.44 osmolar; for the 2 gram per 30.6 mL solutions, 0.42 osmolar. (Isotonic saline = 0.28 osmolar.) CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), 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. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. Methylprednisolone is a potent anti-inflammatory steroid with greater anti-inflammatory potency than prednisolone and even less tendency than prednisolone to induce sodium and water retention. Methylprednisolone sodium succinate has the same metabolic and anti-inflammatory actions as methylprednisolone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. Following the intravenous injection of methylprednisolone sodium succinate, demonstrable effects are evident within one hour and persist for a variable period. Excretion of the administered dose is nearly complete within 12 hours. Thus, if constantly high blood levels are required, injections should be made every 4 to 6 hours. This preparation is also rapidly absorbed when administered intramuscularly and is excreted in a pattern similar to that observed after intravenous injection. INDICATIONS AND USAGE When oral therapy is not feasible, and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intravenous or intramuscular use of SOLU-MEDROL Sterile Powder is indicated as follows: Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. Reference ID: 3032293 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of 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. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis (systemic therapy) and ulcerative colitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults (intravenous administration only; intramuscular administration is contraindicated), pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. Nervous System: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, or craniotomy. Ophthalmic diseases: Sympathetic ophthalmia, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, temporal arteritis, polymyositis, and systemic lupus erythematosus. Reference ID: 3032293 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS SOLU-MEDROL Sterile Powder is contraindicated: • in systemic fungal infections and patients with known hypersensitivity to the product and its constituents. • for intrathecal administration. Reports of severe medical events have been associated with this route of administration. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. Additional contraindication for the use of SOLU-MEDROL Sterile Powder preserved with benzyl alcohol: Formulations preserved with benzyl alcohol are contraindicated for use in premature infants. (See WARNINGS and PRECAUTIONS, Pediatric Use.) WARNINGS General Formulations with preservative (see DESCRIPTION) contain benzyl alcohol, which is potentially toxic when administered locally to neural tissue. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS, Pediatric Use). Injection of SOLU-MEDROL may result in dermal and/or subdermal changes forming depressions in the skin at the injection site. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy who are subjected to any unusual stress before, during, and after the stressful situation. Reference ID: 3032293 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including SOLU-MEDROL, should not be used for the treatment of traumatic brain injury. Cardio-renal Average and large doses of corticosteroids 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. Literature reports suggest an apparent association between the use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Hypothalamic-pituitary adrenal (HPA) axis suppression, Cushing’s syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use. Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. 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. Infections General Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infections with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Do not use intra articularly, intrabursally or for intratendinous administration for local effect in the presence of acute local infection. A study has failed to establish the efficacy of methylprednisolone sodium succinate in the treatment of sepsis syndrome and septic shock. The study also suggests that treatment of these conditions with methylprednisolone sodium succinate may increase the risk of Reference ID: 3032293 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mortality in certain patients (i.e., patients with elevated serum creatinine levels or patients who develop secondary infections after methylprednisolone sodium succinate). Fungal infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions, Amphotericin B injection and potassium-depleting agents). Special pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis 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. There is currently no evidence of benefit from steroids in this condition. Tuberculosis The use of corticosteroids 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 appropriate antituberculous regimen. 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 receiving corticosteroids as replacement therapy, e.g., for Addison’s disease. Reference ID: 3032293 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Viral infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. 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. Neurologic Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS, Gastrointestinal and Neurologic/Psychiatric). 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 be used cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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. 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 congestive heart failure, hypertension, or renal insufficiency. Reference ID: 3032293 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. 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. Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect due to decreased metabolism of corticosteroids in patients with cirrhosis. 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 lead to inhibition of bone growth in pediatric patients 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. Local injection of a steroid into a previously infected site is not usually recommended. Neurologic-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 corticosteroids 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. Elevations of creatine Reference ID: 3032293 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids, and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on 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 Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see Drug Interactions, Hepatic Enzyme Inhibitors). Anticholinesterases: 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. Anticoagulants, oral: 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. Reference ID: 3032293 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory agents (NSAIDs): Concomitant use of aspirin (or other nonsteroidal 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. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination). Reference ID: 3032293 11 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 No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy: Teratogenic effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have 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. Corticosteroids 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. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to continue nursing, or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Some formulations of this product contain benzyl alcohol as a preservative (see DESCRIPTION). Carefully examine vials to determine formulation that is being used. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids 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 Reference ID: 3032293 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, 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 corticosteroids 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. Pediatric patients 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 pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use Clinical studies 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. ADVERSE REACTIONS The following adverse reactions have been reported with SOLU-MEDROL or other corticosteroids: Allergic reactions: Allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, burning or tingling (especially in the perineal area after intravenous injection), cutaneous and subcutaneous atrophy, dry scaly skin, Reference ID: 3032293 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, 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 pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS, Neurologic). Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non- sterile administration (see WARNINGS), malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. Reference ID: 3032293 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION NOTE: Some of the SOLU-MEDROL formulations contain benzyl alcohol (see DESCRIPTION, WARNINGS and PRECAUTIONS, Pediatric Use) Because of possible physical incompatibilities, SOLU-MEDROL should not be diluted or mixed with other solutions. Use only the accompanying diluent or Bacteriostatic Water For Injection with Benzyl Alcohol when reconstituting SOLU-MEDROL (see DESCRIPTION). Use within 48 hours after mixing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. This preparation may be administered by intravenous injection, by intravenous infusion, or by intramuscular injection, the preferred method for initial emergency use being intravenous injection. Following the initial emergency period, consideration should be given to employing a longer acting injectable preparation or an oral preparation. There are reports of cardiac arrhythmias and/or cardiac arrest following the rapid administration of large IV doses of SOLU-MEDROL (greater than 0.5 gram administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of large doses of methylprednisolone sodium succinate, and may be unrelated to the speed or duration of infusion. When high dose therapy is desired, the recommended dose of SOLU-MEDROL Sterile Powder is 30 mg/kg administered intravenously over at least 30 minutes. This dose may be repeated every 4 to 6 hours for 48 hours. In general, high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized; usually not beyond 48 to 72 hours. In other indications, initial dosage will vary from 10 to 40 mg of methylprednisolone depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administrations in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. 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. 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 the corticosteroid for a period of time Reference ID: 3032293 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. SOLU-MEDROL may be administered by intravenous or intramuscular injection or by intravenous infusion, the preferred method for initial emergency use being intravenous injection. To administer by intravenous (or intramuscular) injection, prepare solution as directed. The desired dose may be administered intravenously over a period of several minutes. If desired, the medication may be administered in diluted solutions by adding Water for Injection or other suitable diluent (see below) to the Act-O-Vial and withdrawing the indicated dose. To prepare solutions for intravenous infusion, first prepare the solution for injection as directed. This solution may then be added to indicated amounts of 5% dextrose in water, isotonic saline solution, or 5% dextrose in isotonic saline solution. In pediatric patients, the initial dose of methylprednisolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in three or four divided doses (3.2 to 48 mg/m2bsa/day). The National Heart, Lung, and Blood Institute (NHLBI) recommended dosing for systemic prednisone, prednisolone, or methylprednisolone in pediatric patients 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 the patient achieves a peak expiratory flow rate of 80% of his or her personal best or until 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. Dosage may be reduced for infants and children but should be governed more by the severity of the condition and response of the patient than by age or size. It should not be less than 0.5 mg per kg every 24 hours. Dosage must be decreased or discontinued gradually when the drug has been administered for more than a few days. If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued. Routine laboratory studies, such as urinalysis, two-hour postprandial blood sugar, determination of blood pressure and body weight, and a chest X-ray should be made at regular intervals during prolonged therapy. Upper GI X-rays are desirable in patients with an ulcer history or significant dyspepsia. In treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of methylprednisolone for a week followed by 64 mg every other day for 1 month have been shown to be effective (see PRECAUTIONS, Neurologic-psychiatric). Reference ID: 3032293 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. DIRECTIONS FOR USING THE ACT-O-VIAL SYSTEM 1. Press down on plastic activator to force diluent into the lower compartment. 2. Gently agitate to effect solution. 3. Remove plastic tab covering center of stopper. 4. Sterilize top of stopper with a suitable germicide. 5. Insert needle squarely through center of stopper until tip is just visible. Invert vial and withdraw dose. usage illustration STORAGE CONDITIONS Protect from light. Store unreconstituted product at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Store solution at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Use solution within 48 hours after mixing. HOW SUPPLIED SOLU-MEDROL Sterile Powder preserved with benzyl alcohol is available in the following packages: 17 Reference ID: 3032293 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 40 mg Act-O-Vial System (Single-Use 1 gram Act-O-Vial System (Single-Use Vial) Vial) 1 mL NDC 0009-0113-12 8 mL NDC 0009-3389-01 25 x1 mL NDC 0009-0113-19 500 mg (Multi-Dose Vial) 125 mg Act-O-Vial System (Single-Use 8 mL NDC 0009-0758-01 Vial) 25 x 2 mL NDC 0009-0190-16 1 gram (Multi-Dose Vial) 500 mg Act-O-Vial System (Single-Use 16 mL NDC 0009-0698-01 Vial) 4 mL NDC 0009-0765-02 2 gram Vial with Diluent NDC 0009-0796-01 SOLU-MEDROL Sterile Powder preservative-free is available in the following packages: 40 mg Act-O-Vial System (Single-Use 1 gram Act-O-Vial System (Single-Use Vial) Vial) 25 x1 mL NDC 0009-0039-28 8 mL NDC 0009-0018-20 125 mg Act-O-Vial System (Single-Use Vial) 25 x 2 mL NDC 0009-0047-22 500 mg Act-O-Vial System (Single-Use Vial) 4 mL NDC 0009-0003-02 company logo LAB-0161-3.0 Revised October 2011 Reference ID: 3032293 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.861299	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/011856s103s104lbl.pdf', 'application_number': 11856, 'submission_type': 'SUPPL ', 'submission_number': 104}
10,785	NDA 11-870/S-040 Page 3 DIURIL® (CHLOROTHIAZIDE) ORAL SUSPENSION DESCRIPTION DIURIL* (Chlorothiazide) is a diuretic and antihypertensive. It is 6-chloro-2H-1,2,4-benzothiadiazine 7-sulfonamide 1,1-dioxide. Its empirical formula is C7H6ClN3O4S2 and its structural formula is: structural formula It is a white, or practically white, crystalline powder with a molecular weight of 295.72, which is very slightly soluble in water, but readily soluble in dilute aqueous sodium hydroxide. It is soluble in urine to the extent of about 150 mg per 100 mL at pH 7. DIURIL Oral Suspension contains 250 mg of chlorothiazide per 5 mL, alcohol 0.5 percent, with methylparaben 0.12 percent, propylparaben 0.02 percent, and benzoic acid 0.1 percent added as preservatives. The inactive ingredients are D&C Yellow 10, flavors, glycerin, purified water, sodium saccharin, sucrose and tragacanth. CLINICAL PHARMACOLOGY The mechanism of the antihypertensive effect of thiazides is unknown. DIURIL does not usually affect normal blood pressure. DIURIL affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy. DIURIL 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 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. Pharmacokinetics and Metabolism DIURIL is not metabolized but is eliminated rapidly by the kidney. The plasma half-life of chlorothiazide is 45-120 minutes. After oral doses, 10-15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. INDICATIONS AND USAGE DIURIL is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. DIURIL has also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. * Registered trademark of MERCK & CO., Inc., Whitehouse Station, NJ and is used under license This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-870/S-040 Page 4 DIURIL is indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension. Use in Pregnancy. Routine use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy (see PRECAUTIONS, Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the gravid uterus, is properly treated through elevation of the lower extremities and use of support stockings. Use of diuretics to lower intravascular volume in this instance is illogical and unnecessary. During normal pregnancy there is hypervolemia which is not harmful to the fetus or the mother in the absence of cardiovascular disease. However, it may be associated with edema, rarely generalized edema. If such edema causes discomfort, increased recumbency will often provide relief. Rarely this edema may cause extreme discomfort which is not relieved by rest. In these instances, a short course of diuretic therapy may provide relief and be appropriate. CONTRAINDICATIONS Anuria. Hypersensitivity to this product or to other sulfonamide-derived drugs. WARNINGS Use 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. Thiazides may add to or potentiate the action of other antihypertensive drugs. 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 diuretics (see PRECAUTIONS, Drug Interactions). PRECAUTIONS General All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance: namely, 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-870/S-040 Page 5 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 arrhythmias and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium-sparing diuretics or potassium supplements such as foods with a high potassium content. 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 acute gout may be precipitated in certain patients receiving thiazides. 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 post-sympathectomy 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. Laboratory Tests Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals. Drug Interactions When given concurrently the following drugs may interact with thiazide diuretics. Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-870/S-040 Page 6 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 - Both cholestyramine and colestipol resins have the potential of binding thiazide diuretics and reducing diuretic absorption from the gastrointestinal tract. 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 - generally should not 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 DIURIL. Non-steroidal Anti-inflammatory Drugs Including Selective Cyclooxygenase-2 (COX-2) Inhibitors - In some patients, the administration of a non-steroidal anti-inflammatory agent including a selective COX-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium- sparing and thiazide diuretics. Therefore, when DIURIL and non-steroidal anti-inflammatory agents or selective COX-2 inhibitors are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. In some patients with compromised renal function (e.g., elderly patients or patients who are volume- depleted, including those on diuretic therapy) who are being treated with non-steroidal anti inflammatory drugs, including selective COX-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. These interactions should be considered in patients taking NSAIDs including selective COX-2 inhibitors concomitantly with diuretics and angiotensin II antagonists or ACE inhibitors. Therefore, the combination should be administered with caution, especially in the elderly. Drug/Laboratory Test Interactions Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS, General). Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with chlorothiazide. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-870/S-040 Page 7 Chlorothiazide was not mutagenic in vitro in the Ames microbial mutagen test (using a maximum concentration of 5 mg/plate and Salmonella typhimurium strains TA98 and TA100) and was not mutagenic and did not induce mitotic nondisjunction in diploid-strains of Aspergillus nidulans. Chlorothiazide had no adverse effects on fertility in female rats at doses up to 60 mg/kg/day and no adverse effects on fertility in male rats at doses up to 40 mg/kg/day. These doses are 1.5 and 1 times the recommended maximum human dose, respectively, when compared on a body weight basis. Pregnancy Teratogenic Effects - Pregnancy Category C: Although reproduction studies performed with chlorothiazide doses of 50 mg/kg/day in rabbits, 60 mg/kg/day in rats and 500 mg/kg/day in mice revealed no external abnormalities of the fetus or impairment of growth and survival of the fetus due to chlorothiazide, such studies did not include complete examinations for visceral and skeletal abnormalities. It is not known whether chlorothiazide can cause fetal harm when administered to a pregnant woman; however, thiazides cross the placental barrier and appear in cord blood. DIURIL should be used during pregnancy only if clearly needed (see INDICATIONS AND USAGE). Nonteratogenic Effects: Chlorothiazide may cause fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. Nursing Mothers Because of the potential for serious adverse reactions in nursing infants from DIURIL, 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 There are no well-controlled clinical trials in pediatric patients. Information on dosing in this age group is supported by evidence from empiric use in pediatric patients and published literature regarding the treatment of hypertension in such patients. (See DOSAGE AND ADMINISTRATION, Infants and Children.) Geriatric Use Clinical studies of DIURIL 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 (see WARNINGS). Calculations based on a human body 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 11-870/S-040 Page 8 ADVERSE REACTIONS The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity. Body as a Whole: Weakness. Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs). Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia. Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia. Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura. Metabolic: Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria, hyperuricemia. Musculoskeletal: Muscle spasm. Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, 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. Urogenital: Impotence. Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn. OVERDOSAGE 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. In the event of overdosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment. The degree to which chlorothiazide sodium is removed by hemodialysis has 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 11-870/S-040 Page 9 The oral LD50 of chlorothiazide is 8.5 g/kg, greater than 10 g/kg, and greater than 1 g/kg, in the mouse, rat and dog respectively. DOSAGE AND ADMINISTRATION Therapy should be individualized according to patient response. Use the smallest dosage necessary to achieve the required response. Adults For Edema The usual adult dosage is 500 mg to 1000 mg (10 mL to 20 mL) once or twice a day. Many patients with edema respond to intermittent therapy, i.e., administration on alternate days or on three to five days each week. With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur. For Control of Hypertension The usual adult starting dosage is 500 mg or 1000 mg (10 mL to 20 mL) a day as a single or divided dose. Dosage is increased or decreased according to blood pressure response. Rarely some patients may require up to 2000 mg (40 mL) a day in divided doses. Infants and Children For Diuresis and For Control of Hypertension The usual pediatric dosage is 5 mg to 10 mg per pound (10 mg/kg to 20 mg/kg) per day in single or two divided doses, not to exceed 375 mg per day (2.5 mL to 7.5 mL or ½ to 1½ teaspoonfuls of the oral suspension daily) in infants up to 2 years of age or 1000 mg per day in children 2 to 12 years of age. In infants less than 6 months of age, doses up to 15 mg per pound (30 mg/kg) per day in two divided doses may be required. (See PRECAUTIONS, Pediatric Use.) HOW SUPPLIED DIURIL Oral Suspension, 250 mg of chlorothiazide per 5 mL, is a yellow, creamy suspension, and is supplied as follows: NDC 65649-311-12 bottles of 237 mL. Storage DIURIL Oral Suspension: Keep container tightly closed. Protect from freezing, –20°C (–4°F) and store at room temperature, 15-30°C (59-86°F). Manufactured by: Paddock Laboratories, Inc. Minneapolis, MN 55427 For: Salix Pharmaceuticals, Inc. Morrisville, NC 27560 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-870/S-040 Page 10 VENART-100-0/May 2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:46.915519	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/011870s040lbl.pdf', 'application_number': 11870, 'submission_type': 'SUPPL ', 'submission_number': 40}
10,783	PROVERA® (medroxyprogesterone acetate tablets, USP) WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia.) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders.) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.) Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS, Malignant Neoplasm, Breast Cancer.) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION PROVERA® tablets contain medroxyprogesterone acetate, which is a derivative of progesterone. It is a white to off-white, odorless crystalline powder, stable in air, melting between 200 and 210°C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, structural formula Each PROVERA tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate and the following inactive ingredients: calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, and talc. The 2.5 mg tablet contains FD&C Yellow No. 6. CLINICAL PHARMACOLOGY Medroxyprogesterone acetate (MPA) administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered MPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. Pharmacokinetics The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight PROVERA 2.5 mg tablets or a single administration of two PROVERA 10 mg tablets under fasting conditions. In another study, the steady- state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one PROVERA 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of PROVERA tablets were highly variable and are summarized in Table 1. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA) Tablet Strength C max (ng/mL) T max (h) Auc 0-(∞) (ng·h/mL) t 1/2 (h) Vd/f (L) CL/f (mL/min) Single Dose 2 × 10 mg 8 × 2.5 mg 1.01 (0.599) 0.805 (0.413) 2.65 (1.41) 2.22 (1.39) 6.95 (3.39) 5.62 (2.79) 12.1 (3.49) 11.6 (2.81) 78024 (47220) 62748 (40146) 64110 (42662) 74123 (35126) Multiple Dose 10 mg * 0.71 (0.35) 2.83 (1.83) 6.01 (3.16) 16.6 (15.0) 40564 (38256) 41963 (38402) Following Day 7 dose A. Absorption: No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration. Administration of PROVERA with food increases the bioavailability of MPA. A 10 mg dose of PROVERA, taken immediately before or after a meal, increased MPA Cmax (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food. B. Distribution: MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin. C. Metabolism: Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. D. Excretion: Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. E. Specific Populations Hepatic Insufficiency MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal Insufficiency The effect of renal impairment on the pharmacokinetics of PROVERA has not been studied. F. Drug Interactions Medroxyprogesterone acetate (MPA) is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted. Inducers and/or inhibitors of CYP3A4 may affect the metabolism of MPA. CLINICAL STUDIES Effects on the Endometrium In a 3-year, double-blind, placebo-controlled study of 356 nonhysterectomized, postmenopausal women between 45 and 64 years of age randomized to receive placebo (n=119), 0.625 mg conjugated estrogen only (n=119), or 0.625 mg conjugated estrogen plus cyclic PROVERA (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg PROVERA plus 0.625 mg conjugated estrogens compared to the group receiving 0.625 mg conjugated estrogens only. See Table 2. Table 2. Number (%) of Endometrial Biopsy Changes Since Baseline After 3 Years of Treatment Histological Results Placebo (n=119) CEE † (n=119) PROVERA ‡ + CEE (n=118) Normal/No hyperplasia (%) 116 (97) 45 (38) 112 (95) Simple (cystic) hyperplasia (%) 1 (1) 33 (28) 4 (3) Complex (adenomatous) hyperplasia (%) 1 (1) 27 (22) 2 (2) Atypia (%) 0 14 (12) 0 Adenocarcinoma (%) 1 (1) 0 0 Includes most extreme abnormal result † CEE = conjugated equine estrogens 0.625 mg/day ‡ PROVERA = medroxyprogesterone acetate tablets 10 mg/day for 12 days In a second 1-year study, 832 postmenopausal women between 45 and 65 years of age were treated with daily 0.625 mg conjugated estrogen (days 1-28), plus either 5 mg cyclic PROVERA or 10 mg cyclic PROVERA (days 15-28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic PROVERA (days 15 28) plus daily conjugated estrogens showed a significantly lower rate of hyperplasia as compared to the conjugated estrogens only group. See Table 3. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3. Number (%) of Women with Endometrial Hyperplasia at 1 Year CEE MPA † + CEE * (n=283) MPA 5 mg (n=277) MPA 10 mg (n=272) Cystic hyperplasia (%) 55 (19) 3 (1) 0 Adenomatous hyperplasia without atypia 2 (1) 0 0 * CEE = conjugated equine estrogen 0.625 mg every day of a 28-day cycle. † Cyclic medroxyprogesterone acetate on days 15 to 28 Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women- years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4 : RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS a,b Event Relative Risk CE/MPA vs placebo (95%nCI c) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events Non-fatal MI CHD death 1.23 (0.99-1.53) 1.28 (1.00-1.63) 1.10 (0.70-1.75) 41 31 8 34 25 8 All strokes 1.31 (1.03-1.68) 33 25 Ischemic stroke 1.44 (1.09-1.90) 26 18 Deep vein thrombosisd 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancere 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancerd 0.81 (0.48-1.36) 6 7 Cervical cancerd 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47–0.96) 11 16 Vertebral fracturesd 0.65 (0.46-0.92) 11 17 Lower arm/wrist fracturesd 0.71 (0.59-0.85) 44 62 Total fracturesd 0.76 (0.69-0.83) 152 199 Overall mortalityf 1.00 (0.83-1.19) 52 52 Global Indexg 1.13 (1.02-1.25) 184 165 a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in “global index”. e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g 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, colorectal cancer, hip fracture, or death due to other causes. Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a nonsignificant trend toward reduced risk in overall mortality [hazard ration (HR) 0.69 (95 percent CI, 0.44 1.07)]. Women's Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were aged 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 33 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use). INDICATIONS AND USAGE PROVERA tablets are indicated for the treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. They are also indicated for use in the prevention of endome trial hyperplasia in nonhysterectomized postmenopausal women who are receiving daily oral conjugated estrogens 0.625 mg tablets. CONTRAINDICATIONS PROVERA is contraindicated in women with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of breast cancer. 3. Known or suspected estrogen- or progesterone-dependent neoplasia. 4. Active DVT, PE, or a history of these conditions 5. Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions. 6. Known anaphylactic reaction or angioedema to PROVERA. 7. Known liver impairment or disease. 8. Known or suspected pregnancy. WARNINGS See BOXED WARNINGS. 1. Cardiovascular Disorders. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda a. Stroke In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). (See CLINICAL STUDIES.) The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. b. Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women- years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus 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 plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) 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 plus MPA group and the placebo group in HERS, HERS II, and overall. c. Venous Thromboembolism In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women- years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See CLINICAL STUDIES.) Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens plus progestins 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. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Malignant Neoplasms a. Breast Cancer The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus 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 versus 25 cases per 10,000 women-years, for CE plus 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 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) 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. (See CLINICAL STUDIES.) Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, or routes of administration. 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 healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. b. Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times 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 Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen plus progestin therapy 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 genital 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. c. Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. 3. Probable Dementia In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.) 4. Visual Abnormalities Discontinue estrogen plus progestin therapy 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, estrogen plus progestin therapy should be permanently discontinued. PRECAUTIONS A. General Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 an increased risk of breast cancer. 2. Unexpected abnormal vaginal bleeding In cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated. 3. Elevated blood pressure Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy. 4. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. 5. Hepatic Impairment and/or past history of cholestatic jaundice Estrogens plus progestins may be poorly metabolized in women with impaired liver function. For women 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. 6. Fluid Retention Progestins may cause some degree of fluid retention. Women who have conditions which might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogen plus progestin are prescribed. 7. Hypocalcemia Estrogen plus progestin therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 8. Exacerbation of other conditions Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda B. Patient Information Physicians are advised to discuss the Patient Information leaflet with women for whom they prescribe PROVERA. There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1000 male births. The risk may be increased with exposure to PROVERA. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of PROVERA has not been established. Inform the patient of the importance of reporting exposure to PROVERA in early pregnancy. C. Drug-Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy: 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) levels leading to increased circulating total thyroid hormone levels 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. Women on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda D. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity: Long-term intramuscular administration of medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate to rats and mice. Long-term continuous administration of estrogen plus progestin therapy has shown an increased risk of breast cancer and ovarian cancer. (See WARNINGS and PRECAUTIONS.) Genotoxicity: Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Fertility: Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment. E. Pregnancy Pregnancy Category X: PROVERA should not be used during pregnancy. (See CONTRAINDICATIONS.) There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to PROVERA during the first trimester of pregnancy. However, a clear association between these conditions with use of PROVERA has not been established. F. Nursing Mothers PROVERA should not be used during lactation. Detectable amounts of progestin have been identified in the breast milk of nursing mothers receiving progestins. G. Pediatric Use PROVERA tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population. H. Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing PROVERA alone to determine whether those over 65 years of age differ from younger subjects in their response to PROVERA alone. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See CLINICAL STUDIES.) Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen- alone or estrogen plus progestin when compared to placebo. (See WARNINGS, Probable Dementia.) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia.) ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS, and PRECAUTIONS. 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 practice. The following adverse reactions have been reported in women taking PROVERA tablets, without concomitant estrogens treatment: 1. Genitourinary system Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions. 2. Breasts Breast tenderness, mastodynia or galactorrhea has been reported. 3. Cardiovascular Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported. 4. Gastrointestinal Nausea, cholestatic jaundice. 5. Skin Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported. 6. Eyes Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7. Central nervous system Mental depression, insomnia, somnolence, dizziness, headache, nervousness. 8. Miscellaneous Hypersensitivity reactions (for example, anaphylaxis and anaphylactoid reactions, angioedema), rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance. The following adverse reactions have been reported with estrogen plus progestin therapy. 1. Genitourinary system Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrheal/pelvic pain; 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 gallbladder disease; pancreatitis; enlargement of hepatic hemangiomas. 5. Skin Chloasma or melasma that 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; arthalgias; leg cramps; changes in libido; urticaria, angioedema, Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides. OVERDOSAGE Overdosage of estrogen plus progestin therapy may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of CE plus MPA together with institution of appropriate symptomatic care. DOSAGE AND ADMINISTRATION Secondary Amenorrhea PROVERA tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of PROVERA daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing PROVERA therapy. Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of PROVERA may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of PROVERA daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with PROVERA. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with PROVERA. Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens When estrogen is prescribed for a postmenopausal woman with a uterus, a 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 for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3 to 6 month intervals) to determine if treatment is still necessary (see 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. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PROVERA tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle. Patients should be started at the lowest dose. The lowest effective dose of PROVERA has not been determined. HOW SUPPLIED PROVERA Tablets are available in the following strengths and package sizes: 2.5 mg (scored, round, orange) Bottles of 30 NDC 0009-0064-06 Bottles of 100 NDC 0009-0064-04 5 mg (scored, hexagonal, white) Bottles of 100 NDC 0009-0286-03 10 mg (scored, round, white) Bottles of 100 NDC 0009-0050-02 Bottles of 500 NDC 0009-0050-11 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. “Keep out of reach of children” Rx only company logo LAB-0144- 5.2 Revised May 2015 Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION PROVERA (pro-VE-rah) (medroxyprogesterone acetate tablets, USP) Read this Patient Information before you start taking PROVERA and read what you get each time you refill your PROVERA prescription. There may be new information. This information 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 PROVERA (a progestin hormone)? ● Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (decline in brain function). ● Using estrogens with progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. ● Using estrogens with progestins may increase your chance of getting dementia, based on a study of women age 65 years or older. ● You and your healthcare provider should talk regularly about whether you still need treatment with PROVERA. What is PROVERA? PROVERA is a medicine that contains medroxyprogesterone acetate, a progestin hormone. What is PROVERA used for? PROVERA is used to: • Treat menstrual periods that have stopped or to treat abnormal uterine bleeding. Women with a uterus who are not pregnant, who stop having regular menstrual periods or who begin to have irregular menstrual periods may have a drop in their progesterone level. Talk with your healthcare provider about whether PROVERA is right for you. • Reduce your chances of getting cancer of the uterus (womb). In postmenopausal women with a uterus who use estrogens, taking progestin in combination with estrogen will reduce your chance of getting cancer of the uterus (womb). Who should not take PROVERA? Do not start taking PROVERA if you: • have unusual vaginal bleeding Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • currently have or have had certain cancers Estrogen plus progestin may increase your chance of getting certain types of cancers, including cancer of the breast. If you have or have had cancer, talk with your healthcare provider about whether you should use PROVERA. • had a stroke or heart attack • currently have or have had blood clots • currently have or have had liver problems • are allergic to PROVERA or any of its ingredients See the list of ingredients in PROVERA at the end of this leaflet. • think you may be pregnant PROVERA is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use PROVERA if the test is positive and talk to your healthcare provider. There may be an increased risk of minor birth defects in children whose mothers take PROVERA during the first 4 months of pregnancy. PROVERA should not be used as a test for pregnancy. What should I tell my healthcare provider before taking PROVERA? Before you take PROVERA, tell your healthcare provider if you: • have any other medical problems Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis (severe pelvic pain), lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium in your blood. • are going to have surgery or will be on bed rest Your healthcare provider will let you know if you need to stop taking PROVERA. ● are breast feeding The hormone in PROVERA can pass into your breast milk. Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how PROVERA works. PROVERA may also affect how other medicines work. How should I take PROVERA? Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. The lowest effective dose of PROVERA has not been determined. You Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether you still need treatment with PROVERA. 1. Absence of menstrual period: PROVERA may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. 2. Abnormal Uterine Bleeding: PROVERA may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days. 3. Overgrowth of the lining of the uterus: When used in combination with oral conjugated estrogens in postmenopausal women with a uterus, PROVERA may be given in doses ranging from 5 or 10 mg daily for 12 to 14 straight days per month. What are the possible side effects of PROVERA? The following side effects have been reported with the use of PROVERA alone: • breast tenderness • breast milk secretion • breakthrough bleeding • spotting (minor vaginal bleeding) • irregular periods • amenorrhea (absence of menstrual periods) • vaginal secretions • headaches • nervousness • dizziness • depression • insomnia, sleepiness, fatigue • premenstrual syndrome-like symptoms • thrombophlebitis (inflamed veins) • blood clot • itching, hives, skin rash • acne • hair loss, hair growth • abdominal discomfort • nausea • bloating • fever • increase in weight • swelling • changes in vision and sensitivity to contact lenses Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call your healthcare provider right away if you get hives, problems breathing, swelling of the face, mouth, tongue or neck. The following side effects have been reported with the use of PROVERA with an estrogen. Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include: • heart attack • stroke • blood clots • dementia • breast cancer • cancer of the uterus • cancer of the ovary • high blood pressure • high blood sugar • gallbladder disease • liver problems • changes in your thyroid hormone levels • enlargements of benign tumors (“fibroids”) Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you: • new breast lumps • unusual vaginal bleeding • changes in vision and speech • sudden new severe headaches • severe pains in your chest or legs with or without shortness of breath, weakness and fatigue • memory loss or confusion Less serious, but common side effects include: • headache • breast pain • irregular vaginal bleeding or spotting • stomach or abdominal cramps, bloating • nausea and vomiting • hair loss • fluid retention • vaginal yeast infection Reference ID: 3749814 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 PROVERA with or without estrogen. For more information, ask your healthcare provider or pharmacist for advice about side effects. Tell your healthcare provider if you have side effect that bothers you or does not go away. You may report side effects to Pfizer at 1-800-438-1985 or FDA at 1-800 FDA-1088. What can I do to lower my chances of a serious side effect with PROVERA? • Talk with your healthcare provider regularly about whether you should continue taking PROVERA. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb). • See your healthcare provider right away if you get vaginal bleeding while taking PROVERA. • Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare 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 a higher chance of getting heart disease. Ask your healthcare provider for ways to lower your chance of getting heart disease. General information about safe and effective use of PROVERA • Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. • Do not take PROVERA for conditions for which it was not prescribed. • Do not give PROVERA to other people, even if they have the same symptoms you have. It may harm them. Keep PROVERA out of the reach of children. This leaflet provides a summary of the most important information about PROVERA. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about PROVERA that is written for health professionals. You can get more information by calling the toll-free number, 1-800-438-1985. What are the ingredients in PROVERA? Each PROVERA tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate. Inactive ingredients: calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, talc. The 2.5 mg tablet contains FD&C Yellow No. 6. Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com Rx only company logo LAB-0365-6.1 Revised May 2015 Reference ID: 3749814 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.015605	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011839s079s080lbl.pdf', 'application_number': 11839, 'submission_type': 'SUPPL ', 'submission_number': 80}
10,786	1 [Note: Below is the agreed upon labeling. Double underline font denotes additions to the labeling, and strike-through font denotes deletions from the labeling.] 69-5985-00-1.1 NARDIL® (Phenelzine Sulfate Tablets, USP) DESCRIPTION NARDIL® (phenelzine sulfate) is a potent inhibitor of monoamine oxidase (MAO). Phenelzine sulfate is a hydrazine derivative. It has a molecular weight of 234.27 and is chemically described as C8 H12 N2 • H2SO4. Its chemical structure is shown below: Each NARDIL film-coated tablet for oral administration contains phenelzine sulfate equivalent to 15 mg of phenelzine base and the following inactive ingredients: mannitol, USP; corn starch, NF; croscarmellose sodium, NF; povidone, USP; edetate disodium, USP; magnesium stearate, NF; isopropyl alcohol, USP; purified water, USP; opadry orange Y30-13242A; simethicone emulsion, USP. CLINICAL PHARMACOLOGY Monoamine oxidase is a complex enzyme system, widely distributed throughout the body. Drugs that inhibit monoamine oxidase in the laboratory are associated with a number of clinical effects. Thus, it is unknown whether MAO inhibition per se, other pharmacologic actions, or an interaction of both is responsible for the clinical effects observed. Therefore, the physician should become familiar with all the effects produced by drugs of this class. Pharmacokinetics Absorption – Following a single 30 mg dose of NARDIL® (2 X 15 mg tablets), a mean peak phenelzine plasma concentration (Cmax) of 19.8 ng/mL occurred at a time (Tmax) of 43 minutes postdose. Metabolism – NARDIL® is extensively metabolized, primarily by oxidation via monoamine oxidase. After oral administration of 13C6-phenelzine, 73% of the administered dose was recovered in urine as phenylacetic acid and parahydroxyphenylacetic acid within 96 hours. Acetylation to N2-acetylphenelzine is a minor pathway. Elimination – The mean elimination half-life after a single 30mg dose is 11.6 hours. Multiple dose pharmacokinetics have not been studied in man. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 INDICATIONS AND USAGE NARDIL has been found to be effective in depressed patients clinically characterized as “atypical,” “nonendogenous,” or “neurotic.” These patients often have mixed anxiety and depression and phobic or hypochondriacal features. There is less conclusive evidence of its usefulness with severely depressed patients with endogenous features. NARDIL should rarely be the first antidepressant drug used. Rather, it is more suitable for use with patients who have failed to respond to the drugs more commonly used for these conditions. CONTRAINDICATIONS NARDIL should not be used in patients who are hypersensitive to the drug or its ingredients, with pheochromocytoma, congestive heart failure, a history of liver disease, or abnormal liver function tests. The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients being treated with NARDIL should not take sympathomimetic drugs (including amphetamines, cocaine, methylphenidate, dopamine, epinephrine, and norepinephrine) or related compounds (including methyldopa, L-dopa, L-tryptophan, L-tyrosine, and phenylalanine). Hypertensive crises during NARDIL therapy may also be caused by the ingestion of foods with a high concentration of tyramine or dopamine. Therefore, patients being treated with NARDIL should avoid high protein food that has undergone protein breakdown by aging, fermentation, pickling, smoking, or bacterial contamination. Patients should also avoid cheeses (especially aged varieties), pickled herring, beer, wine, liver, yeast extract (including brewer’s yeast in large quantities), dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna), pods of broad beans (fava beans), and yogurt. Excessive amounts of caffeine and chocolate may also cause hypertensive reactions. NARDIL should not be used in combination with dextromethorphan or with CNS depressants such as alcohol and certain narcotics. Excitation, seizures, delirium, hyperpyrexia, circulatory collapse, coma, and death have been reported in patients receiving MAOI therapy who have been given a single dose of meperidine. NARDIL should not be administered together with or in rapid succession to other MAO inhibitors because HYPERTENSIVE CRISES and convulsive seizures, fever, marked sweating, excitation, delirium, tremor, coma, and circulatory collapse may occur. A List of MAO Inhibitors by Generic Name Follows: pargyline hydrochloride pargyline hydrochloride and methylclothiazide furazolidone isocarboxazid procarbazine tranylcypromine NARDIL should also not be used in combination with buspirone HCl, since several cases of elevated blood pressure have been reported in patients taking MAO inhibitors who This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 were then given buspirone HCl. At least 10 days should elapse between the discontinuation of NARDIL and the institution of another antidepressant or buspirone HCl, or the discontinuation of another MAO inhibitor and the institution of NARDIL. There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxine) have been combined with an MAO inhibitor. Therefore, the concomitant use of NARDIL with serotoninergic agents is contraindicated (see PRECAUTIONS-Drug Interactions). Allow at least five weeks between discontinuation of fluoxetine and initiation of NARDIL and at least 10 days between discontinuation of NARDIL and initiation of fluoxetine, or other serotoninergic agents. Before initiating NARDIL after using other serotoninergic agents, a sufficient amount of time must be allowed for clearance of the serotoninergic agent and its active metabolites. The combination of MAO inhibitors and tryptophan has been reported to cause behavioral and neurologic syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski signs. The concurrent administration of an MAO inhibitor and bupropion hydrochloride (Wellbutrin®) is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion hydrochloride. Patients taking NARDIL should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of NARDIL and spinal anesthesia should be kept in mind. NARDIL should be discontinued at least 10 days prior to elective surgery. MAO inhibitors, including NARDIL, are contraindicated in patients receiving guanethidine. WARNINGS The most serious reactions to NARDIL involve changes in blood pressure. Hypertensive Crises: The most important reaction associated with NARDIL administration is the occurrence of hypertensive crises, which have sometimes been fatal. These crises are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or bradycardia may be present and can be associated with constricting chest pain. NOTE: Intracranial bleeding has been reported in association with the increase in blood pressure. Blood pressure should be observed frequently to detect evidence of any pressor response in all patients receiving NARDIL. Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Recommended treatment in hypertensive crisis: If a hypertensive crisis occurs, NARDIL should be discontinued immediately and therapy to lower blood pressure should be instituted immediately. On the basis of present evidence, phentolamine is recommended. (The dosage reported for phentolamine is 5 mg intravenously.) Care should be taken to administer this drug slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling. Warning to the Patient: All patients should be warned that the following foods, beverages, and medications must be avoided while taking NARDIL, and for two weeks after discontinuing use. Foods and Beverages To Avoid Meat and Fish Pickled herring Liver Dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna) Vegetables Broad bean pods (fava bean pods) Sauerkraut Dairy Products Cheese (cottage cheese and cream cheese are allowed) Yogurt Beverages Beer and wine Alcohol-free and reduced-alcohol beer and wine products Miscellaneous Yeast extract (including brewer’s yeast in large quantities) Meat extract Excessive amounts of chocolate and caffeine Also, any spoiled or improperly refrigerated, handled, or stored protein-rich foods such as meats, fish, and dairy products, including foods that may have undergone protein changes by aging, pickling, fermentation, or smoking to improve flavor should be avoided. OTC Medications To Avoid Cold and cough preparations (including those containing dextromethorphan) Nasal decongestants (tablets, drops, or spray) Hay-fever medications Sinus medications Asthma inhalant medications Antiappetite medicines Weight-reducing preparations “Pep” pills L-tryptophan containing preparations Also, certain prescription drugs should be avoided. Therefore, patients under the care of another physician or dentist should inform him/her that they are taking NARDIL. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Patients should be warned that the use of the above foods, beverages, or medications may cause a reaction characterized by headache and other serious symptoms due to a rise in blood pressure, with the exception of dextromethorphan which may cause reactions similar to those seen with meperidine. Also, there has been a report of an interaction between NARDIL and dextromethorphan (ingested as a lozenge) causing drowsiness and bizarre behavior. Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms. Concomitant Use with Dibenzazepine Derivative Drugs If the decision is made to administer NARDIL concurrently with other antidepressant drugs, or within less than 10 days after discontinuation of antidepressant therapy, the patient should be cautioned by the physician regarding the possibility of adverse drug interaction. A List of Dibenzazepine Derivative Drugs by Generic Name Follows: nortriptyline hydrochloride amitriptyline hydrochloride perphenazine and amitriptyline hydrochloride clomipramine hydrochloride desipramine hydrochloride imipramine hydrochloride doxepin carbamazepine cyclobenzaprine HCl amoxapine maprotiline HCl trimipramine maleate protriptyline HCl mirtazapine NARDIL should be used with caution in combination with antihypertensive drugs, including thiazide diuretics and ß-blockers, since exaggerated hypotensive effects may result. Use in Pregnancy: The safe use of NARDIL during pregnancy or lactation has not been established. The potential benefit of this drug, if used during pregnancy, lactation, or in women of childbearing age, should be weighed against the possible hazard to the mother or fetus. Doses of NARDIL in pregnant mice well exceeding the maximum recommended human dose have caused a significant decrease in the number of viable offspring per mouse. In addition, the growth of young dogs and rats has been retarded by doses exceeding the maximum human dose. Use in Pediatric Patients: NARDIL is not recommended for pediatric patients under 16 years of age, since there are no controlled studies of safety in this age group. NARDIL, as with other hydrazine derivatives, has been reported to induce pulmonary and vascular tumors in an uncontrolled lifetime study in mice. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 PRECAUTIONS In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. It is recommended that careful observations of patients undergoing NARDIL treatment be maintained until control of depression is achieved. If necessary, additional measures (ECT, hospitalization, etc) should be instituted. All patients undergoing treatment with NARDIL should be closely followed for symptoms of postural hypotension. Hypotensive side effects have occurred in hypertensive as well as normotensive and hypotensive patients. Blood pressure usually returns to pretreatment levels rapidly when the drug is discontinued or the dosage is reduced. Because the effect of NARDIL on the convulsive threshold may be variable, adequate precautions should be taken when treating epileptic patients. Of the more severe side effects that have been reported with any consistency, hypomania has been the most common. This reaction has been largely limited to patients in whom disorders characterized by hyperkinetic symptoms coexist with, but are obscured by, depressive affect; hypomania usually appeared as depression improved. If agitation is present, it may be increased with NARDIL. Hypomania and agitation have also been reported at higher than recommended doses or following long-term therapy. NARDIL may cause excessive stimulation in schizophrenic patients; in manic-depressive states it may result in a swing from a depressive to a manic phase. MAO inhibitors, including NARDIL, potentiate hexobarbital hypnosis in animals. Therefore, barbiturates should be given at a reduced dose with NARDIL. MAO inhibitors inhibit the destruction of serotonin and norepinephrine, which are believed to be released from tissue stores by rauwolfia alkaloids. Accordingly, caution should be exercised when rauwolfia is used concomitantly with an MAO inhibitor, including NARDIL. There is conflicting evidence as to whether or not MAO inhibitors affect glucose metabolism or potentiate hypoglycemic agents. This should be kept in mind if NARDIL is administered to diabetics. Drug Interactions In patients receiving nonselective monoamine oxidase (MAO) inhibitors in combination with serotoninergic agents (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxine) there have been reports of serious, sometimes fatal, reactions. Because NARDIL is a monoamine oxidase (MAO) inhibitor, NARDIL should not be used concomitantly with a serotoninergic agent (See CONTRAINDICATIONS). Geriatric Use Clinical studies of NARDIL 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS NARDIL is a potent inhibitor of monoamine oxidase. Because this enzyme is widely distributed throughout the body, diverse pharmacologic effects can be expected to occur. When they occur, such effects tend to be mild or moderate in severity (see below), often subside as treatment continues, and can be minimized by adjusting dosage; rarely is it necessary to institute counteracting measures or to discontinue NARDIL. Common side effects include: Nervous System—Dizziness, headache, drowsiness, sleep disturbances (including insomnia and hypersomnia), fatigue, weakness, tremors, twitching, myoclonic movements, hyperreflexia. Gastrointestinal—Constipation, dry mouth, gastrointestinal disturbances, elevated serum transaminases (without accompanying signs and symptoms). Metabolic—Weight gain. Cardiovascular—Postural hypotension, edema. Genitourinary—Sexual disturbances, eg, anorgasmia and ejaculatory disturbances and impotence. Less common mild to moderate side effects (some of which have been reported in a single patient or by a single physician) include: Nervous System—Jitteriness, palilalia, euphoria, nystagmus, paresthesias. Genitourinary—Urinary retention. Metabolic—Hypernatremia. Dermatologic—Pruritus, skin rash, sweating. Special Senses—Blurred vision, glaucoma. Although reported less frequently, and sometimes only once, additional severe side effects include: Nervous System—Ataxia, shock-like coma, toxic delirium, manic reaction, convulsions, acute anxiety reaction, precipitation of schizophrenia, transient respiratory and cardiovascular depression following ECT. Gastrointestinal—To date, fatal progressive necrotizing hepatocellular damage has been reported in very few patients. Reversible jaundice. Hematologic—Leukopenia. Immunologic—Lupus-like syndrome Metabolic—Hypermetabolic syndrome (which may include, but is not limited to, hyperpyrexia, tachycardia, tachypnea, muscular rigidity, elevated CK levels, metabolic acidosis, hypoxia, coma and may resemble an overdose). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Respiratory—Edema of the glottis. General—Fever associated with increased muscle tone. Withdrawal may be associated with nausea, vomiting, and malaise. An uncommon withdrawal syndrome following abrupt withdrawal of NARDIL has been infrequently reported. Signs and symptoms of this syndrome generally commence 24 to 72 hours after drug discontinuation and may range from vivid nightmares with agitation to frank psychosis and convulsions. This syndrome generally responds to reinstitution of low-dose NARDIL therapy followed by cautious downward titration and discontinuation. DOSAGE AND ADMINISTRATION Initial dose: The usual starting dose of NARDIL is one tablet (15 mg) three times a day. Early phase treatment: Dosage should be increased to at least 60 mg per day at a fairly rapid pace consistent with patient tolerance. It may be necessary to increase dosage up to 90 mg per day to obtain sufficient MAO inhibition. Many patients do not show a clinical response until treatment at 60 mg has been continued for at least 4 weeks. Maintenance dose: After maximum benefit from NARDIL is achieved, dosage should be reduced slowly over several weeks. Maintenance dose may be as low as one tablet, 15 mg, a day or every other day, and should be continued for as long as is required. OVERDOSAGE Note—For management of hypertensive crises see WARNINGS section. Accidental or intentional overdosage may be more common in patients who are depressed. It should be remembered that multiple drugs and/or alcohol may have been ingested. Depending on the amount of overdosage with NARDIL, a varying and mixed clinical picture may develop, including signs and symptoms of central nervous system and cardiovascular stimulation and/or depression. Signs and symptoms may be absent or minimal during the initial 12-hour period following ingestion and may develop slowly thereafter, reaching a maximum in 24-48 hours. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring throughout this period, is essential. Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonus, rigidity, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension, and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. Treatment Intensive symptomatic and supportive treatment may be required. Induction of emesis or gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has been protected against aspiration. Signs and symptoms of central nervous system stimulation, including convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of dilute pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor response. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential. There are no data on the lethal dose in man. The pathophysiologic effects of massive overdosage may persist for several days, since the drug acts by inhibiting physiologic enzyme systems. With symptomatic and supportive measures, recovery from mild overdosage may be expected within 3 to 4 days. Hemodialysis, peritoneal dialysis, and charcoal hemoperfusion may be of value in massive overdosage, but sufficient data are not available to recommend their routine use in these cases. Toxic blood levels of phenelzine have not been established, and assay methods are not practical for clinical or toxicological use. HOW SUPPLIED Each NARDIL tablet is orange, biconvex, film-coated, and engraved with “P-D 270” and contains phenelzine sulfate equivalent to 15 mg of phenelzine base. NDC 0071-0270-24. Bottles of 100 Storage: Store between 15° - 30°C (59° - 86°F). Rx only Revised (month) 2003 Distributed by: A Parke-Davis Division of Pfizer Inc, NY, NY 10017 2003 69-5985-00-1.1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.133082	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/11909slr033_nardil_lbl.pdf', 'application_number': 11909, 'submission_type': 'SUPPL ', 'submission_number': 33}
10,787	NARDIL® (Phenelzine Sulfate Tablets, USP) Suicidality in Children and Adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of NARDIL or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. NARDIL is not approved for use in pediatric patients. (See Warnings and Precautions: Pediatric Use) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorde r (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. DESCRIPTION NARDIL® (phenelzine sulfate) is a potent inhibitor of monoamine oxidase (MAO). Phenelzine sulfate is a hydrazine derivative. It has a molecular weight of 234.27 and is chemically described as C8 H12 N2 • H2SO4. Its chemical structure is shown below: Each NARDIL film-coated tablet for oral administration contains phenelzine sulfate equivalent to 15 mg of phenelzine base and the following inactive ingredients: mannitol, USP; croscarmellose sodium, NF; povidone, USP; edetate disodium, USP; magnesium stearate, NF; isopropyl alcohol, USP; purified water, USP; opadry orange Y30-13242A; simethicone emulsion, USP. CLINICAL PHARMACOLOGY Monoamine oxidase is a complex enzyme system, widely distributed throughout the body. Drugs that inhibit monoamine oxidase in the laboratory are associated with a number of clinical effects. Thus, it is unknown whether MAO inhibition per se, other This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pharmacologic actions, or an interaction of both is responsible for the clinical effects observed. Therefore, the physician should become familiar with all the effects produced by drugs of this class. Pharmacokinetics Absorption – Following a single 30 mg dose of NARDIL® (2 X 15 mg tablets), a mean peak plasma concentration (Cmax) of 19.8 ng/mL occurred at a time (Tmax) of 43 minutes postdose. Metabolism – NARDIL® is extensively metabolized, primarily by oxidation via monoamine oxidase. After oral administration of 13C6-phenelzine, 73% of the administered dose was recovered in urine as phenylacetic acid and parahydroxyphenylacetic acid within 96 hours. Acetylation to N2-acetylphenelzine is a minor pathway. Elimination – The mean elimination half-life after a single 30 mg dose is 11.6 hours. Multiple dose pharmacokinetics have not been studied in man. INDICATIONS AND USAGE NARDIL has been found to be effective in depressed patients clinically characterized as “atypical,” “nonendogenous,” or “neurotic.” These patients often have mixed anxiety and depression and phobic or hypochondriacal features. There is less conclusive evidence of its usefulness with severely depressed patients with endogenous features. NARDIL should rarely be the first antidepressant drug used. Rather, it is more suitable for use with patients who have failed to respond to the drugs more commonly used for these conditions. CONTRAINDICATIONS NARDIL should not be used in patients who are hypersensitive to the drug or its ingredients, with pheochromocytoma, congestive heart failure, severe renal impairment or renal disease, a history of liver disease, or abnormal liver function tests. The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients being treated with NARDIL should not take sympathomimetic drugs (including amphetamines, cocaine, methylphenidate, dopamine, epinephrine, and norepinephrine) or related compounds (including methyldopa, L-dopa, L-tryptophan, L-tyrosine, and phenylalanine). Hypertensive crises during NARDIL therapy may also be caused by the ingestion of foods with a high concentration of tyramine or dopamine. Therefore, patients being treated with NARDIL should avoid high protein food that has undergone protein breakdown by aging, fermentation, pickling, smoking, or bacterial contamination. Patients should also avoid cheeses (especially aged varieties), pickled herring, beer, wine, liver, yeast extract (including brewer’s yeast in large quantities), dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna), pods of broad beans (fava beans), and yogurt. Excessive amounts of caffeine and chocolate may also cause hypertensive reactions. NARDIL should not be used in combination with dextromethorphan or with CNS depressants such as alcohol and certain narcotics. Excitation, seizures, delirium, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hyperpyrexia, circulatory collapse, coma, and death have been reported in patients receiving MAOI therapy who have been given a single dose of meperidine. NARDIL should not be administered together with or in rapid succession to other MAO inhibitors because HYPERTENSIVE CRISES and convulsive seizures, fever, marked sweating, excitation, delirium, tremor, coma, and circulatory collapse may occur. Concomitant use with meperidine is contraindicated (see WARNINGS). A List of MAO Inhibitors by Generic Name Follows: pargyline hydrochloride pargyline hydrochloride and methylclothiazide furazolidone isocarboxazid procarbazine tranylcypromine NARDIL should also not be used in combination with buspirone HCl, since several cases of elevated blood pressure have been reported in patients taking MAO inhibitors who were then given buspirone HCl. At least 14 days should elapse between the discontinuation of NARDIL and the institution of another antidepressant or buspirone HCl, or the discontinuation of another MAO inhibitor and the institution of NARDIL. There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxine) have been combined with an MAO inhibitor. Therefore, the concomitant use of NARDIL with serotoninergic agents is contraindicated (see PRECAUTIONS-Drug Interactions). At least 14 days should elapse between the discontinuation of an MAO inhibitor and the start of a serotonin re-uptake inhibitor or vice-versa, with the exception of fluoxetine. Allow at least five weeks between discontinuation of fluoxetine and initiation of NARDIL and at least 14 days between discontinuation of NARDIL and initiation of fluoxetine, or other serotoninergic agents. Before initiating NARDIL after using other serotoninergic agents, a sufficient amount of time must be allowed for clearance of the serotoninergic agent and its active metabolites. The combination of MAO inhibitors and tryptophan has been reported to cause behavioral and neurologic syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski signs. The concurrent administration of an MAO inhibitor and bupropion hydrochloride (Wellbutrin®) is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion hydrochloride. Patients taking NARDIL should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of NARDIL and spinal anesthesia should be kept in mind. NARDIL should be discontinued at least 10 days prior to elective surgery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MAO inhibitors, including NARDIL, are contraindicated in patients receiving guanethidine. WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short- term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for NARDIL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk of bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that NARDIL is not approved for use in treating bipolar depression. It should be noted that NARDIL is not approved for use in treating any indications in the pediatric population. The most serious reactions to NARDIL involve changes in blood pressure. Hypertensive Crises: The most important reaction associated with NARDIL administration is the occurrence of hypertensive crises, which have sometimes been fatal. These crises are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or bradycardia may be present and can be associated with constricting chest pain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOTE: Intracranial bleeding has been reported in association with the increase in blood pressure. Blood pressure should be observed frequently to detect evidence of any pressor response in all patients receiving NARDIL. Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during therapy. Recommended treatment in hypertensive crisis: If a hypertensive crisis occurs, NARDIL should be discontinued immediately and therapy to lower blood pressure should be instituted immediately. On the basis of present evidence, phentolamine is recommended. (The dosage reported for phentolamine is 5 mg intravenously.) Care should be taken to administer this drug slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling. Warning to the Patient: All patients should be warned that the following foods, beverages, and medications must be avoided while taking NARDIL, and for two weeks after discontinuing use. Foods and Beverages To Avoid Meat and Fish Pickled herring Liver Dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna) Vegetables Broad bean pods (fava bean pods) Sauerkraut Dairy Products Cheese (cottage cheese and cream cheese are allowed) Yogurt Beverages Beer and wine Alcohol-free and reduced-alcohol beer and wine products Miscellaneous Yeast extract (including brewer’s yeast in large quantities) Meat extract Excessive amounts of chocolate and caffeine Also, any spoiled or improperly refrigerated, handled, or stored protein-rich foods such as meats, fish, and dairy products, including foods that may have undergone protein changes by aging, pickling, fermentation, or smoking to improve flavor should be avoided. OTC Medications To Avoid Cold and cough preparations (including those containing dextromethorphan) Nasal decongestants (tablets, drops, or spray) Hay-fever medications Sinus medications Asthma inhalant medications This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antiappetite medicines Weight-reducing preparations “Pep” pills L-tryptophan containing preparations Also, certain prescription drugs should be avoided. Therefore, patients under the care of another physician or dentist should inform him/her that they are taking NARDIL. Patients should be warned that the use of the above foods, beverages, or medications may cause a reaction characterized by headache and other serious symptoms due to a rise in blood pressure, with the exception of dextromethorphan which may cause reactions similar to those seen with meperidine. Also, there has been a report of an interaction between NARDIL and dextromethorphan (ingested as a lozenge) causing drowsiness and bizarre behavior. Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms. Concomitant Use with Dibenzazepine Derivative Drugs If the decision is made to administer NARDIL concurrently with other antidepressant drugs, or within less than 10 days after discontinuation of antidepressant therapy, the patient should be cautioned by the physician regarding the possibility of adverse drug interaction. A List of Dibenzazepine Derivative Drugs by Generic Name Follows: nortriptyline hydrochloride amitriptyline hydrochloride perphenazine and amitriptyline hydrochloride clomipramine hydrochloride desipramine hydrochloride imipramine hydrochloride doxepin carbamazepine cyclobenzaprine HCl amoxapine maprotiline HCl trimipramine maleate protriptyline HCl mirtazapine NARDIL should be used with caution in combination with antihypertensive drugs, including thiazide diuretics and ß-blockers, since exaggerated hypotensive effects may result. Use in Pregnancy: The safe use of NARDIL during pregnancy or lactation has not been established. The potential benefit of this drug, if used during pregnancy, lactation, or in women of childbearing age, should be weighed against the possible hazard to the mother or fetus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Doses of NARDIL in pregnant mice well exceeding the maximum recommended human dose have caused a significant decrease in the number of viable offspring per mouse. In addition, the growth of young dogs and rats has been retarded by doses exceeding the maximum human dose. PRECAUTIONS Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with NARDIL and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for NARDIL. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking NARDIL. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in medication. Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of NARDIL in a child or adolescent must balance the potential risks with the clinical need. Nardil, as with other hydrazine derivatives, has been reported to induce pulmonary and vascular tumors in an uncontrolled lifetime study in mice. In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. It is recommended that careful observations of patients undergoing This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NARDIL treatment be maintained until control of depression is achieved. If necessary, additional measures (ECT, hospitalization, etc) should be instituted. All patients undergoing treatment with NARDIL should be closely followed for symptoms of postural hypotension. Hypotensive side effects have occurred in hypertensive as well as normotensive and hypotensive patients. Blood pressure usually returns to pretreatment levels rapidly when the drug is discontinued or the dosage is reduced. Because the effect of NARDIL on the convulsive threshold may be variable, adequate precautions should be taken when treating epileptic patients. Of the more severe side effects that have been reported with any consistency, hypomania has been the most common. This reaction has been largely limited to patients in whom disorders characterized by hyperkinetic symptoms coexist with, but are obscured by, depressive affect; hypomania usually appeared as depression improved. If agitation is present, it may be increased with NARDIL. Hypomania and agitation have also been reported at higher than recommended doses or following long-term therapy. NARDIL may cause excessive stimulation in schizophrenic patients; in manic-depressive states it may result in a swing from a depressive to a manic phase. NARDIL should be used with caution in diabetes mellitus; increased insulin sensitivity may occur. Requirements for insulin or oral hypoglycemics may be decreased. MAO inhibitors, including NARDIL, potentiate hexobarbital hypnosis in animals. Therefore, barbiturates should be given at a reduced dose with NARDIL. MAO inhibitors inhibit the destruction of serotonin and norepinephrine, which are believed to be released from tissue stores by rauwolfia alkaloids. Accordingly, caution should be exercised when rauwolfia is used concomitantly with an MAO inhibitor, including NARDIL. There is conflicting evidence as to whether or not MAO inhibitors affect glucose metabolism or potentiate hypoglycemic agents. This should be kept in mind if NARDIL is administered to diabetics. Drug Interactions In patients receiving nonselective monoamine oxidase (MAO) inhibitors in combination with serotoninergic agents (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxine) there have been reports of serious, sometimes fatal, reactions. Because NARDIL is a monoamine oxidase (MAO) inhibitor, NARDIL should not be used concomitantly with a serotoninergic agent (See CONTRAINDICATIONS). Administration of guanethidine to patients receiving an MAO inhibitor can produce moderate to severe hypertension due to release of catecholamines. At least two weeks should elapse between withdrawal of the MAO inhibitor and the initiation of guanethidine. (see CONTRAINDICATIONS) Geriatric Use Clinical studies of NARDIL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other 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 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 NARDIL is a potent inhibitor of monoamine oxidase. Because this enzyme is widely distributed throughout the body, diverse pharmacologic effects can be expected to occur. When they occur, such effects tend to be mild or moderate in severity (see below), often subside as treatment continues, and can be minimized by adjusting dosage; rarely is it necessary to institute counteracting measures or to discontinue NARDIL. Common side effects include: Nervous System—Dizziness, headache, drowsiness, sleep disturbances (including insomnia and hypersomnia), fatigue, weakness, tremors, twitching, myoclonic movements, hyperreflexia. Gastrointestinal—Constipation, dry mouth, gastrointestinal disturbances, elevated serum transaminases (without accompanying signs and symptoms). Metabolic—Weight gain. Cardiovascular—Postural hypotension, edema. Genitourinary—Sexual disturbances, eg, anorgasmia and ejaculatory disturbances and impotence. Less common mild to moderate side effects (some of which have been reported in a single patient or by a single physician) include: Nervous System—Jitteriness, palilalia, euphoria, nystagmus, paresthesias. Genitourinary—Urinary retention. Metabolic—Hypernatremia. Dermatologic—Pruritus, skin rash, sweating. Special Senses—Blurred vision, glaucoma. Although reported less frequently, and sometimes only once, additional severe side effects include: Nervous System—Ataxia, shock-like coma, toxic delirium, manic reaction, convulsions, acute anxiety reaction, precipitation of schizophrenia, transient respiratory and cardiovascular depression following ECT. Gastrointestinal—To date, fatal progressive necrotizing hepatocellular damage has been reported in very few patients. Reversible jaundice. Hematologic—Leukopenia. Immunologic—Lupus-like syndrome This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolic—Hypermetabolic syndrome (which may include, but is not limited to, hyperpyrexia, tachycardia, tachypnea, muscular rigidity, elevated CK levels, metabolic acidosis, hypoxia, coma and may resemble an overdose). Respiratory—Edema of the glottis. General—Fever associated with increased muscle tone. Withdrawal may be associated with nausea, vomiting, and malaise. An uncommon withdrawal syndrome following abrupt withdrawal of NARDIL has been infrequently reported. Signs and symptoms of this syndrome generally commence 24 to 72 hours after drug discontinuation and may range from vivid nightmares with agitation to frank psychosis and convulsions. This syndrome generally responds to reinstitution of low-dose NARDIL therapy followed by cautious downward titration and discontinuation. DOSAGE AND ADMINISTRATION Initial dose: The usual starting dose of NARDIL is one tablet (15 mg) three times a day. Early phase treatment: Dosage should be increased to at least 60 mg per day at a fairly rapid pace consistent with patient tolerance. It may be necessary to increase dosage up to 90 mg per day to obtain sufficient MAO inhibition. Many patients do not show a clinical response until treatment at 60 mg has been continued for at least 4 weeks. Maintenance dose: After maximum benefit from NARDIL is achieved, dosage should be reduced slowly over several weeks. Maintenance dose may be as low as one tablet, 15 mg, a day or every other day, and should be continued for as long as is required. OVERDOSAGE Note—For management of hypertensive crises see WARNINGS section. Accidental or intentional overdosage may be more common in patients who are depressed. It should be remembered that multiple drugs and/or alcohol may have been ingested. Depending on the amount of overdosage with NARDIL, a varying and mixed clinical picture may develop, including signs and symptoms of central nervous system and cardiovascular stimulation and/or depression. Signs and symptoms may be absent or minimal during the initial 12-hour period following ingestion and may develop slowly thereafter, reaching a maximum in 24-48 hours. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring throughout this period, is essential. Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonus, rigidity, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension, and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. Treatment Intensive symptomatic and supportive treatment may be required. Induction of emesis or gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda provided the airway has been protected against aspiration. Signs and symptoms of central nervous system stimulation, including convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated with intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of dilute pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor response. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential. There are no data on the lethal dose in man. The pathophysiologic effects of massive overdosage may persist for several days, since the drug acts by inhibiting physiologic enzyme systems. With symptomatic and supportive measures, recovery from mild overdosage may be expected within 3 to 4 days. Hemodialysis, peritoneal dialysis, and charcoal hemoperfusion may be of value in massive overdosage, but sufficient data are not available to recommend their routine use in these cases. Toxic blood levels of phenelzine have not been established, and assay methods are not practical for clinical or toxicological use. HOW SUPPLIED Each NARDIL tablet is orange, biconvex, film-coated, and engraved with “P-D 270” and contains phenelzine sulfate equivalent to 15 mg of phenelzine base. NDC 0071-0350-60. Bottle of 60 Storage: Store between 15° - 30°C (59° - 86°F). Rx only LAB-0201-8.0 Revised July 2006 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions 2. How to try to prevent suicidal thoughts or actions in your child 3. You should watch for certain signs if your child is taking an antidepressant 4. There are benefits and risks when using antidepressants 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child’s life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Whenever an antidepressant is started or its dose is changed, pay close attention to your child. After starting an antidepressant, your child should generally see his or her healthcare provider: • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your healthcare provider’s advice about how often to come back • More often if problems or questions arise (see Section 3) You should call your child’s healthcare provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child’s healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child’s teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms. 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Of all the antidepressants, only fluoxetine (Prozac™ ) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac™ ), sertraline (Zoloft™ ), fluvoxamine, and clomipramine (Anafranil™). Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information. Prozac is a registered trademark of Eli Lilly and Company Zoloft is a registered trademark of Pfizer Pharmaceuticals *Anafranil is a registered trademark of Mallinckrodt Inc. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.250256	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011909s036lbl.pdf', 'application_number': 11909, 'submission_type': 'SUPPL ', 'submission_number': 36}
10,788	1 ATTACHMENT FINAL LABELING MARPLAN® brand of isocarboxazid TABLETS DESCRIPTION Marplan (isocarboxazid), a monoamine oxidase inhibitor, is available for oral administration in 10-mg tablets. Each tablet also contains gelatin, lactose, magnesium stearate, corn starch, talc, FD&C Red No. 3 and FD&C Yellow No. 6. Chemically, isocarboxazid is 5-methyl-3-isoxazolecarboxylic acid 2-benzylhydrazide. The structural formula is: Isocarboxazid is a colorless, crystalline substance with very little taste. CLINICAL PHARMACOLOGY Pharmacodynamics Isocarboxazid is a non-selective hydrazine monoamine oxidase (MAO) inhibitor. In vivo and in vitro studies demonstrated inhibition of MAO in the brain, heart, and liver. The mechanism by which MAO inhibitors act as antidepressants is not fully understood, but is thought to involve the elevation of brain levels of biogenic amines. However, MAO is a complex enzyme system, widely distributed throughout the body, and drugs that inhibit MAO in the laboratory are associated with a number of clinical effects. Thus, it is unknown whether MAO inhibition per se, other pharmacologic actions, or an interaction of both is responsible for the antidepressant effects observed. Pharmacokinetics Marplan pharmacokinetic information is not available. Clinical Efficacy Data The effectiveness of Marplan was demonstrated in two 6-week placebo-controlled studies conducted in adult outpatients with depressive symptoms that corresponded to the DSM-IV category of major depressive disorder. The patients often also had signs and symptoms of anxiety (anxious mood, panic, and/or phobic symptoms). Patients were initiated with a dose of 10 mg bid, with increases This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 every 2 to 4 days, as tolerated, until a therapeutic effect was achieved, up to a maximum dose of 80 mg/day. Doses were administered on a divided schedule ranging from 2 to 4 times a day. The mean dose overall for both studies was approximately 40 mg/day, with very few patients receiving doses greater than 60 mg/day. In both studies at the end of 6 weeks, patients receiving Marplan had significantly greater reduction in signs and symptoms of depression evaluated by the Hamilton Depression Scale, for both the Total Score and the Depressed Mood Score, than patients who received placebo. INDICATIONS AND USAGE Marplan is indicated for the treatment of depression. Because of its potentially serious side effects, Marplan is not an antidepressant of first choice in the treatment of newly diagnosed depressed patients. The efficacy of Marplan in the treatment of depression was established in 6-week controlled trials of depressed outpatients. These patients had symptoms that corresponded to the DSM-IV category of major depressive disorder; however, they often also had signs and symptoms of anxiety (anxious mood, panic, and/or phobic symptoms). (See Clinical Pharmacology) A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The antidepressant effectiveness of Marplan in hospitalized depressed patients, or in endogenomorphically retarded and delusionally depressed patients, has not been adequately studied. The effectiveness of Marplan in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Marplan for extended periods should periodically evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Marplan (isocarboxazid) should not be administered in combination with any of the following: MAO inhibitors or dibenzazepine derivatives; sympathomimetics (including amphetamines); some central nervous system depressants (including narcotics and alcohol); antihypertensive, diuretic, antihistaminic, sedative or anesthetic drugs, buproprion HCL, buspirone HCL, dextromethorphan, cheese or other foods with a high tyramine content; or excessive quantities of caffeine. Marplan (isocarboxazid) should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease, hypertension, or history of headache. Contraindicated Patient Populations This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Hypersensitivity Marplan should not be used in patients with known hypersensitivity to isocarboxazid. Cerebrovascular Disorders Marplan should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease or hypertension. Pheochromocytoma Marplan should not be used in the presence of pheochromocytoma, as such tumors secrete pressor substances whose metabolism may be inhibited by Marplan. Liver Disease Marplan should not be used in patients with a history of liver disease, or in those with abnormal liver function tests. Renal Impairment Marplan should not be used in patients with severe impairment of renal function. Patients with Severe/Frequent Headaches Patients with severe or frequent headaches should not be considered candidates for therapy with Marplan, because headaches during therapy may be the first symptom of a hypertensive reaction to the drug. Contraindicated MAOI-Other Drug Combinations Other MAO inhibitors or with dibenzazepine-related entities Marplan should not be administered together with, or in close proximity to, other MAO inhibitors or dibenzazepine-related entities. Hypertensive crises, severe convulsive seizures, coma, or circulatory collapse may occur in patients receiving such combinations. In patients being transferred to Marplan from another MAO inhibitor or from a dibenzazepine-related entity, a medication-free interval of at least 1 week should be allowed, after which Marplan therapy should be started using half the normal starting dosage for at least the first week of therapy. Similarly, at least 1 week should elapse between the discontinuation of Marplan and initiation of another MAO inhibitor or dibenzazepine-related entity, or the readministration of Marplan. The following list includes some other MAO inhibitors, dibenzazepine-related entities, and tricyclic antidepressants. Generic Name Trademark (Manufacturer) Other MAO Inhibitors This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Furazolidone Furoxone® (Roberts Laboratories) Pargyline HCL Eutonyl® (Abbott Laboratories) Pargyline HCL and methyclothiazide Eutron® (Abbott Laboratories) Phenelzine sulfate Nardil® (Parke-Davis) Procarbazine Matulane® (Roche Laboratories) Tranylcypromine sulfate Parnate® (SmithKline Beecham Pharmaceuticals) Dibenzazepine-Related and Other Tricyclics Amitriptyline HCL Elavil® (Zeneca) Endep® (Roche Products) Perphenazine and amitriptyline HCL Etrafon® (Schering) Triavil® (Merck Sharp & Dohme) Clomipramine hydrochloride Anafranil® (Novartis) Desipramine HCL Norpramin® (Hoechst Marion Roussel) Pertofrane® (Rhône-Poulenc Rorer Pharmaceuticals) Imipramine HCL Janimine® (Abbott Laboratories) Tofranil® (Novartis) Nortriptyline HCL Aventyl® (Eli Lilly & Co.) Pamelor® (Novartis) Protripyline HCL Vivactil® (Merck Sharp & Dohme) Doxepin HCL Adapin® (Fisons) Sinequan® (Pfizer) Carbamazepine Tegretol® (Novartis) Cyclobenzaprine HCL Flexeril® (Merck Sharp & Dohme) Amoxapine Asendin® (Lederle) Maprotiline HCL Ludiomil® (Novartis) Trimipramine maleate Surmontil® (Wyeth-Ayerst Laboratories) Bupropion The concurrent administration of an MAO inhibitor and bupropion hydrochloride (Wellbutrin® and Zyban®, Glaxo Wellcome) is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion hydrochloride. Selective Serotonin Reuptake Inhibitors (SSRIs) Marplan should not be administered in combination with any SSRI. There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation and confusion progressing to delirium and coma) in patients receiving fluoxetine (Prozac®, Lilly) in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Fluoxetine and other SSRIs should therefore not be used in combination with Marplan, or within 14 days of discontinuing therapy with Marplan. As fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine before starting Marplan. At least 2 weeks should be allowed after stopping sertraline (Zoloft®, Pfizer) or paroxetine (Paxil®, SmithKline Beecham Pharmaceuticals) before starting Marplan. In addition, there should be an interval of at least 10 days between discontinuation of Marplan and initiation of fluoxetine or other SSRIs. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Buspirone Marplan should not be used in combination with buspirone HCL (Buspar®, Bristol-Myers Squibb); several cases of elevated blood pressure have been reported in patients taking MAO inhibitors who were then given buspirone HCL. At least 10 days should elapse between the discontinuation of Marplan and the institution of buspirone HCL. Sympathomimetics Marplan should not be administered in combination with sympathomimetics, including amphetamines, or with over-the-counter drugs such as cold, hay fever, or weight-reducing preparations that contain vasoconstrictors. During Marplan therapy, it appears that some patients are particularly vulnerable to the effects of sympathomimetics when the activity of metabolizing enzymes is inhibited. Use of sympathomimetics and compounds such as guanethidine, methyldopa, methylphenidate, reserpine, epinephrine, norepinephrine, phenylalanine, dopamine, levodopa, tyrosine, and tryptophan with Marplan may precipitate hypertension, headache, and related symptoms. The combination of MAO inhibitors and tryptophan has been reported to cause behavioral and neurologic symptoms, including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski signs. Meperidine Meperidine should not be used concomitantly with MAO inhibitors or within 2 or 3 weeks following MAO therapy. Serious reactions have been precipitated with concomitant use, including coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse, and death. It is thought that these reactions may be mediated by accumulation of 5-HT (serotonin) consequent to MAO inhibition. Dextromethorphan Marplan should not be used in combination with dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Cheese or Other Foods with a High Tyramine Content Hypertensive crises have sometimes occurred during Marplan therapy after ingestion of foods with a high tyramine content. In general, patients should avoid protein foods in which aging or protein breakdown is used to increase flavor. In particular, patients should be instructed not to take foods such as cheese (particularly strong or aged varieties), sour cream, Chianti wine, sherry, beer (including non-alcoholic beer), liqueurs, pickled herring, anchovies, caviar, liver, canned figs, raisins, bananas or avocados (particularly if overripe), chocolate, soy sauce, sauerkraut, the pods of broad beans (fava beans), yeast extracts, yogurt, meat extracts, meat prepared with tenderizers, or dry sausage. Anesthetic Agents This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Patients taking Marplan should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of Marplan and spinal anesthesia should be kept in mind. Marplan should be discontinued at least 10 days before elective surgery. CNS Depressants Marplan should not be used in combination with some central nervous system depressants, such as narcotics, barbiturates, or alcohol. Antihypertensives Marplan should not be used in combination with antihypertensive agents, including thiazide diuretics. A marked potentiating effect on these drugs has been reported, resulting in hypotension. Caffeine Excessive use of caffeine in any form should be avoided in patients receiving Marplan. WARNINGS Second Line Status Marplan can cause serious side effects. It is not recommended as initial therapy but should be reserved for patients who have not responded satisfactorily to other antidepressants. Hypertensive Crises The most important reaction associated with MAO inhibitors is the occurrence of hypertensive crises, which have sometimes been fatal, resulting from the co-administration of MAOIs and certain drugs and foods (see Contraindications). These crises are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea or vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), and photophobia. Either tachycardia or bradycardia may be present, and associated constricting chest pain and dilated pupils may occur. Intracranial bleeding, sometimes fatal, has been reported in association with the increase in blood pressure. Blood pressure should be followed closely in patients taking Marplan to detect any pressor response. Therapy should be discontinued immediately if palpitations or frequent headaches occur during Marplan therapy as these symptoms may be prodromal of a hypertensive crisis. If a hypertensive crisis occurs, Marplan should be discontinued, and therapy to lower blood pressure should be instituted immediately. Although there has been no systematic study of treatment of hypertensive crises, phentolamine (available as Regitine®, Novartis) has been used and is recommended at a dosage of 5 mg I.V. Care should be taken to administer the drug slowly in order This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling. Other symptomatic and supportive measures may be desirable in particular cases. Parenteral reserpine should not be used. Warnings to the Patient Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms, i.e., palpitation and/or tachycardia, a sense of constriction in the throat or chest, sweating, dizziness, neck stiffness, nausea, or vomiting. Patients should be warned against eating the foods listed under CONTRAINDICATIONS while on Marplan therapy and should also be told not to drink alcoholic beverages. The patient should also be warned about the possibility of hypotension and faintness, as well as drowsiness sufficient to impair performance of potentially hazardous tasks, such as driving a car or operating machinery. Patients should also be cautioned not to take concomitant medications, whether prescription or over- the-counter drugs such as cold, hay fever, or weight-reducing preparations, without the advice of a physician. They should be advised not to consume excessive amounts of caffeine in any form. Likewise, they should inform their physicians and their dentist about the use of Marplan. Limited Experience with Marplan at Higher Doses Because of the limited experience with systematically monitored patients receiving Marplan at the higher end of the currently recommended dose range of up to 60 mg/day, caution is indicated in patients for whom a dose of 40 mg/day is exceeded (see ADVERSE REACTIONS). PRECAUTIONS General Hypotension Hypotension has been observed during Marplan therapy. Symptoms of postural hypotension are seen most commonly, but not exclusively, in patients with preexistent hypertension; blood pressure usually returns rapidly to pretreatment levels upon discontinuation of the drug. Dosage increases should be made more gradually in patients showing a tendency toward hypotension at the beginning of therapy. Postural hypotension may be relieved by having the patient lie down until blood pressure returns to normal. When Marplan is combined with phenothiazine derivatives or other compounds known to cause hypotension, the possibility of additive hypotensive effects should be considered. Lowered Seizure Threshold Because Marplan lowers the convulsive threshold in some animal experiments, suitable precautions should be taken if epileptic patients are treated. Marplan appears to have varying effects in epileptic patients; while some have a decrease in frequency of seizures, others have more seizures. Drugs that lower the seizure threshold, including MAO inhibitors, should not be used with Amipaque® (metrizamide, Sanofi Winthrop Pharmaceuticals). As with other MAO inhibitors, Marplan should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Hepatotoxicity There is a low incidence of altered liver function or jaundice in patients treated with Marplan. In the past, it was difficult to differentiate most cases of drug-induced hepatocellular jaundice from viral hepatitis although this is no longer true. Periodic liver chemistry tests should be performed during Marplan therapy; use of the drug should be discontinued at the first sign of hepatic dysfunction or jaundice. Suicide In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. Exclusive reliance on drug therapy to prevent suicidal attempts is unwarranted, as there may be a delay in the onset of therapeutic effect or an increase in anxiety or agitation. Also, some patients fail to respond to drug therapy or may respond only temporarily. The strictest supervision, and preferably hospitalization, are required. Use in Patients with Concomitant Illness MAO inhibitors can suppress anginal pain that would otherwise serve as a warning of myocardial ischemia. In patients with impaired renal function, Marplan should be used cautiously to prevent accumulation. Some MAO inhibitors have contributed to hypoglycemic episodes in diabetic patients receiving insulin or glycemic agents. Marplan should therefore be used with caution in diabetics using these drugs. Marplan may aggravate coexisting symptoms in depression, such as anxiety and agitation. Use Marplan with caution in hyperthyroid patients because of their increased sensitivity to pressor amines. Marplan should be used cautiously in hyperactive or agitated patients, as well as in schizophrenic patients, because it may cause excessive stimulation. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with marketed antidepressants. Drug Interactions See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections for information on drug interactions. Marplan should be administered with caution to patients receiving Antabuse® (disulfiram, Wyeth- Ayerst Laboratories). In a single study, rats given high intraperitoneal doses of an MAO inhibitor plus disulfiram experienced severe toxicity, including convulsions and death. Concomitant use of Marplan and other psychotropic agents is generally not recommended because of possible potentiating effects. This is especially true in patients who may subject themselves to an overdosage of drugs. If combination therapy is needed, careful consideration should be given to the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 pharmacology of all agents to be used. The monoamine oxidase inhibitory effects of Marplan may persist for a substantial period after discontinuation of the drug, and this should be borne in mind when another drug is prescribed following Marplan. To avoid potentiation, the physician wishing to terminate treatment with Marplan and begin therapy with another agent should allow for an interval of 10 days. Carcinogenesis, Mutagenesis, Impairment of Fertility Long term studies to evaluate carcinogenic potential have not been conducted with this drug, and there is no information concerning mutagenesis or impairment of fertility. Pregnancy Category C The potential reproductive toxicity of isocarboxazid has not been adequately evaluated in animals. It is also not known whether isocarboxazid can cause embryo/fetal harm when administered to a pregnant woman or can affect reproductive capacity. Marplan should be given to a pregnant woman only if clearly needed. Nursing Mothers Levels of excretion of isocarboxazid and/or its metabolites in human milk have not been determined, and effects on the nursing infant are unknown. Marplan should be used in women who are nursing only if clearly needed. Pediatric Use Marplan is not recommended for use in patients under 16 years of age, as safety and effectiveness in pediatric populations have not been demonstrated. ADVERSE REACTIONS Adverse Findings Observed in Short-Term, Placebo-Controlled Trials Systematically collected data are available from only 86 patients exposed to Marplan, of whom only 52 received doses of $50 mg/day, including only 11 who were dosed at $60 mg/day. Because of the limited experience with systematically monitored patients receiving Marplan at the higher end of the currently recommended dose range of up to 60 mg/day, caution is indicated in patients for whom a dose of 40 mg/day is exceeded (see WARNINGS). The table that follows enumerates the incidence, rounded to the nearest percent, of treatment emergent adverse events that occurred among 86 depressed patients who received Marplan at doses ranging from 20 to 80 mg/day in placebo-controlled trials of 6 weeks in duration. Events included are those occurring in 1% or more of patients treated with Marplan and for which the incidence in patients treated with Marplan was greater than the incidence in placebo-treated patients. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 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 non-drug factors to the adverse event incidence rate in the population studied. The commonly observed adverse event that occurred in Marplan patients with an incidence of 5% or greater and at least twice the incidence in placebo patients were nausea, dry mouth, and dizziness. (see Table). In three clinical trials for which the data were pooled, 4 of 85 (5%) patients who received placebo, 10 of 86 (12%) who received <50 mg of Marplan per day, and 1 of 52 (2%) who received $ 50 mg of Marplan per day prematurely discontinued treatment. The most common reasons for discontinuation were dizziness, orthostatic hypotension, syncope, and dry mouth. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Treatment-Emergent Adverse Events Incidence in Placebo-Controlled Clinical Trials with Marplan Doses of 40 to 80 mg/day1 Body System/ PLACEBO MARPLAN <50 mg MARPLAN $$50 mg Adverse Event (N=85) (N=86) (N=52)2 MISCELLANEOUS Drowsy 0% 4% 0% Anxiety 1% 2% 0% Chills 0% 2% 0% Forgetful 1% 2% 2% Hyperactive 0% 2% 0% Lethargy 0% 2% 2% Sedation 1% 2% 0% Syncope 0% 2% 0% INTEGUMENTARY Sweating 0% 2% 2% MUSCULOSKELETAL Heavy feeling 0% 2% 0% CARDIOVASCULAR Orthostatic hypotension 1% 4% 4% Palpitations 1% 2% 0% GASTROINTESTINAL Dry mouth 4% 9% 6% Constipation 6% 7% 4% Nausea 2% 6% 4% Diarrhea 1% 2% 0% UROGENITAL Impotence 0% 2% 0% Urinary frequency 1% 2% 0% Urinary hesitancy 0% 1% 4% CENTRAL NERVOUS Headache 13% 15% 6% Insomnia 4% 4% 6% Sleep disturbance 0% 5% 2% Tremor 0% 4% 4% Myoclonic jerks 0% 2% 0% Paresthesia 1% 2% 0% SPECIAL SENSES Dizziness 14% 29% 15% 1 Events reported by at least 1% of patients treated with Marplan are presented, except for those which had an incidence on placebo greater than or equal to that on Marplan. 2 All patients also received Marplan at doses # 50 mg. Other Events Observed During the Postmarketing Evaluation of Marplan Isolated cases of akathisia, ataxia, black tongue, coma, dysuria, euphoria, hematologic changes, incontinence, neuritis, photosensitivity, sexual disturbances, spider telangiectases, and urinary retention have been reported. These side effects sometimes necessitate discontinuation of therapy. In rare instances, hallucinations have been reported with high dosages, but they have disappeared upon reduction of dosage or discontinuation of therapy. Toxic amblyopia was reported in one psychiatric patient who had received isocarboxazid for about a year; no causal relationship to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 isocarboxazid was established. Impaired water excretion compatible with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Marplan is not a controlled substance. Physical and Psychological Dependence Marplan has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. There have been reports of drug dependency in patients using doses of Marplan significantly in excess of the therapeutic range. Some of these patients had a history of previous substance abuse. The following withdrawal symptoms have been reported: restlessness, anxiety, depression, confusion, hallucinations, headache, weakness, and diarrhea. Consequently, physicians should carefully evaluate Marplan patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug seeking behavior). OVERDOSAGE The lethal dose of Marplan in humans is not known. There has been one report of a fatality in a patient who ingested 400 mg of Marplan together with an unspecified amount of another drug. Symptoms: Major overdosage may be evidenced by tachycardia, hypotension, coma, convulsions, respiratory depression, sluggish reflexes, pyrexia, and diaphoresis; these signs may persist for 8 to 14 days. Treatment: General supportive measures should be used, along with immediate gastric lavage or emetics. If the latter are given, the danger of aspiration must be borne in mind. An adequate airway should be maintained, with supplemental oxygen if necessary. The mechanism by which amine-oxidase inhibitors produce hypotension is not fully understood, but there is evidence that these agents block the vascular bed response. Thus it is suggested that plasma may be of value in the management of this hypotension. Administration of pressor amines such as Levophed (levarterenol ® bitartrate) may be of limited value (note that their effects may be potentiated by Marplan). Continue treatment for several days until homeostasis is restored. Liver function studies are recommended during the 4 to 6 weeks after recovery, as well as at the time of overdosage. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center on the treatment of any overdose. DOSAGE AND ADMINISTRATION For maximum therapeutic effect, the dosage of Marplan must be individually adjusted on the basis of careful observation of the patient. Dosage should be started with one tablet (10 mg) of Marplan twice daily. If tolerated, dosage may be increased by increments of one tablet (10 mg) every 2 to 4 days to achieve a dosage of four tablets daily (40 mg) by the end of the first week of treatment. Dosage can then be increased by increments of up to 20 mg/week, if needed and tolerated, to a maximum recommended dosage of 60 mg/day. Daily dosage should be divided into two to four doses. After maximum clinical response is achieved, an attempt should be made to reduce the dosage slowly over a period of several weeks without jeopardizing the therapeutic response. Beneficial effect This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 may not be seen in some patients for 3 to 6 weeks. If no response is obtained by then, continued administration is unlikely to help. Because of the limited experience with systematically monitored patients receiving Marplan at the higher end of the currently recommended dose range of up to 60 mg/day, caution is indicated in patients for whom a dose of 40 mg/day is exceeded (see Adverse Reactions). HOW SUPPLIED Tablets, 10 mg isocarboxazid each, peach-colored, scored—bottles of 100 (NDC 0004-0032-01). Rx only Hoffmann-La Roche Inc. 340 Kingsland Street Nutley, New Jersey 07110-1199 Printed in U.S.A. Doc LABMRPLN.AP3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.336350	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/11961lbl.pdf', 'application_number': 11961, 'submission_type': 'SUPPL ', 'submission_number': 17}
10,789	NDA 11-963/S-034 Page 3 Phospholine Iodide® (echothiophate iodide for ophthalmic solution) Rx only DESCRIPTION Chemical name: (2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioate Structural formula [Structure] Echothiophate iodide for ophthalmic solution occurs as a white, crystalline, water-soluble, hygroscopic solid having a slight mercaptan-like odor. When freeze-dried in the presence of potassium acetate, the mixture appears as a white amorphous deposit on the walls of the bottle. Each package contains materials for dispensing 5 mL of eyedrops: (1) bottle containing sterile echothiophate iodide for ophthalmic solution in one of four potencies [1.5 mg (0.03%), 3 mg (0.06%), 6.25 mg (0.125%), or 12.5 mg (0.25%)] as indicated on the label, with 40 mg potassium acetate in each case. Sodium hydroxide or acetic acid may have been incorporated to adjust pH during manufacturing. (2) a 5 mL bottle of sterile diluent containing chlorobutanol (chloral derivative), 0.55%; mannitol, 1.2%; boric acid, 0.06%; and sodium phosphate, 0.026%. (3) sterilized dropper. CLINICAL PHARMACOLOGY Echothiophate iodide for ophthalmic solution is a long-acting cholinesterase inhibitor for topical use which enhances the effect of endogenously liberated acetylcholine in iris, ciliary muscle, and other parasympathetically innervated structures of the eye. It thereby causes miosis, increase in facility of outflow of aqueous humor, fall in intraocular pressure, and potentiation of accommodation. Echothiophate iodide for ophthalmic solution will depress both plasma and erythrocyte cholinesterase levels in most patients after a few weeks of eyedrop therapy. INDICATIONS AND USAGE Glaucoma Chronic open-angle glaucoma. Subacute or chronic angle-closure glaucoma after iridectomy or where surgery is refused or contraindicated. Certain non-uveitic secondary types of glaucoma, especially glaucoma following cataract surgery. Accommodative Esotropia Concomitant esotropias with a significant accommodative component. CONTRAINDICATIONS 1. Active uveal inflammation. 2. Most cases of angle-closure glaucoma, due to the possibility of increasing angle block. 3. Hypersensitivity to the active or inactive ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-963/S-034 Page 4 WARNINGS 1. Succinylcholine should be administered only with great caution, if at all, prior to or during general anesthesia to patients receiving anticholinesterase medication because of possible respiratory or cardiovascular collapse. 2. Caution should be observed in treating glaucoma with echothiophate iodide for ophthalmic solution in patients who are at the same time undergoing treatment with systemic anticholinesterase medications for myasthenia gravis, because of possible adverse additive effects. (See “PRECAUTIONS, Drug Interactions” for further information.) PRECAUTIONS General 1. Gonioscopy is recommended prior to initiation of therapy. Routine examination to detect lens opacity should accompany clinical use of echothiophate iodide for ophthalmic solution. 2. Where there is a quiescent uveitis or a history of this condition, anticholinesterase therapy should be avoided or used cautiously because of the intense and persistent miosis and ciliary muscle contraction that may occur. 3. While systemic effects are infrequent, proper use of the drug requires digital compression of the nasolacrimal ducts for a minute or two following instillation to minimize drainage into the nasal chamber with its extensive absorption area. To prevent possible skin absorption, hands should be washed following instillation. 4. Temporary or permanent discontinuance of medication is necessary if cardiac irregularities occur. 5. Anticholinesterase drugs should be used with extreme caution, if at all, in patients with marked vagotonia, bronchial asthma, spastic gastrointestinal disturbances, peptic ulcer, pronounced bradycardia and hypotension, recent myocardial infarction, epilepsy, parkinsonism, and other disorders that may respond adversely to vagotonic effects. 6. Anticholinesterase drugs should be employed prior to ophthalmic surgery only as a considered risk because of the possible occurrence of hyphema. 7. Echothiophate iodide for ophthalmic solution should be used with great caution, if at all, where there is a prior history of retinal detachment. 8. Temporary discontinuance of medication is necessary if salivation, urinary incontinence, diarrhea, profuse sweating, muscle weakness, or respiratory difficulties occur. 9. Patients receiving echothiophate iodide for ophthalmic solution who are exposed to carbamate- or organophosphatetype insecticides and pesticides (professional gardeners, farmers, workers in plants manufacturing or formulating such products, etc.) should be warned of the additive systemic effects possible from absorption of the pesticide through the respiratory tract or skin. During periods of exposure to such pesticides, the wearing of respiratory masks, and frequent washing and clothing changes may be advisable. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-963/S-034 Page 5 Drug Interactions Echothiophate iodide for ophthalmic solution potentiates other cholinesterase inhibitors such as succinylcholine or organophosphate and carbamate insecticides. Patients undergoing systemic anticholinesterase treatment should be warned of the possible additive effects of echothiophate iodide for ophthalmic solution. Carcinogenesis, Mutagenesis, Impairment of Fertility No data is available regarding carcinogenesis, mutagenesis, and impairment of fertility. Pregnancy Teratogenic Effects – Pregnancy Category C Animal reproduction studies have not been conducted with echothiophate iodide for ophthalmic solution. It is also not known whether P echothiophate iodide for ophthalmic solution can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Echothiophate iodide for ophthalmic solution should be given to a pregnant woman only if clearly needed. Nursing Mothers Because of the potential for serious adverse reactions in nursing infants from echothiophate iodide for ophthalmic solution, 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 been established. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients. ADVERSE REACTIONS 1. Although the relationship, if any, of retinal detachment to the administration of echothiophate iodide for ophthalmic solution has not been established, retinal detachment has been reported in a few cases during the use of echothiophate iodide for ophthalmic solution in adult patients without a previous history of this disorder. 2. Stinging, burning, lacrimation, lid muscle twitching, conjunctival and ciliary redness, browache, induced myopia with visual blurring may occur. 3. Activation of latent iritis or uveitis may occur. 4. Iris cysts may form, and if treatment is continued, may enlarge and obscure vision. This occurrence is more frequent in children. The cysts usually shrink upon discontinuance of the medication, reduction in strength of the drops or frequency of instillation. Rarely, they may rupture or break free into the aqueous. Regular examinations are advisable when the drug is being prescribed for the treatment of accommodative esotropia. 5. Prolonged use may cause conjunctival thickening, obstruction of nasolacrimal canals. 6. Lens opacities occurring in patients under treatment for glaucoma with echothiophate iodide for ophthalmic solution have been reported and similar changes have been produced experimentally in normal monkeys. Routine examinations should accompany clinical use of the drug. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-963/S-034 Page 6 7. Paradoxical increase in intraocular pressure may follow anticholinesterase instillation. This may be alleviated by prescribing a sympathomimetic mydriatic such as phenylephrine. 8. Cardiac irregularities. DOSAGE AND ADMINISTRATION Glaucoma Selection of Therapy – The medication prescribed should be that which will control the intraocular pressure around-the-clock with the least risk of side effects or adverse reactions. “Tonometric glaucoma” (ocular hypertension without other evidence of the disease) is frequently not treated with any medication, and echothiophate iodide for ophthalmic solution (echothiophate iodide) is certainly not recommended for this condition. In early chronic simple glaucoma with field loss or disc changes, pilocarpine is generally used for initial therapy and can be recommended so long as control is thereby maintained over the 24 hours of the day. When this is not the case, echothiophate iodide for ophthalmic solution 0.03% may be effective and probably has no greater potential for side effects. If this dosage is inadequate, epinephrine and a carbonic anhydrase inhibitor may be added to the regimen. When still more effective medication is required, the higher strengths of echothiophate iodide for ophthalmic solution may be prescribed with the recognition that the control of the intraocular pressure should have priority regardless of potential side effects. In secondary glaucoma following cataract surgery, the higher strengths of the drug are frequently needed and are ordinarily very well tolerated. The dosage regimen prescribed should call for the lowest concentration that will control the intraocular pressure around-the-clock. Where tonometry around-the-clock is not feasible, it is suggested that appointments for tension-taking be made at different times of the day so that inadequate control may be more readily detected. Two doses a day are preferred to one in order to maintain as smooth a diurnal tension curve as possible, although a single dose per day or every other day has been used with satisfactory results. Because of the long duration of action of the drug, it is never necessary or desirable to exceed a schedule of twice a day. The daily dose or one of the two daily doses should always be instilled just before retiring to avoid inconvenience due to the miosis. Early Chronic Simple Glaucoma – Echothiophate iodide for ophthalmic solution0.03% instilled twice a day, just before retiring and in the morning, may be prescribed advantageously for cases of early chronic simple glaucoma that are not controlled around-the-clock with other less potent agents. Because of prolonged action, control during the night and early morning hours may then sometimes be DIRECTIONS FOR PREPARING EYEDROPS 1. Use aseptic technique. 2. Tear off aluminum seals, and remove and discard rubber plugs from both drug and diluent containers. 3. Pour diluent into drug container. 4. Remove dropper assembly from its sterile wrapping. Holding dropper assembly by the screw cap and, WITHOUT COMPRESSING RUBBER BULB, insert into drug container and screw down tightly. 5. Shake for several seconds to ensure mixing. 6. Do not cover nor obliterate instructions to patient regarding storage of eyedrops. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-963/S-034 Page 7 obtained. A change in therapy is indicated if, at any time, the tension fails to remain at an acceptable level on this regimen. Advanced Chronic Simple Glaucoma and Glaucoma Secondary to Cataract Surgery – These cases may respond satisfactorily to echothiophate iodide for ophthalmic solution 0.03% twice a day as above. When the patient is being transferred to echothiophate iodide for ophthalmic solution because of unsatisfactory control with pilocarpine, carbachol, epinephrine, etc., one of the higher strengths, 0.06%, 0.125%, or 0.25% will usually be needed. In this case, a brief trial with the 0.03% eyedrops will be advantageous in that the higher strengths will then be more easily tolerated. Concomitant Therapy – Echothiophate iodide for ophthalmic solution may be used concomitantly with epinephrine, a carbonic anhydrase inhibitor, or both. Technique – Good technique in the administration of echothiophate iodide for ophthalmic solution requires that finger pressure at the inner canthus should be exerted for a minute or two following instillation of the eyedrops, to minimize drainage into the nose and throat. Excess solution around the eye should be removed with tissue and any medication on the hands should be rinsed off. Accommodative Esotropia (Pediatric Use) In Diagnosis – One drop of 0.125% may be instilled once a day in both eyes on retiring, for a period of two or three weeks. If the esotropia is accommodative, a favorable response will usually be noted which may begin within a few hours. In Treatment – Echothiophate iodide for ophthalmic solution is prescribed at the lowest concentration and frequency which gives satisfactory results. After the initial period of treatment for diagnostic purposes, the schedule may be reduced to 0.125% every other day or 0.06% every day. These dosages can often be gradually lowered as treatment progresses. The 0.03% strength has proven to be effective in some cases. The maximum usually recommended dosage is 0.125% once a day, although more intensive therapy has been used for short periods. Technique – (See “DOSAGE AND ADMINISTRATION, Glaucoma.”) Duration of Treatment – In diagnosis, only a short period is required and little time will be lost in instituting other procedures if the esotropia proves to be unresponsive. In therapy, there is no definite limit so long as the drug is well tolerated. However, if the eyedrops, with or without eyeglasses, are gradually withdrawn after about a year or two and deviation recurs, surgery should be considered. As with other miotics, tolerance may occasionally develop after prolonged use. In such cases, a rest period will restore the original activity of the drug. HOW SUPPLIED Each package contains sterile echothiophate iodide for ophthalmic solution, sterile diluent, and dropper for dispensing 5 mL eyedrops of the strength indicated on the label. Four potencies are available: NDC 0046-1062-05.......................................... 1.5 mg package for 0.03% White amorphous deposit on bottle walls. Aluminum crimp seal is blue. NDC 0046-1064-05.............................................3 mg package for 0.06% White amorphous deposit on bottle walls. Aluminum crimp seal is red. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 11-963/S-034 Page 8 NDC 0046-1065-05...................................... 6.25 mg package for 0.125% White amorphous deposit on bottle walls. Aluminum crimp seal is green. NDC 0046-1066-05........................................ 12.5 mg package for 0.25% White amorphous deposit on bottle walls. Aluminum crimp seal is yellow. HANDLING AND STORAGE: Store under refrigeration (2°-8° C). Reconstituted product may be stored at room temperature (approximately 25° C) for up to four weeks. Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 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/ --------------------- Janice Soreth 3/9/2006 02:33:26 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.407793	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/011963s034lbl.pdf', 'application_number': 11963, 'submission_type': 'SUPPL ', 'submission_number': 34}
10,790	COGENTIN® (benztropine mesylate injection) Rx Only DESCRIPTION Benztropine mesylate is a synthetic compound containing structural features found in atropine and diphenhydramine. It is designated chemically as 8-azabicyclo[3.2.1] octane, 3-(diphenylmethoxy)-,endo, methanesulfonate. Its empirical formula is C21H25NO•CH4O3S, and its structural formula is: structural formula Benztropine mesylate is a crystalline white powder, very soluble in water, and has a molecular weight of 403.54. COGENTIN (benztropine mesylate) is supplied as a sterile injection for intravenous and intramuscular use. Each milliliter of the injection contains: Benztropine mesylate…………………………………………………………………..1 mg Sodium chloride……………………………………………………….........................9 mg Water for injection q.s…………………………………………………………………..1 mL ACTIONS COGENTIN possesses both anticholinergic and antihistaminic effects, although only the former have been established as therapeutically significant in the management of parkinsonism. Page 1 of 7 Reference ID: 3296967 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In the isolated guinea pig ileum, the anticholinergic activity of this drug is about equal to that of atropine; however, when administered orally to unanesthetized cats, it is only about half as active as atropine. In laboratory animals, its antihistaminic activity and duration of action approach those of pyrilamine maleate. INDICATIONS For use as an adjunct in the therapy of all forms of parkinsonism (see DOSAGE AND ADMINISTRATION). Useful also in the control of extrapyramidal disorders (except tardive dyskinesia – see PRECAUTIONS) due to neuroleptic drugs (e.g., phenothiazines). CONTRAINDICATIONS Hypersensitivity to any component of COGENTIN injection. Because of its atropine-like side effects, this drug is contraindicated in pediatric patients under three years of age, and should be used with caution in older pediatric patients. WARNINGS Safe use in pregnancy has not been established. COGENTIN may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. When COGENTIN is given concomitantly with phenothiazines, haloperidol, or other drugs with anticholinergic or antidopaminergic activity, patients should be advised to report gastrointestinal complaints, fever or heat intolerance promptly. Paralytic ileus, hyperthermia and heat stroke, all of which have sometimes been fatal, have occurred in patients taking anticholinergic-type antiparkinsonism drugs, including COGENTIN, in combination with phenothiazines and/or tricyclic antidepressants. Since COGENTIN contains structural features of atropine, it may produce anhidrosis. For this reason, it should be administered with caution during hot weather, especially when given concomitantly with other atropine-like drugs to the chronically ill, the alcoholic, those who have central nervous system disease, and those who do manual labor in a hot environment. Anhidrosis may occur more readily when some disturbance of sweating already exists. If there is evidence of anhidrosis, the possibility of hyperthermia should be considered. Dosage should be decreased at the discretion of the physician so that the ability to maintain body heat equilibrium by Page 2 of 7 Reference ID: 3296967 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda perspiration is not impaired. Severe anhidrosis and fatal hyperthermia have occurred. PRECAUTIONS General: Since COGENTIN has cumulative action, continued supervision is advisable. Patients with a tendency to tachycardia and patients with prostatic hypertrophy should be observed closely during treatment. Dysuria may occur, but rarely becomes a problem. Urinary retention has been reported with COGENTIN. The drug may cause complaints of weakness and inability to move particular muscle groups, especially in large doses. For example, if the neck has been rigid and suddenly relaxes, it may feel weak, causing some concern. In this event, dosage adjustment is required. Mental confusion and excitement may occur with large doses, or in susceptible patients. Visual hallucinations have been reported occasionally. Furthermore, in the treatment of extrapyramidal disorders due to neuroleptic drugs (e.g., phenothiazines), in patients with mental disorders, occasionally there may be intensification of mental symptoms. In such cases, antiparkinsonian drugs can precipitate a toxic psychosis. Patients with mental disorders should be kept under careful observation, especially at the beginning of treatment or if dosage is increased. Tardive dyskinesia may appear in some patients on long-term therapy with phenothiazines and related agents, or may occur after therapy with these drugs have been discontinued. Antiparkinsonism agents do not alleviate the symptoms of tardive dyskinesia, and in some instances may aggravate them. COGENTIN is not recommended for use in patients with tardive dyskinesia. The physician should be aware of the possible occurrence of glaucoma. Although the drug does not appear to have any adverse effect on simple glaucoma, it probably should not be used in angle-closure glaucoma. Drug Interactions: Antipsychotic drugs such as phenothiazines or haloperidol; tricyclic antidepressants (see WARNINGS). Pediatric Use: Because of the atropine-like side effects, COGENTIN should be used with caution in pediatric patients over three years of age (see CONTRAINDICATIONS). Geriatric Use: Clinical studies of COGENTIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from Page 3 of 7 Reference ID: 3296967 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 start at the low end of the dosing range (see DOSAGE AND ADMINISTRATION) and the dose should be increased only as needed with monitoring for the emergence of adverse events (see PRECAUTIONS and ADVERSE REACTIONS). ADVERSE REACTIONS The adverse reactions below, most of which are anticholinergic in nature, have been reported and within each category are listed in order of decreasing severity. Cardiovascular: Tachycardia. Digestive: Paralytic ileus, constipation, vomiting, nausea, dry mouth. If dry mouth is so severe that there is difficulty in swallowing or speaking, or loss of appetite and weight, reduce dosage, or discontinue the drug temporarily. Slight reduction in dosage may control nausea and still give sufficient relief of symptoms. Vomiting may be controlled by temporary discontinuation, followed by resumption at a lower dosage. Nervous System: Toxic psychosis, including confusion, disorientation, memory impairment, visual hallucinations; exacerbation of pre-existing psychotic symptoms; nervousness; depression; listlessness; numbness of fingers. Special Senses: Blurred vision, dilated pupils. Urogenital: Urinary retention, dysuria. Metabolic/Immune or Skin: Occasionally, an allergic reaction, e.g., skin rash, develops. If this cannot be controlled by dosage reduction, the medication should be discontinued. Other: Heat stroke, hyperthermia, fever. To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck Inc. at 1-800 455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DOSAGE AND ADMINISTRATION Since there is no significant difference in onset of effect after intravenous or intramuscular injection, usually there is no need to use the intravenous route. The Page 4 of 7 Reference ID: 3296967 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drug is quickly effective after either route, with improvement sometimes noticeable a few minutes after injection. In emergency situations, when the condition of the patient is alarming, 1 to 2 mL of the injection normally will provide quick relief. If the parkinsonian effect begins to return, the dose can be repeated. Because of cumulative action, therapy should be initiated with a low dose which is increased gradually at five or six-day intervals to the smallest amount necessary for optimal relief. Increases should be made in increments of 0.5 mg, to a maximum of 6 mg, or until optimal results are obtained without excessive adverse reactions. Postencephalitic and Idiopathic Parkinsonism: The following dosing guidelines were written in reference to both benztropine mesylate tablets and COGENTIN Injection. Benztropine mesylate tablets should be used when patients are able to take oral medication. The usual daily dose is 1 to 2 mg, with a range of 0.5 to 6 mg parenterally. As with any agent used in parkinsonism, dosage must be individualized according to age and weight, and the type of parkinsonism being treated. Generally, older patients, and thin patients cannot tolerate large doses. Most patients with postencephalitic parkinsonism need fairly large doses and tolerate them well. Patients with a poor mental outlook are usually poor candidates for therapy. In idiopathic parkinsonism, therapy may be initiated with a single daily dose of 0.5 to 1 mg at bedtime. In some patients, this will be adequate; in others 4 to 6 mg a day may be required. In postencephalitic parkinsonism, therapy may be initiated in most patients with 2 mg a day in one or more doses. In highly sensitive patients, therapy may be initiated with 0.5 mg at bedtime, and increased as necessary. Some patients experience greatest relief when given the entire dose at bedtime; others react more favorably to divided doses, two to four times a day. Frequently, one dose a day is sufficient, and divided doses may be unnecessary or undesirable. The long duration of action of this drug makes it particularly suitable for bedtime medication when its effects may last throughout the night, enabling patients to turn in bed during the night more easily, and to rise in the morning. When COGENTIN is started, do not terminate therapy with other antiparkinsonian agents abruptly. If the other agents are to be reduced or discontinued, it must be done gradually. Many patients obtain greatest relief with combination therapy. COGENTIN may be used concomitantly with SINEMET (Ccarbidopa- Levodopalevodopa), or with levodopa, in which case dosage adjustment may be required in order to maintain optimum response. Page 5 of 7 Reference ID: 3296967 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug-Induced Extrapyramidal Disorders: In treating extrapyramidal disorders due to neuroleptic drugs (e.g., phenothiazines), the recommended dosage is 1 to 4 mg once or twice a day parenterally. Dosage must be individualized according to the need of the patient. Some patients require more than recommended; others do not need as much. In acute dystonic reactions, 1 to 2 mL of the injection usually relieves the condition quickly. When extrapyramidal disorders develop soon after initiation of treatment with neuroleptic drugs (e.g., phenothiazines), they are likely to be transient. One to 2 mg of COGENTIN two or three times a day usually provides relief within one or two days. If such disorders recur, COGENTIN can be reinstituted. Certain drug-induced extrapyramidal disorders that develop slowly may not respond to COGENTIN. OVERDOSAGE Manifestations: May be any of those seen in atropine poisoning or antihistamine overdosage: CNS depression, preceded or followed by stimulation; confusion; nervousness; listlessness; intensification of mental symptoms or toxic psychosis in patients with mental illness being treated with neuroleptic drugs (e.g., phenothiazines); hallucinations (especially visual); dizziness; muscle weakness; ataxia; dry mouth; mydriasis; blurred vision; palpitations; tachycardia; elevated blood pressure; nausea; vomiting; dysuria; numbness of fingers; dysphagia; allergic reactions, e.g., skin rash; headache; hot, dry, flushed skin; delirium; coma; shock; convulsions; respiratory arrest; anhidrosis; hyperthermia; glaucoma; constipation. Treatment: Physostigmine salicylate, 1 to 2 mg, SC or IV, reportedly will reverse symptoms of anticholinergic intoxication. A second injection may be given after 2 hours if required. Otherwise treatment is symptomatic and supportive. Maintain respiration. A short-acting barbiturate may be used for CNS excitement, but with caution to avoid subsequent depression; supportive care for depression (avoid convulsant stimulants such as picrotoxin, pentylenetetrazol, or bemegride); artificial respiration for severe respiratory depression; a local miotic for mydriasis and cycloplegia; ice bags or other cold applications and alcohol sponges for hyperpyrexia, a vasopressor and fluids for circulatory collapse. Darken room for photophobia. Duvoisin, R.C.; Katz, R.J.; Amer. Med. Ass. 206: 1963-1965, Nov. 25, 1968. HOW SUPPLIED Page 6 of 7 Reference ID: 3296967 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Injection COGENTIN, 1 mg per mL, is a clear, colorless solution and is supplied as follows: NDC 67386-611-52 in boxes of 5 x 2 mL ampuls. Recommended Storage: Store at 20-25°C (68-77°F). See USP controlled room temperature. Manufactured by: Hospira, Inc., McPherson, KS 67460, U.S.A. For: Lundbeck Inc., Deerfield, IL 60015, U.S.A. Lundbeck ® Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Revised April 2013 Page 7 of 7 Reference ID: 3296967 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.409442	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012015s027lbl.pdf', 'application_number': 12015, 'submission_type': 'SUPPL ', 'submission_number': 27}
10,792	Cyclophosphamide for Injection, USP Cyclophosphamide Tablets, USP DESCRIPTION Cyclophosphamide for Injection, USP is a sterile white powder containing cyclophosphamide monohydrate. Cyclophosphamide Tablets, USP are for oral use and contain 25 mg or 50 mg cyclophosphamide (anhydrous). Inactive ingredients in cyclophosphamide tablets are: acacia, FD&C Blue No. 1, D&C Yellow No. 10 Aluminum Lake, lactose, magnesium stearate, starch, stearic acid and talc. Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide is a white crystalline powder with the molecular formula C7H15Cl2N2O2PH2O and a molecular weight of 279.1. The chemical name for cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate. Cyclophosphamide is soluble in water, saline, or ethanol and has the following structural formula: chemical structure CLINICAL PHARMACOLOGY Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA. Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites, but from 5 to 25% of the dose is excreted in urine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma. Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug is low but some metabolites are bound to an extent greater than 60%. It has not been demonstrated that any single metabolite is responsible for either the therapeutic or toxic effects of cyclophosphamide. Although elevated levels of metabolites of 1 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda cyclophosphamide have been observed in patients with renal failure, increased clinical toxicity in such patients has not been demonstrated. INDICATIONS AND USAGE Malignant Diseases Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. The following malignancies are often susceptible to cyclophosphamide treatment: 1. Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma. 2. Multiple myeloma. 3. Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in children (cyclophosphamide given during remission is effective in prolonging its duration). 4. Mycosis fungoides (advanced disease). 5. Neuroblastoma (disseminated disease). 6. Adenocarcinoma of the ovary. 7. Retinoblastoma. 8. Carcinoma of the breast. Nonmalignant Disease Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children: Cyclophosphamide is useful in carefully selected cases of biopsy proven “minimal change” nephrotic syndrome in children but should not be used as primary therapy. In children whose disease fails to respond adequately to appropriate adrenocorticosteroid therapy or in whom the adrenocorticosteroid therapy produces or threatens to produce intolerable side effects, cyclophosphamide may induce a remission. Cyclophosphamide is not indicated for the nephrotic syndrome in adults or for any other renal disease. CONTRAINDICATIONS Continued use of cyclophosphamide is contraindicated in patients with severely depressed bone marrow function. Cyclophosphamide is contraindicated in patients who 2 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda have demonstrated a previous hypersensitivity to it. See WARNINGS and PRECAUTIONS. WARNINGS Carcinogenesis, Mutagenesis, and Impairment of Fertility Second malignancies have developed in some patients treated with cyclophosphamide used alone or in association with other antineoplastic drugs and/or modalities. Most frequently, they have been urinary bladder, myeloproliferative, or lymphoproliferative malignancies. Second malignancies most frequently were detected in patients treated for primary myeloproliferative or lymphoproliferative malignancies or nonmalignant disease in which immune processes are believed to be involved pathologically. In some cases, the second malignancy developed several years after cyclophosphamide treatment had been discontinued. In a single breast cancer trial utilizing two to four times the standard dose of cyclophosphamide in conjunction with doxorubicin a small number of cases of secondary acute myeloid leukemia occurred within two years of treatment initiation. Urinary bladder malignancies generally have occurred in patients who previously had hemorrhagic cystitis. In patients treated with cyclophosphamide containing regimens for a variety of solid tumors, isolated case reports of secondary malignancies have been published. One case of carcinoma of the renal pelvis was reported in a patient receiving long-term cyclophosphamide therapy for cerebral vasculitis. The possibility of cyclophosphamide-induced malignancy should be considered in any benefit-to-risk assessment for use of the drug. Cyclophosphamide can cause fetal harm when administered to a pregnant woman and such abnormalities have been reported following cyclophosphamide therapy in pregnant women. Abnormalities were found in two infants and a six-month-old fetus born to women treated with cyclophosphamide. Ectrodactylia was found in two of the three cases. Normal infants have also been born to women treated with cyclophosphamide during pregnancy, including the first trimester. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of 3 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients. Amenorrhea associated with decreased estrogen and increased gonadotropin secretion develops in a significant proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. Girls treated with cyclophosphamide during prepubescence generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late prepubescence has been reported. Girls treated with cyclophosphamide during prepubescence subsequently have conceived. Men treated with cyclophosphamide may develop oligospermia or azoospermia associated with increased gonadotropin but normal testosterone secretion. Sexual potency and libido are unimpaired in these patients. Boys treated with cyclophosphamide during prepubescence develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Men temporarily rendered sterile by cyclophosphamide have subsequently fathered normal children. Urinary System Hemorrhagic cystitis may develop in patients treated with cyclophosphamide. Rarely, this condition can be severe and even fatal. Fibrosis of the urinary bladder, sometimes extensive, also may develop with or without accompanying cystitis. Atypical urinary bladder epithelial cells may appear in the urine. These adverse effects appear to depend on the dose of cyclophosphamide and the duration of therapy. Such bladder injury is thought to be due to cyclophosphamide metabolites excreted in the urine. Forced fluid intake helps to assure an ample output of urine, necessitates frequent voiding, and reduces the time the drug remains in the bladder. This helps to prevent cystitis. Hematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but it may persist. Medical and/or surgical supportive treatment may be required, rarely, to treat protracted cases of severe hemorrhagic cystitis. It is usually necessary to discontinue cyclophosphamide therapy in instances of severe hemorrhagic cystitis. 4 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiac Toxicity Although a few instances of cardiac dysfunction have been reported following use of recommended doses of cyclophosphamide, no causal relationship has been established. Acute cardiac toxicity has been reported with doses as low as 2.4 g/m2 to as high as 26 g/m2, usually as a portion of an intensive antineoplastic multi-drug regimen or in conjunction with transplantation procedures. In a few instances with high doses of cyclophosphamide, severe, and sometimes fatal, congestive heart failure has occurred after the first cyclophosphamide dose. Histopathologic examination has primarily shown hemorrhagic myocarditis. Hemopericardium has occurred secondary to hemorrhagic myocarditis and myocardial necrosis. Pericarditis has been reported independent of any hemopericardium. No residual cardiac abnormalities, as evidenced by electrocardiogram or echocardiogram appear to be present in patients surviving episodes of apparent cardiac toxicity associated with high doses of cyclophosphamide. Cyclophosphamide has been reported to potentiate doxorubicin-induced cardiotoxicity. Infections Treatment with cyclophosphamide may cause significant suppression of immune responses. Serious, sometimes fatal, infections may develop in severely immunosuppressed patients. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop viral, bacterial, fungal, protozoan, or helminthic infections. Other Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported. 5 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Special attention to the possible development of toxicity should be exercised in patients being treated with cyclophosphamide if any of the following conditions are present. 1. Leukopenia 2. Thrombocytopenia 3. Tumor cell infiltration of bone marrow 4. Previous X-ray therapy 5. Previous therapy with other cytotoxic agents 6. Impaired hepatic function 7. Impaired renal function Laboratory Tests During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression. Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis. Drug Interactions The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic administration of high doses of phenobarbital. The physician should be alert for possible combined drug actions, desirable or undesirable, involving cyclophosphamide even though cyclophosphamide has been used successfully concurrently with other drugs, including other cytotoxic drugs. Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of succinylcholine chloride. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted. Adrenalectomy Since cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment of the doses of both replacement steroids and cyclophosphamide may be necessary for the adrenalectomized patient. 6 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Wound Healing Cyclophosphamide may interfere with normal wound healing. Carcinogenesis, Mutagenesis, and Impairment of Fertility See WARNINGS for information on carcinogenesis, mutagenesis, and impairment of fertility. Pregnancy Pregnancy Category D—See WARNINGS. Nursing Mothers Cyclophosphamide is excreted in breast milk. Because of the potential for serious adverse reactions and the potential for tumorigenicity shown for cyclophosphamide in humans, 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 safety profile of cyclophosphamide in pediatric patients is similar to that of the adult population (see ADVERSE REACTIONS). Geriatric Use Insufficient data from clinical studies of cyclophosphamide for malignant lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are available for patients 65 years of age and older to determine whether they respond differently than younger patients. In two clinical trials in which cyclophosphamide was compared with paclitaxel, each in combination with cisplatin, for the treatment of advanced ovarian carcinoma, 154 (28%) of 552 patients who received cyclophosphamide plus cisplatin were 65 years or older. Subset analyses (<65 versus >65 years) from these trials, published reports of clinical trials of cyclophosphamide containing regimens in breast cancer and non-Hodgkin’s lymphoma, and postmarketing experience suggest that elderly patients may be more susceptible to cyclophosphamide toxicities. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and adjusting as necessary based on patient 7 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda response (see DOSAGE AND ADMINISTRATION: Treatment of Malignant Diseases). ADVERSE REACTIONS Information on adverse reactions associated with the use of cyclophosphamide is arranged according to body system affected or type of reaction. The adverse reactions are listed in order of decreasing incidence. The most serious adverse reactions are described in the WARNINGS section. Reproductive System See WARNINGS for information on impairment of fertility. Digestive System Nausea and vomiting commonly occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. These adverse drug effects generally remit when cyclophosphamide treatment is stopped. Skin and Its Structures Alopecia occurs commonly in patients treated with cyclophosphamide. The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or color. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. Very rare reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received during postmarketing surveillance; due to the nature of spontaneous adverse event reporting, a definitive causal relationship to cyclophosphamide has not been established. Hematopoietic System Leukopenia occurs in patients treated with cyclophosphamide, is related to the dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 cells/mm3 develops commonly in patients treated with an initial loading dose of the drug, and less frequently in patients maintained on smaller doses. The degree of neutropenia is 8 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients. Thrombocytopenia or anemia develops occasionally in patients treated with cyclophosphamide. These hematologic effects usually can be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukopenia usually begins in 7 to 10 days after cessation of therapy. Urinary System See WARNINGS for information on cystitis and urinary bladder fibrosis. Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with cyclophosphamide. Such lesions usually resolve following cessation of therapy. Infections See WARNINGS for information on reduced host resistance to infections. Carcinogenesis See WARNINGS for information on carcinogenesis. Respiratory System Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis has been reported in patients receiving high doses of cyclophosphamide over a prolonged period. Other Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported. SIADH (syndrome of inappropriate ADH secretion) has been reported with the use of cyclophosphamide. Malaise and asthenia have been reported as part of the postmarketing experience. 9 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE No specific antidote for cyclophosphamide is known. Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur. DOSAGE AND ADMINISTRATION Treatment of Malignant Diseases Adults and Children When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 40 to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 to 15 mg/kg given every 7 to 10 days or 3 to 5 mg/kg twice weekly. Oral cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing. Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage. Transient decreases in the total white blood cell count to 2000 cells/mm3 (following short courses) or more persistent reduction to 3000 cells/mm3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia. When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as well as that of the other drugs. Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. Patients with compromised renal function may show some measurable changes in pharmacokinetic parameters of cyclophosphamide metabolism, but there is no consistent evidence indicating a need for cyclophosphamide dosage modification in patients with renal function impairment. 10 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment of Nonmalignant Diseases Biopsy Proven “Minimal Change’’ Nephrotic Syndrome in Children An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is recommended. In males, the incidence of oligospermia and azoospermia increases if the duration of cyclophosphamide treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility. Adrenocorticosteroid therapy may be tapered and discontinued during the course of cyclophosphamide therapy. See PRECAUTIONS concerning hematologic monitoring. Cyclophosphamide for Injection Preparation and Handling of Solutions Intravenous administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Cyclophosphamide does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. USE ASEPTIC TECHNIQUE. Cyclophosphamide may be prepared for intravenous administration using any of the following methods. Add the diluent to the vial and shake it vigorously to dissolve. If the powder fails to dissolve immediately and completely, it is advisable to allow the vial to stand for a few minutes. Use the quantity of diluent shown below to reconstitute the product: Dosage Strength Contains Cyclophosphamide Monohydrate Quantity of Diluent Approximate Cyclophosphamide Concentration 500 mg 534.5 mg 25 mL 2% (20 mg per mL) 1 g 1069.0 mg 50 mL 2 g 2138.0 mg 100 mL 11 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For Direct Intravenous Injection Cyclophosphamide reconstituted to 2% concentration in 0.9% sterile sodium chloride can be injected directly. Cyclophosphamide reconstituted to 2% concentration in Sterile Water for Injection, USP is hypotonic and should not be injected directly. For Intravenous Infusion Cyclophosphamide should first be reconstituted in 0.9% Sodium Chloride or Sterile Water for Injection, USP to a 2% concentration (20 mg per mL) and then further diluted for infusion to a minimum concentration of 0.2% (2 mg per mL) with any of the following diluents:  Dextrose Injection, USP (5% dextrose)  Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride)  Sodium Chloride Injection, USP (0.45% sterile sodium chloride) Storage Unopened vials of cyclophosphamide are stable until the date indicated on the package when stored at or below 25°C (77°F). If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as follows: Diluent Storage Room Temperature Refrigerated Reconstituted Solution (Without Further Dilution) 0.9% Sterile Sodium Chloride up to 24 hrs up to 6 days Further Diluted Solutions1 Sodium Chloride Injection, USP (0.45% sterile sodium chloride) up to 24 hrs up to 6 days Dextrose Injection, USP (5% dextrose) up to 24 hrs up to 36 hrs Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride) up to 24 hrs up to 36 hrs 1 Storage time is the total time cyclophosphamide is in solution (including reconstitution). Cyclophosphamide (prepared for intravenous administration) is chemically and physically stable for the period of time as shown in the above table. 12 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Oral Administration Liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir, N.F. Such preparations should be stored under refrigeration in glass containers and used within 14 days. HOW SUPPLIED Cyclophosphamide for Injection, USP contains cyclophosphamide monohydrate and is supplied in vials for single dose use. Cyclophosphamide for injection, USP U.S. Patent No. 4,537,883 NDC 0015-0502-41 500 mg vial, carton of 1 NDC 0015-0505-41 1.0 g vial, carton of 1 NDC 0015-0506-41 2.0 g vial, carton of 1 Store vials at or below 25C (77F). During transport or storage of cyclophosphamide vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide. Vials containing melted substance can be visually differentiated. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials. Do not use cyclophosphamide vials if there are signs of melting. Cyclophosphamide Tablets, 25 mg and Cyclophosphamide Tablets, 50 mg, are white tablets with blue flecks containing 25 mg and 50 mg cyclophosphamide (anhydrous), respectively. Cyclophosphamide tablets, USP NDC 0015-0503-01 50 mg, bottles of 100 NDC 0015-0504-01 25 mg, bottles of 100 Store tablets at or below 25C (77F); tablets will withstand brief exposure to temperatures up to 30°C (86 F) but should be protected from temperatures above 30C (86 F). 13 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Caution should be exercised when handling and preparing the cyclophosphamide sterile powder for injection, or bottles containing cyclophosphamide tablets. The handling and preparation of cyclophosphamide should always be in accordance with current guidelines1-4 on safe handling of cytotoxic agents. To minimize the risk of dermal exposure, always wear gloves when handling vials containing cyclophosphamide sterile powder for injection, or bottles containing cyclophosphamide tablets. The coating of the cyclophosphamide tablets prevents direct contact of persons handling the tablets with the active substance. However, to prevent inadvertent exposure to the active substance, the cyclophosphamide tablets should not be divided or crushed. Personnel should avoid exposure to broken tablets. If contact with broken tablets occurs, wash immediately and thoroughly. More information is available in the references listed below. 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. Vials Manufactured by: Baxter Healthcare Corporation Deerfield, Illinois 60015 USA Vials Made in Germany Tablets Manufactured for: Baxter Healthcare Corporation Deerfield, Illinois 60015 USA 1175025A2 Revised April 2012 1050971A4 USA 5638 0612 C 669 14 Reference ID: 3110031 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.627412	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/012141s089lbl.pdf', 'application_number': 12141, 'submission_type': 'SUPPL ', 'submission_number': 89}
10,793	_______________________________________________________________________________________________________________________________________ ______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CYCLOPHOSPHAMIDE safely and effectively. See full prescribing information for CYCLOPHOSPHAMIDE. -----------------------WARNINGS AND PRECAUTIONS---------------------  Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections – Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. (5.1) CYCLOPHOSPHAMIDE injection, for intravenous use CYCLOPHOSPHAMIDE tablets, for oral use Initial U.S. Approval: 1959 ----------------------------INDICATIONS AND USAGE--------------------------- Cyclophosphamide is an alkylating drug indicated for treatment of:  Malignant Diseases: malignant lymphomas: Hodgkin’s disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma (1.1)  Minimal Change Nephrotic Syndrome in Pediatric Patients: biopsy proven minimal change nephrotic syndrome patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy (1.2) Limitations of Use: The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established. ----------------------DOSAGE AND ADMINISTRATION------------------------ Malignant Diseases: Adult and Pediatric Patients (2.1)  Intravenous: Initial course for patients with no hematologic deficiency: 40 mg per kg to 50 mg per kg in divided doses over 2 to 5 days. Other regimens include 10 mg per kg to 15 mg per kg given every 7 to 10 days or 3 mg per kg to 5 mg per kg twice weekly.  Oral: Usually 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing. Minimal Change Nephrotic Syndrome in Pediatric Patients (2.2)  Recommended oral dose: 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg). Treatment beyond 90 days increases the probability of sterility in males. ---------------------DOSAGE FORMS AND STRENGTHS----------------------  Injection, lyophilized powder: 500 mg, 1 g, and 2 g (3)  Tablet: 25 mg and 50 mg (3) -------------------------------CONTRAINDICATIONS------------------------------  Hypersensitivity to cyclophosphamide (4)  Urinary outflow obstruction (4)  Urinary Tract and Renal Toxicity – Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur. Exclude or correct any urinary tract obstructions prior to treatment. (5.2)  Cardiotoxicity – Myocarditis, myopericarditis, pericardial effusion, arrythmias and congestive heart failure, which may be fatal, have been reported. Monitor patients, especially those with risk factors for cardiotoxicity or pre-existing cardiac disease. (5.3)  Pulmonary Toxicity – Pneumonitis, pulmonary fibrosis and pulmonary veno-occlusive disease leading to respiratory failure may occur. Monitor patients for signs and symptoms of pulmonary toxicity. (5.4)  Secondary malignancies (5.5)  Veno-occlusive Liver Disease - Fatal outcome can occur. (5.6)  Embryo-Fetal Toxicity - Can cause fetal harm. Advise female patients of reproductive potential to avoid pregnancy. (5.7, 8.1, 8.6) ------------------------------ADVERSE REACTIONS------------------------------- Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------USE IN SPECIFIC POPULATIONS--------------------  Nursing Mothers: Discontinue drug or nursing. (8.3)  Females and males of reproductive potential: Counsel patients on pregnancy prevention and planning. (8.6)  Renal Patients: Monitor for toxicity in patients with moderate and severe renal impairment. (8.7, 12.3) See 17 for PATIENT COUNSELING INFORMATION Revised: 05/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Malignant Diseases 1.2 Minimal Change Nephrotic Syndrome in Pediatric Patients 2 DOSAGE AND ADMINISTRATION 2.1 Dosing for Malignant Diseases 2.2 Dosing for Minimal Change Nephrotic Syndrome in Pediatric Patients 2.3 Preparation, Handling and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections 5.2 Urinary Tract and Renal Toxicity 5.3 Cardiotoxicity 5.4 Pulmonary Toxicity 5.5 Secondary Malignancies 5.6 Veno-occlusive Liver Disease 5.7 Embryo-Fetal Toxicity 5.8 Infertility 5.9 Impairment of Wound Healing 5.10 Hyponatremia 6 ADVERSE REACTIONS 6.1 Common Adverse Reactions 6.2 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 Females and Males of Reproductive Potential 8.7 Use in Patients with Renal Impairment 8.8 Use in Patients with Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3304966 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 Malignant Diseases Cyclophosphamide is indicated for the treatment of:  malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma  multiple myeloma  leukemias: chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia (cyclophosphamide given during remission is effective in prolonging its duration)  mycosis fungoides (advanced disease)  neuroblastoma (disseminated disease)  adenocarcinoma of the ovary  retinoblastoma  carcinoma of the breast Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. 1.2 Minimal Change Nephrotic Syndrome in Pediatric Patients: Cyclophosphamide is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatrics patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy. Limitations of Use: The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established. 2. DOSAGE AND ADMINISTRATION During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, cyclophosphamide should be administered in the morning. 2.1 Dosing for Malignant Diseases Adults and Pediatric Patients Intravenous When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 40 mg per kg to 50 mg per kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 mg per kg to 15 mg per kg given every 7 to 10 days or 3 mg per kg to 5 mg per kg twice weekly. Oral Oral cyclophosphamide dosing is usually in the range of 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage. When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as well as that of the other drugs. 2.2 Dosing for Minimal Change Nephrotic Syndrome in Pediatric Patients An oral dose of 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg) is recommended. Treatment beyond 90 days increases the probability of sterility in males [see Use in Specific Populations (8.4)]. 2.3 Preparation, Handling and Administration Handle and dispose of cyclophosphamide in a manner consistent with other cytotoxic drugs.1 Caution should be exercised when handling and preparing Cyclophosphamide for Injection, USP (lyophilized powder), or bottles containing cyclophosphamide tablets. To minimize the risk of dermal exposure, always wear gloves when handling vials containing Cyclophosphamide for Injection, USP (lyophilized powder), or bottles containing cyclophosphamide tablets. The coating of the cyclophosphamide tablets prevents direct contact of persons handling the tablets with the active substance. However, to prevent inadvertent exposure to the active substance, the cyclophosphamide tablets should not be cut, chewed, or crushed. Personnel should avoid exposure to broken tablets. If contact with broken tablets occurs, wash hands immediately and thoroughly. Cyclophosphamide for Injection, USP Intravenous Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use cyclophosphamide vials if there are signs of melting. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials. Cyclophosphamide does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. Use aseptic technique. For Direct Intravenous Injection Reconstitute Cyclophosphamide with 0.9% Sodium Chloride Injection, USP only, using the volumes listed below in Table 1. Gently swirl the vial to dissolve the drug completely. Do not use Sterile Water for Injection, USP because it results in a hypotonic solution and should not be injected directly. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Reconstitution for Direct Intravenous Injection Strength Volume of 0.9% Sodium Chloride Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL For Intravenous Infusion Reconstitution of Cyclophosphamide: Reconstitute Cyclophosphamide using 0.9% Sodium Chloride Injection, USP or Sterile Water for Injection, USP with the volume of diluent listed below in Table 2. Add the diluent to the vial and gently swirl to dissolve the drug completely. Table 2: Reconstitution in preparation for Intravenous Infusion Strength Volume of Diluent Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL Dilution of Reconstituted Cyclophosphamide: Further dilute the reconstituted Cyclophosphamide solution to a minimum concentration of 2 mg per mL with any of the following diluents:  5% Dextrose Injection, USP  5% Dextrose and 0.9% Sodium Chloride Injection, USP  0.45% Sodium Chloride Injection, USP To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.g., facial swelling, headache, nasal congestion, scalp burning), cyclophosphamide should be injected or infused very slowly. Duration of the infusion also should be appropriate for the volume and type of carrier fluid to be infused. Storage of Reconstituted and Diluted Cyclophosphamide Solution: If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 3: Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3: Storage of Cyclophosphamide Solutions Diluent Storage Room Temperature Refrigerated Reconstituted Solution (Without Further Dilution) 0.9% Sodium Chloride Injection, USP up to 24 hrs Up to 6 days Sterile Water for Injection, USP Do not store; use immediately Diluted Solutions1 0.45% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 5% Dextrose Injection, USP up to 24 hrs up to 36 hrs 5% Dextrose and 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 36 hrs 1 Storage time is the total time cyclophosphamide is in solution including the time it is reconstituted in 0.9% Sterile Sodium Chloride Injection, USP or Sterile Water for Injection, USP. Use of Reconstituted Solution for Oral Administration Liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir, National Formulary (NF) Such preparations should be stored under refrigeration in glass containers and used within 14 days. 3. DOSAGE FORMS AND STRENGTHS Cyclophosphamide for Injection, USP (lyophilized powder) is a sterile white cake available in  500 mg  1 g  2 g Cyclophosphamide Tablets, USP are white tablets with blue flecks available in  25 mg  50 mg 4. CONTRAINDICATIONS  Hypersensitivity Cyclophosphamide is contraindicated in patients who have a history of severe hypersensitivity reactions to it, any of its metabolites, or to other components of the product. Anaphylactic reactions including death have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents can occur.  Urinary Outflow Obstruction Cyclophosphamide is contraindicated in patients with urinary outflow obstruction [see Warnings and Precautions (5.2)]. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5. WARNINGS AND PRECAUTIONS 5.1 Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated [see Adverse Reactions (6.2)]. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or antivirals may also be indicated. Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be administered to patients with neutrophils ≤1,500/mm3 and platelets < 50,000/mm3. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy. 5.2 Urinary Tract and Renal Toxicity Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide. Before starting treatment, exclude or correct any urinary tract obstructions [see Contraindications (4)]. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity. 5.3 Cardiotoxicity Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide. The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with pre existing cardiac disease. Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease. 5.4 Pulmonary Toxicity Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide. Monitor patients for signs and symptoms of pulmonary toxicity. 5.5 Secondary Malignancies Cyclophosphamide is genotoxic [see Nonclinical Toxicology (13.1)]. Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens. The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis. 5.6 Veno-occlusive Liver Disease Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide. Other risk factors predisposing to the development of VOD include preexisting disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance status. 5.7 Embryo-Fetal Toxicity Cyclophosphamide can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Exposure to cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment and for up to 1 year after completion of therapy [see Use in Specific Populations (8.6)]. 5.8 Infertility Male and female reproductive function and fertility may be impaired in patients being treated with cyclophosphamide. Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients. Advise patients on the potential risks for infertility [see Use in Specific Populations (8.4 and 8.6)]. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.9 Impairment of Wound Healing Cyclophosphamide may interfere with normal wound healing. 5.10 Hyponatremia Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported. 6. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. • Hypersensitivity [see Contraindications (4)] • Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions (5.1)] • Urinary Tract and Renal Toxicity [see Warnings and Precautions (5.2)] • Cardiotoxicity [see Warnings and Precautions (5.3)] • Pulmonary Toxicity [see Warnings and Precautions (5.4)] • Secondary Malignancies [see Warnings and Precautions (5.5)] • Veno-occlusive Liver Disease [see Warnings and Precautions (5.6)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.7)] • Reproductive System Toxicity [see Warnings and Precautions (5.8) and Use in Specific Populations (8.4 and 8.6)] • Impaired Wound Healing [see Warnings and Precautions (5.9)] • Hyponatremia [see Warnings and Precautions (5.10)] 6.1 Common Adverse Reactions Hematopoietic system: Neutropenia occurs in patients treated with cyclophosphamide. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients. Gastrointestinal system: Nausea and vomiting occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. Skin and its structures: Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. 6.2 Postmarketing Experience The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Because they are reported from a population from unknown size, precise estimates of frequency cannot be made. Cardiac: cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion (progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation. Congenital, Familial and Genetic: intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity (including myelosuppression, gastroenteritis). Ear and Labyrinth: deafness, hearing impaired, tinnitus. Endocrine: water intoxication. Eye: visual impairment, conjunctivitis, lacrimation. Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation. General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache. Hematologic: myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic syndrome (with thrombotic microangiopathy). Hepatic: veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal, hepatic enzymes increased. Immune: immunosuppression, anaphylactic shock and hypersensitivity reaction. Infections: The following manifestations have been associated with myelosuppression and immunosuppression caused by cyclophosphamide: increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal and, parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), Pneumocystis jiroveci, herpes zoster, Strongyloides, sepsis and septic shock. Investigations: blood lactate dehydrogenase increased, C-reactive protein increased. Metabolism and Nutrition: hyponatremia, fluid retention, blood glucose increased, blood glucose decreased. Musculoskeletal and Connective Tissue: rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia. Neoplasms: acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid cancer. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervous System: encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia. Pregnancy: premature labor. Psychiatric: confusional state. Renal and Urinary: renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells. Reproductive System: infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy, azoospermia, oligospermia. Respiratory: pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea. Skin and Subcutaneous Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis. Tumor lysis syndrome: like other cytotoxic drugs, cyclophosphamide may induce tumor-lysis syndrome and hyperuricemia in patients with rapidly growing tumors. Vascular: pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing, hot flush. 7. DRUG INTERACTIONS Cyclophosphamide is a pro-drug that is activated by cytochrome P450s [see Clinical Pharmacology (12.3)]. An increase of the concentration of cytotoxic metabolites may occur with:  Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-based regimens was found to be associated with a higher Incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Combined or sequential use of cyclophosphamide and other agents with similar toxicities can potentiate toxicities.  Increased hematotoxicity and/or immunosuppression may result from a combined effect of cyclophosphamide and, for example:  ACE inhibitors: ACE inhibitors can cause leukopenia.  Natalizumab  Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.  Thiazide diuretics  Zidovudine Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example:  Anthracyclines  Cytarabine  Pentostatin  Radiation therapy of the cardiac region  Trastuzumab  Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example:  Amiodarone  G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony- stimulating factor): Reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GMCSF.  Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example:  Amphotericin B  Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin  Increase in other toxicities:  Azathioprine: Increased risk of hepatotoxicity (liver necrosis)  Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.  Protease inhibitors: Increased incidence of mucositis  Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment. Etanercept: In patients with Wegener’s granulomatosis, the addition of etanercept to standard treatment, including cyclophosphamide, was associated with a higher incidence of non-cutaneous malignant solid tumors. Metronidazole: Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity. Tamoxifen: Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications. Coumarins: Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide. Cyclosporine: Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease. Depolarizing muscle relaxants: Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine). If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary Cyclophosphamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and published reports of effects in pregnant patients or animals. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Human Data Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide. Animal Data Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification. 8.3 Nursing Mothers Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in nursing infants from cyclophosphamide, 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 Pre-pubescent girls treated with cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause. Pre-pubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. 8.5 Geriatric Use There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than 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 Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda greater frequency of decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy. 8.6 Females and Males of Reproductive Potential Contraception Pregnancy should be avoided during treatment with cyclophosphamide because of the risk of fetal harm [see Use in Specific Populations (8.1)]. Female patients of reproductive potential should use highly effective contraception during and for up to 1 year after completion of treatment. Male patients who are sexually active with female partners who are or may become pregnant should use a condom during and for at least 4 months after treatment. Infertility Females Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment. Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months [see Nonclinical Toxicology (13.1)]. Males Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion. 8.7 Use in Patients with Renal Impairment In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity [see Clinical Pharmacology (12.3)]. Monitor patients with severe renal impairment (CrCl =10 mL/min to 24 mL/min) for signs and symptoms of toxicity. Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered. 8.8 Use in Patients with Hepatic Impairment Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4 hydroxyl metabolite, potentially reducing efficacy [see Clinical Pharmacology (12.3)]. 10. OVERDOSAGE No specific antidote for cyclophosphamide is known. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur. Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis [see Warnings and Precautions (5.1, 5.2, 5.3, and 5.6)]. Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic toxicity in particular. Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication. Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose. 11. DESCRIPTION Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. The chemical name for cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, and has the following structural formula: structural formula Cyclophosphamide has a molecular formula of C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline, or ethanol. Cyclophosphamide for Injection, USP is a sterile white cake available as 500 mg, 1 g, and 2 g strength vials.  500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide and 375 mg mannitol  1 g vial contains 1069.0 mg cyclophosphamide monohydrate equivalent to 1 g cyclophosphamide and 750 mg mannitol  2 g vial contains 2138.0 mg cyclophosphamide monohydrate equivalent to 2 g cyclophosphamide and 1500 mg mannitol Cyclophosphamide Tablets, USP are for oral use and contain 25 mg or 50 mg cyclophosphamide (anhydrous). Inactive ingredients in Cyclophosphamide Tablets are: acacia, FD&C Blue No. 1, D&C Yellow No. 10 Aluminum Lake, lactose, magnesium stearate, starch, stearic acid and talc. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action is thought to involve cross-linking of tumor cell DNA. 12.2 Pharmacodynamics Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. 12.3 Pharmacokinetics Following IV administration, elimination half-life (t ½) ranges from 3 to 12 hours with total body clearance (CL) values of 4 to 5.6 L/h. Pharmacokinetics are linear over the dose range used clinically. When cyclophosphamide was administered at 4.0 g/m2 over a 90 minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug. Absorption After oral administration, peak concentrations of cyclophosphamide occurred at one hour. Area under the curve ratio for the drug after oral and IV administration (AUCpo : AUCiv) ranged from 0.87 to 0.96. Distribution Approximately 20% of cyclophosphamide is protein bound, with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%. Volume of distribution approximates total body water (30 to 50 L). Metabolism The liver is the major site of cyclophosphamide activation. Approximately 75% of the administered dose of cyclophosphamide is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6 displaying the highest 4-hydroxylase activity. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of cyclophosphamide may be directly detoxified by side chain oxidation, leading to the formation of inactive metabolites 2-dechloroethylcyclophosphamide. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide in patients. Cyclophosphamide appears to induce its own metabolism. Auto-induction results in an increase in the total clearance, increased formation of 4-hydroxyl metabolites and shortened t1/2 values following repeated administration at 12- to 24-hour interval. Elimination Cyclophosphamide is primarily excreted as metabolites. 10 to 20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration. Special Populations Renal Impairment Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The pharmacokinetics of cyclophosphamide were determined following one-hour intravenous infusion to renally impaired patients. The results demonstrated that the systemic exposure to cyclophosphamide increased as the renal function decreased. Mean dose-corrected AUC increased by 38% in the moderate renal group, (Creatinine clearance (CrCl of 25 to 50 mL/min), by 64% in the severe renal group (CrCl of 10 to 24 mL/min) and by 23% in the hemodialysis group (CrCl of < 10mL/min) compared to the control group. The increase in exposure was significant in the severe group (p>0.05); thus, patients with severe renal impairment should be closely monitored for toxicity [see Use in Specific Populations (8.7)]. The dialyzability of cyclophosphamide was investigated in four patients on long-term hemodialysis. Dialysis clearance calculated by arterial-venous difference and actual drug recovery in dialysate averaged 104 mL/min, which is in the range of the metabolic clearance of 95 mL/min for the drug. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The elimination half-life (t1/2) was 3.3 hours in patients during hemodialysis, a 49% reduction of the 6.5 hours to t1/2 reported in uremic patients. Reduction in t1/2, larger dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, suggest that cyclophosphamide is dialyzable. Hepatic Impairment Total body clearance (CL) of cyclophosphamide is decreased by 40% in patients with severe hepatic impairment and elimination half-life (t½) is prolonged by 64%. Mean CL and t½ were 45 ± 8.6 L/kg and 12.5 ± 1.0 hours respectively, in patients with severe hepatic impairment and 63 ± 7.6 L/kg and 7.6 ± 1.4 hours respectively in the control group [see Use in Specific Populations (8.8)]. 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see Warnings and Precautions (5.5)]. Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies. Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see Use in Specific Populations (8.6)]. 15. REFERENCES 1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. 16. HOW SUPPLIED/STORAGE AND HANDLING Cyclophosphamide for Injection, USP (lyophilized powder) is a sterile white cake containing cyclophosphamide and mannitol and is supplied in vials for single dose use. Cyclophosphamide for Injection, USP Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10019-988-01 500 mg vial, carton of 1 10019-989-01 1 g vial, carton of 1 10019-990-01 2 g vial, carton of 1 Store vials at or below 25°C (77°F). During transport or storage of cyclophosphamide vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide [see Dosage and Administration (2.3)]. Cyclophosphamide Tablets, USP are white tablets with blue flecks containing 25 mg and 50 mg cyclophosphamide, respectively. Cyclophosphamide Tablets, USP 10019-984-09 50 mg, bottles of 100 10019-982-09 25 mg, bottles of 100 Store tablets at or below 25°C (77°F). Tablets will withstand brief exposure to temperatures up to 30°C (86°F) but should be protected from temperatures above 30°C (86°F). Cyclophosphamide is an antineoplastic product. Follow special handling and disposal procedures.1 17. PATIENT COUNSELING INFORMATION Advise the patient of the following:  Inform patients of the possibility of myelosuppression, immunosuppression, and infections. Explain the need for routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever [see Warnings and Precautions (5.1)].  Advise the patient to report urinary symptoms (patients should report if their urine has turned a pink or red color) and the need for increasing fluid intake and frequent voiding [see Warnings and Precautions (5.2)].  Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.3)].  Warn patients of the possibility of developing non-infectious pneumonitis. Advise patients to report promptly any new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].  Advise female patients of reproductive potential to use highly effective contraception during treatment and for up to 1 year after completion of therapy. There is a potential for harm to a fetus if a patient becomes pregnant during this period. Patients should immediately contact their healthcare provider if they become pregnant or if pregnancy is suspected during this period [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].  Advise male patients who are sexually active with a female partner who is or may become pregnant to use condoms during treatment and for up to 4 months after completion of therapy. There is a potential for harm to a fetus if a patient fathers a child during this period. Patients should immediately contact their healthcare provider if their female partner becomes pregnant or if pregnancy is suspected during this period [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)]. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Advise nursing mothers treated with cyclophosphamide to discontinue nursing or discontinue cyclophosphamide, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.3)].  Explain to patients that side effects such as nausea, vomiting, stomatitis, impaired wound healing, amenorrhea, premature menopause, sterility and hair loss may be associated with cyclophosphamide administration. Other undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) could affect the ability to drive or use machines [see Adverse Reactions (6.1 and 6.2)].  Instruct the patient to swallow cyclophosphamide tablets whole. Do not cut, chew, or crush tablets [see Dosage and Administration (2.3)].  Advise caregivers to wear gloves when handling bottles containing cyclophosphamide tablets and avoid exposure to broken tablets. If contact with broken tablets occurs, wash hands immediately and thoroughly [see Dosage and Administration (2.3)]. Baxter Vials Manufactured by: Tablets Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Germany Baxter is a trademark of Baxter International Inc. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.810624	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112lbl.pdf', 'application_number': 12141, 'submission_type': 'SUPPL ', 'submission_number': 90}
10,791	1 KENALOG®-10 INJECTION triamcinolone acetonide injectable suspension, USP NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL For Intra-articular or Intralesional Use Only NOT FOR INTRAVENOUS, INTRAMUSCULAR, INTRAOCULAR, EPIDURAL, OR INTRATHECAL USE DESCRIPTION Kenalog®-10 Injection (triamcinolone acetonide injectable suspension, USP) is triamcinolone acetonide, a synthetic glucocorticoid corticosteroid with marked anti-inflammatory action, in a sterile aqueous suspension suitable for intralesional and intra-articular injection. THIS FORMULATION IS SUITABLE FOR INTRA-ARTICULAR AND INTRALESIONAL USE ONLY. Each mL of the sterile aqueous suspension provides 10 mg triamcinolone acetonide, with sodium chloride for isotonicity, 0.9% (w/v) benzyl alcohol as a preservative, 0.75% carboxymethylcellulose sodium, and 0.04% polysorbate 80; sodium hydroxide or hydrochloric acid may have been added to adjust pH between 5.0 and 7.5. At the time of manufacture, the air in the container is replaced by nitrogen. The chemical name for triamcinolone acetonide is 9-Fluoro-11β,16α,17,21-tetrahydroxy- pregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. Its structural formula is: Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 MW 434.50 CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Synthetic analogs such as triamcinolone are primarily used for their anti-inflammatory effects in disorders of many organ systems. INDICATIONS AND USAGE The intra-articular or soft tissue administration of Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis, or osteoarthritis. The intralesional administration of Kenalog-10 Injection is indicated for alopecia areata; discoid lupus erythematosus; keloids; localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; necrobiosis lipoidica diabeticorum. Kenalog-10 Injection may also be useful in cystic tumors of an aponeurosis or tendon (ganglia). Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 CONTRAINDICATIONS Kenalog-10 Injection is contraindicated in patients who are hypersensitive to any components of this product (see WARNINGS: General). Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. WARNINGS General Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS: Pediatric Use). Because Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) is a suspension, it should not be administered intravenously. Strict aseptic technique is mandatory. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Cases of serious anaphylactic reactions and anaphylactic shock, including death, have been reported in individuals receiving triamcinolone acetonide injection, regardless of the route of administration. Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Kenalog-10 Injection is a long-acting preparation, and is not suitable for use in acute stress situations. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an intravenous corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including Kenalog-10 Injection, should not be used for the treatment of traumatic brain injury. Cardio-Renal Average and large doses of corticosteroids 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 they are used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. 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 Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS: Drug Interactions: Amphotericin B injection and potassium-depleting agents). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, or Toxoplasma. It is recommended that latent amebiasis 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 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 cannot be predicted. Immunization Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, eg, for Addison’s disease. Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. 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. Neurologic Epidural and intrathecal administration of this product is not recommended. Reports of serious medical events, including death, have been associated with epidural and intrathecal routes of corticosteroid administration (see ADVERSE REACTIONS: Gastrointestinal and Neurologic/Psychiatric). 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. Adequate studies to demonstrate the safety of Kenalog Injection use by intraturbinal, subconjunctival, sub-Tenons, retrobulbar, and intraocular (intravitreal) injections have not been performed. Endophthalmitis, eye inflammation, increased intraocular pressure, and visual disturbances including vision loss have been reported with intravitreal administration. Administration of Kenalog Injection intraocularly or into the nasal turbinates is not recommended. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Intraocular injection of corticosteroid formulations containing benzyl alcohol, such as Kenalog Injection, is not recommended because of potential toxicity from the benzyl alcohol. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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. 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 congestive heart failure, hypertension, 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. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Intra-Articular and Soft Tissue Administration Intra-articularly injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS: Musculoskeletal). Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (ie, 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 lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (ie, postmenopausal women) before initiating corticosteroid therapy. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 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 (eg, myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (eg, 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. Psychiatric 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 corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids, and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on 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. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Drug Interactions Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (ie, amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases: 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. Anticoagulants, oral: 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. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic enzyme inducers (eg, barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory drugs) 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. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections: Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects: Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids 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 corticosteroids are administered to a nursing woman. Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids 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). Other indications for pediatric use of corticosteroids, eg, 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. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 The adverse effects of corticosteroids 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. Pediatric patients 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 (ie, cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use No overall differences in safety or effectiveness were observed between elderly 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. ADVERSE REACTIONS (listed alphabetically under each subsection) The following adverse reactions may be associated with corticosteroid therapy: Allergic reactions: Anaphylactoid reaction, anaphylaxis including anaphylactic reactions and anaphylactic shock, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, 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 pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration [see WARNINGS: Neurologic]), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra- articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke (including brainstem) have been reported after epidural administration of corticosteroids (see WARNINGS: Neurologic). Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION General NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS). 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. 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 the corticosteroid 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. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 In pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in 3 or 4 divided doses (3.2 to 48 mg/m2bsa/day). 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. Intra-Articular Administration Dosage The initial dose of Kenalog-10 Injection for intra-articular administration may vary from 2.5 mg to 5 mg for smaller joints and from 5 mg to 15 mg for larger joints, depending on the specific disease entity being treated. Single injections into several joints, up to a total of 20 mg or more, have been given. Intralesional For intralesional administration, the initial dose per injection site will vary depending on the specific disease entity and lesion being treated. The site of injection and volume of injection should be carefully considered due to the potential for cutaneous atrophy. Multiple sites separated by one centimeter or more may be injected, keeping in mind that the greater the total volume employed the more corticosteroid becomes available for systemic absorption and systemic effects. Such injections may be repeated, if necessary, at weekly or less frequent intervals. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Localization of Doses The lower dosages in the initial dosage range of triamcinolone acetonide may produce the desired effect when the corticosteroid is administered to provide a localized concentration. The site and volume of the injection should be carefully considered when triamcinolone acetonide is administered for this purpose. Administration STRICT ASEPTIC TECHNIQUE IS MANDATORY. The vial should be shaken before use to ensure a uniform suspension. Prior to withdrawal, the suspension should be inspected for clumping or granular appearance (agglomeration). An agglomerated product results from exposure to freezing temperatures and should not be used. After withdrawal, inject without delay to prevent settling in the syringe. Injection Technique For treatment of joints, the usual intra-articular injection technique should be followed. If an excessive amount of synovial fluid is present in the joint, some, but not all, should be aspirated to aid in the relief of pain and to prevent undue dilution of the steroid. With intra-articular administration, prior use of a local anesthetic may often be desirable. Care should be taken with this kind of injection, particularly in the deltoid region, to avoid injecting the suspension into the tissues surrounding the site, since this may lead to tissue atrophy. In treating acute nonspecific tenosynovitis, care should be taken to ensure that the injection of Kenalog-10 Injection is made into the tendon sheath rather than the tendon substance. Epicondylitis may be treated by infiltrating the preparation into the area of greatest tenderness. Intralesional For treatment of dermal lesions, Kenalog-10 Injection should be injected directly into the lesion, ie, intradermally or subcutaneously. For accuracy of dosage measurement and ease of administration, it is preferable to employ a tuberculin syringe and a small-bore needle (23-25 gauge). Ethyl chloride spray may be used to alleviate the discomfort of the injection. Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 HOW SUPPLIED Kenalog®-10 Injection (triamcinolone acetonide injectable suspension, USP) is supplied in 5 mL multiple-dose vials (NDC 0003-0494-20) providing 10 mg triamcinolone acetonide per mL. Storage Store at controlled room temperature, 20°–25°C (68°–77°F), avoid freezing and protect from light. Bristol-Myers Squibb Company Princeton, NJ 08543 USA Product of Italy 1221154A5 Rev June 2011 Reference ID: 2961557 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.928168	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/012041s038lbl.pdf', 'application_number': 12041, 'submission_type': 'SUPPL ', 'submission_number': 38}
10,795	NDA 12-151/S-062 Page 2 Aldactone® spironolactone tablets, USP WARNING Aldactone has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). Aldactone should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided. DESCRIPTION Aldactone oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone, 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate, which has the following structural formula: Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Inactive ingredients include calcium sulfate, corn starch, flavor, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. ACTIONS / CLINICAL PHARMACOLOGY Mechanism of action: Aldactone (spironolactone) is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Aldactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Aldactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule. Aldosterone antagonist activity: Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and the nephrotic syndrome. By competing with aldosterone for receptor sites, Aldactone provides effective therapy for the edema and ascites in those conditions. Aldactone counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy. Aldactone is effective in lowering the systolic and diastolic blood pressure in patients with primary hyperaldosteronism. It is also effective in most cases of essential hypertension, despite the fact that aldosterone secretion may be within normal limits in benign essential hypertension. Through its action in antagonizing the effect of aldosterone, Aldactone inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 3 Aldactone has not been demonstrated to elevate serum uric acid, to precipitate gout, or to alter carbohydrate metabolism. Pharmacokinetics: Aldactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible, together with Aldactone, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (Aldactone film-coated tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a low-fat breakfast and blood was drawn thereafter. Accumulation Factor: AUC (0-24 hr, day 15)/AUC (0-24 hr, day 1) Mean Peak Serum Concentration Mean (SD) Post-Steady State Half-Life 7-α-(thiomethyl) spirolactone (TMS) 1.25 391 ng/mL at 3.2 hr 13.8 hr (6.4) (terminal) 6-ß-hydroxy-7-α- (thiomethyl) spirolactone (HTMS) 1.50 125 ng/mL at 5.1 hr 15.0 hr (4.0) (terminal) Canrenone (C) 1.41 181 ng/mL at 4.3 hr 16.5 hr (6.3) (terminal) Spironolactone 1.30 80 ng/mL at 2.6 hr Approximately 1.4 hr (0.5) (ß half-life) The pharmacological activity of spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively. In humans the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile. The effect of food on spironolactone absorption (two 100 mg Aldactone tablets) was assessed in a single-dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known. CLINICAL STUDIES Severe heart failure: The Randomized Aldactone Evaluation Study (RALES) was a multinational, double-blind study in patients with an ejection fraction of ≤ 35%, a history of New York Heart This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 4 Association (NYHA) class IV heart failure within 6 months, and class III-IV heart failure at the time of randomization. All patients were required to be taking a loop diuretic and, if tolerated, an ACE inhibitor. Patients with a baseline serum creatinine of >2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of >5.0 mEq/L were excluded. Patients were randomized 1:1 to spironolactone 25 mg orally once daily or matching placebo. Follow- up visits and laboratory measurements (including serum potassium and creatinine) were performed every four weeks for the first 12 weeks, then every 3 months for the first year, and then every 6 months thereafter. Dosing could be withheld for serious hyperkalemia or if the serum creatinine increased to >4.0 mg/dL. Patients who were intolerant of the initial dosage regimen had their dose decreased to one tablet every other day at one to four weeks. Patients who were tolerant of one tablet daily at 8 weeks may have had their dose increased to two tablets daily at the discretion of the investigator. RALES enrolled 1,663 patients (3% U.S.) at 195 centers in 15 countries between March 24, 1995, and December 31, 1996. The study population was primarily white (87%, with 7% black, 2% Asian, and 4% other), male (73%), and elderly (median age 67). The median ejection fraction was 0.26. Seventy percent were NYHA class III and 29% class IV. The presumed etiology of heart failure was ischemic in 55%, and non-ischemic in 45%. There was a history of myocardial infarction in 28%, of hypertension in 24%, and of diabetes in 22%. The median baseline serum creatinine was 1.2 mg/dL and the median baseline creatinine clearance was 57 mL/min. The mean daily dose at study end for the patients randomized to spironolactone was 26 mg. Concomitant medications included a loop diuretic in 100% of patients and an ACE inhibitor in 97%. Other medications used at any time during the study included digoxin (78%), anticoagulants (58%), aspirin (43%), and beta-blockers (15%). The primary endpoint for RALES was time to all-cause mortality. RALES was terminated early, after a mean follow-up of 24 months, because of significant mortality benefit detected on a planned interim analysis. The survival curves by treatment group are shown in Figure 1. Figure 1. Survival by Treatment Group in RALES This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 5 Spironolactone reduced the risk of death by 30% compared to placebo (p<0.001; 95% confidence interval 18% to 40%). Spironolactone reduced the risk of cardiac death, primarily sudden death and death from progressive heart failure by 31% compared to placebo (p <0.001; 95% confidence interval 18% to 42%). Spironolactone also reduced the risk of hospitalization for cardiac causes (defined as worsening heart failure, angina, ventricular arrhythmias or myocardial infarction) by 30% (p <0.001 95% confidence interval 18% to 41%). Changes in NYHA class were more favorable with spironolactone: In the spironolactone group, NYHA class at the end of the study improved in 41% of patients and worsened in 38% compared to improved in 33% and worsened in 48% in the placebo group (P <0.001). Mortality hazard ratios for some subgroups are shown in Figure 2. The favorable effect of spironolactone on mortality appeared similar for both genders and all age groups except patients younger than 55; there were too few non-whites in RALES to draw any conclusions about differential effects by race. Spironolactone’s benefit appeared greater in patients with low baseline serum potassium levels and less in patients with ejection fractions <0.2. These subgroup analyses must be interpreted cautiously. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 6 Figure 2. Hazard Ratios of All-Cause Mortality by Subgroup in RALES 0 .2 0 .4 0 .6 0 .8 1 .0 1 .2 1 .4 S u b g ro u p A ll A ge (yr) S ex R a c e L V E F (% ) H ea rt F a ilu re N Y H A D ia b etes S er C reatin in e (m g/d L ) C r C leara nc e (m L/m in /1 .7 3 s q m ) P o tassiu m (m m o l/L) D ig ox in A C E I B eta B lo c k er L e v el < 5 9 5 9 -6 6 6 7 -7 2 > 7 2 F em ale M a le W h ite B lac k O thers < 2 3 2 3 -2 9 > 2 9 N o n-Isc h em ic Isch em ic III IV N o Y es < 1 .2 > = 1 .2 < 1 4.4 4 1 4 .4 4 -18 .64 > 1 8.6 4 < 3 .9 3 .9 -4 .3 4 .3 -4 .6 > = 4 .6 N o Y es N o Y es N o Y es N 16 6 3 4 0 1 4 0 1 4 0 2 4 5 9 4 4 6 12 1 7 14 4 0 1 2 0 1 0 3 5 6 5 5 0 2 5 9 5 7 5 4 9 0 7 11 7 3 4 8 3 12 7 4 3 8 9 8 1 9 8 3 6 5 1 6 5 1 7 5 1 8 3 1 4 3 5 8 5 4 2 4 2 9 4 4 4 12 1 9 6 8 15 9 5 14 8 6 1 7 7 S p iro n o la c to n e b ette r P laceb o b etter H R a n d 9 5 % C I Figure 2: The size of each box is proportional to the sample size as well as the event rate. ACEI denotes angiotensin-converting enzyme inhibitor, LVEF denotes left ventricular ejection fraction, Cr Clearance denotes creatinine clearance and Ser Creatinine denotes serum creatinine. INDICATIONS AND USAGE Aldactone (spironolactone) is indicated in the management of: Primary hyperaldosteronism for: Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial. Short-term preoperative treatment of patients with primary hyperaldosteronism. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 7 Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery. Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism). Edematous conditions for patients with: Congestive heart failure: For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures. Aldactone is also indicated for patients with congestive heart failure taking digitalis when other therapies are considered inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: Aldosterone levels may be exceptionally high in this condition. Aldactone is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. The nephrotic syndrome: For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension Usually in combination with other drugs, Aldactone is indicated for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate. Hypokalemia For the treatment of patients with hypokalemia when other measures are considered inappropriate or inadequate. Aldactone is also indicated for the prophylaxis of hypokalemia in patients taking digitalis when other measures are considered inadequate or inappropriate. Severe heart failure (NYHA class III – IV) To increase survival, and to reduce the need for hospitalization for heart failure when used in addition to standard therapy. Usage in Pregnancy. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Aldactone is indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Precautions: Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 8 will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate. CONTRAINDICATIONS Aldactone is contraindicated for patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, or hyperkalemia. WARNINGS Potassium supplementation. Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with Aldactone therapy. Excessive potassium intake may cause hyperkalemia in patients receiving Aldactone (see Precautions: General). Aldactone should not be administered concurrently with other potassium-sparing diuretics. Aldactone, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when Aldactone is given concomitantly with these drugs. Hyperkalemia in patients with severe heart failure. Hyperkalemia may be fatal. It is critical to monitor and manage serum potassium in patients with severe heart failure receiving Aldactone. Avoid using other potassium-sparing diuretics. Avoid using oral potassium supplements in patients with serum potassium > 3.5 mEq/L. RALES excluded patients with a serum creatinine > 2.5 mg/dL or a recent increase in serum creatinine > 25%. The recommended monitoring for potassium and creatinine is one week after initiation or increase in dose of Aldactone, monthly for the first 3 months, then quarterly for a year, and then every 6 months. Discontinue or interrupt treatment for serum potassium > 5 mEq/L or for serum creatinine > 4 mg/dL. (See CLINICAL STUDIES, Severe heart failure, and DOSAGE AND ADMINISTRATION, Severe heart failure.) Aldactone should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Lithium generally should not be given with diuretics (see Precautions: Drug interactions). PRECAUTIONS General: All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance, e.g., hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hyperkalemia. 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 the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal. Consequently, no potassium supplement should ordinarily be given with Aldactone. Concomitant administration of potassium-sparing diuretics and ACE inhibitors or nonsteroidal anti- inflammatory drugs (NSAIDs), e.g., indomethacin, has been associated with severe hyperkalemia. If hyperkalemia is suspected (warning signs include paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia and shock), an electrocardiogram This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 9 (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes. If hyperkalemia is present, Aldactone should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function. Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be caused or aggravated, especially when Aldactone is administered in combination with other diuretics, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening. Aldactone therapy may cause a transient elevation of BUN, especially in patients with preexisting renal impairment. Aldactone may cause mild acidosis. Gynecomastia may develop in association with the use of Aldactone; physicians should be alert to its possible onset. The development of gynecomastia appears to be related to both dosage level and duration of therapy and is normally reversible when Aldactone is discontinued. In rare instances some breast enlargement may persist when Aldactone is discontinued. Information for patients: Patients who receive Aldactone should be advised to avoid potassium supplements and foods containing high levels of potassium, including salt substitutes. Laboratory tests: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments. Drug interactions: ACE inhibitors: Concomitant administration of ACE inhibitors with potassium-sparing diuretics has been associated with severe hyperkalemia. Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur. Pressor amines (e.g., norepinephrine): Aldactone reduces the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with Aldactone. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant may result. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 10 Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing and thiazide diuretics. Combination of NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when Aldactone and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Digoxin: Aldactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. It may be necessary to reduce the maintenance and digitalization doses when Aldactone is administered, and the patient should be carefully monitored to avoid over or underdigitalization. Drug/Laboratory test interactions: Several reports of possible interference with digoxin radioimmunoassay by Aldactone, or its metabolites, have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay-specific) has been fully established. Carcinogenesis, mutagenesis, impairment of fertility: Orally administered Aldactone has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150 and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, 100 and 150 mg Aldactone/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females. A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to Aldactone and whose primary metabolite, canrenone, is also a major product of Aldactone in man) for a period of one year. In two- year studies in the rat, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular and mammary tumors. Neither Aldactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither Aldactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, Aldactone has been reported to be negative in some mammalian mutagenicity tests in vitro and inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others. In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg Aldactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), Aldactone was found to increase the length of the estrous cycle by prolonging diestrus during This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 11 treatment and inducing constant diestrus during a two-week post-treatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility and fecundity. Aldactone (100 mg/kg/day), administered i.p. to female mice during a two-week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating. Pregnancy: Teratogenic effects. Pregnancy Category C. Teratology studies with Aldactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryotoxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its anti-androgenic activity and the requirement of testosterone for male morphogenesis, Aldactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of Aldactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well-controlled studies with Aldactone in pregnant women. Aldactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of Aldactone in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus. Nursing mothers: Canrenone, a major (and active) metabolite of Aldactone, appears in human breast milk. Because Aldactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted. Pediatric use: Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity. Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting. Endocrine: Gynecomastia (see Precautions), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding. Carcinoma of the breast has been reported in patients taking Aldactone but a cause and effect relationship has not been established. Hematologic: Agranulocytosis. Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 12 Metabolism: Hyperkalemia (see Warnings and Precautions). Nervous system /psychiatric: Mental confusion, ataxia, headache, drowsiness, lethargy. Liver / biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with Aldactone administration. Renal: Renal dysfunction (including renal failure). OVERDOSAGE The oral LD50 of Aldactone is greater than 1,000 mg/kg in mice, rats, and rabbits. Acute overdosage of Aldactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function. Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, Aldactone should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. DOSAGE AND ADMINISTRATION Primary hyperaldosteronism. Aldactone may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets. Long test: Aldactone is administered at a daily dosage of 400 mg for three to four weeks. Correction of hypokalemia and of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism. Short test: Aldactone is administered at a daily dosage of 400 mg for four days. If serum potassium increases during Aldactone administration but drops when Aldactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered. After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, Aldactone may be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, Aldactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient. Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). An initial daily dosage of 100 mg of Aldactone administered in either single or divided doses is recommended, but may range from 25 to 200 mg daily. When given as the sole agent for diuresis, Aldactone should be continued for at least five days at the initial dosage level, after which it may be adjusted to the optimal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 13 therapeutic or maintenance level administered in either single or divided daily doses. If, after five days, an adequate diuretic response to Aldactone has not occurred, a second diuretic which acts more proximally in the renal tubule may be added to the regimen. Because of the additive effect of Aldactone when administered concurrently with such diuretics, an enhanced diuresis usually begins on the first day of combined treatment; combined therapy is indicated when more rapid diuresis is desired. The dosage of Aldactone should remain unchanged when other diuretic therapy is added. Essential hypertension. For adults, an initial daily dosage of 50 to 100 mg of Aldactone administered in either single or divided doses is recommended. Aldactone may also be given with diuretics which act more proximally in the renal tubule or with other antihypertensive agents. Treatment with Aldactone should be continued for at least two weeks, since the maximum response may not occur before this time. Subsequently, dosage should be adjusted according to the response of the patient. Hypokalemia. Aldactone in a dosage ranging from 25 mg to 100 mg daily is useful in treating a diuretic-induced hypokalemia, when oral potassium supplements or other potassium-sparing regimens are considered inappropriate. Severe heart failure (NYHA class III – IV). Treatment should be initiated with Aldactone 25 mg once daily if the patient’s serum potassium is ≤5.0 mEq/L and the patient’s serum creatinine is ≤ 2.5 mg/dL. Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily as clinically indicated. Patients who do not tolerate 25 mg once-daily dose may have their dosage reduced to 25 mg every other day. SEE WARNINGS: Hyperkalemia in patients with severe heart failure for advice on monitoring serum potassium and serum creatinine. HOW SUPPLIED Aldactone 25 mg tablets are round, light yellow, film-coated, with SEARLE and 1001 debossed on one side and ALDACTONE and 25 on the other side, supplied as: NDC Number Size 0025-1001-31 bottle of 100 0025-1001-51 bottle of 500 0025-1001-55 bottle of 2500 Aldactone 50 mg tablets are oval, light orange, scored, film-coated, with SEARLE and 1041 debossed on the scored side and ALDACTONE and 50 on the other side, supplied as: NDC Number Size 0025-1041-31 bottle of 100 0025-1041-34 carton of 100 unit dose Aldactone 100 mg tablets are round, peach-colored, scored, film-coated, with SEARLE and 1031 debossed on the scored side and ALDACTONE and 100 on the other side, supplied as: NDC Number Size 0025-1031-31 bottle of 100 0025-1031-34 carton of 100 unit dose Store below 77°F (25°C). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-151/S-062 Page 14 Rx only LAB-0231-4.0 Revised January 2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.981408	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/012151s062lbl.pdf', 'application_number': 12151, 'submission_type': 'SUPPL ', 'submission_number': 62}
10,794	_______________________________________________________________________________________________________________________________________ ______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CYCLOPHOSPHAMIDE safely and effectively. See full prescribing information for CYCLOPHOSPHAMIDE. -----------------------WARNINGS AND PRECAUTIONS---------------------  Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections – Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. (5.1) CYCLOPHOSPHAMIDE injection, for intravenous use CYCLOPHOSPHAMIDE tablets, for oral use Initial U.S. Approval: 1959 ----------------------------INDICATIONS AND USAGE--------------------------- Cyclophosphamide is an alkylating drug indicated for treatment of:  Malignant Diseases: malignant lymphomas: Hodgkin’s disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma (1.1)  Minimal Change Nephrotic Syndrome in Pediatric Patients: biopsy proven minimal change nephrotic syndrome patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy (1.2) Limitations of Use: The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established. ----------------------DOSAGE AND ADMINISTRATION------------------------ Malignant Diseases: Adult and Pediatric Patients (2.1)  Intravenous: Initial course for patients with no hematologic deficiency: 40 mg per kg to 50 mg per kg in divided doses over 2 to 5 days. Other regimens include 10 mg per kg to 15 mg per kg given every 7 to 10 days or 3 mg per kg to 5 mg per kg twice weekly.  Oral: Usually 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing. Minimal Change Nephrotic Syndrome in Pediatric Patients (2.2)  Recommended oral dose: 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg). Treatment beyond 90 days increases the probability of sterility in males. ---------------------DOSAGE FORMS AND STRENGTHS----------------------  Injection, lyophilized powder: 500 mg, 1 g, and 2 g (3)  Tablet: 25 mg and 50 mg (3) -------------------------------CONTRAINDICATIONS------------------------------  Hypersensitivity to cyclophosphamide (4)  Urinary outflow obstruction (4)  Urinary Tract and Renal Toxicity – Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur. Exclude or correct any urinary tract obstructions prior to treatment. (5.2)  Cardiotoxicity – Myocarditis, myopericarditis, pericardial effusion, arrythmias and congestive heart failure, which may be fatal, have been reported. Monitor patients, especially those with risk factors for cardiotoxicity or pre-existing cardiac disease. (5.3)  Pulmonary Toxicity – Pneumonitis, pulmonary fibrosis and pulmonary veno-occlusive disease leading to respiratory failure may occur. Monitor patients for signs and symptoms of pulmonary toxicity. (5.4)  Secondary malignancies (5.5)  Veno-occlusive Liver Disease - Fatal outcome can occur. (5.6)  Embryo-Fetal Toxicity - Can cause fetal harm. Advise female patients of reproductive potential to avoid pregnancy. (5.7, 8.1, 8.6) ------------------------------ADVERSE REACTIONS------------------------------- Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------USE IN SPECIFIC POPULATIONS--------------------  Nursing Mothers: Discontinue drug or nursing. (8.3)  Females and males of reproductive potential: Counsel patients on pregnancy prevention and planning. (8.6)  Renal Patients: Monitor for toxicity in patients with moderate and severe renal impairment. (8.7, 12.3) See 17 for PATIENT COUNSELING INFORMATION Revised: 05/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Malignant Diseases 1.2 Minimal Change Nephrotic Syndrome in Pediatric Patients 2 DOSAGE AND ADMINISTRATION 2.1 Dosing for Malignant Diseases 2.2 Dosing for Minimal Change Nephrotic Syndrome in Pediatric Patients 2.3 Preparation, Handling and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections 5.2 Urinary Tract and Renal Toxicity 5.3 Cardiotoxicity 5.4 Pulmonary Toxicity 5.5 Secondary Malignancies 5.6 Veno-occlusive Liver Disease 5.7 Embryo-Fetal Toxicity 5.8 Infertility 5.9 Impairment of Wound Healing 5.10 Hyponatremia 6 ADVERSE REACTIONS 6.1 Common Adverse Reactions 6.2 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 Females and Males of Reproductive Potential 8.7 Use in Patients with Renal Impairment 8.8 Use in Patients with Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3304966 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 Malignant Diseases Cyclophosphamide is indicated for the treatment of:  malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma  multiple myeloma  leukemias: chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia (cyclophosphamide given during remission is effective in prolonging its duration)  mycosis fungoides (advanced disease)  neuroblastoma (disseminated disease)  adenocarcinoma of the ovary  retinoblastoma  carcinoma of the breast Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. 1.2 Minimal Change Nephrotic Syndrome in Pediatric Patients: Cyclophosphamide is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatrics patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy. Limitations of Use: The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established. 2. DOSAGE AND ADMINISTRATION During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, cyclophosphamide should be administered in the morning. 2.1 Dosing for Malignant Diseases Adults and Pediatric Patients Intravenous When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 40 mg per kg to 50 mg per kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 mg per kg to 15 mg per kg given every 7 to 10 days or 3 mg per kg to 5 mg per kg twice weekly. Oral Oral cyclophosphamide dosing is usually in the range of 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage. When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as well as that of the other drugs. 2.2 Dosing for Minimal Change Nephrotic Syndrome in Pediatric Patients An oral dose of 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg) is recommended. Treatment beyond 90 days increases the probability of sterility in males [see Use in Specific Populations (8.4)]. 2.3 Preparation, Handling and Administration Handle and dispose of cyclophosphamide in a manner consistent with other cytotoxic drugs.1 Caution should be exercised when handling and preparing Cyclophosphamide for Injection, USP (lyophilized powder), or bottles containing cyclophosphamide tablets. To minimize the risk of dermal exposure, always wear gloves when handling vials containing Cyclophosphamide for Injection, USP (lyophilized powder), or bottles containing cyclophosphamide tablets. The coating of the cyclophosphamide tablets prevents direct contact of persons handling the tablets with the active substance. However, to prevent inadvertent exposure to the active substance, the cyclophosphamide tablets should not be cut, chewed, or crushed. Personnel should avoid exposure to broken tablets. If contact with broken tablets occurs, wash hands immediately and thoroughly. Cyclophosphamide for Injection, USP Intravenous Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use cyclophosphamide vials if there are signs of melting. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials. Cyclophosphamide does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. Use aseptic technique. For Direct Intravenous Injection Reconstitute Cyclophosphamide with 0.9% Sodium Chloride Injection, USP only, using the volumes listed below in Table 1. Gently swirl the vial to dissolve the drug completely. Do not use Sterile Water for Injection, USP because it results in a hypotonic solution and should not be injected directly. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Reconstitution for Direct Intravenous Injection Strength Volume of 0.9% Sodium Chloride Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL For Intravenous Infusion Reconstitution of Cyclophosphamide: Reconstitute Cyclophosphamide using 0.9% Sodium Chloride Injection, USP or Sterile Water for Injection, USP with the volume of diluent listed below in Table 2. Add the diluent to the vial and gently swirl to dissolve the drug completely. Table 2: Reconstitution in preparation for Intravenous Infusion Strength Volume of Diluent Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL Dilution of Reconstituted Cyclophosphamide: Further dilute the reconstituted Cyclophosphamide solution to a minimum concentration of 2 mg per mL with any of the following diluents:  5% Dextrose Injection, USP  5% Dextrose and 0.9% Sodium Chloride Injection, USP  0.45% Sodium Chloride Injection, USP To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.g., facial swelling, headache, nasal congestion, scalp burning), cyclophosphamide should be injected or infused very slowly. Duration of the infusion also should be appropriate for the volume and type of carrier fluid to be infused. Storage of Reconstituted and Diluted Cyclophosphamide Solution: If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 3: Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3: Storage of Cyclophosphamide Solutions Diluent Storage Room Temperature Refrigerated Reconstituted Solution (Without Further Dilution) 0.9% Sodium Chloride Injection, USP up to 24 hrs Up to 6 days Sterile Water for Injection, USP Do not store; use immediately Diluted Solutions1 0.45% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 5% Dextrose Injection, USP up to 24 hrs up to 36 hrs 5% Dextrose and 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 36 hrs 1 Storage time is the total time cyclophosphamide is in solution including the time it is reconstituted in 0.9% Sterile Sodium Chloride Injection, USP or Sterile Water for Injection, USP. Use of Reconstituted Solution for Oral Administration Liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir, National Formulary (NF) Such preparations should be stored under refrigeration in glass containers and used within 14 days. 3. DOSAGE FORMS AND STRENGTHS Cyclophosphamide for Injection, USP (lyophilized powder) is a sterile white cake available in  500 mg  1 g  2 g Cyclophosphamide Tablets, USP are white tablets with blue flecks available in  25 mg  50 mg 4. CONTRAINDICATIONS  Hypersensitivity Cyclophosphamide is contraindicated in patients who have a history of severe hypersensitivity reactions to it, any of its metabolites, or to other components of the product. Anaphylactic reactions including death have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents can occur.  Urinary Outflow Obstruction Cyclophosphamide is contraindicated in patients with urinary outflow obstruction [see Warnings and Precautions (5.2)]. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5. WARNINGS AND PRECAUTIONS 5.1 Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated [see Adverse Reactions (6.2)]. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or antivirals may also be indicated. Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be administered to patients with neutrophils ≤1,500/mm3 and platelets < 50,000/mm3. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy. 5.2 Urinary Tract and Renal Toxicity Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide. Before starting treatment, exclude or correct any urinary tract obstructions [see Contraindications (4)]. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity. 5.3 Cardiotoxicity Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide. The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with pre existing cardiac disease. Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease. 5.4 Pulmonary Toxicity Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide. Monitor patients for signs and symptoms of pulmonary toxicity. 5.5 Secondary Malignancies Cyclophosphamide is genotoxic [see Nonclinical Toxicology (13.1)]. Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens. The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis. 5.6 Veno-occlusive Liver Disease Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide. Other risk factors predisposing to the development of VOD include preexisting disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance status. 5.7 Embryo-Fetal Toxicity Cyclophosphamide can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Exposure to cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment and for up to 1 year after completion of therapy [see Use in Specific Populations (8.6)]. 5.8 Infertility Male and female reproductive function and fertility may be impaired in patients being treated with cyclophosphamide. Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients. Advise patients on the potential risks for infertility [see Use in Specific Populations (8.4 and 8.6)]. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.9 Impairment of Wound Healing Cyclophosphamide may interfere with normal wound healing. 5.10 Hyponatremia Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported. 6. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. • Hypersensitivity [see Contraindications (4)] • Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions (5.1)] • Urinary Tract and Renal Toxicity [see Warnings and Precautions (5.2)] • Cardiotoxicity [see Warnings and Precautions (5.3)] • Pulmonary Toxicity [see Warnings and Precautions (5.4)] • Secondary Malignancies [see Warnings and Precautions (5.5)] • Veno-occlusive Liver Disease [see Warnings and Precautions (5.6)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.7)] • Reproductive System Toxicity [see Warnings and Precautions (5.8) and Use in Specific Populations (8.4 and 8.6)] • Impaired Wound Healing [see Warnings and Precautions (5.9)] • Hyponatremia [see Warnings and Precautions (5.10)] 6.1 Common Adverse Reactions Hematopoietic system: Neutropenia occurs in patients treated with cyclophosphamide. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients. Gastrointestinal system: Nausea and vomiting occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. Skin and its structures: Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. 6.2 Postmarketing Experience The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Because they are reported from a population from unknown size, precise estimates of frequency cannot be made. Cardiac: cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion (progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation. Congenital, Familial and Genetic: intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity (including myelosuppression, gastroenteritis). Ear and Labyrinth: deafness, hearing impaired, tinnitus. Endocrine: water intoxication. Eye: visual impairment, conjunctivitis, lacrimation. Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation. General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache. Hematologic: myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic syndrome (with thrombotic microangiopathy). Hepatic: veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal, hepatic enzymes increased. Immune: immunosuppression, anaphylactic shock and hypersensitivity reaction. Infections: The following manifestations have been associated with myelosuppression and immunosuppression caused by cyclophosphamide: increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal and, parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), Pneumocystis jiroveci, herpes zoster, Strongyloides, sepsis and septic shock. Investigations: blood lactate dehydrogenase increased, C-reactive protein increased. Metabolism and Nutrition: hyponatremia, fluid retention, blood glucose increased, blood glucose decreased. Musculoskeletal and Connective Tissue: rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia. Neoplasms: acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid cancer. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervous System: encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia. Pregnancy: premature labor. Psychiatric: confusional state. Renal and Urinary: renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells. Reproductive System: infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy, azoospermia, oligospermia. Respiratory: pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea. Skin and Subcutaneous Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis. Tumor lysis syndrome: like other cytotoxic drugs, cyclophosphamide may induce tumor-lysis syndrome and hyperuricemia in patients with rapidly growing tumors. Vascular: pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing, hot flush. 7. DRUG INTERACTIONS Cyclophosphamide is a pro-drug that is activated by cytochrome P450s [see Clinical Pharmacology (12.3)]. An increase of the concentration of cytotoxic metabolites may occur with:  Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-based regimens was found to be associated with a higher Incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Combined or sequential use of cyclophosphamide and other agents with similar toxicities can potentiate toxicities.  Increased hematotoxicity and/or immunosuppression may result from a combined effect of cyclophosphamide and, for example:  ACE inhibitors: ACE inhibitors can cause leukopenia.  Natalizumab  Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.  Thiazide diuretics  Zidovudine Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example:  Anthracyclines  Cytarabine  Pentostatin  Radiation therapy of the cardiac region  Trastuzumab  Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example:  Amiodarone  G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony- stimulating factor): Reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GMCSF.  Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example:  Amphotericin B  Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin  Increase in other toxicities:  Azathioprine: Increased risk of hepatotoxicity (liver necrosis)  Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.  Protease inhibitors: Increased incidence of mucositis  Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment. Etanercept: In patients with Wegener’s granulomatosis, the addition of etanercept to standard treatment, including cyclophosphamide, was associated with a higher incidence of non-cutaneous malignant solid tumors. Metronidazole: Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity. Tamoxifen: Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications. Coumarins: Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide. Cyclosporine: Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease. Depolarizing muscle relaxants: Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine). If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary Cyclophosphamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and published reports of effects in pregnant patients or animals. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Human Data Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide. Animal Data Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification. 8.3 Nursing Mothers Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in nursing infants from cyclophosphamide, 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 Pre-pubescent girls treated with cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause. Pre-pubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. 8.5 Geriatric Use There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than 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 Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda greater frequency of decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy. 8.6 Females and Males of Reproductive Potential Contraception Pregnancy should be avoided during treatment with cyclophosphamide because of the risk of fetal harm [see Use in Specific Populations (8.1)]. Female patients of reproductive potential should use highly effective contraception during and for up to 1 year after completion of treatment. Male patients who are sexually active with female partners who are or may become pregnant should use a condom during and for at least 4 months after treatment. Infertility Females Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment. Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months [see Nonclinical Toxicology (13.1)]. Males Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion. 8.7 Use in Patients with Renal Impairment In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity [see Clinical Pharmacology (12.3)]. Monitor patients with severe renal impairment (CrCl =10 mL/min to 24 mL/min) for signs and symptoms of toxicity. Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered. 8.8 Use in Patients with Hepatic Impairment Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4 hydroxyl metabolite, potentially reducing efficacy [see Clinical Pharmacology (12.3)]. 10. OVERDOSAGE No specific antidote for cyclophosphamide is known. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur. Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis [see Warnings and Precautions (5.1, 5.2, 5.3, and 5.6)]. Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic toxicity in particular. Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication. Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose. 11. DESCRIPTION Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. The chemical name for cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, and has the following structural formula: structural formula Cyclophosphamide has a molecular formula of C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline, or ethanol. Cyclophosphamide for Injection, USP is a sterile white cake available as 500 mg, 1 g, and 2 g strength vials.  500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide and 375 mg mannitol  1 g vial contains 1069.0 mg cyclophosphamide monohydrate equivalent to 1 g cyclophosphamide and 750 mg mannitol  2 g vial contains 2138.0 mg cyclophosphamide monohydrate equivalent to 2 g cyclophosphamide and 1500 mg mannitol Cyclophosphamide Tablets, USP are for oral use and contain 25 mg or 50 mg cyclophosphamide (anhydrous). Inactive ingredients in Cyclophosphamide Tablets are: acacia, FD&C Blue No. 1, D&C Yellow No. 10 Aluminum Lake, lactose, magnesium stearate, starch, stearic acid and talc. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action is thought to involve cross-linking of tumor cell DNA. 12.2 Pharmacodynamics Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. 12.3 Pharmacokinetics Following IV administration, elimination half-life (t ½) ranges from 3 to 12 hours with total body clearance (CL) values of 4 to 5.6 L/h. Pharmacokinetics are linear over the dose range used clinically. When cyclophosphamide was administered at 4.0 g/m2 over a 90 minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug. Absorption After oral administration, peak concentrations of cyclophosphamide occurred at one hour. Area under the curve ratio for the drug after oral and IV administration (AUCpo : AUCiv) ranged from 0.87 to 0.96. Distribution Approximately 20% of cyclophosphamide is protein bound, with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%. Volume of distribution approximates total body water (30 to 50 L). Metabolism The liver is the major site of cyclophosphamide activation. Approximately 75% of the administered dose of cyclophosphamide is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6 displaying the highest 4-hydroxylase activity. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of cyclophosphamide may be directly detoxified by side chain oxidation, leading to the formation of inactive metabolites 2-dechloroethylcyclophosphamide. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide in patients. Cyclophosphamide appears to induce its own metabolism. Auto-induction results in an increase in the total clearance, increased formation of 4-hydroxyl metabolites and shortened t1/2 values following repeated administration at 12- to 24-hour interval. Elimination Cyclophosphamide is primarily excreted as metabolites. 10 to 20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration. Special Populations Renal Impairment Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The pharmacokinetics of cyclophosphamide were determined following one-hour intravenous infusion to renally impaired patients. The results demonstrated that the systemic exposure to cyclophosphamide increased as the renal function decreased. Mean dose-corrected AUC increased by 38% in the moderate renal group, (Creatinine clearance (CrCl of 25 to 50 mL/min), by 64% in the severe renal group (CrCl of 10 to 24 mL/min) and by 23% in the hemodialysis group (CrCl of < 10mL/min) compared to the control group. The increase in exposure was significant in the severe group (p>0.05); thus, patients with severe renal impairment should be closely monitored for toxicity [see Use in Specific Populations (8.7)]. The dialyzability of cyclophosphamide was investigated in four patients on long-term hemodialysis. Dialysis clearance calculated by arterial-venous difference and actual drug recovery in dialysate averaged 104 mL/min, which is in the range of the metabolic clearance of 95 mL/min for the drug. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The elimination half-life (t1/2) was 3.3 hours in patients during hemodialysis, a 49% reduction of the 6.5 hours to t1/2 reported in uremic patients. Reduction in t1/2, larger dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, suggest that cyclophosphamide is dialyzable. Hepatic Impairment Total body clearance (CL) of cyclophosphamide is decreased by 40% in patients with severe hepatic impairment and elimination half-life (t½) is prolonged by 64%. Mean CL and t½ were 45 ± 8.6 L/kg and 12.5 ± 1.0 hours respectively, in patients with severe hepatic impairment and 63 ± 7.6 L/kg and 7.6 ± 1.4 hours respectively in the control group [see Use in Specific Populations (8.8)]. 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see Warnings and Precautions (5.5)]. Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies. Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see Use in Specific Populations (8.6)]. 15. REFERENCES 1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. 16. HOW SUPPLIED/STORAGE AND HANDLING Cyclophosphamide for Injection, USP (lyophilized powder) is a sterile white cake containing cyclophosphamide and mannitol and is supplied in vials for single dose use. Cyclophosphamide for Injection, USP Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10019-988-01 500 mg vial, carton of 1 10019-989-01 1 g vial, carton of 1 10019-990-01 2 g vial, carton of 1 Store vials at or below 25°C (77°F). During transport or storage of cyclophosphamide vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide [see Dosage and Administration (2.3)]. Cyclophosphamide Tablets, USP are white tablets with blue flecks containing 25 mg and 50 mg cyclophosphamide, respectively. Cyclophosphamide Tablets, USP 10019-984-09 50 mg, bottles of 100 10019-982-09 25 mg, bottles of 100 Store tablets at or below 25°C (77°F). Tablets will withstand brief exposure to temperatures up to 30°C (86°F) but should be protected from temperatures above 30°C (86°F). Cyclophosphamide is an antineoplastic product. Follow special handling and disposal procedures.1 17. PATIENT COUNSELING INFORMATION Advise the patient of the following:  Inform patients of the possibility of myelosuppression, immunosuppression, and infections. Explain the need for routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever [see Warnings and Precautions (5.1)].  Advise the patient to report urinary symptoms (patients should report if their urine has turned a pink or red color) and the need for increasing fluid intake and frequent voiding [see Warnings and Precautions (5.2)].  Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.3)].  Warn patients of the possibility of developing non-infectious pneumonitis. Advise patients to report promptly any new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].  Advise female patients of reproductive potential to use highly effective contraception during treatment and for up to 1 year after completion of therapy. There is a potential for harm to a fetus if a patient becomes pregnant during this period. Patients should immediately contact their healthcare provider if they become pregnant or if pregnancy is suspected during this period [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].  Advise male patients who are sexually active with a female partner who is or may become pregnant to use condoms during treatment and for up to 4 months after completion of therapy. There is a potential for harm to a fetus if a patient fathers a child during this period. Patients should immediately contact their healthcare provider if their female partner becomes pregnant or if pregnancy is suspected during this period [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)]. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Advise nursing mothers treated with cyclophosphamide to discontinue nursing or discontinue cyclophosphamide, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.3)].  Explain to patients that side effects such as nausea, vomiting, stomatitis, impaired wound healing, amenorrhea, premature menopause, sterility and hair loss may be associated with cyclophosphamide administration. Other undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) could affect the ability to drive or use machines [see Adverse Reactions (6.1 and 6.2)].  Instruct the patient to swallow cyclophosphamide tablets whole. Do not cut, chew, or crush tablets [see Dosage and Administration (2.3)].  Advise caregivers to wear gloves when handling bottles containing cyclophosphamide tablets and avoid exposure to broken tablets. If contact with broken tablets occurs, wash hands immediately and thoroughly [see Dosage and Administration (2.3)]. Baxter Vials Manufactured by: Tablets Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Germany Baxter is a trademark of Baxter International Inc. Reference ID: 3304966 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:47.986362	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112lbl.pdf', 'application_number': 12142, 'submission_type': 'SUPPL ', 'submission_number': 112}
10,796	Aldactone® spironolactone tablets, USP WARNING ALDACTONE has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). ALDACTONE should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided. DESCRIPTION ALDACTONE oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone, 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21 carboxylic acid γ-lactone acetate, which has the following structural formula: structural formula Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Inactive ingredients include calcium sulfate, corn starch, flavor, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. ACTIONS / CLINICAL PHARMACOLOGY Mechanism of action: ALDACTONE (spironolactone) is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. ALDACTONE causes increased amounts of sodium and water to be excreted, while potassium is retained. ALDACTONE acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule. Aldosterone antagonist activity: Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and nephrotic syndrome. By competing with aldosterone for receptor sites, ALDACTONE provides effective therapy for the edema and ascites in those conditions. ALDACTONE counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy. ALDACTONE is effective in lowering the systolic and diastolic blood pressure in patients with primary hyperaldosteronism. It is also effective in most cases of essential Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hypertension, despite the fact that aldosterone secretion may be within normal limits in benign essential hypertension. Through its action in antagonizing the effect of aldosterone, ALDACTONE inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss. ALDACTONE has not been demonstrated to elevate serum uric acid, to precipitate gout, or to alter carbohydrate metabolism. Pharmacokinetics: ALDACTONE is rapidly and extensively metabolized. Sulfur- containing products are the predominant metabolites and are thought to be primarily responsible, together with ALDACTONE, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (ALDACTONE film-coated tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a low-fat breakfast and blood was drawn thereafter. Accumulation Factor: AUC (0-24 hr, Mean Peak Mean (SD) day 15)/AUC Serum Post Steady (0-24 hr, day 1) Concentration State Half-Life 7-α-(thiomethyl) 1.25 391 ng/mL 13.8 hr (6.4) spirolactone (TMS) at 3.2 hr (terminal) 6-ß-hydroxy-7-α- 1.50 125 ng/mL 15.0 hr (4.0) (thiomethyl) at 5.1 hr (terminal) spirolactone (HTMS) Canrenone (C) 1.41 181 ng/mL 16.5 hr (6.3) at 4.3 hr (terminal) Spironolactone 1.30 80 ng/mL Approximately at 2.6 hr 1.4 hr (0.5) (ß half-life) The pharmacological activity of spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively. In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile. The effect of food on spironolactone absorption (two 100 mg ALDACTONE tablets) was assessed in a single-dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known. CLINICAL STUDIES Severe heart failure: The Randomized Aldactone Evaluation Study (RALES) was a multinational, double-blind study in patients with an ejection fraction of ≤ 35%, a history of New York Heart Association (NYHA) class IV heart failure within 6 months, and class III – IV heart failure at the time of randomization. All patients were required to be taking a loop diuretic and, if tolerated, an ACE inhibitor. Patients with a baseline serum creatinine of >2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of >5.0 mEq/L were excluded. Patients were randomized 1:1 to spironolactone 25 mg orally once daily or matching placebo. Follow-up visits and laboratory measurements (including serum potassium and creatinine) were performed every four weeks for the first 12 weeks, then every 3 months for the first year, and then every 6 months thereafter. Dosing could be withheld for serious hyperkalemia or if the serum creatinine increased to >4.0 mg/dL. Patients who were intolerant of the initial dosage regimen had their dose decreased to one tablet every other day at one to four weeks. Patients who were tolerant of one tablet daily at 8 weeks may have had their dose increased to two tablets daily at the discretion of the investigator. RALES enrolled 1663 patients (3% U.S.) at 195 centers in 15 countries between March 24, 1995 and December 31, 1996. The study population was primarily white (87%, with 7% black, 2% Asian, and 4% other), male (73%), and elderly (median age 67). The median ejection fraction was 0.26. Seventy percent were NYHA class III and 29% class IV. The presumed etiology of heart failure was ischemic in 55%, and non-ischemic in 45%. There was a history of myocardial infarction in 28%, of hypertension in 24%, and of diabetes in 22%. The median baseline serum creatinine was 1.2 mg/dL and the median baseline creatinine clearance was 57 mL/min. The mean daily dose at study end for the patients randomized to spironolactone was 26 mg. Concomitant medications included a loop diuretic in 100% of patients and an ACE inhibitor in 97%. Other medications used at any time during the study included digoxin (78%), anticoagulants (58%), aspirin (43%), and beta-blockers (15%). The primary endpoint for RALES was time to all-cause mortality. RALES was terminated early, after a mean follow-up of 24 months, because of significant mortality benefit detected on a planned interim analysis. The survival curves by treatment group are shown in Figure 1. Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 1. Survival by Treatment Group in RALES graph Spironolactone reduced the risk of death by 30% compared to placebo (p<0.001; 95% confidence interval 18% to 40%). Spironolactone reduced the risk of cardiac death, primarily sudden death, and death from progressive heart failure by 31% compared to placebo (p <0.001; 95% confidence interval 18% to 42%). Spironolactone also reduced the risk of hospitalization for cardiac causes (defined as worsening heart failure, angina, ventricular arrhythmias, or myocardial infarction) by 30% (p <0.001 95% confidence interval 18% to 41%). Changes in NYHA class were more favorable with spironolactone: In the spironolactone group, NYHA class at the end of the study improved in 41% of patients and worsened in 38% compared to improved in 33% and worsened in 48% in the placebo group (p <0.001). Mortality hazard ratios for some subgroups are shown in Figure 2. The favorable effect of spironolactone on mortality appeared similar for both genders and all age groups except patients younger than 55; there were too few non-whites in RALES to draw any conclusions about differential effects by race. Spironolactone’s benefit appeared greater in patients with low baseline serum potassium levels and less in patients with ejection fractions <0.2. These subgroup analyses must be interpreted cautiously. Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 2. Hazard Ratios of All-Cause Mortality by Subgroup in RALES S u b g r o u p A l l A g e ( y r ) S e x R a c e L V E F (% ) H e a r t F a i l u r e N Y H A D i a b e t e s S e r C r e a t i n i n e ( m g / d L ) C r C l e a r a n c e ( m L / m i n / 1 . 7 3 s q m ) P o t a ss i u m (m m o l / L ) D i g o x i n A C E I B e t a B l o c k e r L e v e l < 5 9 5 9 -6 6 6 7 -7 2 > 7 2 F e m a l e M ale W h i t e B l a c k O t h e r s < 2 3 2 3 -2 9 > 2 9 N o n -I s c h e m i c Is c h e m i c I I I IV N o Y es < 1 . 2 > = 1 . 2 < 1 4 . 4 4 1 4 .4 4 -1 8 . 6 4 > 1 8 . 6 4 < 3 . 9 3 . 9 -4 . 3 4 . 3 -4 . 6 > = 4 . 6 N o Y es N o Y es N o Y es H R an d 9 5 % C I N graph 1 6 6 3 4 0 1 4 0 1 4 0 2 4 5 9 4 4 6 1 2 1 7 1 4 4 0 1 2 0 1 0 3 5 6 5 5 0 2 5 9 5 7 5 4 9 0 7 1 1 7 3 4 8 3 1 2 7 4 3 8 9 8 1 9 8 3 6 5 1 6 5 1 7 5 1 8 3 1 4 3 5 8 5 4 2 4 2 9 4 4 4 1 2 1 9 6 8 1 5 9 5 1 4 8 6 1 7 7 0 .2 0 . 4 0 . 6 0 . 8 1 . 0 1 . 2 1 . 4 S p i r o n o l a c t o n e b e t t e r P l a c e b o b e t t e r Figure 2: The size of each box is proportional to the sample size as well as the event rate. LVEF denotes left ventricular ejection fraction, Ser Creatinine denotes serum creatinine, Cr Clearance denotes creatinine clearance, and ACEI denotes angiotensin-converting enzyme inhibitor. INDICATIONS AND USAGE ALDACTONE (spironolactone) is indicated in the management of: Primary hyperaldosteronism for: Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial. Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Short-term preoperative treatment of patients with primary hyperaldosteronism. Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery. Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism). Edematous conditions for patients with: Congestive heart failure: For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures. ALDACTONE is also indicated for patients with congestive heart failure taking digitalis when other therapies are considered inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: Aldosterone levels may be exceptionally high in this condition. ALDACTONE is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. Nephrotic syndrome: For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension ALDACTONE 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. 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 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. Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. Usually in combination with other drugs, ALDACTONE is indicated for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate. Hypokalemia For the treatment of patients with hypokalemia when other measures are considered inappropriate or inadequate. ALDACTONE is also indicated for the prophylaxis of hypokalemia in patients taking digitalis when other measures are considered inadequate or inappropriate. Severe heart failure (NYHA class III – IV) To increase survival, and to reduce the need for hospitalization for heart failure when used in addition to standard therapy. Usage in Pregnancy. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. ALDACTONE is indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Precautions: Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda this edema may cause extreme discomfort that is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate. CONTRAINDICATIONS ALDACTONE is contraindicated for patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, hyperkalemia, Addison’s disease or other conditions associated with hyperkalemia, and with concomitant use of eplerenone. WARNINGS Potassium supplementation. Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with ALDACTONE therapy. Excessive potassium intake may cause hyperkalemia in patients receiving ALDACTONE (see Precautions: General). Concomitant administration of ALDACTONE with the following drugs or potassium sources may lead to severe hyperkalemia: • other potassium-sparing diuretics • ACE inhibitors • angiotensin II antagonists • aldosterone blockers • non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin • heparin and low molecular weight heparin • other drugs known to cause hyperkalemia • potassium supplements • diet rich in potassium • salt substitutes containing potassium ALDACTONE should not be administered concurrently with other potassium-sparing diuretics. ALDACTONE, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when ALDACTONE is given concomitantly with these drugs. Hyperkalemia in patients with severe heart failure. Hyperkalemia may be fatal. It is critical to monitor and manage serum potassium in patients with severe heart failure receiving ALDACTONE. Avoid using other potassium-sparing diuretics. Avoid using oral potassium supplements in patients with serum potassium > 3.5 mEq/L. RALES excluded patients with a serum creatinine > 2.5 mg/dL or a recent increase in serum creatinine > 25%. The recommended monitoring for potassium and creatinine is one week after initiation or increase in dose of ALDACTONE, monthly for the first 3 months, then quarterly for a year, and then every 6 months. Discontinue or interrupt treatment for serum potassium > 5 mEq/L or for serum creatinine > 4 mg/dL. (See Clinical Studies: Severe heart failure, and Dosage and Administration: Severe heart failure.) ALDACTONE should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lithium generally should not be given with diuretics (see Precautions: Drug interactions). PRECAUTIONS General: All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance, e.g., hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hyperkalemia. 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 the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal. Consequently, no potassium supplement should ordinarily be given with ALDACTONE. If hyperkalemia is suspected (warning signs include paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock), an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes. If hyperkalemia is present, ALDACTONE should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These may include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid- acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function. Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be caused or aggravated, especially when ALDACTONE is administered in combination with other diuretics, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening. ALDACTONE therapy may cause a transient elevation of BUN, especially in patients with pre-existing renal impairment. ALDACTONE may cause mild acidosis. Gynecomastia may develop in association with the use of ALDACTONE; physicians should be alert to its possible onset. The development of gynecomastia appears to be Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda related to both dosage level and duration of therapy and is normally reversible when ALDACTONE is discontinued. In rare instances, some breast enlargement may persist when ALDACTONE is discontinued. Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined. Information for patients: Patients who receive ALDACTONE should be advised to avoid potassium supplements and foods containing high levels of potassium, including salt substitutes. Laboratory tests: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments. Drug interactions: ACE inhibitors: Concomitant administration of ACE inhibitors with potassium-sparing diuretics has been associated with severe hyperkalemia. Angiotensin II antagonists, aldosterone blockers, heparin, low molecular weight heparin, and other drugs known to cause hyperkalemia: Concomitant administration may lead to severe hyperkalemia. Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur. Pressor amines (e.g., norepinephrine): ALDACTONE reduces the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with ALDACTONE. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant may result. Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing, and thiazide diuretics. Combination of NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when ALDACTONE and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digoxin: ALDACTONE has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. It may be necessary to reduce the maintenance and digitalization doses when ALDACTONE is administered, and the patient should be carefully monitored to avoid over- or under- digitalization. Cholestyramine: Hyperkalemic metabolic acidosis has been reported in patients given ALDACTONE concurrently with cholestyramine. Drug/Laboratory test interactions: Several reports of possible interference with digoxin radioimmunoassay by ALDACTONE, or its metabolites, have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay-specific) has been fully established. Carcinogenesis, mutagenesis, impairment of fertility: Orally administered ALDACTONE has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150, and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, 100, and 150 mg ALDACTONE/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females. A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to ALDACTONE and whose primary metabolite, canrenone, is also a major product of ALDACTONE in man) for a period of one year. In two-year studies in the rat, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors. Neither ALDACTONE nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither ALDACTONE nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, ALDACTONE has been reported to be negative in some mammalian mutagenicity tests in vitro and inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others. Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg ALDACTONE/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), ALDACTONE was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two-week post-treatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility, and fecundity. ALDACTONE (100 mg/kg/day), administered i.p. to female mice during a two-week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating. Pregnancy: Teratogenic effects. Pregnancy Category C. Teratology studies with ALDACTONE have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryotoxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, ALDACTONE may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of ALDACTONE exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well- controlled studies with ALDACTONE in pregnant women. ALDACTONE has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of ALDACTONE in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus. Nursing mothers: Canrenone, a major (and active) metabolite of ALDACTONE, appears in human breast milk. Because ALDACTONE has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted. Pediatric use: Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity. Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting. Reproductive: Gynecomastia (see Precautions), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast pain. Carcinoma of the breast has been reported in patients taking ALDACTONE but a cause and effect relationship has not been established. Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia. Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis. Metabolism: Hyperkalemia, electrolyte disturbances (see Warnings and Precautions). Musculoskeletal: Leg cramps. Nervous system /psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness. Liver / biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with ALDACTONE administration. Renal: Renal dysfunction (including renal failure). Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritis. OVERDOSAGE The oral LD50 of ALDACTONE is greater than 1000 mg/kg in mice, rats, and rabbits. Acute overdosage of ALDACTONE may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function. Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, ALDACTONE should be discontinued immediately. With severe Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hyperkalemia, the clinical situation dictates the procedures to be employed. These may include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. DOSAGE AND ADMINISTRATION Primary hyperaldosteronism. ALDACTONE may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets. Long test: ALDACTONE is administered at a daily dosage of 400 mg for three to four weeks. Correction of hypokalemia and of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism. Short test: ALDACTONE is administered at a daily dosage of 400 mg for four days. If serum potassium increases during ALDACTONE administration but drops when ALDACTONE is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered. After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, ALDACTONE may be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, ALDACTONE may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient. Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). An initial daily dosage of 100 mg of ALDACTONE administered in either single or divided doses is recommended, but may range from 25 to 200 mg daily. When given as the sole agent for diuresis, ALDACTONE should be continued for at least five days at the initial dosage level, after which it may be adjusted to the optimal therapeutic or maintenance level administered in either single or divided daily doses. If, after five days, an adequate diuretic response to ALDACTONE has not occurred, a second diuretic that acts more proximally in the renal tubule may be added to the regimen. Because of the additive effect of ALDACTONE when administered concurrently with such diuretics, an enhanced diuresis usually begins on the first day of combined treatment; combined therapy is indicated when more rapid diuresis is desired. The dosage of ALDACTONE should remain unchanged when other diuretic therapy is added. Essential hypertension. For adults, an initial daily dosage of 50 to 100 mg of ALDACTONE administered in either single or divided doses is recommended. ALDACTONE may also be given with diuretics that act more proximally in the renal tubule or with other antihypertensive agents. Treatment with ALDACTONE should be continued for at least two weeks since the maximum response may not occur before this time. Subsequently, dosage should be adjusted according to the response of the patient. Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c o mpany logo Hypokalemia. ALDACTONE in a dosage ranging from 25 mg to 100 mg daily is useful in treating a diuretic-induced hypokalemia, when oral potassium supplements or other potassium-sparing regimens are considered inappropriate. Severe heart failure in conjunction with standard therapy (NYHA class III – IV). Treatment should be initiated with ALDACTONE 25 mg once daily if the patient’s serum potassium is ≤5.0 mEq/L and the patient’s serum creatinine is ≤ 2.5 mg/dL. Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily as clinically indicated. Patients who do not tolerate 25 mg once daily may have their dosage reduced to 25 mg every other day. See Warnings: Hyperkalemia in patients with severe heart failure for advice on monitoring serum potassium and serum creatinine. HOW SUPPLIED ALDACTONE 25 mg tablets are round, light yellow, film-coated, with SEARLE and 1001 debossed on one side and ALDACTONE and 25 on the other side, supplied as: NDC Number Size 0025-1001-31 bottle of 100 ALDACTONE 50 mg tablets are oval, light orange, scored, film-coated, with SEARLE and 1041 debossed on the scored side and ALDACTONE and 50 on the other side, supplied as: NDC Number Size 0025-1041-31 bottle of 100 ALDACTONE 100 mg tablets are round, peach-colored, scored, film-coated, with SEARLE and 1031 debossed on the scored side and ALDACTONE and 100 on the other side, supplied as: NDC Number Size 0025-1031-31 bottle of 100 Store below 77°F (25°C). Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LAB-0231-7.x Revised June 2013 Reference ID: 3323473 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:48.202050	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012151s071lbl.pdf', 'application_number': 12151, 'submission_type': 'SUPPL ', 'submission_number': 71}
10,797	Aldactone® spironolactone tablets, USP WARNING ALDACTONE has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). ALDACTONE should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided. DESCRIPTION ALDACTONE oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone, 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21 carboxylic acid γ-lactone acetate, which has the following structural formula: structural formula Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Inactive ingredients include calcium sulfate, corn starch, flavor, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. ACTIONS / CLINICAL PHARMACOLOGY Mechanism of action: ALDACTONE (spironolactone) is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. ALDACTONE causes increased amounts of sodium and water to be excreted, while potassium is retained. ALDACTONE acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule. Aldosterone antagonist activity: Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and nephrotic syndrome. By competing with aldosterone for receptor sites, ALDACTONE provides effective therapy for the edema and ascites in those conditions. ALDACTONE counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy. ALDACTONE is effective in lowering the systolic and diastolic blood pressure in patients with primary hyperaldosteronism. It is also effective in most cases of essential Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hypertension, despite the fact that aldosterone secretion may be within normal limits in benign essential hypertension. Through its action in antagonizing the effect of aldosterone, ALDACTONE inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss. ALDACTONE has not been demonstrated to elevate serum uric acid, to precipitate gout, or to alter carbohydrate metabolism. Pharmacokinetics: ALDACTONE is rapidly and extensively metabolized. Sulfur- containing products are the predominant metabolites and are thought to be primarily responsible, together with ALDACTONE, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (ALDACTONE film-coated tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a low-fat breakfast and blood was drawn thereafter. Accumulation Factor: 7-α-(thiomethyl) spirolactone (TMS) AUC (0-24 hr, day 15)/AUC (0-24 hr, day 1) 1.25 Mean Peak Serum Concentration 391 ng/mL at 3.2 hr Mean (SD) Post Steady- State Half-Life 13.8 hr (6.4) (terminal) 6-ß-hydroxy-7-α (thiomethyl) spirolactone (HTMS) 1.50 125 ng/mL at 5.1 hr 15.0 hr (4.0) (terminal) Canrenone (C) Spironolactone 1.41 1.30 181 ng/mL at 4.3 hr 80 ng/mL at 2.6 hr 16.5 hr (6.3) (terminal) Approximately 1.4 hr (0.5) (ß half-life) The pharmacological activity of spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively. In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile. The effect of food on spironolactone absorption (two 100 mg ALDACTONE tablets) was assessed in a single-dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known. CLINICAL STUDIES Severe heart failure: The Randomized Aldactone Evaluation Study (RALES) was a multinational, double-blind study in patients with an ejection fraction of ≤ 35%, a history of New York Heart Association (NYHA) class IV heart failure within 6 months, and class III – IV heart failure at the time of randomization. All patients were required to be taking a loop diuretic and, if tolerated, an ACE inhibitor. Patients with a baseline serum creatinine of >2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of >5.0 mEq/L were excluded. Patients were randomized 1:1 to spironolactone 25 mg orally once daily or matching placebo. Follow-up visits and laboratory measurements (including serum potassium and creatinine) were performed every four weeks for the first 12 weeks, then every 3 months for the first year, and then every 6 months thereafter. Dosing could be withheld for serious hyperkalemia or if the serum creatinine increased to >4.0 mg/dL. Patients who were intolerant of the initial dosage regimen had their dose decreased to one tablet every other day at one to four weeks. Patients who were tolerant of one tablet daily at 8 weeks may have had their dose increased to two tablets daily at the discretion of the investigator. RALES enrolled 1663 patients (3% U.S.) at 195 centers in 15 countries between March 24, 1995 and December 31, 1996. The study population was primarily white (87%, with 7% black, 2% Asian, and 4% other), male (73%), and elderly (median age 67). The median ejection fraction was 0.26. Seventy percent were NYHA class III and 29% class IV. The presumed etiology of heart failure was ischemic in 55%, and non-ischemic in 45%. There was a history of myocardial infarction in 28%, of hypertension in 24%, and of diabetes in 22%. The median baseline serum creatinine was 1.2 mg/dL and the median baseline creatinine clearance was 57 mL/min. The mean daily dose at study end for the patients randomized to spironolactone was 26 mg. Concomitant medications included a loop diuretic in 100% of patients and an ACE inhibitor in 97%. Other medications used at any time during the study included digoxin (78%), anticoagulants (58%), aspirin (43%), and beta-blockers (15%). The primary endpoint for RALES was time to all-cause mortality. RALES was terminated early, after a mean follow-up of 24 months, because of significant mortality benefit detected on a planned interim analysis. The survival curves by treatment group are shown in Figure 1. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 1. Survival by Treatment Group in RALES graph Spironolactone reduced the risk of death by 30% compared to placebo (p<0.001; 95% confidence interval 18% to 40%). Spironolactone reduced the risk of cardiac death, primarily sudden death, and death from progressive heart failure by 31% compared to placebo (p <0.001; 95% confidence interval 18% to 42%). Spironolactone also reduced the risk of hospitalization for cardiac causes (defined as worsening heart failure, angina, ventricular arrhythmias, or myocardial infarction) by 30% (p <0.001 95% confidence interval 18% to 41%). Changes in NYHA class were more favorable with spironolactone: In the spironolactone group, NYHA class at the end of the study improved in 41% of patients and worsened in 38% compared to improved in 33% and worsened in 48% in the placebo group (p <0.001). Mortality hazard ratios for some subgroups are shown in Figure 2. The favorable effect of spironolactone on mortality appeared similar for both genders and all age groups except patients younger than 55; there were too few non-whites in RALES to draw any conclusions about differential effects by race. Spironolactone’s benefit appeared greater in patients with low baseline serum potassium levels and less in patients with ejection fractions <0.2. These subgroup analyses must be interpreted cautiously. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 2. Hazard Ratios of All-Cause Mortality by Subgroup in RALES S u b g r o u p A ll A ge (yr) S ex R a c e L V E F (% ) H ear t F a i lu re N Y H A D ia bet es S er C reatin in e (m g/dL) C r C le ara n c e (m L/m in /1 .7 3 s q m ) P o t assium (m m o l /L) D ig o x i n A C E I B et a B l o c k e r L e v e l H R a n d 9 5 % C I g r aph S p i ro n o l a c t o n e b e tte r N P l aceb o b e tte r Figure 2: The size of each box is proportional to the sample size as well as the event rate. LVEF denotes left ventricular ejection fraction, Ser Creatinine denotes serum creatinine, Cr Clearance denotes creatinine clearance, and ACEI denotes angiotensin-converting enzyme inhibitor. INDICATIONS AND USAGE ALDACTONE (spironolactone) is indicated in the management of: Primary hyperaldosteronism for: Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Short-term preoperative treatment of patients with primary hyperaldosteronism. Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery. Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism). Edematous conditions for patients with: Congestive heart failure: For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures. ALDACTONE is also indicated for patients with congestive heart failure taking digitalis when other therapies are considered inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: Aldosterone levels may be exceptionally high in this condition. ALDACTONE is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. Nephrotic syndrome: For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension ALDACTONE 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. 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 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. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. Usually in combination with other drugs, ALDACTONE is indicated for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate. Hypokalemia For the treatment of patients with hypokalemia when other measures are considered inappropriate or inadequate. ALDACTONE is also indicated for the prophylaxis of hypokalemia in patients taking digitalis when other measures are considered inadequate or inappropriate. Severe heart failure (NYHA class III – IV) To increase survival, and to reduce the need for hospitalization for heart failure when used in addition to standard therapy. Usage in Pregnancy. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. ALDACTONE is indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Precautions: Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda this edema may cause extreme discomfort that is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate. CONTRAINDICATIONS ALDACTONE is contraindicated for patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, hyperkalemia, Addison’s disease, and with concomitant use of eplerenone. WARNINGS Potassium supplementation. Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with ALDACTONE therapy. Excessive potassium intake may cause hyperkalemia in patients receiving ALDACTONE (see Precautions: General). Concomitant administration of ALDACTONE with the following drugs or potassium sources may lead to severe hyperkalemia: • other potassium-sparing diuretics • ACE inhibitors • angiotensin II antagonists • aldosterone blockers • non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin • heparin and low molecular weight heparin • other drugs or conditions known to cause hyperkalemia • potassium supplements • diet rich in potassium • salt substitutes containing potassium ALDACTONE should not be administered concurrently with other potassium-sparing diuretics. ALDACTONE, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when ALDACTONE is given concomitantly with these drugs. Hyperkalemia in patients with severe heart failure. Hyperkalemia may be fatal. It is critical to monitor and manage serum potassium in patients with severe heart failure receiving ALDACTONE. Avoid using other potassium-sparing diuretics. Avoid using oral potassium supplements in patients with serum potassium > 3.5 mEq/L. RALES excluded patients with a serum creatinine > 2.5 mg/dL or a recent increase in serum creatinine > 25%. The recommended monitoring for potassium and creatinine is one week after initiation or increase in dose of ALDACTONE, monthly for the first 3 months, then quarterly for a year, and then every 6 months. Discontinue or interrupt treatment for serum potassium > 5 mEq/L or for serum creatinine > 4 mg/dL. (See Clinical Studies: Severe heart failure, and Dosage and Administration: Severe heart failure.) ALDACTONE should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lithium generally should not be given with diuretics (see Precautions: Drug interactions). PRECAUTIONS General: All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance, e.g., hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hyperkalemia. 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 the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal. Consequently, no potassium supplement should ordinarily be given with ALDACTONE. If hyperkalemia is suspected (warning signs include paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock), an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes. If hyperkalemia is present, ALDACTONE should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These may include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid- acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function. Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be caused or aggravated, especially when ALDACTONE is administered in combination with other diuretics, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening. ALDACTONE therapy may cause a transient elevation of BUN, especially in patients with pre-existing renal impairment. ALDACTONE may cause mild acidosis. Gynecomastia may develop in association with the use of ALDACTONE; physicians should be alert to its possible onset. The development of gynecomastia appears to be Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda related to both dosage level and duration of therapy and is normally reversible when ALDACTONE is discontinued. In rare instances, some breast enlargement may persist when ALDACTONE is discontinued. Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined. Information for patients: Patients who receive ALDACTONE should be advised to avoid potassium supplements and foods containing high levels of potassium, including salt substitutes. Laboratory tests: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments. Drug interactions: ACE inhibitors: Concomitant administration of ACE inhibitors with potassium-sparing diuretics has been associated with severe hyperkalemia. Angiotensin II antagonists, aldosterone blockers, heparin, low molecular weight heparin, and other drugs known to cause hyperkalemia: Concomitant administration may lead to severe hyperkalemia. Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur. Pressor amines (e.g., norepinephrine): ALDACTONE reduces the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with ALDACTONE. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant may result. Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing, and thiazide diuretics. Combination of NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when ALDACTONE and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digoxin: ALDACTONE has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. It may be necessary to reduce the maintenance and digitalization doses when ALDACTONE is administered, and the patient should be carefully monitored to avoid over- or under- digitalization. Cholestyramine: Hyperkalemic metabolic acidosis has been reported in patients given ALDACTONE concurrently with cholestyramine. Drug/Laboratory test interactions: Several reports of possible interference with digoxin radioimmunoassay by ALDACTONE, or its metabolites, have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay-specific) has been fully established. Carcinogenesis, mutagenesis, impairment of fertility: Orally administered ALDACTONE has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150, and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, 100, and 150 mg ALDACTONE/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females. A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to ALDACTONE and whose primary metabolite, canrenone, is also a major product of ALDACTONE in man) for a period of one year. In two-year studies in the rat, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors. Neither ALDACTONE nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither ALDACTONE nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, ALDACTONE has been reported to be negative in some mammalian mutagenicity tests in vitro and inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg ALDACTONE/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), ALDACTONE was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two-week post-treatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility, and fecundity. ALDACTONE (100 mg/kg/day), administered i.p. to female mice during a two-week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating. Pregnancy: Teratogenic effects. Pregnancy Category C. Teratology studies with ALDACTONE have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryotoxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, ALDACTONE may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of ALDACTONE exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well- controlled studies with ALDACTONE in pregnant women. ALDACTONE has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of ALDACTONE in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus. Nursing mothers: Canrenone, a major (and active) metabolite of ALDACTONE, appears in human breast milk. Because ALDACTONE has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted. Pediatric use: Safety and effectiveness in pediatric patients have not been established. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity. Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting. Reproductive: Gynecomastia (see Precautions), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast pain. Carcinoma of the breast has been reported in patients taking ALDACTONE but a cause and effect relationship has not been established. Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia. Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis. Metabolism: Hyperkalemia, electrolyte disturbances (see Warnings and Precautions). Musculoskeletal: Leg cramps. Nervous system /psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness. Liver / biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with ALDACTONE administration. Renal: Renal dysfunction (including renal failure). Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritis. OVERDOSAGE The oral LD50 of ALDACTONE is greater than 1000 mg/kg in mice, rats, and rabbits. Acute overdosage of ALDACTONE may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function. Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, ALDACTONE should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These may include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. DOSAGE AND ADMINISTRATION Primary hyperaldosteronism. ALDACTONE may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets. Long test: ALDACTONE is administered at a daily dosage of 400 mg for three to four weeks. Correction of hypokalemia and of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism. Short test: ALDACTONE is administered at a daily dosage of 400 mg for four days. If serum potassium increases during ALDACTONE administration but drops when ALDACTONE is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered. After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, ALDACTONE may be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, ALDACTONE may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient. Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). An initial daily dosage of 100 mg of ALDACTONE administered in either single or divided doses is recommended, but may range from 25 to 200 mg daily. When given as the sole agent for diuresis, ALDACTONE should be continued for at least five days at the initial dosage level, after which it may be adjusted to the optimal therapeutic or maintenance level administered in either single or divided daily doses. If, after five days, an adequate diuretic response to ALDACTONE has not occurred, a second diuretic that acts more proximally in the renal tubule may be added to the regimen. Because of the additive effect of ALDACTONE when administered concurrently with such diuretics, an enhanced diuresis usually begins on the first day of combined treatment; combined therapy is indicated when more rapid diuresis is desired. The dosage of ALDACTONE should remain unchanged when other diuretic therapy is added. Essential hypertension. For adults, an initial daily dosage of 50 to 100 mg of ALDACTONE administered in either single or divided doses is recommended. ALDACTONE may also be given with diuretics that act more proximally in the renal tubule or with other antihypertensive agents. Treatment with ALDACTONE should be Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda continued for at least two weeks since the maximum response may not occur before this time. Subsequently, dosage should be adjusted according to the response of the patient. Hypokalemia. ALDACTONE in a dosage ranging from 25 mg to 100 mg daily is useful in treating a diuretic-induced hypokalemia, when oral potassium supplements or other potassium-sparing regimens are considered inappropriate. Severe heart failure in conjunction with standard therapy (NYHA class III – IV). Treatment should be initiated with ALDACTONE 25 mg once daily if the patient’s serum potassium is ≤5.0 mEq/L and the patient’s serum creatinine is ≤ 2.5 mg/dL. Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily as clinically indicated. Patients who do not tolerate 25 mg once daily may have their dosage reduced to 25 mg every other day. See Warnings: Hyperkalemia in patients with severe heart failure for advice on monitoring serum potassium and serum creatinine. HOW SUPPLIED ALDACTONE 25 mg tablets are round, light yellow, film-coated, with SEARLE and 1001 debossed on one side and ALDACTONE and 25 on the other side, supplied as: NDC Number Size 0025-1001-31 bottle of 100 ALDACTONE 50 mg tablets are oval, light orange, scored, film-coated, with SEARLE and 1041 debossed on the scored side and ALDACTONE and 50 on the other side, supplied as: NDC Number Size 0025-1041-31 bottle of 100 ALDACTONE 100 mg tablets are round, peach-colored, scored, film-coated, with SEARLE and 1031 debossed on the scored side and ALDACTONE and 100 on the other side, supplied as: NDC Number Size 0025-1031-31 bottle of 100 Store below 77°F (25°C). Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LAB-0231-8.x Revised Month 2014 Reference ID: 3646990 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:48.280282	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/012151s072lbl.pdf', 'application_number': 12151, 'submission_type': 'SUPPL ', 'submission_number': 72}
10,798	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLUOROURACIL injection safely and effectively. See full prescribing information for FLUOROURACIL injection. FLUOROURACIL injection, for intravenous use Initial U.S. Approval: 1962 ---------------------------- RECENT MAJOR CHANGES ------------------ Dosage and Administration (2) 07/2016 ---------------------------- INDICATIONS AND USAGE -------------------- Fluorouracil is a nucleoside metabolic inhibitor indicated for the treatment of patients with  Adenocarcinoma of the Colon and Rectum (1.1)  Adenocarcinoma of the Breast (1.2)  Gastric Adenocarcinoma (1.3)  Pancreatic Adenocarcinoma (1.4) ----------------------- DOSAGE AND ADMINISTRATION ---------------  Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous infusion. (2.1)  See Full Prescribing Information for dose individualization (2.1) and dose modifications due to adverse reactions (2.6)  See Full Prescribing Information for recommended doses of fluorouracil for adenocarcinoma of the colon and rectum (2.2) and for recommended doses of fluorouracil as a component of a chemotherapy regimen for adenocarcinoma of the breast (2.3), gastric adenocarcinoma (2.4), pancreatic adenocarcinoma (2.5)  Pharmacy Bulk Package: Prepare doses for more than one patient in a Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs. Do not inject entire contents of vial directly into patients. Use within 4 hours of puncture (2.7, 2.8) ---------------------- DOSAGE FORMS AND STRENGTHS ------------- Injection: 2.5 g in a 50 mL vial in a pharmacy bulk package (3) ------------------------------- CONTRAINDICATIONS --------------------- None (4) ------------------------- WARNINGS AND PRECAUTIONS ------------------  Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase Activity: Withhold or permanently discontinue fluorouracil in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of dipyrimidine dehydrogenase (DPD) activity. No fluorouracil dose has been proven safe in patients with absent DPD activity. (5.1)  Cardiotoxicity: Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure. Withhold fluorouracil for cardiac toxicity. (5.2)  Hyperammonemic Encephalopathy: Altered mental status, confusion, disorientation, coma, or ataxia with elevated serum ammonia level can occur within 72 hours of initiation of fluorouracil. Withhold fluorouracil and initiate ammonia-lowering therapy. (5.3)  Neurologic Toxicity: Fluorouracil can cause acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. (5.4)  Diarrhea: Fluorouracil can cause severe diarrhea. Withhold fluorouracil for severe diarrhea until resolved. (5.5)  Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome): Fluorouracil can cause hand-foot syndrome. If severe, discontinue fluorouracil until resolved or decreased to Grade 1, then resume at a reduced dose. (5.6)  Myelosuppression: Fluorouracil can cause severe and fatal myelosuppression. Withhold fluorouracil until severe myelosuppression resolves, then resume at a reduced dose. (5.7)  Mucositis: Fluorouracil can cause severe mucositis. Discontinue fluorouracil until resolved or decreased to Grade 1, then resume at a reduced dose. (5.8)  Increased Risk of Elevated INR with Warfarin: Concurrent administration with warfarin can result in clinically significant increases in coagulation parameters: Closely monitor INR and prothrombin time. (5.9)  Embryofetal Toxicity: Fluorouracil can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus. (5.10, 8.1, 8.6) ------------------------------ADVERSE REACTIONS ----------------------- To report SUSPECTED ADVERSE REACTIONS, contact Spectrum Pharmaceuticals, Inc. at 1-888-292-9617 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ----------------------- USE IN SPECIFIC POPULATIONS ---------------  Nursing Mothers: Discontinue drug or discontinue nursing. (8.3)  Females and Males of Reproductive Potential: Provide pregnancy planning and prevention counseling. (5.10, 8.1, 8.6) See 17 for PATIENT COUNSELING INFORMATION Revised: 07/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Adenocarcinoma of the Colon and Rectum 1.2 Adenocarcinoma of the Breast 1.3 Gastric Adenocarcinoma 1.4 Pancreatic Adenocarcinoma 2 DOSAGE AND ADMINISTRATION 2.1 General Dosage Information 2.2 Recommended Dosage for Adenocarcinoma of the Colon and Rectum 2.3 Recommended Dosage for Adenocarcinoma of the Breast 2.4 Recommended Dosage for Gastric Adenocarcinoma 2.5 Recommended Dosage for Pancreatic Adenocarcinoma 2.6 Dose Modifications 2.7 Preparation for Administration 2.8 Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase (DPD) Activity 5.2 Cardiotoxicity 5.3 Hyperammonemic Encephalopathy 5.4 Neurologic Toxicity 5.5 Diarrhea 5.6 Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome) 5.7 Myelosuppression 5.8 Mucositis 5.9 Increased Risk of Elevated International Normalized Ratio (INR) with Warfarin 5.10 Embryofetal Toxicity 6 ADVERSE REACTIONS 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Anticoagulants and CYP 2C9 Substrates 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Females and Males of Reproductive Potential 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3965252 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 Fluorouracil is indicated for the treatment of patients with: 1.1 Adenocarcinoma of the Colon and Rectum 1.2 Adenocarcinoma of the Breast 1.3 Gastric Adenocarcinoma 1.4 Pancreatic Adenocarcinoma 2 DOSAGE AND ADMINISTRATION 2.1 General Dosage Information Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous infusion. Do not inject the entire contents of the vial directly into patients. Individualize the dose and dosing schedule of fluorouracil based on tumor type, the specific regimen administered, disease state, response to treatment, and patient risk factors. 2.2 Recommended Dosage for Adenocarcinoma of the Colon and Rectum  The recommended dose of fluorouracil, administered in an infusional regimen in combination with leucovorin alone, or in combination with leucovorin and oxaliplatin or irinotecan, is 400 mg/m2 by intravenous bolus on Day 1, followed by 2400 mg/m2 to 3000 mg/m2 intravenously as a continuous infusion over 46 hours every two weeks.  The recommended dose of fluorouracil, if administered in a bolus dosing regimen in combination with leucovorin, is 500 mg/m2 by intravenous bolus on Days 1, 8, 15, 22, 29, and 36 in 8-week cycles. 2.3 Recommended Dosage for Adenocarcinoma of the Breast  The recommended dose of fluorouracil, administered as a component of a cyclophosphamide-based multidrug regimen, is 500 mg/m2 or 600 mg/m2 intravenously on Days 1 and 8 every 28 days for 6 cycles. 2.4 Recommended Dosage for Gastric Adenocarcinoma  The recommended dose of fluorouracil, administered as a component of a platinum-containing multidrug chemotherapy regimen, is 200 mg/m2 to 1000 mg/m2 intravenously as a continuous infusion over 24 hours. The frequency of dosing in each cycle and the length of each cycle will depend on the dose of fluorouracil and the specific regimen administered. 2.5 Recommended Dosage for Pancreatic Adenocarcinoma  The recommended dose of fluorouracil, administered as an infusional regimen in combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin, is 400 mg/m2 intravenous bolus on Day 1, followed by 2400 mg/m2 intravenously as a continuous infusion over 46 hours every two weeks. 2.6 Dose Modifications Withhold fluorouracil for any of the following:  Development of angina, myocardial infarction/ischemia, arrhythmia, or heart failure in patients with no history of coronary artery disease or myocardial dysfunction [see Warnings and Precautions (5.2)]  Hyperammonemic encephalopathy [see Warnings and Precautions (5.3)]  Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances [see Warnings and Precautions (5.4)]  Grade 3 or 4 diarrhea [see Warnings and Precautions (5.5)]  Grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions (5.6)]  Grade 3 or 4 mucositis [see Warnings and Precautions (5.8)]  Grade 4 myelosuppression [see Warnings and Precautions (5.7)] Upon resolution or improvement to Grade 1 diarrhea, mucositis, myelosuppression, or palmar-plantar erythrodysesthesia, resume fluorouracil administration at a reduced dose. There is no recommended dose for resumption of fluorouracil administration following development of any of the following adverse reactions:  Cardiac toxicity  Hyperammonemic encephalopathy Reference ID: 3965252 Page 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances 2.7 Preparation for Administration Fluorouracil is supplied in a pharmacy bulk package consisting of a vial. The pharmacy bulk package can be used to prepare doses for more than one patient. It is not supplied with a sterile transfer device, which is required for dispensing when multiple doses will be prepared from the single vial. The 50 mL vial is only intended for preparation in a Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs [see References (15)]. Store vial at room temperature. Using aseptic conditions, penetrate the container closure once with a suitable sterile transfer device or dispensing set that allows measured distribution of the contents. Record the date and time the vial was opened on the vial label. Discard the pharmacy bulk package 4 hours after penetration of the container closure. Withdraw the calculated dose for an individual patient into a sterile syringe. Inspect the solution in syringe for particulate matter and discoloration prior to administration or further dilution. Discard syringe if the solution is discolored or contains particulate matter. 2.8 Administration Do not administer in the same intravenous line concomitantly with other medicinal products. For bolus administration, store undiluted fluorouracil in the syringe for up to 4 hours at room temperature (25°C). Administer fluorouracil as an intravenous bolus through an established intravenous line. Store diluted solutions of fluorouracil for up to 4 hours at room temperature (25°C) prior to administration to the patient. For intravenous infusion regimens, administer through a central venous line using an infusion pump. 3 DOSAGE FORMS AND STRENGTHS Fluorouracil injection is supplied as a pharmacy bulk package as a vial containing 2.5 g/50 mL (50 mg/mL) fluorouracil. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase (DPD) Activity Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No fluorouracil dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test. 5.2 Cardiotoxicity Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure, based on postmarketing reports. Reported risk factors for cardiotoxicity are administration by continuous infusion rather than intravenous bolus and presence of coronary artery disease. Withhold fluorouracil for cardiotoxicity. The risks of resumption of fluorouracil in patients with cardiotoxicity that has resolved have not been established. 5.3 Hyperammonemic Encephalopathy Fluorouracil can cause hyperammonemic encephalopathy in the absence of liver disease or other identifiable cause, based on postmarketing reports. Signs or symptoms of hyperammonemic encephalopathy began within 72 hours after initiation of fluorouracil infusion; these included altered mental status, confusion, disorientation, coma, or ataxia, in the presence of concomitant elevated serum ammonia level. Withhold fluorouracil for hyperammonemic encephalopathy and initiate ammonia-lowering therapy. The risks of resumption of fluorouracil in patients with hyperammonemic encephalopathy that has resolved have not been Reference ID: 3965252 Page 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda established. 5.4 Neurologic Toxicity Fluorouracil can cause neurologic toxicity, including acute cerebellar syndrome and other neurologic events, based on postmarketing reports. Neurologic symptoms included confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. There are insufficient data on the risks of resumption of fluorouracil in patients with neurologic toxicity that has resolved. 5.5 Diarrhea Fluorouracil can cause severe diarrhea. Withhold fluorouracil for Grade 3 or 4 diarrhea until resolved or decreased in intensity to Grade 1, then resume fluorouracil at a reduced dose. Administer fluids, electrolyte replacement, or antidiarrheal treatments as necessary. 5.6 Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome) Fluorouracil can cause palmar-plantar erythrodysesthesia, also known as hand-foot syndrome (HFS). Symptoms of HFS include a tingling sensation, pain, swelling, and erythema with tenderness, and desquamation. HFS occurs more commonly when fluorouracil is administered as a continuous infusion than when fluorouracil is administered as a bolus injection, and has been reported to occur more frequently in patients with previous exposure to chemotherapy. HFS is generally observed after 8-9 weeks of fluorouracil administration but may occur earlier. Institute supportive measures for symptomatic relief of HFS. Withhold fluorouracil administration for Grade 2 or 3 HFS; resume fluorouracil at a reduced dose when HFS is completely resolved or decreased in severity to Grade 1. 5.7 Myelosuppression Fluorouracil can cause severe and fatal myelosuppression which may include neutropenia, thrombocytopenia, and anemia. The nadir in neutrophil counts commonly occurs between 9 and 14 days after fluorouracil administration. Obtain complete blood counts prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as needed. Withhold fluorouracil until Grade 4 myelosuppression resolves; resume fluorouracil at a reduced dose when myelosuppression has resolved or improved to Grade 1 in severity. 5.8 Mucositis Mucositis, stomatitis or esophagopharyngitis, which may lead to mucosal sloughing or ulceration, can occur with fluorouracil. The incidence is reported to be higher with administration of fluorouracil by intravenous bolus compared with administration by continuous infusion. Withhold fluorouracil administration for Grade 3 or 4 mucositis; resume fluorouracil at a reduced dose once mucositis has resolved or decreased in severity to Grade 1. 5.9 Increased Risk of Elevated International Normalized Ratio (INR) with Warfarin Clinically significant elevations in coagulation parameters have been reported during concomitant use of warfarin and fluorouracil. Closely monitor patients receiving concomitant coumarin-derivative anticoagulants such as warfarin for INR or prothrombin time in order to adjust the anticoagulant dose accordingly [see Drug Interactions (7)]. 5.10 Embryofetal Toxicity Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant woman. In animal studies, administration of fluorouracil at doses lower than a human dose of 12 mg/kg caused teratogenicity. 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 hazard to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 3 months following cessation of therapy with fluorouracil [see Use in Specific Populations (8.1, 8.6), Clinical Pharmacology (12.1), and Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling:  Increased risk of serious or fatal adverse reactions in patients with low or absent dipyrimidine dehydrogenase activity [see Warnings and Precautions (5.1)]  Cardiotoxicity [see Warnings and Precautions (5.2)]  Hyperammonemic encephalopathy [see Warnings and Precautions (5.3)]  Neurologic toxicity [see Warnings and Precautions (5.4)] Reference ID: 3965252 Page 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Diarrhea [see Warnings and Precautions (5.5)]  Palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions (5.6)]  Myelosuppression [see Warnings and Precautions (5.7)]  Mucositis [see Warnings and Precautions (5.8)]  Increased risk of elevated INR when administrated with warfarin [see Warnings and Precautions (5.9)] 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fluorouracil. 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. Hematologic: pancytopenia [see Warnings and Precautions (5.7)] Gastrointestinal: gastrointestinal ulceration, nausea, vomiting Allergic Reactions: anaphylaxis and generalized allergic reactions Neurologic: nystagmus, headache Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or increased pigmentation of the skin; vein pigmentation Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia Psychiatric: euphoria Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails) 7 DRUG INTERACTIONS 7.1 Anticoagulants and CYP 2C9 Substrates Elevated coagulation times have been reported in patients taking fluorouracil concomitantly with warfarin. While pharmacokinetic data are not available to assess the effect of fluorouracil administration on warfarin pharmacokinetics, the elevation of coagulation times that occurs with the fluorouracil prodrug capecitabine is accompanied by an increase in warfarin concentrations. Thus, the interaction may be due to inhibition of cytochrome P450 2C9 by fluorouracil or its metabolites. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies with fluorouracil in pregnant women. Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant woman. Administration of fluorouracil to rats and mice during selected periods of organogenesis, at doses lower than a human dose of 12 mg/kg, caused embryolethality and teratogenicity. Malformations included cleft palate and skeletal defects. In monkeys, maternal doses of fluorouracil higher than an approximate human dose of 12 mg/kg resulted in abortion. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Clinical Pharmacology (12.1)]. Animal Data Malformations including cleft palate, skeletal defects and deformed appendages (paws and tails) were observed when fluorouracil was administered by intraperitoneal injection to mice at doses at or above 10 mg/kg (approximately 0.06 times a human dose of 12 mg/kg on a mg/m2 basis) for 4 days during the period of organogenesis. Similar results were observed in hamsters administered fluorouracil intramuscularly at doses lower than those administered in commonly used clinical treatment regimens. In rats, administration of fluorouracil by intraperitoneal injection at doses greater than 15 mg/kg (approximately 0.2 times a human dose of 12 mg/kg on a mg/m2 basis) for a single day during organogenesis resulted in delays in growth and malformations including micro anophthalmos. In monkeys, administration of fluorouracil during organogenesis at doses approximately equal to a human dose of 12 mg/kg on a mg/m2 basis resulted in abortion; at a 50% lower dose, resorptions and decreased fetal body weights were reported. 8.3 Nursing Mothers It is not known whether fluorouracil or its metabolites are present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from fluorouracil, 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. Reference ID: 3965252 Page 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda s t r uctural formula 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Reported clinical experience has not identified differences in safety or effectiveness between the elderly and younger patients. 8.6 Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with fluorouracil and for up to 3 months following cessation of therapy [see Use in Specific Populations (8.1)]. Males Fluorouracil may damage spermatozoa. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months following cessation of therapy with fluorouracil [see Nonclinical Toxicology (13.1)]. Infertility Females Advise females of reproductive potential that, based on animal data, fertility may be impaired while receiving fluorouracil [see Nonclinical Toxicology (13.1)]. Males Advise males of reproductive potential that, based on animal data, fertility may be impaired while receiving fluorouracil [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE Administer uridine triacetate within 96 hours following the end of fluorouracil infusion for management of fluorouracil overdose. 11 DESCRIPTION Fluorouracil injection, a nucleoside metabolic inhibitor, is a colorless to faint yellow, aqueous, sterile, nonpyrogenic injectable solution available in a pharmacy bulk package, a sterile preparation that contains doses for multiple patients for intravenous administration. Each mL contains 50 mg fluorouracil in water for injection, USP. The pH is adjusted to approximately 9.2 with sodium hydroxide. Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. Its structural formula is: Molecular weight: 130.08 g/mole 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fluorouracil is a nucleoside metabolic inhibitor that interferes with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA); these affect rapidly growing cells and may lead to cell death. Fluorouracil is converted to three main active metabolites: 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), 5-fluorouridine-5′ triphosphate (FUTP) and 5-fluoro-2′-deoxyuridine-5′-triphosphate (FdUTP). These metabolites have several effects including the inhibition of thymidylate synthase by FdUMP, incorporation of FUTP into RNA and incorporation of FdUTP into DNA. 12.3 Pharmacokinetics Distribution Following bolus intravenous injection, fluorouracil distributes throughout the body including the intestinal mucosa, bone marrow, Reference ID: 3965252 Page 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda liver, cerebrospinal fluid and brain tissue. Elimination Following bolus intravenous injection, 5 – 20 % of the parent drug is excreted unchanged in the urine in six hours. The remaining percentage of the administered dose is metabolized, primarily in the liver. The metabolites of fluorouracil (e.g., urea and α-fluoro-ß alanine) are excreted in the urine over 3 to 4 hours. Following bolus intravenous injection of fluorouracil, as a single agent, the elimination half-life increased with dose from 8 to 20 minutes. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with fluorouracil. Fluorouracil was mutagenic in vitro in the bacterial reverse mutation (Ames) assay and induced chromosomal aberrations in hamster fibroblasts in vitro and in mouse bone marrow in the in vivo mouse micronucleus assay. Administration of fluorouracil intraperitoneally to male rats at dose levels equal to or greater than 1.7-fold the human dose of 12 mg/kg induced chromosomal aberrations in spermatogonia and inhibition of spermatogonia differentiation resulting in transient infertility. In female rats, intraperitoneal administration of fluorouracil during the pre-ovulatory phases of oogenesis at dose levels equal to or greater than 0.33 times a human dose of 12 mg/kg resulted in decreased incidence of fertile matings, increased pre- implantation loss, and fetotoxicity. 15 REFERENCES "OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fluorouracil injection is supplied in a pharmacy bulk package available in a box containing one vial, as listed below:  NDC 68152-106-06: one box with one vial, containing 2.5 g/50 mL (50 mg/mL) fluorouracil 16.2 Storage Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use. Fluorouracil is a cytotoxic drug. Follow applicable special handling and disposable procedures [see References (15)]. 17 PATIENT COUNSELING INFORMATION Advise:  Patients to notify their healthcare provider if they have a known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity, they are at an increased risk of severe and life-threatening mucositis, diarrhea, neutropenia and neurotoxicity [see Warnings and Precautions (5.1)].  Patients of the risk of cardiotoxicity. Advise patients to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.2)].  Patients to immediately contact their healthcare provider or go to an emergency room for new onset of confusion, disorientation, or otherwise altered mental status; difficulty with balance or coordination; or visual disturbances [see Warnings and Precautions (5.3, 5.4)].  Patients to contact their healthcare provider for severe diarrhea or for painful mouth sores with decreased oral intake of food or fluids [see Warnings and Precautions (5.5, 5.8)].  Patients to contact their healthcare provider for tingling or burning, redness, flaking, swelling, blisters, or sores on the palms of their hands or soles of their feet [see Warnings and Precautions (5.6)].  Patients of the importance of keeping appointments for blood tests. Instruct patients to monitor their temperature on a daily basis and to immediately contact their healthcare provider for fever or other signs of infection [see Warnings and Precautions (5.7)].  Patients to notify their healthcare provider of all drugs they are taking, including warfarin or other coumarin-derivative anticoagulants. Advise patients of the importance of keeping appointments for blood tests [see Warnings and Reference ID: 3965252 Page 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Precautions (5.9)].  Females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with fluorouracil and for up to 3 months after the last dose of fluorouracil. Instruct female patients to contact their healthcare provider if they become pregnant, if pregnancy occurs during fluorouracil treatment or during the 3 months following the last dose [see Warnings and Precautions (5.10), Use in Specific Populations (8.1 and 8.6), and Nonclinical Toxicology (13.1)].  Females and males of reproductive potential may have impaired fertility while receiving fluorouracil, based on animal data [see Use in Specific Populations (8.6) and Nonclinical Toxicology (13.1)].  Nursing mothers to discontinue nursing [see Use in Specific Populations (8.3)]. Fluorouracil injection Manufactured for: Spectrum Pharmaceuticals, Inc. Irvine, CA 92618 Reference ID: 3965252 Page 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:48.430260	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012209s040lbl.pdf', 'application_number': 12209, 'submission_type': 'SUPPL ', 'submission_number': 40}
10,799	NDC 0409-1036-30 30 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 1% STERILE INJECTION NDC 0409-1036-30 C-400 30 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 1% STERILE INJECTION For PERIPHERAL NERVE BLOCK, CAUDAL, EPIDURAL, and INFILTRATION ANESTHESIA Not for spinal anesthesia. Not intended for dental use. only NDC 0409-1036-30 30 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 1% STERILE INJECTION NDC 0409-1036-30 30 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 1% STERILE INJECTION Dosage: See package insert. No preservative added. Discard unused portion after initial use. Vial may be autoclaved. ©Hospira 2005 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA TEST-2 (01) 0 030409 103630 7 Each mL contains 10 mg mepivacaine hydrochloride, 6.6 mg sodium chloride, 0.3 mg potassium chloride, and 0.33 mg calcium chloride in Water for Injection. pH adjusted with NaOH or HCl. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] NSN 6505-00-754-0076 ---------- ----------------------------- ---- ------- ------------------------------------------ ---------------------- ---- ------ ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ------ -- -------- -------- ------- ----- --- PRESERVATIVE-FREE PRESERVATIVE-FREE PRESERVATIVE-FREE PRESERVATIVE-FREE ------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) TEST-1 (01) 0 030409 103850 9 ----------------------------- ---- ------- ------------------------------------------ ---------------------- ---- ------ ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ------ -- -------- -------- ------- ----- --- --------------- NDC 0409-1038-50 50 mL Multiple-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 1% STERILE INJECTION Each mL contains 10 mg mepivacaine hydrochloride, 7 mg sodium chloride, and 1 mg methylparaben as preservative in Water for Injection. pH adjusted with NaOH or HCl. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] NSN 6505-00-754-0085 ©Hospira 2005 Printed in USA Hospira, Inc. Lake Forest, IL 60045 USA NDC 0409-1038-50 50 mL Multiple-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 1% STERILE INJECTION NDC 0409-1038-50 C-390 50 mL Multiple-Dose Vial Carbocaine® mepivacaine hydrochloride injection, USP 1% STERILE INJECTION For INFILTRATION and PERIPHERAL NERVE BLOCK only Not for epidural, caudal, or spinal anesthesia. Not intended for dental use. only NDC 0409-1038-50 50 mL Multiple-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 1% STERILE INJECTION Dosage: See package insert. Vial may be autoclaved. ------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) TEST-3 (01) 0 030409 104130 1 ----------------------------- ---- ------- ------------------------------------------ ---------------------- ---- ------ ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- - ------ -------- -------- -------- ----- --- --------------- NDC 0409-1041-30 30 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP STERILE INJECTION 1.5% Each mL contains 15 mg mepivacaine hydrochloride, 5.6 mg sodium chloride, 0.3 mg potassium chloride, and 0.33 mg calcium chloride in Water for Injection. pH adjusted with NaOH or HCl. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] NSN 6505-00-914-1742 ©Hospira 2005 Printed in USA Hospira, Inc. Lake Forest, IL 60045 USA NDC 0409-1041-30 30 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP STERILE INJECTION 1.5% NDC 0409-1041-30 C-430 30 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP STERILE INJECTION For PERIPHERAL NERVE BLOCK, CAUDAL and EPIDURAL ANESTHESIA Not for spinal anesthesia. Not intended for dental use. 1.5% NDC 0409-1041-30 30 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP STERILE INJECTION 1.5% Dosage: See package insert. No preservative added. Discard unused portion after initial use. Vial may be autoclaved. only PRESERVATIVE-FREE PRESERVATIVE-FREE PRESERVATIVE-FREE PRESERVATIVE-FREE ------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) NDC 0409-1067-20 20 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP STERILE INJECTION NDC 0409-1067-20 C-440 20 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP STERILE INJECTION For PERIPHERAL NERVE BLOCK, CAUDAL and EPIDURAL ANESTHESIA Not for spinal anesthesia. Not intended for dental use. only Each mL contains 20 mg mepivacaine hydrochloride, 4.6 mg sodium chloride, 0.3 mg potassium chloride, and 0.33 mg calcium chloride in Water for Injection. pH adjusted with NaOH or HCl. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] NSN 6505-00-727-3207 NDC 0409-1067-20 20 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP STERILE INJECTION NDC 0409-1067-20 20 mL Single-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP STERILE INJECTION Dosage: See package insert. No preservative added. Discard unused portion after initial use. Vial may be autoclaved. ©Hospira 2005 Printed in USA Hospira, Inc. Lake Forest, IL 60045 USA (01) 0 030409 106720 2 TEST-4 2% 2% 2% 2% ___________ ____ ________ _______________________ __________ ___ _____ ______________ _______________ _______________ ___ ____ ________ __________ __ ________ __ ____ ___ ____ ____ _____ __ _______ ___ _____ PRESERVATIVE-FREE PRESERVATIVE-FREE PRESERVATIVE-FREE PRESERVATIVE-FREE (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) TEST-5 (01) 0 030409 204750 0 ----------------------------- ---- ------- ------------------------------------------ ---------------------- ---- ------ ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ------ -- -------- -------- --- ----- --- --------------- NDC 0409-2047-50 50 mL Multiple-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 2% STERILE INJECTION NDC 0409-2047-50 50 mL Multiple-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 2% STERILE INJECTION NDC 0409-2047-50 C-410 50 mL Multiple-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 2% STERILE INJECTION NDC 0409-2047-50 50 mL Multiple-Dose Vial Carbocaine ® mepivacaine hydrochloride injection, USP 2% STERILE INJECTION Each mL contains 20 mg mepivacaine hydrochloride, 5 mg sodium chloride, and 1 mg methylparaben as preservative in Water for Injection. pH adjusted with NaOH or HCI. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] ©Hospira 2005 Printed in USA Hospira, Inc. Lake Forest, IL 60045 USA For PERIPHERAL NERVE BLOCK only Not for epidural, caudal infiltration, or spinal anesthesia. Not intended for dental use. only Dosage: See package insert. Vial may be autoclaved. ------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) 30 mL SINGLE-DOSE VIAL–STERILE INJECTION C-400 Carbocaine ® 1% mepivacaine hydrochloride injection, USP For PERIPHERAL NERVE BLOCK, CAUDAL, EPIDURAL, and INFILTRATION ANESTHESIA Not for Spinal Anesthesia. Not intended for dental use. NDC 0409-1036-30 (01) 0 030409 103630 7 ------------- - -------- Hospira, Inc., Lake Forest, IL 60045 USA ----------------------------------- --------------- ----- -------- --------------------- --------------------- ----------------------- ------------- --------------- ---- ------------- --- ------- ----- ------ -------- -------- --- ------- ----- -------- --------------- only TEST-8 Each mL contains 10 mg mepivacaine HCl, 6.6 mg sodium chloride, 0.3 mg potassium chloride, and 0.33 mg calcium chloride in Water for Injection. pH adjusted with NaOH or HCl. No preservative added. Dosage: See package insert. Vial may be autoclaved. Discard unused portion after initial use. ©Hospira 2005 Printed in USA PRESERVATIVE-FREE ------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) 50 mL MULTIPLE-DOSE VIAL – STERILE INJECTION NDC 0409-1038-50 C-390 HOSPIRA, INC., LAKE FOREST, IL 60045 USA For INFILTRATION and PERIPHERAL NERVE BLOCK Only Not for epidural, caudal, or spinal anesthesia. Not intended for dental use. ©Hospira 2005 Printed in USA (01) 0 030409 103850 9 TEST-6 ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ------------- --------------- ---- ------------- --- ------- ----- ------ - ------ -------- --- ------- ----- -------- only Carbocaine ® 1% mepivacaine hydrochloride injection, USP --------------- Each mL contains 10 mg mepivacaine HCl, 7 mg sodium chloride, and 1 mg methylparaben as preservative in Water for Injection. pH adjusted with NaOH or HCl. Dosage: See package insert. Vial may be autoclaved. ------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) 30 mL SINGLE-DOSE VIAL – STERILE INJECTION NDC 0409-1041-30 C-430 HOSPIRA, INC., LAKE FOREST, IL 60045 USA For PERIPHERAL NERVE BLOCK, CAUDAL and EPIDURAL ANESTHESIA Not for spinal anesthesia. Not intended for dental use. ©Hospira 2005 Printed in USA (01) 0 030409 104130 1 TEST-9 ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ------------- --------------- ---- ------------- --- ------- ----- ------ - ------ -------- --- -------- ----- -------- only Carbocaine ® 1.5% mepivacaine hydrochloride injection, USP --------------- Each mL contains 15 mg mepivacaine HCl, 5.6 mg sodium chloride, 0.3 mg potassium chloride, and 0.33 mg calcium chloride in Water for Injection. pH adjusted with NaOH or HCl. No preservative added. Dosage: See package insert. Vial may be autoclaved. Discard unused portion after initial use. PRESERVATIVE-FREE ------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) Carbocaine® 2% mepivacaine hydrochloride injection, USP For NERVE BLOCK, CAUDAL, EPIDURAL, and INFILTRATION ANESTHESIA Not for spinal anesthesia. Not intended for dental use. (01) 0 030409 106720 2 NDC 0409-1067-20 C-440 Hospira, Inc., Lake Forest, IL 60045 USA Printed in USA TEST-10 only ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ------------- --------------- ---- ------------- --- ------- ----- ------ - ------- -------- --- ------ ----- -------- ---------- Each 1 mL contains 20 mg mepivacaine HCl, 4.6 mg sodium chloride, 0.3 mg potassium chloride, and 0.33 mg calcium chloride in Water for Injection. pH adjusted with NaOH or HCl. No preservative added. Dosage: See package insert. Vial may be autoclaved. Discard unused portion after initial use. ©Hospira 2005 20 mL SINGLE-DOSE VIAL – STERILE INJECTION PRESERVATIVE-FREE ------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) 50 mL MULTIPLE-DOSE VIAL – STERILE INJECTION NDC 0409-2047-50 C-410 HOSPIRA, INC., LAKE FOREST, IL 60045 USA For PERIPHERAL NERVE BLOCK Only Not for epidural, caudal infiltration or spinal anesthesia. Not intended for dental use. (01) 0 030409 204750 0 TEST-7 ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ------------- --------------- ---- ------------- --- ------- ----- ------ - ------ -------- --- --- ----- -------- only Carbocaine ® 2% mepivacaine hydrochloride injection, USP --------------- Each mL contains 20 mg mepivacaine HCl, 5 mg sodium chloride, and 1 mg methylparaben as preservative in Water for Injection. pH adjusted with NaOH or HCl. Dosage: See package insert. Vial may be autoclaved. ©Hospira 2005 Printed in USA ------ (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4)	custom-source	2025-02-12T13:43:48.507896	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/012250s028lbl.pdf', 'application_number': 12250, 'submission_type': 'SUPPL ', 'submission_number': 28}
10,800	Attachment 1 Page 1 Class Suicidality Labeling Language for Antidepressants [This section should be located at the beginning of the package insert with bolded font and enclosed in a black box] [Insert established name] Suicidality in Children and Adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Insert established name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. [Insert established name] is not approved for use in pediatric patients. (See Warnings and Precautions: Pediatric Use) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. [This section should be located under WARNINGS. Please note that the title of this section should be bolded, and it should be the first paragraph in this section.] WARNINGS-Clinical Worsening and Suicide Risk Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. A causal role for antidepressants in inducing suicidality has been established in pediatric patients. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 1 Page 2 There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for [Insert established name] should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 1 Page 3 above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established name] is not approved for use in treating bipolar depression. [This section should be located under PRECAUTIONS, Information for Patients.] Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with [Insert established name] and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Adolescents is available for [Insert established name]. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking [Insert established name]. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. [This section should be located under PRECAUTIONS, Pediatric Use.] Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of [Insert established name] in a child or adolescent must balance the potential risks with the clinical need. Nardil, as with other hydrazine derivatives, has been reported to induce pulmonary and vascular tumors in an uncontrolled lifetime study in mice. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 1 Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions 2. How to try to prevent suicidal thoughts or actions in your child 3. You should watch for certain signs if your child is taking an antidepressant 4. There are benefits and risks when using antidepressants 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. Whenever an antidepressant is started or its dose is changed, pay close attention to your child. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 2 After starting an antidepressant, your child should generally see his or her healthcare provider: • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your healthcare provider's advice about how often to come back • More often if problems or questions arise (see other side) You should call your child's healthcare provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child's healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms. 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) . This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 3 Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:48.559700	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/12342s055lbl.pdf', 'application_number': 12342, 'submission_type': 'SUPPL ', 'submission_number': 55}
10,801	PRESCRIBING INFORMATION PARNATE® (tranylcypromine sulfate) tablets 10 mg Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of PARNATE or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PARNATE is not approved for use in pediatric patients. (See WARNINGS TO PHYSICIANS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.) DESCRIPTION Chemically, tranylcypromine sulfate is (±)-trans-2-phenylcyclopropylamine sulfate (2:1). Each round, rose-red, film-coated tablet is debossed with the product name PARNATE and SB and contains tranylcypromine sulfate equivalent to 10 mg of tranylcypromine. Inactive ingredients consist of cellulose, citric acid, croscarmellose sodium, D&C Red No. 7, FD&C Blue No. 2, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, lactose, magnesium stearate, talc, titanium dioxide, and trace amounts of other inactive ingredients. ACTION Tranylcypromine is a non-hydrazine monoamine oxidase inhibitor with a rapid onset of activity. It increases the concentration of epinephrine, norepinephrine, and serotonin in storage sites throughout the nervous system and, in theory, this increased concentration of monoamines in the brain stem is the basis for its antidepressant activity. When tranylcypromine is withdrawn, monoamine oxidase activity is recovered in 3 to 5 days, although the drug is excreted in 24 hours. INDICATIONS For the treatment of Major Depressive Episode Without Melancholia. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PARNATE should be used in adult patients who can be closely supervised. It should rarely be the first antidepressant drug given. Rather, the drug is suited for patients who have failed to respond to the drugs more commonly administered for depression. The effectiveness of PARNATE has been established in adult outpatients, most of whom had a depressive illness which would correspond to a diagnosis of Major Depressive Episode Without Melancholia. As described in the American Psychiatric Association’s Diagnostic and Statistical Manual, third edition (DSM III), Major Depressive Episode implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning and includes at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and suicidal ideation or attempts. The effectiveness of PARNATE in patients who meet the criteria for Major Depressive Episode with Melancholia (endogenous features) has not been established. SUMMARY OF CONTRAINDICATIONS PARNATE should not be administered in combination with any of the following: MAO inhibitors or dibenzazepine derivatives; sympathomimetics (including amphetamines); some central nervous system depressants (including narcotics and alcohol); antihypertensive, diuretic, antihistaminic, sedative, or anesthetic drugs; bupropion HCl; buspirone HCl; dextromethorphan; cheese or other foods with a high tyramine content; or excessive quantities of caffeine. PARNATE should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease, hypertension, or history of headache. (For complete discussion of contraindications and warnings, see below.) CONTRAINDICATIONS PARNATE is contraindicated: 1. In patients with cerebrovascular defects or cardiovascular disorders PARNATE should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease or hypertension. 2. In the presence of pheochromocytoma PARNATE should not be used in the presence of pheochromocytoma since such tumors secrete pressor substances. 3. In combination with MAO inhibitors or with dibenzazepine-related entities PARNATE should not be administered together or in rapid succession with other MAO inhibitors or with dibenzazepine-related entities. Hypertensive crises or severe convulsive seizures may occur in patients receiving such combinations. In patients being transferred to PARNATE from another MAO inhibitor or from a dibenzazepine-related entity, allow a medication-free interval of at least a week, then initiate PARNATE using half the normal starting dosage for at least the first week of therapy. Similarly, 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda at least a week should elapse between the discontinuance of PARNATE and the administration of another MAO inhibitor or a dibenzazepine-related entity, or the readministration of PARNATE. The following list includes some other MAO inhibitors, dibenzazepine-related entities and tricyclic antidepressants, and the companies which market them. Other MAO Inhibitors Generic Name Source Furazolidone Isocarboxazid Marplan® (Oxford Pharm Services) Pargyline HCl Pargyline HCl and methyclothiazide Phenelzine sulfate Nardil® (Pfizer) Procarbazine HCl Matulane® (Sigma Tau) Dibenzazepine-Related and Other Tricyclics Generic Name Source Amitriptyline HCl (Sandoz) Perphenazine and amitriptyline HCl (Sandoz) Clomipramine hydrochloride Anafranil® (Mallinckrodt) Desipramine HCl (Sandoz) Imipramine HCl (Sandoz) Tofranil® (Mallinckrodt) Nortriptyline HCl (Mylan) Pamelor® (Mallinckrodt) Protriptyline HCl Vivactil® (Odyssey Pharmaceuticals, Inc.) Doxepin HCl Sinequan® (Pfizer) Carbamazepine Tegretol® (Novartis) Cyclobenzaprine HCl (Mylan) Flexeril® (McNeil) Amoxapine (Watson) Maprotiline HCl (Mylan) Trimipramine maleate Surmontil® (Odyssey Pharmaceuticals, Inc.) 4. In combination with bupropion The concurrent administration of an MAO inhibitor and bupropion hydrochloride (Wellbutrin®, Wellbutrin SR®, Wellbutrin XL®, Zyban®, GlaxoSmithKline) is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion hydrochloride. 5. In combination with selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs) As a general rule, PARNATE should not be administered in combination with any SSRI or SNRI. There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving a SSRI (e.g., fluoxetine, Prozac®, Eli Lilly and Company) or a SNRI (e.g., venlafaxine, Effexor®, Effexor XR®, Wyeth) in combination with a monoamine oxidase inhibitor 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (MAOI), and in patients who have recently discontinued a SSRI or SNRIand are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore SSRIs and SNRIs should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI. At least 2 weeks should be allowed after stopping sertraline (Zoloft®, Pfizer) or paroxetine (Paxil®, Paxil CR®, GlaxoSmithKline) before starting an MAOI. At least one week should be allowed after stopping a SNRI (e.g., venlafaxine) before starting a MAOI. 6. In combination with buspirone PARNATE should not be used in combination with buspirone HCl, since several cases of elevated blood pressure have been reported in patients taking MAO inhibitors who were then given buspirone HCl. At least 10 days should elapse between the discontinuation of PARNATE and the institution of buspirone HCl. 7. In combination with sympathomimetics PARNATE should not be administered in combination with sympathomimetics, including amphetamines, and over-the-counter drugs such as cold, hay fever or weight-reducing preparations that contain vasoconstrictors. During therapy with PARNATE, it appears that certain patients are particularly vulnerable to the effects of sympathomimetics when the activity of certain enzymes is inhibited. Use of sympathomimetics and compounds such as guanethidine, methyldopa, reserpine, dopamine, levodopa, and tryptophan with PARNATE may precipitate hypertension, headache, and related symptoms. The combination of MAOIs and tryptophan has been reported to cause behavioral and neurologic syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski's signs. 8. In combination with meperidine Do not use meperidine concomitantly with MAO inhibitors or within 2 or 3 weeks following MAOI therapy. Serious reactions have been precipitated with concomitant use, including coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse, and death. It is thought that these reactions may be mediated by accumulation of 5-HT (serotonin) consequent to MAO inhibition. 9. In combination with dextromethorphan The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. 10. In combination with cheese or other foods with a high tyramine content Hypertensive crises have sometimes occurred during therapy with PARNATE after ingestion of foods with a high tyramine content. In general, the patient should avoid protein foods in which aging or protein breakdown is used to increase flavor. In particular, patients should be instructed not to take foods such as cheese (particularly strong or aged varieties), sour cream, Chianti wine, sherry, beer (including nonalcoholic beer), liqueurs, pickled herring, anchovies, caviar, liver, canned figs, dried fruits (raisins, prunes, etc.), bananas, raspberries, avocados, overripe fruit, chocolate, soy sauce, sauerkraut, the pods of broad beans (fava beans), yeast extracts, yogurt, meat extracts, or meat prepared with tenderizers. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11. In patients undergoing elective surgery Patients taking PARNATE should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of PARNATE and spinal anesthesia should be kept in mind. PARNATE should be discontinued at least 10 days prior to elective surgery. ADDITIONAL CONTRAINDICATIONS In general, the physician should bear in mind the possibility of a lowered margin of safety when PARNATE is administered in combination with potent drugs. 1. PARNATE should not be used in combination with some central nervous system depressants such as narcotics and alcohol, or with hypotensive agents. A marked potentiating effect on these classes of drugs has been reported. 2. Anti-parkinsonism drugs should be used with caution in patients receiving PARNATE since severe reactions have been reported. 3. PARNATE should not be used in patients with a history of liver disease or in those with abnormal liver function tests. 4. Excessive use of caffeine in any form should be avoided in patients receiving PARNATE. WARNINGS TO PHYSICIANS Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short- term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo- controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short- term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1. Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for PARNATE should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that PARNATE is not approved for use in treating bipolar depression. PARNATE is a potent agent with the capability of producing serious side effects. PARNATE is not recommended in those depressive reactions where other antidepressant drugs may be effective. It should be reserved for patients who can be closely supervised and who have not responded satisfactorily to the drugs more commonly administered for depression. Before prescribing, the physician should be completely familiar with the full material on dosage, side effects, and contraindications on these pages, with the principles of MAO inhibitor therapy and the side effects of this class of drugs. Also, the physician should be familiar with the symptomatology of mental depressions and alternate methods of treatment to aid in the careful selection of patients for therapy with PARNATE. Pregnancy Warning: Use of any drug in pregnancy, during lactation or in women of childbearing age requires that the potential benefits of the drug be weighed against its possible hazards to mother and child. Animal reproductive studies show that PARNATE passes through the placental barrier into the fetus of the rat, and into the milk of the lactating dog. The absence of a harmful action of PARNATE on fertility or on postnatal development by either prenatal treatment or from the milk of treated animals has not been demonstrated. Tranylcypromine is excreted in human milk. WARNING TO THE PATIENT Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms, i.e., palpitation and/or tachycardia, a sense of constriction in the throat or chest, sweating, dizziness, neck stiffness, nausea, or vomiting. Patients should be warned against eating the foods listed in Section 11 under Contraindications while on therapy with PARNATE. Also, they should be told not to drink alcoholic beverages. The patient should also be warned about the possibility of hypotension and 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda faintness, as well as drowsiness sufficient to impair performance of potentially hazardous tasks such as driving a car or operating machinery. Patients should also be cautioned not to take concomitant medications, whether prescription or over-the-counter drugs such as cold, hay fever, or weight-reducing preparations, without the advice of a physician. They should be advised not to consume excessive amounts of caffeine in any form. Likewise, they should inform other physicians, and their dentist, about their use of PARNATE. See PRECAUTIONS—Information for Patients for information regarding clinical worsening and suicide risk. WARNINGS Hypertensive Crisis: The most important reaction associated with PARNATE is the occurrence of hypertensive crises which have sometimes been fatal. These crises are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea or vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), and photophobia. Either tachycardia or bradycardia may be present, and associated constricting chest pain and dilated pupils may occur. Intracranial bleeding, sometimes fatal in outcome, has been reported in association with the paradoxical increase in blood pressure. In all patients taking PARNATE, blood pressure should be followed closely to detect evidence of any pressor response. It is emphasized that full reliance should not be placed on blood pressure readings, but that the patient should also be observed frequently. Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during therapy with PARNATE. These signs may be prodromal of a hypertensive crisis. Important: Recommended treatment in hypertensive crises If a hypertensive crisis occurs, PARNATE should be discontinued and therapy to lower blood pressure should be instituted immediately. Headache tends to abate as blood pressure is lowered. On the basis of present evidence, phentolamine is recommended. (The dosage reported for phentolamine is 5 mg I.V.) Care should be taken to administer this drug slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling. Other symptomatic and supportive measures may be desirable in particular cases. Do not use parenteral reserpine. PRECAUTIONS Hypotension: Hypotension has been observed during therapy with PARNATE. Symptoms of postural hypotension are seen most commonly but not exclusively in patients with pre-existent hypertension; blood pressure usually returns rapidly to pretreatment levels upon discontinuation of the drug. At doses above 30 mg daily, postural hypotension is a major side effect and may result in syncope. Dosage increases should be made more gradually in patients showing a 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda tendency toward hypotension at the beginning of therapy. Postural hypotension may be relieved by having the patient lie down until blood pressure returns to normal. Also, when PARNATE is combined with those phenothiazine derivatives or other compounds known to cause hypotension, the possibility of additive hypotensive effects should be considered. There have been reports of drug dependency in patients using doses of tranylcypromine significantly in excess of the therapeutic range. Some of these patients had a history of previous substance abuse. The following withdrawal symptoms have been reported: restlessness, anxiety, depression, confusion, hallucinations, headache, weakness, and diarrhea. Drugs which lower the seizure threshold, including MAO inhibitors, should not be used with Amipaque®. As with other MAO inhibitors, PARNATE should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure. MAO inhibitors may have the capacity to suppress anginal pain that would otherwise serve as a warning of myocardial ischemia. The usual precautions should be observed in patients with impaired renal function since there is a possibility of cumulative effects in such patients. Older patients may suffer more morbidity than younger patients during and following an episode of hypertension or malignant hyperthermia. Older patients have less compensatory reserve to cope with any serious adverse reaction. Therefore, PARNATE should be used with caution in the elderly population. Although excretion of PARNATE is rapid, inhibition of MAO may persist up to 10 days following discontinuation. Because the influence of PARNATE on the convulsive threshold is variable in animal experiments, suitable precautions should be taken if epileptic patients are treated. Some MAO inhibitors have contributed to hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents. Therefore, PARNATE should be used with caution in diabetics using these drugs. PARNATE may aggravate coexisting symptoms in depression, such as anxiety and agitation. Use PARNATE with caution in hyperthyroid patients because of their increased sensitivity to pressor amines. PARNATE should be administered with caution to patients receiving Antabuse®†. In a single study, rats given high intraperitoneal doses of d or l isomers of tranylcypromine sulfate plus disulfiram experienced severe toxicity including convulsions and death. Additional studies in rats given high oral doses of racemic tranylcypromine sulfate (PARNATE) and disulfiram produced no adverse interaction. Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with PARNATE and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for PARNATE. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking PARNATE. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of PARNATE in a child or adolescent must balance the potential risks with the clinical need. ADVERSE REACTIONS Overstimulation which may include increased anxiety, agitation, and manic symptoms is usually evidence of excessive therapeutic action. Dosage should be reduced, or a phenothiazine tranquilizer should be administered concomitantly. Patients may experience restlessness or insomnia; may notice some weakness, drowsiness, episodes of dizziness or dry mouth; or may report nausea, diarrhea, abdominal pain, or constipation. Most of these effects can be relieved by lowering the dosage or by giving suitable concomitant medication. Tachycardia, significant anorexia, edema, palpitation, blurred vision, chills, and impotence have each been reported. Headaches without blood pressure elevation have occurred. Rare instances of hepatitis, skin rash, and alopecia have been reported. Impaired water excretion compatible with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. Tinnitus, muscle spasm, tremors, myoclonic jerks, numbness, paresthesia, urinary retention, and retarded ejaculation have been reported. Hematologic disorders including anemia, leukopenia, agranulocytosis, and thrombocytopenia have been reported. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Post-Introduction Reports: The following are spontaneously reported adverse events temporally associated with use of PARNATE. No clear relationship between PARNATE and these events has been established. Localized scleroderma, flare-up of cystic acne, ataxia, confusion, disorientation, memory loss, urinary frequency, urinary incontinence, urticaria, fissuring in corner of mouth, akinesia. DOSAGE AND ADMINISTRATION Dosage should be adjusted to the requirements of the individual patient. Improvement should be seen within 48 hours to 3 weeks after starting therapy. The usual effective dosage is 30 mg per day, usually given in divided doses. If there are no signs of improvement after a reasonable period (up to 2 weeks), then the dosage may be increased in 10 mg per day increments at intervals of 1 to 3 weeks; the dosage range may be extended to a maximum of 60 mg per day from the usual 30 mg per day. OVERDOSAGE Symptoms: The characteristic symptoms that may be caused by overdosage are usually those described above. However, an intensification of these symptoms and sometimes severe additional manifestations may be seen, depending on the degree of overdosage and on individual susceptibility. Some patients exhibit insomnia, restlessness and anxiety, progressing in severe cases to agitation, mental confusion, and incoherence. Hypotension, dizziness, weakness, and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. A few patients have displayed hypertension with severe headache and other symptoms. Rare instances have been reported in which hypertension was accompanied by twitching or myoclonic fibrillation of skeletal muscles with hyperpyrexia, sometimes progressing to generalized rigidity and coma. Treatment: Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. Telephone numbers for the certified Poison Control Centers are listed in the Physicians’ Desk Reference (PDR). Treatment should normally consist of general supportive measures, close observation of vital signs and steps to counteract specific symptoms as they occur, since MAO inhibition may persist. The management of hypertensive crises is described under WARNINGS in the HYPERTENSIVE CRISES section. External cooling is recommended if hyperpyrexia occurs. Barbiturates have been reported to help relieve myoclonic reactions, but frequency of administration should be controlled carefully because PARNATE may prolong barbiturate activity. When hypotension requires treatment, the standard measures for managing circulatory shock should be initiated. If pressor agents are used, the rate of infusion should be regulated by careful observation of the patient because an exaggerated pressor response sometimes occurs in the presence of MAO inhibition. Remember that the toxic effect of PARNATE may be delayed or prolonged following the last dose of the 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drug. Therefore, the patient should be closely observed for at least a week. It is not known if tranylcypromine is dialyzable. HOW SUPPLIED PARNATE is supplied as round, rose-red, film-coated tablets debossed with the product name PARNATE and SB and contains tranylcypromine sulfate equivalent to 10 mg of tranylcypromine, in bottles of 100 with a desiccant. 10 mg 100’s: NDC 0007-4471-20 Store between 15° and 30°C (59° and 86°F). metrizamide, The Sanofi-Aventis Group. †disulfiram, Odyssey Pharmaceuticals, Inc. Medication Guide Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions PARNATE® (PAR-nate) (tranylcypromine sulfate) Tablets Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • All risks and benefits of treatment with antidepressant medicines • All treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Trouble sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking (mania) • Other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. July 2008 PRT:4MG 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Company logo GlaxoSmithKline Research Triangle Park, NC 27709 ©2008, GlaxoSmithKline. All rights reserved. November 2008 PRT:74PI 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:48.750886	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/012342s061lbl.pdf', 'application_number': 12342, 'submission_type': 'SUPPL ', 'submission_number': 61}
10,802	SOMA® COMPOUND CIV (carisoprodol and aspirin tablets, USP) for Oral Use DESCRIPTION Soma Compound (carisoprodol and aspirin tablets, USP) is a fixed-dose combination product containing the following two products: • 200 mg of carisoprodol, a centrally-acting muscle relaxant • 325 mg of aspirin, an analgesic with antipyretic and anti-inflammatory properties. It is available as a two-layered, white and orange, round tablet for oral administration. Carisoprodol: Chemically, carisoprodol is N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate and its molecular formula is C12H24N2O4, with a molecular weight of 260.33. The structural formula of carisoprodol is: structural formula Aspirin: Chemically, aspirin (acetylsalicyclic acid) is 2-(acetyloxy)-, benzoic acid and its molecular formula is C9H8O4, with a molecular weight of 180.16. The structural formula of aspirin is: structural formula Other ingredients in the Soma Compound drug product are croscarmellose sodium, FD&C Red #40, FD&C Yellow #6, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, starch, and stearic acid. CLINICAL PHARMACOLOGY Mechanism of Action Carisoprodol: The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified. In animal studies, muscle relaxation induced by carisoprodol is associated with altered interneuronal activity in the spinal cord and in the descending reticular formation of the brain. 1 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Aspirin: The mechanism of action of aspirin in relieving pain is by inhibition of the body’s production of prostaglandins, which are thought to cause pain sensations by stimulating muscle contractions and dilating blood vessels. Pharmacodynamics Carisoprodol: Carisoprodol is a centrally-acting muscle relaxant that does not directly relax skeletal muscles. A metabolite of carisoprodol, meprobamate, has anxiolytic and sedative properties. The degree to which these properties of meprobamate contribute to the safety and efficacy of carisoprodol is unknown. Aspirin: Aspirin is a non-narcotic analgesic with anti-inflammatory and anti-pyretic activity. Inhibition of prostaglandin biosynthesis appears to account for most of its anti-inflammatory and for at least part of its analgesic and antipyretic properties. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever. Aspirin can cause serious gastrointestinal injury including bleeding, obstruction, and perforations from ulcers possibly by inhibition of the production of prostaglandins, compromising the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing (see WARNINGS). Aspirin inhibits platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Pharmacokinetics Carisoprodol: The pharmacokinetics of carisoprodol and its metabolite meprobamate were studied in a study of 24 healthy subjects (12 male and 12 female) who received single doses of 350 mg of carisoprodol (see Table 1). The Cmax of meprobamate was 2.5 ± 0.5 μg/mL (mean ± SD) after administration of a single 350 mg dose of carisoprodol, which is approximately 30% of the Cmax of meprobamate (approximately 8 μg/mL) after administration of a single 400 mg dose of meprobamate. Table 1. Pharmacokinetic Parameters of Carisoprodol and Meprobamate (Mean ± SD, n=24) carisoprodol meprobamate Cmax (μg/mL) 1.8 ± 1.0 2.5 ± 0.5 AUCinf (μg·hour/mL) 7.0 ± 5.0 46 ± 9.0 Tmax (hour) 1.7 ± 0.8 4.5 ± 1.9 T1/2 (hour) 2.0 ± 0.5 9.6 ± 1.5 Absorption: Absolute bioavailability of carisoprodol has not been determined. After administration of a single dose of 350 mg of carisoprodol, the mean time to peak plasma concentrations (Tmax) of carisoprodol was approximately 1.5 to 2 hours. Co-administration of a high-fat meal with 350 mg of carisoprodol had no effect on the pharmacokinetics of 2 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda carisoprodol. Metabolism: The major pathway of carisoprodol metabolism is via the liver by cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism (see Patients with Reduced CYP2C19 Activity below). Elimination: Carisoprodol is eliminated by both renal and non-renal routes with a terminal elimination half-life of approximately 2 hours after administration of a single dose of 350 mg of carisoprodol. The half-life of meprobamate is approximately 10 hours after administration of a single dose of 350 mg of carisoprodol. Gender: Exposure of carisoprodol is higher in female than in male subjects (approximately 30 to 50% on a weight adjusted basis). Overall exposure of meprobamate is comparable between female and male subjects. Patients with Reduced CYP2C19 Activity: Carisoprodol should be used with caution in patients with reduced CYP2C19 activity. Published studies indicate that patients who are poor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3 to 5% and in Asians is approximately 15 to 20%. Aspirin: Absorption: The rate of aspirin absorption from the gastrointestinal (GI) tract is dependent upon the presence or absence of food, gastric pH (the presence or absence of GI antacids), and other physiologic factors. Following absorption, aspirin is hydrolyzed to salicylic acid in the gut wall and during first-pass metabolism with peak plasma levels of salicylic acid occurring within 1 to 2 hours of dosing. Distribution: Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, kidneys, heart, and lungs. The protein binding of salicylate is concentration dependent, i.e., nonlinear. At plasma concentrations of salicylic acid < 100 µg/mL and > 400 µg/mL, approximately 90 and 76 percent of plasma salicylate is bound to albumin, respectively. Metabolism: Aspirin, which has a half-life of about 15 minutes, is hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin may not be detectable 1 to 2 hours after dosing. Salicylic acid, which has a plasma half-life of approximately 6 hours, is conjugated in the liver to form salicyluric acid, salicyl phenolic glucuronide, salicyl acyl glucuronide, gentisic acid, and gentisuric acid. At higher serum concentrations of salicylic acid, the total clearance of salicylic acid decreases due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses of aspirin (e.g., > 10 grams), the plasma half-life of salicylic acid may be increased to over 20 hours. 3 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elimination: The elimination of salicylic acid is constant in relation to the plasma salicylic acid concentration. Following therapeutic doses of aspirin, approximately 75, 10, 10, and 5 percent is found excreted in the urine as salicyluric acid, salicylic acid, a phenolic glucuronide of salicylic acid, and an acyl glucuronide of salicylic acid, respectively. As the urinary pH rises above 6.5, the renal clearance of free salicylate increases from less than 5 percent to greater than 80 percent. Alkalinization of the urine is a key concept in the management of salicylate overdose (see OVERDOSAGE, Treatment of Overdosage). Clearance of salicylic acid is also reduced in patients with renal impairment. INDICATIONS AND USAGE Soma Compound is indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults. Soma Compound should only be used for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use has not been established and because acute, painful musculoskeletal conditions are generally of short duration (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Soma Compound contraindicated in patients with a history of: • a serious GI complication (i.e., bleeding, perforations, obstruction) due to aspirin use • aspirin induced asthma (a symptom complex which occurs in patients who have asthma, rhinosinusitis, and nasal polyps who develop a severe, potentially fatal bronchospasm shortly after taking aspirin or other NSAIDs) • hypersensitivity reaction to a carbamate such as meprobamate • acute intermittent porphyria WARNINGS Carisoprodol: Sedation Carisoprodol has sedative properties and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. There have been post-marketing reports of motor vehicle accidents associated with the use of carisoprodol. Since the sedative effects of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Drug Dependence, Withdrawal, and Abuse Carisoprodol, the active ingredient in SOMA, has been subject to abuse, dependence, withdrawal, misuse, and criminal diversion (see DRUG ABUSE AND DEPENDENCE). Abuse of SOMA poses a risk of overdose which may lead to death, CNS and respiratory depression, hypotension, seizures and other disorders (see OVERDOSAGE). Post-marketing cases of carisoprodol abuse and dependence have been reported in patients with 4 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda prolonged use and a history of drug abuse. Although most of these patients took other drugs of abuse, some patients solely abused carisoprodol. Withdrawal symptoms have been reported following abrupt cessation of SOMA after prolonged use. Reported withdrawal symptoms included insomnia, vomiting, abdominal cramps, headache, tremors, muscle twitching, ataxia, hallucinations, and psychosis. One of carisoprodol’s metabolites, meprobamate (a controlled substance), may also cause dependence (see CLINICAL PHARMACOLOGY). To reduce the risk of SOMA abuse, assess the risk of abuse prior to prescribing. After prescribing, limit the length of treatment to three weeks for the relief of acute musculoskeletal discomfort, keep careful prescription records, monitor for signs of abuse and overdose, and educate patients and their families about abuse and on proper storage and disposal. Aspirin: Serious Gastrointestinal Adverse Reactions Aspirin can cause serious gastrointestinal (GI) adverse reactions including bleeding, perforation, and obstruction of the stomach, small intestine, or large intestine, which can be fatal. Aspirin- associated serious GI adverse reactions can occur anywhere along the GI tract, at any time, with or without warning symptoms. Patients at higher risk of aspirin-associated serious upper GI adverse reactions include patients with a history of aspirin-associated GI bleeding from ulcers (complicated ulcers), a history of aspirin-associated ulcers (uncomplicated ulcers), geriatric patients, patients with poor baseline health status, patients taking higher doses of aspirin, and patients taking concomitant anticoagulants, NSAIDs, and/or large amounts of alcohol. To minimize the risk for an aspirin-associated GI serious adverse reaction, the lowest effective aspirin dose should be used for the shortest possible duration. Anaphylaxis and Anaphylactoid Reactions Aspirin may cause an increased risk of serious anaphylaxis and anaphylactoid reactions, which can occur in patients without known prior exposure to aspirin (see CONTRAINDICATIONS). Patients with a serious anaphalaxis or anaphylactoid reaction should receive emergency care. PRECAUTIONS Patients with impaired renal or hepatic function The safety and pharmacokinetics of Soma Compound in patients with renal or hepatic impairment have not been evaluated. Carisoprodol: Since carisoprodol is excreted by the kidney and is metabolized in the liver, caution should be exercised if carisoprodol is administered to patients with impaired renal or hepatic function. Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis. Seizures There have been post-marketing reports of seizures in patients who received carisoprodol. Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol) (see OVERDOSAGE). 5 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Aspirin: Gastrointestinal Adverse Reactions In addition to serious gastrointestinal adverse reactions, the use of aspirin is also associated with gastritis, gastrointestinal erosions, abdominal pain, heartburn, vomiting, and nausea (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Information for Patients: Patients should be advised to contact their health care provider if they experience any adverse reactions to Soma Compound. Carisoprodol: 1. Patients should be advised that carisoprodol may cause drowsiness and/or dizziness, and has been associated with motor vehicle accidents. Patients should be advised to avoid taking carisoprodol before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery (see WARNINGS, Sedation). 2. Patients should be advised to avoid alcoholic beverages while taking carisoprodol and to check with their doctor before taking other CNS depressants such as benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or other sedatives (see WARNINGS, Sedation). 3. Patients should be advised that treatment with carisoprodol should be limited to acute use (up to two or three weeks) for the relief of acute, musculoskeletal discomfort. In the post- marketing experience with carisoprodol, cases of dependence, withdrawal, and abuse have been reported with prolonged use. If the musculoskeletal symptoms still persist, patients should contact their healthcare provider for further evaluation. Aspirin: 1. Patients should be warned that aspirin can cause epigastric discomfort, gastric and duodenal ulcers, and serious GI adverse reactions, such as bleeding, perforation, and/or obstruction of the stomach or intestines, which may result in hospitalization and death. Although serious GI bleeding can occur without warning symptoms (e.g., hematemesis, melena, hematochezia), patients should be alert for these symptoms and should seek urgent medical care if any of these indicative symptoms occur (see WARNINGS, Serious Gastrointestinal Adverse Reactions). In addition, patients should be alert for symptoms of ulcers (e.g., night time epigastric discomfort, vomiting, weight loss) and should seek medical attention if these symptoms occur. Patients who consume three or more alcoholic drinks every day should be counseled about the GI bleeding risks involved with the use of aspirin with alcohol. 2. Patients should be informed of the symptoms of an anaphylactoid reaction or anaphylaxis (e.g., hives, difficulty breathing, swelling of the face or throat). If these symptoms occur, patients should be instructed to seek immediate emergency help. Drug Interactions: 6 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carisoprodol: The sedative effects of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Concomitant use of carisoprodol and meprobamate, a metabolite of carisoprodol, is not recommended (see WARNINGS, Sedation). Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see CLINICAL PHARMACOLOGY). Coadministration of CYP2C19 inhibitors, such as omeprazole or fluvoxamine, with carisoprodol could result in increased exposure of carisoprodol and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such as rifampin or St. John’s Wort, with carisoprodol could result in decreased exposure of carisoprodol and increased exposure of meprobamate. Low dose aspirin also showed an induction effect on CYP2C19. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown. Aspirin: Clinically important interactions may occur when certain drugs or alcohol are administered concomitantly with aspirin. Alcohol: Concomitant use of aspirin with ≥ 3 alcoholic drinks may increase the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Anticoagulants: Concomitant use of aspirin with anticoagulants (e.g., heparin, warfarin, clopidogrel) increases the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Additionally, aspirin can displace warfarin from protein binding sites, leading to prolongation of the international normalized ratio (INR). Antihypertensives: The concomitant administration of aspirin with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and diuretics may diminish the hypotensive effects of these anti-hypertensive products due to aspirin’s inhibition of renal prostaglandins, which may lead to decreased renal blood flow and increased sodium and fluid retention. Concomitant use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide due to competition at the renal tubule for secretion. Corticosteroids: Concomitant administration of aspirin and corticosteriods may decrease salicylate plasma levels. Methotrexate: Aspirin may enhance the toxicity of methotrexate due to displacement of methotrexate from its plasma protein binding sites and/or reduction of the renal clearance of methotrexate. Nonsteroidal anti-inflammatory drugs (NSAIDs): The concurrent use of aspirin with selective and nonselective NSAIDs increases the risk of serious GI adverse reactions (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin 7 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and sulfonylureas leading to hypoglycemia. Products that effect urinary pH: Ammonium chloride and other drugs that acidify the urine can elevate plasma salicylate concentrations. In contrast, antacids, by alkalinizing the urine, may decrease plasma salicylate concentrations. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid and sulfinpyrazone. Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies of carcinogenesis have been done with Soma Compound. Carisoprodol: Long term studies in animals have not been performed to evaluate the carcinogenic potential of carisoprodol. Carisoprodol was not formally evaluated for genotoxicity. In published studies, carisoprodol was mutagenic in the in vitro mouse lymphoma cell assay in the absence of metabolizing enzymes, but was not mutagenic in the presence of metabolizing enzymes. Carisoprodol was clastogenic in the in vitro chromosomal aberration assay using Chinese hamster ovary cells with or without the presence of metabolizing enzymes. Other types of genotoxic tests resulted in negative findings. Carisoprodol was not mutagenic in the Ames reverse mutation assay using S. typhimurium strains with or without metabolizing enzymes, and was not clastogenic in an in vivo mouse micronucleus assay of circulating blood cells. Carisoprodol was not formally evaluated for effects on fertility. Published reproductive studies of carisoprodol in mice found no alteration in fertility although an alteration in reproductive cycles characterized by a greater time spent in estrus was observed at a carisoprodol dose of 1200 mg/kg/day. In a 13-week toxicology study that did not determine fertility, mouse testes weight and sperm motility were reduced at a dose of 1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day, corresponding to approximately 2.6 times the human equivalent dosage of 350 mg four times a day, based on a body surface area comparison. The significance of these findings for human fertility is not known. Aspirin: Administration of aspirin for 68 weeks in the feed of rats was not carcinogenic. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Aspirin has been shown to inhibit ovulation in rats (see Pregnancy.) Pregnancy: Pregnancy Category D. It is not known whether Soma Compound can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adequate animal reproduction studies have not been conducted with Soma Compound. Soma Compound should be given to a pregnant woman only if clearly needed. 8 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carisoprodol: There are no data on the use of carisoprodol during human pregnancy. Animal studies indicate that carisoprodol crosses the placenta and results in adverse effects on fetal growth and postnatal survival. The primary metabolite of carisoprodol, meprobamate, is an approved anxiolytic. Retrospective, post-marketing studies do not show a consistent association between maternal use of meprobamate and an increased risk for particular congenital malformations. Teratogenic effects: Animal studies have not adequately evaluated the teratogenic effects of carisoprodol. There was no increase in the incidence of congenital malformations noted in reproductive studies in rats, rabbits, and mice treated with meprobamate. Retrospective, post- marketing studies of meprobamate during human pregnancy were equivocal for demonstrating an increased risk of congenital malformations following first trimester exposure. Across studies that indicated an increased risk, the types of malformations were inconsistent. Nonteratogenic effects: In animal studies, carisoprodol reduced fetal weights, postnatal weight gain, and postnatal survival at maternal doses equivalent to 1 to 1.5 times the human dose (based on a body surface area comparison). Rats exposed to meprobamate in-utero showed behavioral alterations that persisted into adulthood. For children exposed to meprobamate in-utero, one study found no adverse effects on mental or motor development or IQ scores. Carisoprodol should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Aspirin: Teratogenic effects: Prior to 30 weeks gestation, aspirin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, aspirin should be avoided by pregnant women as premature closure of the fetal ductus arteriosus which may result in fetal pulmonary hypertension and fetal death. Salicylate products have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths, and neonatal death. Studies in rodents have shown salicylates to be teratogenic when given in early gestation, and embryocidal when given in later gestation in doses considerably greater than usual therapeutic doses in humans. Labor and Delivery: Carisoprodol: There is no information about the effects of carisoprodol on the mother and the fetus during labor and delivery. Aspirin: Ingestion of aspirin within one week of delivery or during labor may prolong delivery or lead to excessive blood loss in the mother, fetus, or neonate. Prolonged labor due to prostaglandin inhibition has been reported with aspirin use. Nursing Mothers: Carisoprodol: Very limited data in humans show that carisoprodol is present in breast milk and may reach concentrations two to four times the maternal plasma concentrations. In one case report, a breast-fed infant received about 4 to 6% of the maternal daily dose through breast milk 9 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and experienced no adverse effects. However, milk production was inadequate and the baby was supplemented with formula. In lactation studies in mice, female pup survival and pup weight at weaning were decreased. This information suggests that maternal use of carisoprodol may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when carisoprodol is administered to a nursing woman. Aspirin: Nursing mothers should avoid the use of aspirin because salicylate is excreted in breast milk which may lead to bleeding in the infant. Pediatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound in pediatric patients less than 16 years of age have not been established. Geriatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound in patients over 65 years old have not been established. ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions which have occurred with the administration of the individual products alone may also occur with the use of Soma Compound. The following events have been reported during post-approval individual use of carisoprodol and aspirin. 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. Carisoprodol: The following events have been reported during post-approval use of carisoprodol. 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. Cardiovascular: Tachycardia, postural hypotension, and facial flushing (see OVERDOSAGE). Central Nervous System: Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, insomnia, and seizures (see OVERDOSAGE). Gastrointestinal: Nausea, vomiting, and epigastric discomfort. Hematologic: Leukopenia, pancytopenia Aspirin: The most common adverse reactions associated with the use of aspirin have been gastrointestinal, including abdominal pain, anorexia, nausea, vomiting, gastritis, and occult bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions and PRECAUTIONS, Gastrointestinal Adverse Reactions). Other adverse reactions associated with the use of aspirin include elevated liver enzymes, rash, pruritus, purpura, intracranial hemorrhage, interstitial nephritis, acute renal failure, and tinnitus. Tinnitus may be a symptom of high serum salicylate levels (see OVERDOSAGE). 10 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DRUG ABUSE AND DEPENDENCE Controlled Substance SOMA contains carisoprodol, a Schedule IV controlled substance. Carisoprodol has been subject to abuse, misuse, and criminal diversion for nontherapeutic use (see WARNINGS). Abuse Abuse of carisoprodol poses a risk of overdosage which may lead to death, CNS and respiratory depression, hypotension, seizures and other disorders (see WARNINGS). Patients at high risk of SOMA abuse may include those with prolonged use of carisoprodol, with a history of drug abuse, or those who use SOMA in combination with other abused drugs. Prescription drug abuse is the intentional non-therapeutic use of a drug, even once, for its rewarding psychological or physiological effects. Drug addiction, which develops after repeated drug abuse, is characterized by a strong desire to take a drug despite harmful consequences, difficulty in controlling its use, giving a higher priority to drug use that to obligations, increased tolerance, and sometimes physical withdrawal. Drug abuse and drug addiction are separate and distinct from physical dependence and tolerance (for example, abuse or addiction may not be accompanied by tolerance or physical dependence) (see DEPENDENCE). Dependence Tolerance is when a patient’s reaction to a specific dosage and concentration is progressively reduced, in the absence of disease progression, requiring an increase in the dosage to maintain the same. Physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Both tolerance and physical dependence have been reported with the prolonged use of SOMA. Reported withdrawal symptoms with SOMA include insomnia, vomiting, abdominal cramps, headache, tremors, muscle twitching, anxiety, ataxia, hallucinations, and psychosis. Instruct patients taking large doses of SOMA or those taking the drug for a prolonged time to not abruptly stop SOMA (see WARNINGS). OVERDOSAGE Signs and Symptoms: Any of the following signs and symptoms which have been reported with overdose of the individual products may occur with overdose of Soma Compound and may be modified to a varying degree by the effects of the other products present in Soma Compound. Carisoprodol: Overdosage of carisoprodol commonly produces CNS depression. Death, coma, respiratory depression, hypotension, seizures, delirium, hallucinations, dystonic reactions, nystagmus, blurred vision, mydriasis, euphoria, muscular incoordination, rigidity, and/or headache have been reported with carisoprodol overdosage. Serotonin syndrome has been reported with carisoprodol intoxication. Many of the carisoprodol overdoses have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol). The effects of an overdose of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) can be additive even when one of the drugs 11 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda has been taken in the recommended dosage. Fatal accidental and non-accidental overdoses of carisoprodol have been reported alone or in combination with CNS depressants. Aspirin: Salicylate toxicity may result from an overdose of an acute ingestion or chronic intoxication. Mild to moderate salicylate poisoning is usually associated with plasma salicylic concentrations about 200 µg/mL and is characterized by tinnitus, hearing difficulty, headache, dim vision, dizziness, tachypnea, increased thirst, nausea, vomiting, sweating, and diarrhea. In the early stages of overdose, CNS stimulation and respiratory alkalosis can occur; however, in the later stages CNS depression and metabolic acidosis can occur. Symptoms and signs of severe salicylate poisoning, associated with plasma salicylic concentrations greater than 400 µg/mL, include hyperthermia, dehydration, delirium, GI hemorrhage, pulmonary edema, and CNS depression (e.g., coma). Death is usually due to respiratory failure or cardiovascular collapse. Overdose of aspirin in pediatric patients: Salicylate poisoning should be considered in pediatric patients with symptoms of vomiting, hyperpnea, and hyperthermia. Salicylate poisoning should be considered in infants with metabolic acidosis and all pediatric patients with severe salicylate poisoning. Treatment of Overdosage: Provide symptomatic and supportive treatment, as indicated. For more information on the management of an overdose of Soma Compound (carisoprodol and aspirin tablets, USP), contact a Poison Control Center. Carisoprodol: Basic life support measures should be instituted as dictated by the clinical presentation of the carisoprodol overdose. Vomiting should not be induced due to the risk of CNS and respiratory depression and subsequent aspiration. Circulatory support should be administered with volume infusion and vasopressor agents if needed. Seizures should be treated with intravenous benzodiazepines and the reoccurrence of seizures may be treated with phenobarbital. In cases of severe CNS depression, airway protective reflexes may be compromised and tracheal intubation should be considered for airway protection and respiratory support. For decontamination in cases of severe toxicity, activated charcoal should be considered in a hospital setting in patients with large overdoses who present early and are not demonstrating CNS depression and can protect their airway. Aspirin: Since there are no specific antidotes for salicylate poisoning, the aim of treatment is to enhance elimination of salicylate; reduce further salicylate absorption; correct fluid, electrolyte, or acid/base imbalances; and provide cardio-respiratory support. The acid-base status should be followed closely with serial serum pH determinations (using arterial blood gas). If acidosis is present, intravenous sodium bicarbonate should be given, along with adequate hydration, until salicylate levels decrease to within the therapeutic range. To enhance elimination, forced diuresis and alkalinization of the urine may be beneficial. Gastric emptying and/or lavage are recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal is beneficial, if less than 3 hours 12 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda have passed since ingestion. Charcoal absorption should not be employed prior to emesis and lavage. In patients with renal insufficiency or in cases of life-threatening aspirin intoxication, hemodialysis or peritoneal dialysis is usually required. Additional treatment of aspirin overdose in pediatric patients: Pediatric patients should be sponged with tepid water. Infusion of glucose may be required to control hypoglycemia. Exchange transfusion may be indicated in infants and young children. DOSAGE AND ADMINISTRATION The recommended dose of Soma Compound is 1 or 2 tablets, four times daily in adults. One Soma Compound tablet contains 200 mg of carisoprodol and 325 mg of aspirin. The maximum daily dose (i.e., two tablets taken four times daily) will provide 1600 mg of carisoprodol and 2600 mg of aspirin per day. The recommended maximum duration of Soma Compound use is up to two or three weeks. HOW SUPPLIED Soma Compound (carisoprodol and aspirin) Tablets are round, convex, two-layered and inscribed on the white layer with SOMA C and on the light orange layer with WALLACE 2103. The tablets are available in bottles of 100 (NDC 0037-2103-01) and 500 (NDC 0037-2103-03) and unit-dose packages of 100 (NDC 0037-2103-85). Storage: Store at controlled room temperature 20- 25° C (68 to 77° F). Protect from moisture. Dispense in a tight container. company logo ©2013 Meda Pharmaceuticals Inc. Revised 1/2013 13 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:48.812377	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012365s039lbl.pdf', 'application_number': 12365, 'submission_type': 'SUPPL ', 'submission_number': 39}
10,803	SOMA® COMPOUND with CODEINE (carisoprodol, aspirin, and codeine phosphate, USP) tablets for oral use Warning: May be habit-forming. CIII DESCRIPTION Soma Compound with Codeine (carisoprodol, aspirin, and codeine phosphate tablets, USP) is a fixed-dose combination product containing the following three products: • 200 mg of carisoprodol, a centrally-acting muscle relaxant • 325 mg of aspirin, an analgesic with antipyretic and anti-inflammatory properties • 16 mg of codeine phosphate, a centrally-acting narcotic analgesic. It is available as a two-layered, white and yellow, oval-shaped tablet for oral administration. Carisoprodol: Chemically, carisoprodol is N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate and its molecular formula is C12H24N2O4, with a molecular weight of 260.33. The Chemical Structure Aspirin: Chemically, aspirin (acetylsalicyclic acid) is 2-(acetyloxy)-, benzoic acid and its molecular formula is C9H8O4, with a molecular weight of 180.16. The structural formula of aspirin is: Chemical Structure Codeine Phosphate: Chemically, codeine phosphate is 7,8-Didehydro-4,5α-epoxy-3-methoxy 17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate and its molecular formula is C18H24NO7P, with a molecular weight of 406.37. The structural formula of codeine phosphate is: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chemical Structture Other ingredients in the Soma Compound with Codeine drug product are croscarmellose sodium, D&C Yellow #10, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, sodium metabisulfite, starch, and stearic acid. CLINICAL PHARMACOLOGY Mechanism of Action Carisoprodol: The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified. In animal studies, muscle relaxation induced by carisoprodol is associated with altered interneuronal activity in the spinal cord and in the descending reticular formation of the brain. Aspirin: The mechanism of action of aspirin in relieving pain is by inhibition of the body’s production of prostaglandins, which are thought to cause pain sensations by stimulating muscle contractions and dilating blood vessels. Codeine Phosphate: The precise mechanism of action of codeine phosphate, an opioid agonist, in relieving pain has not been established. The binding of codeine phosphate to mu, delta, and kappa opioid receptors in the central nervous system (CNS) may change the perception of pain. The analgesic activity of codeine phosphate is probably due to its conversion to morphine. Pharmacodynamics Carisoprodol: Carisoprodol is a centrally-acting muscle relaxant that does not directly relax skeletal muscles. A metabolite of carisoprodol, meprobamate, has anxiolytic and sedative properties. The degree to which these properties of meprobamate contribute to the safety and efficacy of Soma Compound with Codeine is unknown. Aspirin: Aspirin is a non-narcotic analgesic with anti-inflammatory and anti-pyretic activity. Inhibition of prostaglandin biosynthesis appears to account for most of its anti-inflammatory and for at least part of its analgesic and antipyretic properties. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever. Aspirin can cause serious gastrointestinal injury including bleeding, obstruction, and perforations from ulcers possibly by inhibition of the production of prostaglandins, compromising the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing (see WARNINGS). Aspirin inhibits platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Codeine Phosphate: Codeine Phosphate is a centrally-acting narcotic analgesic. Its actions are qualitatively similar to morphine, but its potency is substantially less. Opioids, including codeine phosphate have the following effects: • respiratory depression by a direct effect on the brainstem respiratory centers • depression of the cough reflex by direct effect on the cough center in the medulla • constriction of the pupils (i.e., miosis) • decreased gastric, biliary, and pancreatic secretions • reduction in the motility of the stomach and small and large intestine which results in constipation and delayed digestion. • nausea and vomiting by directly stimulating the chemoreceptor trigger zone • increased biliary tract pressure as a result of spasm of the sphincter of Oddi • peripheral vasodilatation which may result in orthostatic hypotension • histamine release which may result in pruritus, flushing, and sweating. • increased tone of the bladder detrusor muscle, ureters, and vesical sphincter which may result in urinary retention Pharmacokinetics Carisoprodol: The pharmacokinetics of carisoprodol and its metabolite meprobamate were studied in a study of 24 healthy subjects (12 male and 12 female) who received single doses of 350 mg of carisoprodol (see Table 1). The Cmax of meprobamate was 2.5 ± 0.5 μg/mL (mean ± SD) after administration of a single 350 mg dose of carisoprodol, which is approximately 30% of the Cmax of meprobamate (approximately 8 μg/mL) after administration of a single 400 mg dose of meprobamate. Table 1. Pharmacokinetic Parameters of Carisoprodol and Meprobamate (Mean ± SD, n=24) carisoprodol meprobamate Cmax (μg/mL) 1.8 ± 1.0 2.5 ± 0.5 AUCinf (μghour/mL) 7.0 ± 5.0 46 ± 9.0 Tmax (hour) 1.7 ± 0.8 4.5 ± 1.9 T1/2 (hour) 2.0 ± 0.5 9.6 ± 1.5 Absorption: Absolute bioavailability of carisoprodol has not been determined. After administration of a single dose of 350 mg of carisoprodol, the mean time to peak plasma concentrations (Tmax) of carisoprodol was approximately 1.5 to 2 hours. Co-administration of a high-fat meal with 350 mg of carisoprodol had no effect on the pharmacokinetics of carisoprodol. Metabolism: The major pathway of carisoprodol metabolism is via the liver by cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism (see Patients with Reduced CYP2C19 Activity below). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elimination: Carisoprodol is eliminated by both renal and non-renal routes with a terminal elimination half-life of approximately 2 hours after administration of a single dose of 350 mg of carisoprodol. The half-life of meprobamate is approximately 10 hours after administration of a single dose of 350 mg of carisoprodol. Gender: Exposure of carisoprodol is higher in female than in male subjects (approximately 30 to 50% on a weight adjusted basis). Overall exposure of meprobamate is comparable between female and male subjects. Patients with Reduced CYP2C19 Activity: Carisoprodol should be used with caution in patients with reduced CYP2C19 activity. Published studies indicate that patients who are poor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3 to 5% and in Asians is approximately 15 to 20%. Aspirin: Absorption: The rate of aspirin absorption from the gastrointestinal (GI) tract is dependent upon the presence or absence of food, gastric pH (the presence or absence of GI antacids), and other physiologic factors. Following absorption, aspirin is hydrolyzed to salicylic acid in the gut wall and during first-pass metabolism with peak plasma levels of salicylic acid occurring within 1 to 2 hours of dosing. Distribution: Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, kidneys, heart, and lungs. The protein binding of salicylate is concentration dependent, i.e., nonlinear. At plasma concentrations of salicylic acid < 100 µg/mL and > 400 µg/mL, approximately 90 and 76 percent of plasma salicylate is bound to albumin, respectively. Metabolism: Aspirin, which has a half-life of about 15 minutes, is hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin may not be detectable 1 to 2 hours after dosing. Salicylic acid, which has a plasma half life of approximately 6 hours, is conjugated in the liver to form salicyluric acid, salicyl phenolic glucuronide, salicyl acyl glucuronide, gentisic acid, and gentisuric acid. At higher serum concentrations of salicylic acid, the total clearance of salicylic acid decreases due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses of aspirin (e.g., > 10 grams), the plasma half-life of salicylic acid may be increased to over 20 hours. Elimination: The elimination of salicylic acid is constant in relation to the plasma salicylic acid concentration. Following therapeutic doses of aspirin, approximately 75, 10, 10, and 5 percent is found excreted in the urine as salicyluric acid, salicylic acid, a phenolic glucuronide of salicylic acid, and an acyl glucuronide of salicylic acid, respectively. As the urinary pH rises above 6.5, the renal clearance of free salicylate increases from less than 5 percent to greater than 80 percent. Alkalinization of the urine is a key concept in the management of salicylate overdose (see OVERDOSAGE, Treatment of Overdosage.) Clearance of salicylic acid is also reduced in patients with renal impairment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Codeine Phosphate: Absorption: Codeine is readily absorbed from the GI tract. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. Distribution: Codeine is rapidly distributed from the intravascular spaces to the tissues with preferential uptake by the liver, spleen, and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration of codeine does not correlate with brain concentration of codeine or the relief of pain. Metabolism: The plasma half-life of codeine is about 2.9 hours. Elimination: 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. INDICATIONS AND USAGE Soma Compound with Codeine is indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults. Soma Compound with Codeine should only be used for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use has not been established and because acute, painful musculoskeletal conditions are generally of short duration (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Soma Compound with Codeine is contraindicated in patients with a history of: • a serious GI complication (i.e., bleeding, perforations, obstruction) due to aspirin use • aspirin induced asthma (a symptom complex which occurs in patients who have asthma, rhinosinusitis, and nasal polyps who develop a severe, potentially fatal brochospasm shortly after taking aspirin or other NSAIDs) • hypersensitivity reaction to a carbamate such as meprobamate • acute intermittent porphyria WARNINGS Carisoprodol: Sedation Carisoprodol may have sedative properties and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. Since the sedative effects of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Dependence, Withdrawal, and Abuse In the postmarketing experience with carisoprodol, cases of dependence, withdrawal, and abuse have been reported with prolonged use. Most cases of dependence, withdrawal, and abuse occurred in patients who have had a history of addiction or who used carisoprodol in combination with other drugs with abuse potential. Withdrawal symptoms have been reported following abrupt cessation after prolonged use. To reduce the chance of carisoprodol dependence, withdrawal, or abuse, carisoprodol should be used with caution in addiction prone patients and in patients taking other CNS depressants including alcohol, and carisoprodol should be not be used more than two to three weeks for the relief of acute musculoskeletal discomfort. One of the metabolites of carisoprodol, meprobamate (a controlled substance), may cause dependence (see CLINICAL PHARMACOLOGY). Aspirin: Serious Gastrointestinal Adverse Reactions Aspirin can cause serious gastrointestinal (GI) adverse reactions including bleeding, perforation, and obstruction of the stomach, small intestine, or large intestine, which can be fatal. Aspirin-associated serious GI adverse reactions can occur anywhere along the GI tract, at any time, with or without warning symptoms. Patients at higher risk of aspirin-associated serious upper GI adverse reactions include patients with a history of aspirin-associated GI bleeding from ulcers (complicated ulcers), a history of aspirin-associated ulcers (uncomplicated ulcers), geriatric patients, patients with poor baseline health status, patients taking higher doses of aspirin, and patients taking concomitant anticoagulants, NSAIDs, and/or large amounts of alcohol. To minimize the risk for an aspirin-associated GI serious adverse reaction, the lowest effective aspirin dose should be used for the shortest possible duration. Anaphylaxis and Anaphylactoid Reactions Aspirin may cause an increased risk of serious anaphylaxis and anaphylactoid reactions, which can occur in patients without known prior exposure to aspirin (see CONTRAINDICATIONS). Patients with a serious anaphalaxis or anaphylactoid reaction should receive emergency care. Codeine Phosphate: Respiratory Depression Respiratory depression is a serious adverse reaction of opioid agonists, including codeine phosphate. Opioid-associated respiratory depression is more likely to occur in geriatric patients, debilitated patients, in non-tolerant patients who are given large initial doses of opioids, and in patients who are receiving concomitant respiratory depressants (e.g., other opioids, benzodiazepines, tricyclic antidepressants, phenothiazines, skeletal muscle relaxants, alcohol). In addition, patients with chronic obstructive pulmonary disease (COPD), restrictive lung disease, decreased respiratory drive, and/or respiratory depression are at greater risk of opioid-associated respiratory depression. Opioid-associated respiratory depression may be increased in patients with increased intracranial pressure (e.g., patients with head trauma, intracranial lesions). Abuse and Diversion Codeine phosphate is a Schedule III controlled substance. Administration of opioids including codeine phosphate has been associated with abuse. Healthcare professionals should contact This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent or detect abuse or diversion of codeine phosphate. Dependence and Tolerance Use of opioids, including codeine phosphate, can result in psychological and/or physical dependence. Withdrawal symptoms associated with abrupt opioid discontinuation include restlessness, irritability, anxiety, lacrimation, rhinorrhea, sweating, chills, mydriasis, insomnia, diarrhea, tachypnea, tachycardia, and/or hypertension. The use of opioids, including codeine phosphate, use can result in tolerance ─ the need for increasing doses to maintain a desired effect in the absence of other factors (e.g., disease progression). Gastrointestinal Obstruction Opioids, including codeine phosphate may cause gastrointestinal obstruction. Sedation Opioids, including codeine phosphate, may impair the metal and physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Since the sedative effects of codeine phosphate and other CNS depressants (e.g., other opioids, benzodiazepines, tricyclic antidepressants, skeletal muscle relaxants, alcohol) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Hypotension The use of opioids, including codeine phosphate, may cause hypotension. Opioid- associated hypotension is more likely in patients with dehydration or with the concomitant use of drugs associated with hypotension. PRECAUTIONS Patients with impaired renal or hepatic function The safety and pharmacokinetics of Soma Compound with Codeine in patients with renal or hepatic impairment have not been evaluated. Carisoprodol: Since carisoprodol is excreted by the kidney and is metabolized in the liver, caution should be exercised if carisoprodol is administered to patients with impaired renal or hepatic function. Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis. Seizures There have been postmarketing reports of seizures in patients who received carisoprodol. Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol) (see OVERDOSAGE). Aspirin: Gastrointestinal Adverse Reactions In addition to serious gastrointestinal adverse reactions, the use of aspirin is also associated with gastritis, gastrointestinal erosions, abdominal pain, heartburn, vomiting, and nausea (see WARNINGS, Serious Gastrointestinal Adverse Reactions). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Codeine Phosphate: Obscuring Medical Conditions Opioids, including codeine phosphate, may obscure the clinical course of patients with head injuries because of the CNS depressive effects of opioids. In addition, opioids, including codeine phosphate, may obscure the symptoms and/or signs that are used for the diagnosis or for the monitoring of patients with acute abdominal conditions. Ultra-rapid Metabolizers of Codeine Some patients may be ultra-rapid metabolizers of codeine phosphate due to a specific CYP2D62x2 genotype. These patients convert codeine into its active metabolite, morphine, more rapidly and completely than patients who are normal metabolizers of codeine, resulting in higher than expected serum morphine levels. Even at labeled dosage regimens of codeine phosphate, patients who are ultra-rapid metabolizers may experience overdose symptoms such respiratory depression, extreme sleepiness, or delirium. Toxic serum levels of morphine have been reported in infants of nursing mothers who may be ultra-rapid metabolizers (see PRECAUTIONS, Nursing Mothers). The prevalence of this CYP2D6 phenotype has been estimated at 16 to 28% in North Africans, Ethiopians, and Arabs; 1 to 10% in Caucasians; 3% in African Americans; and 0.5 to 1% in Chinese, Japanese, and Hispanics. Data is not available for other ethnic groups. When healthcare providers prescribe codeine-containing products, they should choose the lowest effective dose for the shortest period of time. Use in Patients with Pancreatic or Biliary Duct Disease Opioids, including codeine phosphate, should be used with caution in patients with pancreatic or biliary duct disease because opioids may cause spasm of the sphincter of Oddi and diminish pancreatic and/or biliary secretions. Information for Patients: Patients should be advised to contact their health care provider if they experience any adverse reactions to Soma Compound with Codeine. Carisoprodol: 1. Since carisoprodol may cause drowsiness and/or dizziness, patients should be advised to assess their individual response to carisoprodol before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery (see WARNINGS, Sedation). 2. Patients should be advised to avoid alcoholic beverages while taking carisoprodol and to check with their doctor before taking other CNS depressants such as benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or other sedatives (see WARNINGS, Sedation). 3. Patients should be advised that treatment with carisoprodol should be limited to acute use (up to two or three weeks) for the relief of acute, musculoskeletal discomfort. If symptoms still persist, patients should contact their healthcare provider for further evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Aspirin: 4. Patients should be warned that aspirin can cause epigastric discomfort, gastric and duodenal ulcers, and serious GI adverse reactions, such as bleeding, perforation, and/or obstruction of the stomach or intestines, which may result in hospitalization and death. Although serious GI bleeding can occur without warning symptoms (e.g., hematemesis, melena, hematochezia), patients should be alert for these symptoms and should seek urgent medical care if any of these indicative symptoms occur (see WARNINGS, Serious Gastrointestinal Adverse Reactions). In addition, patients should be alert for symptoms of ulcers (e.g., night time epigastric discomfort, vomiting, weight loss) and should seek medical attention if these symptoms occur. Patients who consume three or more alcoholic drinks every day should be counseled about the GI bleeding risks involved with the use of aspirin with alcohol. 5. Patients should be informed of the symptoms of an anaphylactoid reaction or anaphylaxis (e.g., hives, difficulty breathing, swelling of the face or throat). If these symptoms occur, patients should be instructed to seek immediate emergency help. Codeine Phosphate: 6. Since codeine phosphate may cause drowsiness and/or dizziness, patients should be advised to assess their individual response to codeine phosphate before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery (see WARNINGS, Sedation). 7. Patients should be advised to avoid alcoholic beverages while taking codeine phosphate and to check with their doctor before taking other CNS depressants such as other opioids, benzodiazepines, tricyclic antidepressants, sedating antihistamines, or other sedatives (see WARNINGS, Respiratory Depression and Sedation). 8. Patients should be advised that codeine phosphate is a controlled substance. Codeine phosphate can result in psychological and physical dependence (see WARNINGS, Dependence and Tolerance). 9. Codeine phosphate tablets should be placed in a secure place out of the reach of children. 10. Patients should be advised that opioids, including codeine phosphate, can cause constipation and appropriate measures should be taken to reduce the risk of constipation (e.g., dietary changes, laxatives). 11. Patients should be advised that opioids, including codeine phosphate have been associated with hypotension and gastrointestinal obstruction (WARNINGS, hypotension and gastrointestinal obstruction). 12. Patients should be advised that a subset of people who use codeine (ultra-rapid metabolizers) may convert codeine into its active metabolite, morphine, resulting that higher than expected exposure of morphine which can lead to increased opioid toxicity (see PRECAUTIONS, Ultra-rapid Metabolizers of Codeine). 13. Nursing mothers using codeine should be informed that a subset of people who use codeine (ultra-rapid metabolizers) may convert codeine into its active metabolite, morphine, resulting that higher than expected exposure of morphine which can lead to toxic serum This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda levels of morphine in infants of nursing mothers. Nursing mothers should be informed how to recognize the symptoms of morphine toxicity in their infants, such as sedation, difficulty breastfeeding, breathing difficulties, and decreased tone (see PRECAUTIONS, Ultra-rapid Metabolizers of Codeine). Drug Interactions Carisoprodol: The sedative effects of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Concomitant use of carisoprodol and meprobamate, a metabolite of carisoprodol, is not recommended (see WARNINGS, Sedation). Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see CLINICAL PHARMACOLOGY). Coadministration of CYP2C19 inhibitors, such as omeprazole or fluvoxamine, with carisoprodol could result in increased exposure of carisoprodol and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such as rifampin or St. John’s Wort, with carisoprodol could result in decreased exposure of carisoprodol and increased exposure of meprobamate. Low dose aspirin also showed an induction effect on CYP2C19. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown. Aspirin: Clinically important interactions may occur when certain drugs or alcohol are administered concomitantly with aspirin. Alcohol: Concomitant use of aspirin with ≥ 3 alcoholic drinks may increase the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Anticoagulants: Concomitant use of aspirin with anticoagulants (e.g., heparin, warfarin, clopidogrel) increases the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Additionally, aspirin can displace warfarin from protein binding sites, leading to prolongation of the international normalized ratio (INR). Antihypertensives: The concomitant administration of aspirin with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and diuretics may diminish the hypotensive effects of these anti-hypertensive products due to aspirin’s inhibition of renal prostaglandins, which may lead to decreased renal blood flow and increased sodium and fluid retention. Concomitant use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide due to competition at the renal tubule for secretion. Corticosteroids: Concomitant administration of aspirin and corticosteriods may decrease salicylate plasma levels. Methotrexate: Aspirin may enhance the toxicity of methotrexate due to displacement of methotrexate from its plasma protein binding sites and/or reduction of the renal clearance of methotrexate. Nonsteroidal anti-inflammatory drugs (NSAIDs): The concurrent use of aspirin with selective and nonselective NSAIDs increases the risk of serious GI adverse reactions (see WARNINGS, Serious Gastrointestinal Adverse Reactions). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Products that effect urinary pH: Ammonium chloride and other drugs that acidify the urine can elevate plasma salicylate concentrations. In contrast, antacids, by alkalinizing the urine, may decrease plasma salicylate concentrations. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid and sulfinpyrazone. Codeine Phosphate: The sedative effects of codeine phosphate and other CNS depressants (e.g., alcohol, benzodiazepines, other opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously (see WARNINGS, Respiratory Depression and Sedation). Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies of carcinogenesis have been done with Soma Compound with Codeine. Carisoprodol: Long term studies in animals have not been performed to evaluate the carcinogenic potential of carisoprodol. Carisoprodol was not formally evaluated for genotoxicity. In published studies, carisoprodol was mutagenic in the in vitro mouse lymphoma cell assay in the absence of metabolizing enzymes, but was not mutagenic in the presence of metabolizing enzymes. Carisoprodol was clastogenic in the in vitro chromosomal aberration assay using Chinese hamster ovary cells with or without the presence of metabolizing enzymes. Other types of genotoxic tests resulted in negative findings. Carisoprodol was not mutagenic in the Ames reverse mutation assay using S. typhimurium strains with or without metabolizing enzymes, and was not clastogenic in an in vivo mouse micronucleus assay of circulating blood cells. Carisoprodol was not formally evaluated for effects on fertility. Published reproductive studies of carisoprodol in mice found no alteration in fertility although an alteration in reproductive cycles characterized by a greater time spent in estrus was observed at a carisoprodol dose of 1200 mg/kg/day. In a 13-week toxicology study that did not determine fertility, mouse testes weight and sperm motility were reduced at a dose of 1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day, corresponding to approximately 2.6 times the human equivalent dosage of 350 mg four times a day, based on a body surface area comparison. The significance of these findings for human fertility is not known. Aspirin: Administration of aspirin for 68 weeks in the feed of rats was not carcinogenic. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Aspirin has been shown to inhibit ovulation in rats (see Pregnancy.) Pregnancy: Pregnancy Category D. It is not known whether Soma Compound with Codeine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adequate animal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reproduction studies have not been conducted with Soma Compound with Codeine. Soma Compound with Codeine should be given to a pregnant woman only if clearly needed. Carisoprodol: There are no data on the use of carisoprodol during human pregnancy. Animal studies indicate that carisoprodol crosses the placenta and results in adverse effects on fetal growth and postnatal survival. The primary metabolite of carisoprodol, meprobamate, is an approved anxiolytic. Retrospective, post-marketing studies do not show a consistent association between maternal use of meprobamate and an increased risk for particular congenital malformations. Teratogenic effects: Animal studies have not adequately evaluated the teratogenic effects of carisoprodol. There was no increase in the incidence of congenital malformations noted in reproductive studies in rats, rabbits, and mice treated with meprobamate. Retrospective, post- marketing studies of meprobamate during human pregnancy were equivocal for demonstrating an increased risk of congenital malformations following first trimester exposure. Across studies that indicated an increased risk, the types of malformations were inconsistent. Nonteratogenic effects: In animal studies, carisoprodol reduced fetal weights, postnatal weight gain, and postnatal survival at maternal doses equivalent to 1 to 1.5 times the human dose (based on a body surface area comparison). Rats exposed to meprobamate in-utero showed behavioral alterations that persisted into adulthood. For children exposed to meprobamate in- utero, one study found no adverse effects on mental or motor development or IQ scores. Carisoprodol should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Aspirin: Teratogenic effects: Prior to 30 weeks gestation, aspirin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, aspirin should be avoided by pregnant women as premature closure of the fetal ductus arteriosus which may result in fetal pulmonary hypertension and fetal death. Salicylate products have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths, and neonatal death. Studies in rodents have shown salicylates to be teratogenic when given in early gestation, and embryocidal when given in later gestation in doses considerably greater than usual therapeutic doses in humans. Labor and Delivery Carisoprodol: There is no information about the effects of carisoprodol on the mother and the fetus during labor and delivery. Aspirin: Ingestion of aspirin within one week of delivery or during labor may prolong delivery or lead to excessive blood loss in the mother, fetus, or neonate. Prolonged labor due to prostaglandin inhibition has been reported with aspirin use. Codeine Phosphate: The use of codeine phosphate during labor may lead to respiratory depression in the neonate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers Carisoprodol: Very limited data in humans show that carisoprodol is present in breast milk and may reach concentrations two to four times the maternal plasma concentrations. In one case report, a breast-fed infant received about 4 to 6% of the maternal daily dose through breast milk and experienced no adverse effects. However, milk production was inadequate and the baby was supplemented with formula. In lactation studies in mice, female pup survival and pup weight at weaning were decreased. This information suggests that maternal use of carisoprodol may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when carisoprodol is administered to a nursing woman. Aspirin: Nursing mothers should avoid the use of aspirin because salicylate is excreted in breast milk which may lead to bleeding in the infant. Codeine Phosphate: 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. Despite the common use of codeine products to manage postpartum pain, reports of codeine- associated adverse reactions in nursing infants are rare. Nursing mothers who are ultra-rapid metabolizers of codeine have higher-than-expected levels of morphine (the active metabolite of codeine) in their blood, leading to higher levels of morphine in their breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, in nursing mothers who are ultra-rapid metabolizers of codeine, the maternal use of codeine can lead to serious adverse reactions, including death; in their nursing infants and in the nursing mothers (see PRECAUTIONS, Ultra-rapid Metabolizers of Codeine). Prior to prescribing nursing mothers codeine phosphate, 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 the infant. 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. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. Pediatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound with Codeine in pediatric patients less than 16 years of age have not been established. Geriatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound with Codeine in patients over 65 years old have not been established. ADVERSE REACTIONS The following adverse reactions which have occurred with the administration of the individual products alone may also occur with the use of Soma Compound with Codeine. The following events have been reported during post-approval individual use of carisoprodol, aspirin, and codeine. 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carisoprodol: Cardiovascular: Tachycardia, postural hypotension, and facial flushing (see OVERDOSAGE). Central Nervous System: Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, insomnia, and seizures (see OVERDOSAGE). Gastrointestinal: Nausea, vomiting, and epigastric discomfort. Hematologic: Leukopenia, pancytopenia Aspirin: The most common adverse reactions associated with the use of aspirin have been gastrointestinal, including abdominal pain, anorexia, nausea, vomiting, gastritis, and occult bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions and PRECAUTIONS, Gastrointestinal Adverse Reactions). Other adverse reactions associated with the use of aspirin include elevated liver enzymes, rash, pruritus, purpura, intracranial hemorrhage, interstitial nephritis, acute renal failure, and tinnitus. Tinnitus may be a sign of high serum salicylate levels (see OVERDOSAGE). Codeine phosphate: Nausea, vomiting, constipation, miosis, sedation, and dizziness. DRUG ABUSE AND DEPENDENCE – Controlled Substance: Schedule C-III (see WARNINGS). OVERDOSAGE Signs and Symptoms: Any of the following signs and symptoms which have been reported with overdose of the individual products may occur with overdose of Soma Compound with Codeine and may be modified to a varying degree by the effects of the other products present in Soma Compound with Codeine. Carisoprodol: Overdosage of carisoprodol commonly produces CNS depression. Death, coma, respiratory depression, hypotension, seizures, delirium, hallucinations, dystonic reactions, nystagmus, blurred vision, mydriasis, euphoria, muscular incoordination, rigidity, and/or headache have been reported with SOMA overdosage. Many of the carisoprodol overdoses have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol). The effects of an overdose of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) can be additive even when one of the drugs has been taken in the recommended dosage. Fatal accidental and non-accidental overdoses of carisoprodol have been reported alone or in combination with CNS depressants. Aspirin: Salicylate toxicity may result from an overdose of an acute ingestion or chronic intoxication. Mild to moderate salicylate poisoning is usually associated with plasma salicylic concentrations about 200 µg/mL and is characterized by tinnitus, hearing difficulty, headache, dim vision, dizziness, tachypnea, increased thirst, nausea, vomiting, sweating, and diarrhea. In the early stages of overdose, CNS stimulation and respiratory alkalosis can occur; however, in the later stages CNS depression and metabolic acidosis can occur. Symptoms and signs of severe salicylate poisoning, associated with plasma salicylic concentrations greater than 400 µg/mL, include hyperthermia, dehydration, delirium, GI This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hemorrhage, pulmonary edema, and CNS depression (e.g., coma). Death is usually due to respiratory failure or cardiovascular collapse. Overdose of aspirin in pediatric patients: Salicylate poisoning should be considered in pediatric patients with symptoms of vomiting, hyperpnea, and hyperthermia. Salicylate poisoning should be considered in infants with metabolic acidosis and all pediatric patients with severe salicylate poisoning. Codeine Phosphate: Acute overdose of opioids, including codeine phosphate, is characterized by CNS depression (somnolence progressing to coma), respiratory depression, hypotension, miosis, skeletal muscle flaccidity, and cold and clammy skin. Treatment of Overdosage: Provide symptomatic and supportive treatment, as indicated. For more information on the management of an overdose of Soma Compound with Codeine (carisoprodol, aspirin, and codeine phosphate, USP) tablets, contact a Poison Control Center. Carisoprodol: Basic life support measures should be instituted as dictated by the clinical presentation of the carisoprodol overdose. Induced emesis is not recommended due to the risk of CNS and respiratory depression, which may increase the risk of aspiration pneumonia. Gastric lavage should be considered soon after ingestion (within one hour). Circulatory support should be administered with volume infusion and vasopressor agents if needed. Seizures should be treated with intravenous benzodiazepines and the reoccurrence of seizures may be treated with phenobarbital. In cases of severe CNS depression, airway protective reflexes may be compromised and tracheal intubation should be considered for airway protection and respiratory support. The following types of treatment have been used successfully with an overdose of meprobamate, a metabolite of carisoprodol: activated charcoal (oral or via nasogastric tube), forced diuresis, peritoneal dialysis, and hemodialysis (carisoprodol is also dialyzable). Careful monitoring of urinary output is necessary and overhydration should be avoided. Observe for possible relapse due to incomplete gastric emptying and delayed absorption. Aspirin: Since there are no specific antidotes for salicylate poisoning, the aim of treatment is to enhance elimination of salicylate; reduce further salicylate absorption; correct fluid, electrolyte, or acid/base imbalances; and provide cardio-respiratory support. The acid-base status should be followed closely with serial serum pH determinations (using arterial blood gas). If acidosis is present, intravenous sodium bicarbonate should be given, along with adequate hydration, until salicylate levels decrease to within the therapeutic range. To enhance elimination, forced diuresis and alkalinization of the urine may be beneficial. Gastric emptying and/or lavage are recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal is beneficial, if less than 3 hours have passed since ingestion. Charcoal absorption should not be employed prior to emesis and lavage. In patients with renal insufficiency or in cases of life-threatening aspirin intoxication, hemodialysis or peritoneal dialysis is usually required. Additional treatment of aspirin overdose in pediatric patients: Pediatric patients should be sponged with tepid water. Infusion of glucose may be required to control hypoglycemia. Exchange transfusion may be indicated in infants and young children. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Codeine Phosphate: After a severe opioid overdose, primary attention should be given to the need for re-establishment of a patent airway and institution of assisted ventilation. Elimination or evacuation of gastric contents may be necessary in order to eliminate unabsorbed drug. Before attempting treatment by gastric emptying or activated charcoal, care should be taken to secure the airway. Pure opioid antagonists (e.g., naloxone, nalmefene) are specific antidotes to severe respiratory and CNS depression resulting from opioid overdose. If the response to these opioid antagonists is sub-optimal, additional antagonist should be administered. Since the duration of action of codeine may exceed that of the opioid antagonist, the patient’s respiratory status should be continuously monitored for the need for additional doses of antagonist to maintain adequate respiration. DOSAGE AND ADMINISTRATION The recommended dose of Soma Compound with Codeine is 1 or 2 tablets, four times daily in adults. One Soma Compound with Codeine tablet contains 200 mg of carisoprodol, 325 mg of aspirin, and 16 mg of codeine phosphate. The maximum daily dose (i.e., two tablets taken four times daily) will provide 1600 mg of carisoprodol, 2600 mg of aspirin, and 128 mg of codeine phosphate per day. The recommended maximum duration of Soma Compound with Codeine use is up to two or three weeks. HOW SUPPLIED Soma Compound with Codeine (carisoprodol 200 mg, aspirin 325 mg, and codeine phosphate, 16 mg) Tablets are oval, convex, two-layered and inscribed on the white layer with SOMA CC and on the yellow layer with WALLACE 2403. The tablets are available in bottles of 100 (NDC 0037-2403-01). Storage: Store at controlled room temperature 15°- 30°C (59°- 86°F). Protect from moisture. Dispense in a tight, light-resistant container. Meda Pharmaceuticals, Inc. Somerset, NJ 08873 IN-095E2-14 Revised 10/08 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:48.882824	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/012366s031lbl.pdf', 'application_number': 12366, 'submission_type': 'SUPPL ', 'submission_number': 31}
10,805	SOMA® COMPOUND with CODEINE CIII (carisoprodol, aspirin and codeine phosphate, USP) Tablets for Oral Use Warning: May be habit-forming. DESCRIPTION Soma Compound with Codeine (carisoprodol, aspirin, and codeine phosphate tablets, USP) is a fixed-dose combination product containing the following three products:  200 mg of carisoprodol, a centrally-acting muscle relaxant  325 mg of aspirin, an analgesic with antipyretic and anti-inflammatory properties  16 mg of codeine phosphate, a centrally-acting narcotic analgesic. It is available as a two-layered, white and yellow, oval-shaped tablet for oral administration. Carisoprodol: Chemically, carisoprodol is N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate and its molecular formula is C12H24N2O4, with a molecular weight of 260.33. The structural formula of carisoprodol is: structural formula Aspirin: Chemically, aspirin (acetylsalicyclic acid) is 2-(acetyloxy)-, benzoic acid and its molecular formula is C9H8O4, with a molecular weight of 180.16. The structural formula of aspirin is: structural formula Codeine Phosphate: Chemically, codeine phosphate is 7,8-Didehydro-4,5α-epoxy-3-methoxy 17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate and its molecular formula is C18H24NO7P, with a molecular weight of 406.37. The structural formula of codeine phosphate is: 1 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Other ingredients in the Soma Compound with Codeine drug product are croscarmellose sodium, D&C Yellow #10, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, sodium metabisulfite, starch, and stearic acid. CLINICAL PHARMACOLOGY Mechanism of Action Carisoprodol: The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified. In animal studies, muscle relaxation induced by carisoprodol is associated with altered interneuronal activity in the spinal cord and in the descending reticular formation of the brain. Aspirin: The mechanism of action of aspirin in relieving pain is by inhibition of the body’s production of prostaglandins, which are thought to cause pain sensations by stimulating muscle contractions and dilating blood vessels. Codeine Phosphate: The precise mechanism of action of codeine phosphate, an opioid agonist, in relieving pain has not been established. The binding of codeine phosphate to mu, delta, and kappa opioid receptors in the central nervous system (CNS) may change the perception of pain. The analgesic activity of codeine phosphate is probably due to its conversion to morphine. Pharmacodynamics Carisoprodol: Carisoprodol is a centrally-acting muscle relaxant that does not directly relax tense skeletal muscles. A metabolite of carisoprodol, meprobamate, has anxiolytic and sedative properties. The degree to which these properties of meprobamate contribute to the safety and efficacy of Soma Compound with Codeine is unknown. Aspirin: Aspirin is a non-narcotic analgesic with anti-inflammatory and anti-pyretic activity. Inhibition of prostaglandin biosynthesis appears to account for most of its anti-inflammatory and for at least part of its analgesic and antipyretic properties. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever. Aspirin can cause serious gastrointestinal injury including bleeding, obstruction, and perforations from ulcers possibly by inhibition of the production of prostaglandins, compromising the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing (see WARNINGS). Aspirin inhibits 2 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Codeine Phosphate: Codeine phosphate is a centrally-acting narcotic analgesic. Its actions are qualitatively similar to morphine, but its potency is substantially less. Opioids, including codeine phosphate have the following effects:  respiratory depression by a direct effect on the brainstem respiratory centers  depression of the cough reflex by direct effect on the cough center in the medulla  constriction of the pupils (i.e., miosis)  decreased gastric, biliary, and pancreatic secretions  reduction in the motility of the stomach and small and large intestine which results in constipation and delayed digestion  nausea and vomiting by directly stimulating the chemoreceptor trigger zone  increased biliary tract pressure as a result of spasm of the sphincter of Oddi  peripheral vasodilatation which may result in orthostatic hypotension  histamine release which may result in pruritus, flushing, and sweating  increased tone of the bladder detrusor muscle, ureters, and vesical sphincter which may result in urinary retention Pharmacokinetics Carisoprodol: The pharmacokinetics of carisoprodol and its metabolite meprobamate were studied in a study of 24 healthy subjects (12 male and 12 female) who received single doses of 350 mg of carisoprodol (see Table 1). The Cmax of meprobamate was 2.5 ± 0.5 μg/mL (mean ± SD) after administration of a single 350 mg dose of carisoprodol, which is approximately 30% of the Cmax of meprobamate (approximately 8 μg/mL) after administration of a single 400 mg dose of meprobamate. Table 1: Pharmacokinetic Parameters of Carisoprodol and Meprobamate (Mean ± SD, n=24) Carisoprodol Meprobamate Cmax (μg/mL) 1.8 ± 1.0 2.5 ± 0.5 AUCinf (μg·hour/mL) 7.0 ± 5.0 46 ± 9.0 Tmax (hour) 1.7 ± 0.8 4.5 ± 1.9 T1/2 (hour) 2.0 ± 0.5 9.6 ± 1.5 Absorption: Absolute bioavailability of carisoprodol has not been determined. After administration of a single dose of 350 mg of carisoprodol, the mean time to peak plasma concentrations (Tmax) of carisoprodol was approximately 1.5 to 2 hours. Co-administration of a high-fat meal with 350 mg of carisoprodol had no effect on the pharmacokinetics of carisoprodol. 3 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolism: The major pathway of carisoprodol metabolism is via the liver by cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism (see Patients with Reduced CYP2C19 Activity below). Elimination: Carisoprodol is eliminated by both renal and non-renal routes with a terminal elimination half-life of approximately 2 hours after administration of a single dose of 350 mg of carisoprodol. The half-life of meprobamate is approximately 10 hours after administration of a single dose of 350 mg of carisoprodol. Gender: Exposure of carisoprodol is higher in females than in male subjects (approximately 30 to 50% on a weight adjusted basis). Overall exposure of meprobamate is comparable between female and male subjects. Patients with Reduced CYP2C19 Activity: Carisoprodol should be used with caution in patients with reduced CYP2C19 activity. Published studies indicate that patients who are poor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3 to 5% and in Asians is approximately 15 to 20%. Aspirin: Absorption: The rate of aspirin absorption from the gastrointestinal (GI) tract is dependent upon the presence or absence of food, gastric pH (the presence of absence of GI antacids), and other physiologic factors. Following absorption, aspirin is hydrolyzed to salicylic acid in the gut wall and during first-pass metabolism with peak plasma levels of salicylic acid occurring within 1 to 2 hours of dosing. Distribution: Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, kidneys, heart, and lungs. The protein binding of salicylate is concentration dependent, i.e., nonlinear. At plasma concentrations of salicylic acid, < 100 μg/mL and > 400 μg/mL, approximately 90 and 76 percent of plasma salicylate is bound to albumin, respectively. Metabolism: Aspirin, which has a half-life of about 15 minutes, is hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin may not be detectable 1 to 2 hours after dosing. Salicylic acid, which has a plasma half-life of approximately 6 hours, is conjugated in the liver to form salicyluric acid, salicyl phenolic glucuronide, salicyl acyl glucuronide, gentisic acid, and gentisuric acid. At higher serum concentrations of salicylic acid, the total clearance of salicylic acid decreases due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses of aspirin (e.g., > 10 grams), the plasma half-life of salicylic acid may be increased to over 20 hours. Elimination: The elimination of salicylic acid is constant in relation to the plasma salicylic acid concentration. Following therapeutic doses of aspirin, approximately 75, 10, 10, and 5 percent is 4 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda found excreted in the urine as salicyluric acid, salicylic acid, a phenolic glucuronide of salicylic acid, and an acyl glucuronide of salicylic acid, respectively. As the urinary pH rises above 6.5, the renal clearance of free salicylate increases from less than 5 percent to greater than 80 percent. Alkalinization of the urine is a key concept in the management of salicylate overdose (see OVERDOSAGE, Treatment of Overdosage). Clearance of salicylic acid is also reduced in patients with renal impairment. Codeine Phosphate: Absorption: Codeine is readily absorbed from the GI tract. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. Distribution: Codeine is rapidly distributed from the intravascular spaces to the tissues with preferential uptake by the liver, spleen, and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration of codeine does not correlate with brain concentration of codeine or the relief of pain. Metabolism: The plasma half-life of codeine is about 2.9 hours. Elimination: 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. INDICATIONS AND USAGE Soma Compound with Codeine is indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults. Soma Compound with Codeine should only be used for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use has not been established and because acute, painful musculoskeletal conditions are generally of short duration (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Soma Compound with Codeine is contraindicated in patients with a history of:  a serious GI complication (i.e., bleeding, perforations, obstruction) due to aspirin use  aspirin induced asthma (a symptom complex with occurs in patients who have asthma, rhinosinusitis, and nasal polyps who develop a severe, potentially fatal bronchospasm shortly after taking aspirin or other NSAIDs)  hypersensitivity reaction to carbamate such as meprobamate  acute intermittent prophyria WARNINGS 5 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carisoprodol: Sedation Carisoprodol has sedative properties and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. There have been post-marketing reports of motor vehicle accidents associated with the use of carisoprodol. Since the sedative effects of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricylic antidepressants) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Drug Dependence, Withdrawal, and Abuse Carisoprodol, the active ingredient in SOMA, has been subject to abuse, dependence, withdrawal, misuse, and criminal diversion (see DRUG ABUSE AND DEPENDENCE). Abuse of SOMA poses a risk of overdose which may lead to death, CNS and respiratory depression, hypotension, seizures and other disorders (see OVERDOSAGE). Post-marketing cases of carisoprodol abuse and dependence have been reported in patients with prolonged use and a history of drug abuse. Although most of these patients took other drugs of abuse, some patients solely abused carisoprodol. Withdrawal symptoms have been reported following abrupt cessation of SOMA after prolonged use. Reported withdrawal symptoms included insomnia, vomiting, abdominal cramps, headache, tremors, muscle twitching, ataxia, hallucinations, and psychosis. One of carisoprodol’s metabolites meprobamate, (a controlled substance), may also cause dependence (see CLINICAL PHARMACOLOGY). To reduce the risk of SOMA abuse, assess the risk of abuse prior to prescribing. After prescribing, limit the length of treatment to three weeks for the relief of acute musculoskeletal discomfort, keep careful prescription records, monitor for signs of abuse and overdose, and educate patients and their families about abuse and on proper storage and disposal. Aspirin: Serious Gastrointestinal Adverse Reactions Aspirin can cause serious gastrointestinal (GI) adverse reactions including bleeding, perforation, and obstruction of the stomach, small intestine, or large intestine, which can be fatal. Aspirin- associated serious GI adverse reactions can occur anywhere along the GI tract, at any time, with or without warning symptoms. Patients at higher risk of aspirin-associated serious upper GI adverse reactions include patients with a history of aspirin associated GI bleeding from ulcers (complicated ulcers), a history of aspirin-associated ulcers (uncomplicated ulcers), geriatric patients, patients with poor baseline health status, patients taking higher doses of aspirin, and patients taking concomitant anticoagulants, NSAIDs, and/or large amounts of alcohol. To minimize the risk for aspirin-associated GI serious adverse reactions, the lowest effective aspirin dose should be used for the shortest possible duration. Anaphylaxis and Anaphylactoid Reactions 6 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Aspirin may cause an increased risk of serious anaphylaxis and anaphylactoid reactions, which can occur in patients without known prior exposure to aspirin (see CONTRAINDICATIONS). Patients with a serious anaphylaxis and anaphylactoid reaction should receive emergency care. Codeine Phosphate: Respiratory Depression Respiratory depression is a serious adverse reaction of opioid agonists, including codeine phosphate. Opioid-associated respiratory depression is more likely to occur in geriatric patients, debilitated patients, in non-tolerant patients who are given large initial doses of opioids, and in patients who are receiving concomitant respiratory depressants (e.g. other opioids, benzodiazepines, tricyclic antidepressants, phenothiazines, skeletal muscle relaxants, alcohol). In addition, patients with chronic obstructive pulmonary disease (COPD), restrictive lung disease, decreased respiratory drive, and/or respiratory depression are at a greater risk of opioid- associated respiratory depression. Opioid-associated respiratory depression may be increased in patients with increased intracranial pressure (e.g., patients with head trauma, intracranial lesions). Abuse and Diversion Codeine phosphate is a Schedule III controlled substance. Administration of opioids including codeine phosphate has been associated with abuse. Healthcare professionals should contact their State Professional Licensing Board or State Substances Authority for information on how to prevent or detect abuse or diversion of codeine phosphate. Dependence and Tolerance Use of opioids, including codeine phosphate, can result in psychological and/or physical dependence. Withdrawal symptoms associated with abrupt opioid discontinuation include restlessness, irritability, anxiety, lacrimation, rhinorrhea, sweating, chills, mydriasis, insomnia, diarrhea, tachypnea, tachycardia, and/or hypertension. The use of opioids, including codeine phosphate, use can result in tolerance – the need for increasing doses to maintain a desired effect in the absence of other factors (e.g., disease progression). Gastrointestinal Obstruction Opioids, including codeine phosphate, may cause gastrointestinal obstruction. Sedation Opioids, including codeine phosphate, may impair the mental and physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. Since the sedative effects of codeine phosphate and other CNS depressants (e.g., other opioids, benzodiazepines, tricyclic antidepressants, skeletal muscle relaxants, alcohol) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Hypotension 7 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The use of opioids, including codeine phosphate, may cause hypotension. Opioid-associated hypotension is more likely in patients with dehydration or with the concomitant use of drugs associated with hypotension. PRECAUTIONS Patients with impaired renal or hepatic function The safety and pharmacokinetics of Soma Compound with Codeine in patients with renal or hepatic impairment have not been evaluated. Carisoprodol: Since carisoprodol is excreted by the kidney and is metabolized in the liver, caution should be exercised if carisoprodol is administered to patients with impaired renal or hepatic function. Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis. Seizures There have been post-marketing reports of seizures in patients who received carisoprodol. Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol) (see OVERDOSAGE). Aspirin: Gastrointestinal Adverse Reactions In addition to serious gastrointestinal adverse reactions, the use of aspirin is also associated with gastritis, gastrointestinal erosions, abdominal pain, heartburn, vomiting, and nausea (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Codeine Phosphate: Obscuring Medical Conditions Opioids, including codeine phosphate, may obscure the clinical course of patients with head injuries because of the CNS depressive effects of opioids. In addition, opioids, including codeine phosphate, may obscure the symptoms and/or signs that are used for the diagnosis or for the monitoring of patients with acute abdominal conditions. Ultra-rapid Metabolizers of Codeine Some patients may be ultra-rapid metabolizers of codeine phosphate due to a specific CYP2D6*2x2 genotype. These patients convert codeine into its active metabolite, morphine, more rapidly and completely than patients who are normal metabolizers of codeine, resulting in higher than expected serum morphine levels. Even at labeled dosage regimens of codeine phosphate, patients who are ultra-rapid metabolizers may experience overdose symptoms such as respiratory depression, extreme sleepiness, or delirium. Toxic serum levels of morphine have been reported in infants of nursing mothers who may be ultra-rapid metabolizers (see PRECAUTIONS, Nursing Mothers). The prevalence of this CYP2D6 phenotype has been estimated at 16 to 28% in North Africans, Ethiopians, and Arabs; 1 to 10% in Caucasians; 3% in 8 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda African Americans; and 0.5 to 1% in Chinese, Japanese, and Hispanics. Data are not available for other ethnic groups. When healthcare providers prescribe codeine-containing products, they should choose the lowest effective dose for the shortest period of time. Use in Patients with Pancreatic or Biliary Duct Disease Opioids, including codeine phosphate, should be used with caution in patients with pancreatic or biliary duct disease because opioids may cause spasm of the sphincter of Oddi and diminish pancreatic and/or biliary secretions. Information for Patients: Patients should be advised to contact their health care provider if they experience any adverse reactions to Soma Compound with Codeine. Carisoprodol: 1. Patients should be advised that carisoprodol may cause drowsiness and/or dizziness, and has been associated with motor vehicle accidents. Patients should be advised to avoid taking carisoprodol before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery (see WARNINGS, Sedation). 2. Patients should be advised to avoid alcoholic beverages while taking carisoprodol and to check with their doctor before taking other CNS depressants such as benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or other sedatives (see WARNINGS, Sedation). 3. Patients should be advised that treatment with carisoprodol should be limited to acute use (up to two or three weeks) for the relief of acute, musculoskeletal discomfort. In the post-marketing experience with carisoprodol, cases of dependence, withdrawal, and abuse have been reported with prolonged use. If musculoskeletal symptoms still persist, patients should contact their healthcare provider for further evaluation. Aspirin: 1. Patients should be warned that aspirin can cause epigastric discomfort, gastric and duodenal ulcers, and serious GI adverse reactions, such as bleeding, perforations, and/or obstruction of the stomach or intestines, which may result in hospitalization and death. Although serious GI bleeding can occur without warning symptoms (e.g., hematemesis, melena, hematochezia), patients should be alert for these symptoms and should seek urgent medical care if any of these indicative symptoms occur (see WARNINGS, Serious Gastrointestinal Adverse Reactions). In addition, patients should be alert for symptoms of ulcers (e.g., night time epigastric discomfort, vomiting, weight loss) and should seek medical attention if these symptoms occur. Patients who consume three or more alcoholic drinks a day should be counseled about the GI bleeding risks involved with the use of aspirin with alcohol. 9 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Patients should be informed of the symptoms of an anaphylactoid reaction or anaphylaxis (e.g., hives, difficulty breathing, swelling of face or throat). If these symptoms occur, patients should be instructed to seek immediate emergency help. Codeine Phosphate: 1. Since codeine phosphate may cause drowsiness and/or dizziness, patients should be advised to assess their individual response to codeine phosphate before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery (see WARNING, Sedation). 2. Patients should be advised to avoid alcoholic beverages while taking codeine phosphate and to check with their doctor before taking other CNS depressants such as other opioids, benzodiazepines, tricyclic antidepressants, sedating antihistamines, or other sedatives (see WARNINGS, Respiratory Depression and Sedation). 3. Patients should be advised that codeine phosphate is a controlled substance. Codeine phosphate can result in psychological and physical dependence (see WARNING, Dependence and Tolerance). 4. Codeine phosphate tablets should be placed in a secure place out of the reach of children 5. Patients should be advised that opioids, including codeine phosphate, can cause constipation and appropriate measures should be taken to reduce the risk of constipation (e.g., dietary changes, laxatives). 6. Patients should be advised that opioids, including codeine phosphate, have been associated with hypotension and gastrointestinal obstruction (WARNINGS, Hypotension, Gastrointestinal Obstruction). 7. Patients should be advised that a subset of people who use codeine (ultra-rapid metabolizers) may convert codeine into its active metabolite, morphine, resulting that higher than expected exposure of morphine which can lead to increased opioid toxicity (see PRECAUTIONS, Ultra-rapid Metabolizers of Codeine). 8. Nursing mothers using codeine should be informed that a subset of people who use codeine (ultra-rapid metabolizers) may convert codeine into its active metabolite, morphine, resulting that higher than expected exposure of morphine which can lead to toxic serum levels of morphine in infants of nursing mothers. Nursing mothers should be informed how to recognize the symptoms of morphine toxicity in their infants, such as sedation, difficulty breastfeeding, breathing difficulties, and decreased tone (see PRECAUTIONS, Ultra-rapid Metabolizers of Codeine). Drug Interactions 10 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carisoprodol: The sedative effect of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Concomitant use of carisoprodol and meprobamate, a metabolite of carisoprodol, is not recommended (see WARNINGS, Sedation). Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see CLINICAL PHARMACOLOGY). Co-administration of CYP2C19 inhibitors, such as omeprazole or fluvoxamine, with carisoprodol could result in increased exposure of carisoprodol and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such as rifampin or St. John’s Wort, with carisoprodol could result in decreased exposure of carisoprodol and increased exposure of meprobamate. Low dose aspirin also showed an induction effect of CYP2C19. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown. Aspirin: Clinically important interactions may occur when certain drugs or alcohol are administered concomitantly with aspirin. Alcohol: Concomitant use of aspirin with ≥ 3 alcoholic drinks may increase the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Anticoagulants: Concomitant use of aspirin and anticoagulants (e.g., heparin, warfarin, clopidogrel) increase the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Additionally, aspirin can displace warfarin from protein binding sites, leading to prolongation of the international normalized ratio (INR). Antihypertensives: The concomitant administration of aspirin with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and diuretics may diminish the hypotensive effects of these anti-hypertensive products due to aspirin’s inhibition of renal prostaglandins, which may lead to decreased renal blood flow and increased sodium and fluid retention. Concomitant use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide due to competition at the renal tubule for secretion. Corticosteroids: Concomitant administration of aspirin and corticosteroids may decrease salicylate plasma levels. Methotrexate: Aspirin may enhance the toxicity of methotrexate due to displacement of methotrexate from its plasma protein binding sites and/or reduction of the renal clearance of methotrexate. Nonsteroidal anti-inflammatory drugs (NSAIDs): The concurrent use of aspirin with selective and nonselective NSAIDs increases the risk of serious GI adverse reactions (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. 11 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Products that effect urinary pH: Ammonium chloride and other drugs that acidify the urine can elevate plasma salicylate concentrations. In contrast, antacids, by alkalinizing the urine, may decrease plasma salicylate concentrations. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid and sulfinpyrazone. Codeine Phosphate: The sedative effects of codeine phosphate and other CNS depressants (e.g., alcohol, benzodiazepines, other opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously (see WARNINGS, Respiratory Depression and Sedation). Carcinogens, Mutagenesis, Impairments of Fertility: No long-term studies of carcinogens have been done with Soma Compound with Codeine. Carisoprodol: Long term studies in animals have not been performed to evaluate the carcinogenic potential of carisoprodol. Carisoprodol was not formally evaluated for genotoxicity. In published studies, carisoprodol was mutagenic in the in vitro mouse lymphoma cell assay in the absence of metabolizing enzymes, but was not mutagenic in the presence of metabolizing enzymes. Carisoprodol was clastogenic in the in vitro chromosomal aberration assay using Chinese hamster ovary cells with or without the presence of metabolizing enzymes. Other types of genotoxic tests resulted in negative findings. Carisoprodol was not mutagenic in the Ames reverse mutation assay using S. typhimurium strains with or without metabolizing enzymes, and was not clastogenic in an in vitro mouse micronucleus assay of circulating blood cells. Carisoprodol was not formally evaluated for effects on fertility. Published reproductive studies of carisoprodol in mice found no alteration in fertility although an alteration in reproductive cycles characterized by a greater time spend in estrus was observed at a carisoprodol dose of 1200 mg/kg/day. In a 13-week toxicology study that did not determine fertility, mouse testes weight and sperm motility were reduced at a dose of 1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day, corresponding to approximately 2.6 times the human equivalent dosage of 350 mg four times a day, based on a body surface area comparison. The significance of these findings for human fertility is not known. Aspirin: Administration of aspirin for 68 weeks in the feed of rats was not carcinogenic. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Aspirin has been shown to inhibit ovulation in rats (see Pregnancy). Pregnancy: Pregnancy Category D. It is not known whether Soma Compound with Codeine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adequate animal reproduction studies 12 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda have not been conducted with Soma Compound with Codeine. Soma Compound with Codeine should be given to a pregnant woman only if clearly needed. Carisoprodol: There are no data on the use of carisoprodol during human pregnancy. Animal studies indicate that carisoprodol crosses the placenta and results in adverse effects on fetal growth and postnatal survival. The primary metabolite of carisoprodol, meprobamate, is an approved anxiolytic. Retrospective, post-marketing studies do not show a consistent association between maternal use of meprobamate and an increased risk for particular congenital malformations. Teratogenic effects: Animal studies have not adequately evaluated the teratogenic effects of carisoprodol. There was no increase in the incidence of congenital malformations noted in the reproductive studies in rats, rabbits, and mice treated with meprobamate. Retrospective, post- marketing studies of meprobamate during human pregnancy were equivocal for demonstrating an increased risk of congenital malformations following the first trimester exposure. Across studies that indicated an increased risk, the types of malformations were inconsistent. Nonteratogenic effects: In animal studies, carisoprodol reduced fetal weights, postnatal weight gain, and postnatal survival at maternal doses equivalent to 1 to 1.5 times the human dose (based on a body surface area comparison). Rats exposed to meprobamate in-utero showed behavioral alterations that persisted into adulthood. For children exposed to meprobamate in-utero, one study found no adverse effects on mental or motor development or IQ scores. Carisoprodol should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Aspirin: Teratogenic effects: Prior to 30 weeks gestation, aspirin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, aspirin should be avoided by pregnant women as premature closure of the fetal ductus arteriosus which may result in fetal pulmonary hypertension and fetal death. Salicylate products have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths, and neonatal death. Studies in rodents have shown salicylates to be teratogenic when given in early gestation, and embryocidal when given in later gestation in doses considerably greater than usual therapeutic doses in humans. Labor and Delivery Carisoprodol: There is no information about the effects of carisoprodol on the mother and the fetus during labor and delivery. Aspirin: Ingestion of aspirin within one week of delivery or during labor may prolong delivery or lead to excessive blood loss in the mother, fetus, or neonate. Prolonged labor due to prostaglandin inhibition has been reported with aspirin use. Codeine Phosphate: The use of codeine phosphate during labor may lead to respiratory depression in the neonate. 13 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers Carisoprodol: Very limited data in humans show that carisoprodol is present in breast milk and may reach concentrations two to four times the maternal plasma concentrations. In one case report, a breast-fed infant received about 4 to 6% of the maternal daily dose though breast milk and experienced no adverse effects. However, milk production was inadequate and the baby was supplemented with formula. In lactation studies in mice, female pup survival and pup weight at weaning was decreased. This information suggests that maternal use of carisoprodol may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when carisoprodol is administered to a nursing woman. Aspirin: Nursing mothers should avoid the use of aspirin because salicylate is excreted in breast milk which may lead to bleeding in the infant. Codeine Phosphate: 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. Despite the common use of codeine products to manage postpartum pain, reports of codeine- associated adverse reactions in nursing infants are rare. Nursing mothers who are ultra-rapid metabolizers of codeine have higher-than-expected levels of morphine (the active metabolite of codeine) in their blood, leading to higher levels of morphine in their breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, in nursing mothers who are ultra-rapid metabolizers of codeine, the maternal use of codeine can lead to serious adverse reactions, including death; in their nursing infants and in the nursing mothers (see PRECAUTIONS, Ultra-rapid Metabolizers of Codeine). Prior to prescribing nursing mothers codeine phosphate, 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 the infant. 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. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. Pediatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound with Codeine in pediatric patients less than 16 years of age have not been established. Geriatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound with Codeine in geriatric patients over 65 years of age have not been established. ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions which have occurred with the administration of the individual products alone may also occur with the use of Soma Compound with Codeine. The following 14 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda events have been reported during post-approval individual use of carisoprodol, aspirin, and codeine. 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. Carisoprodol: Cardiovascular: Tachycardia, postural hypotension, and facial flushing (see OVERDOSAGE). Central Nervous System: Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, insomnia, and seizures (see OVERDOSAGE). Gastrointestinal: Nausea, vomiting, and epigastric discomfort. Hematologic: Leukopenia, pancytopenia. Aspirin: The most common adverse reactions associated with the use of aspirin have been gastrointestinal, including both abdominal pain, anorexia, nausea, vomiting, gastritis, and occult bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions and PRECAUTIONS, Gastrointestinal Adverse Reactions). Other adverse reactions associated with the use of aspirin include elevated liver enzymes, rash, pruritus, purpura, intracranial hemorrhage, interstitial nephritis, acute renal failure, and tinnitus. Tinnitus may be a sign of high serum salicylate levels (see OVERDOSAGE). Codeine Phosphate: Nausea, vomiting, constipation, miosis, sedation, dizziness. DRUG ABUSE AND DEPENDENCE – Controlled Substance: Schedule C-III (see WARNINGS). Controlled Substance SOMA contains carisoprodol, a Schedule IV controlled substance. Carisoprodol has been subject to abuse, misuse, and criminal diversion for nontherapeutic use (see WARNINGS). Abuse Abuse of carisoprodol poses a risk of overdosage which may lead to death, CNS and respiratory depression, hypotension, seizures and other disorders (see WARNINGS). Patients at high risk of SOMA abuse may include those with prolonged use of carisoprodol, with a history of drug abuse, or those who use SOMA in combination with other abused drugs. Prescription drug abuse is the intentional non-therapeutic use of a drug, even once, for its rewarding psychological or physiological effects. Drug addiction, which develops after repeated drug abuse, is characterized by a strong desire to take a drug despite harmful consequences, difficulty in controlling its use, giving a higher priority to drug use than to obligations, increased tolerance, and sometimes physical withdrawal. Drug abuse and drug addiction are separate and distinct from physical dependence and tolerance (for example, abuse or addiction may not be accompanied by tolerance or physical dependence) (see DEPENDENCE). 15 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dependence Tolerance is when a patient’s reaction to a specific dosage and concentration is progressively reduced, in the absence of disease progression, requiring an increase in the dosage to maintain the same. Physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Both tolerance and physical dependence have been reported with the prolonged use of SOMA. Reported withdrawal symptoms with SOMA include insomnia, vomiting, abdominal cramps, headache, tremors, muscle twitching, anxiety, ataxia, hallucinations, and psychosis. Instruct patients taking large doses of SOMA or those taking the drug for a prolonged time to not abruptly stop SOMA (see WARNINGS). OVERDOSAGE Signs and Symptoms: Any of the following signs and symptoms which have been reported with overdose of the individual products may occur with overdose of Soma Compound with Codeine and may be modified to a varying degree by the effects of the other products present in Soma Compound with Codeine. Carisoprodol: Overdosage of carisoprodol commonly produces CNS depression. Death, coma, respiratory depression, hypotension, seizures, delirium, hallucinations, dystonic reactions, nystagmus, blurred vision, mydriasis, euphoria, muscular incoordination, rigidity, and/or headache have been reported with SOMA overdosage. Serotonin syndrome has been reported with carisoprodol intoxication. Many of the carisoprodol overdoses have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol). The effects of an overdose of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) can be additive even when one of the drugs has been taken in the recommended dosage. Fatal accidental and non-accidental overdoses of carisoprodol have been reported alone or in combination with CNS depressants. Aspirin: Salicylate toxicity may result from an overdose of an acute ingestion or chronic intoxication. Mild to moderate salicylate poisoning is usually associated with plasma salicylic concentrations about 200 μg/mL and is characterized by tinnitus, hearing difficulty, headache, dim vision, dizziness, tachypnea, increased thirst, nausea, vomiting, sweating, and diarrhea. In the early stages of overdose, CNS stimulation and respiratory alkalosis can occur; however, in the later stages CNS depression and metabolic acidosis can occur. Symptoms and signs of severe salicylate poisoning, associated with plasma salicylic concentrations greater that 400 μg/mL, include hyperthermia, dehydration, delirium, GI hemorrhage, pulmonary edema, and CNS depression (e.g., coma). Death is usually due to respiratory failure or cardiovascular collapse. Overdose of aspirin in pediatric patients: Salicylate poisoning should be considered in pediatric patients with symptoms of vomiting, hyperpnea, and hyperthermia. Salicylate poisoning should 16 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be considered in infants with metabolic acidosis and all pediatric patients with severe salicylate poisoning. Codeine Phosphate: Acute overdose of opioids, including codeine phosphate, is characterized by CNS depression (somnolence progressing to coma), respiratory depression, hypotension, miosis, skeletal muscle flaccidity, and cold and clammy skin. Treatment of Overdosage: Provide symptomatic and supportive treatment, as indicated. For more information on the management of an overdose of Soma Compound with Codeine (carisoprodol, aspirin, and codeine phosphate, USP) tablets, contact a Poison Control Center. Carisoprodol: Basic life support measures should be instituted as dictated by the clinical presentation of the carisoprodol overdose. Vomiting should not be induced due to the risk of CNS and respiratory depression, and subsequent aspiration. Gastric lavage should be considered soon after ingestion (within one hour). Circulatory support should be administered with volume infusion and vasopressor agents if needed. Seizures should be treated with intravenous benzodiazepines and the reoccurrence of seizures may be treated with phenobarbital. In cases of severe CNS depression, airway protective reflexes may be compromised and tracheal intubation should be considered for airway protection and respiratory support. For decontamination in cases of severe toxicity, activated charcoal should be considered in a hospital setting in patients with large overdoses who present early and are not demonstrating CNS depression and can protect their airway. Aspirin: Since there are no specific antidotes for salicylate poisoning, the aim of the treatment is to enhance elimination of salicylate; reduce further salicylate absorption; correct fluid, electrolyte, or acid/base imbalances; and provide cardio-respiratory support. The acid-base status should be followed closely with serial serum pH determinations (using arterial blood gas). If acidosis is present, intravenous sodium bicarbonate should be given, along with adequate hydration, until salicylate levels decrease to within the therapeutic range. To enhance elimination, forced diuresis and alkalinization of the urine may be beneficial. Gastric emptying and/or lavage are recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal is beneficial, if less than 3 hours have passed since ingestion. Charcoal absorption should not be employed prior to emesis and lavage. In patients with renal insufficiency or in cases of life- threatening aspirin intoxication, hemodialysis or peritoneal dialysis is usually required. Additional treatment of aspirin overdose in pediatric patients: Pediatric patients should be sponged with tepid water. Infusion of glucose may be required to control hypoglycemia. Exchange transfusion may be indicated in infants and young children. Codeine Phosphate: After a severe opioid overdose, primary attention should be given to the need for re-establishment of a patent airway and institution of assisted ventilation. Elimination or evacuation of gastric contents may be necessary in order to eliminate unabsorbed drug. Before attempting treatment by gastric emptying or activated charcoal, care should be taken to secure the airway. Pure opioid antagonist (e.g., naloxone, nalmefene) are specific antidotes to severe respiratory and CNS depression resulting from opioid overdose. If the response to these 17 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda opioid antagonists is sub-optimal, additional antagonist should be administered. Since the duration of action of codeine may exceed that of the opioid antagonist, the patient’s respiratory status should be continuously monitored for the need for additional doses of antagonist to maintain adequate respiration. DOSAGE AND ADMINISTRATION The recommended daily dose of Soma Compound with Codeine is 1 or 2 tablets, four times daily in adults. One Soma Compound with Codeine tablet contains 200 mg of carisoprodol, 325 mg of aspirin, and 16 mg of codeine phosphate. The maximum daily dose (i.e., two tablets taken four times daily) will provide 1600 mg of carisoprodol, 2600 mg of aspirin, and 128 mg of codeine phosphate per day. The recommended maximum duration of Soma Compound with Codeine use is up to two or three weeks. HOW SUPPLIED Soma Compound with Codeine (carisoprodol 200 mg, aspirin 325 mg, and codeine phosphate, 16 mg) Tablets are oval, convex, two-layered, and inscribed on the white layer with SOMA CC and on the yellow layer with WALLACE 2403. The tablets are available in bottles of 100 (NDC 0037-2403-01). Storage: Store at controlled room temperature 15°-30°C (59°-86°F). Protect from moisture. Dispense in a tight, light-resistant container. company logo ©2013 Meda Pharmaceuticals Inc. Revised 1/2013 18 Reference ID: 3253736 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.060956	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012366s033lbl.pdf', 'application_number': 12366, 'submission_type': 'SUPPL ', 'submission_number': 33}
10,804	SOMA® COMPOUND with CODEINE (carisoprodol, aspirin and codeine phosphate, USP) tablets for oral use Warning: May be habit-forming. CIII DESCRIPTION Soma Compound with Codeine (carisoprodol, aspirin, and codeine phosphate tablets, USP) is a fixed-dose combination product containing the following three products: • 200 mg of carisoprodol, a centrally-acting muscle relaxant • 325 mg of aspirin, an analgesic with antipyretic and anti-inflammatory properties • 16 mg of codeine phosphate, a centrally-acting narcotic analgesic. It is available as a two-layered, white and yellow, oval-shaped tablet for oral administration. Carisoprodol: Chemically, carisoprodol is N-isopropyl-2-methyl-2-propyl-1,3 propanediol dicarbamate and its molecular formula is C12H24N2O4, with a molecular weight of 260.33. The structural formula of carisoprodol is: Structural Formula Aspirin: Chemically, aspirin (acetylsalicyclic acid) is 2-(acetyloxy)-, benzoic acid and its molecular formula is C9H8O4, with a molecular weight of 180.16. The structural formula of aspirin is: Structural Formula Codeine Phosphate: Chemically, codeine phosphate is 7,8-Didehydro-4,5α-epoxy-3 methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate and its molecular formula is C18H24NO7P, with a molecular weight of 406.37. The structural formula of codeine phosphate is: 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Structural Formula Other ingredients in the Soma Compound with Codeine drug product are croscarmellose sodium, D&C Yellow #10, hypromellose, magnesium stearate, microcrystalline cellulose, povidine, sodium metabisulfite, starch, and stearic acid. CLINICAL PHARMACOLOGY Mechanism of Action Carisoprodol: The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified. In animal studies, muscle relaxation induced by carisoprodol is associated with altered interneuronal activity in the spinal cord and in the descending reticular formation of the brain. Aspirin: The mechanism of action of aspirin in relieving pain is by inhibition of the body’s production of prostaglandins, which are thought to cause pain sensations by stimulating muscle contractions and dilating blood vessels. Codeine Phosphate: The precise mechanism of action of codeine phosphate, an opioid agonist, in relieving pain has not been established. The binding of codeine phosphate to mu, delta, and kappa opioid receptors in the central nervous system (CNS) may change the perception of pain. The analgesic activity of codeine phosphate is probably due to its conversion to morphine. Pharmacodynamics Carisoprodol: Carisoprodol is a centrally-acting muscle relaxant that does not directly relax tense skeletal muscles. A metabolite of carisoprodol, meprobamate, has anxiolytic and sedative properties. The degree to which these properties of meprobamate contribute to the safety and efficacy of Soma Compound with Codeine is unknown. Aspirin: Aspirin is a non-narcotic analgesic with anti-inflammatory and anti-pyretic activity. Inhibition of prostaglandin biosynthesis appears to account for most of its anti inflammatory and for at least part of its analgesic and antipyretic properties. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever. Aspirin can cause serious gastrointestinal injury including bleeding, obstruction, and perforations from ulcers possibly by inhibition of the production of prostaglandins, compromising the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing (see WARNINGS). Aspirin inhibits platelet aggregation by irreversibly 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Codeine Phosphate: Codeine phosphate is a centrally-acting narcotic analgesic. Its actions are qualitatively similar to morphine, but its potency is substantially less. Opioids, including codeine phosphate have the following effects: • respiratory depression by a direct effect on the brainstem respiratory centers • depression of the cough reflex by direct effect on the cough center in the medulla • constriction of the pupils (i.e., miosis) • decreased gastric, biliary, and pancreatic secretions • reduction in the motility of the stomach and small and large intestine which results in constipation and delayed digestion • nausea and vomiting by directly stimulating the chemoreceptor trigger zone • increased biliary tract pressure as a result of spasm of the sphincter of Oddi • peripheral vasodilatation which may result in orthostatic hypotension • histamine release which may result in pruritus, flushing, and sweating • increased tone of the bladder detrusor muscle, ureters, and vesical sphincter which may result in urinary retention Pharmacokinetics Carisoprodol: The pharmacokinetics of carisoprodol and its metabolite meprobamate were studied in a study of 24 healthy subjects (12 male and 12 female) who received single doses of 350 mg of carisoprodol (see Table 1). The Cmax of meprobamate was 2.5 ± 0.5 µg/mL (mean ± SD) after administration of a single 350 mg dose of carisoprodol, which is approximately 30% of the Cmax of meprobamate (approximately 8 µg/mL) after administration of a single 400 mg dose of meprobamate. Table 1: Pharmacokinetic Parameters of Carisoprodol and Meprobamate (Mean ± SD, n=24) Carisoprodol Meprobamate Cmax (µg/mL) 1.8 ± 1.0 2.5 ± 0.5 AUCinf (µg·hour/mL) 7.0 ± 5.0 46 ± 9.0 Tmax (hour) 1.7 ± 0.8 4.5 ± 1.9 T1/2 (hour) 2.0 ± 0.5 9.6 ± 1.5 Absorption: Absolute bioavailability of carisoprodol has not been determined. After administration of a single dose of 350 mg of carisoprodol, the mean time to peak plasma concentrations (Tmax) of carisoprodol was approximately 1.5 to 2 hours. Co administration of a high-fat meal with 350 mg of carisoprodol had no effect on the pharmacokinetics of carisoprodol. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolism: The major pathway of carisoprodol metabolism is via the liver by cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism (see Patients with Reduced CYP2C19 Activity below). Elimination: Carisoprodol is eliminated by both renal and non-renal routes with a terminal elimination half-life of approximately 2 hours after administration of a single dose of 350 mg of carisoprodol. The half-life of meprobamate is approximately 10 hours after administration of a single dose of 350 mg of carisoprodol. Gender: Exposure of carisoprodol is higher in females than in male subjects (approximately 30 to 50% on a weight adjusted basis). Overall exposure of meprobamate is comparable between female and male subjects. Patients with Reduced CYP2C19 Activity: Carisoprodol should be used with caution in patients with reduced CYP2C19 activity. Published studies indicate that patients who are poor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3 to 5% and in Asians is approximately 15 to 20%. Aspirin: Absorption: The rate of aspirin absorption from the gastrointestinal (GI) tract is dependent upon the presence or absence of food, gastric pH (the presence of absence of GI antacids), and other physiologic factors. Following absorption, aspirin is hydrolyzed to salicylic acid in the gut wall and during first-pass metabolism with peak plasma levels of salicylic acid occurring within 1 to 2 hours of dosing. Distribution: Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, kidneys, heart, and lungs. The protein binding of salicylate is concentration dependent, i.e., nonlinear. At plasma concentrations of salicylic acid, < 100 µg/mL and > 400 µg/mL, approximately 90 and 76 percent of plasma salicylate is bound to albumin, respectively. Metabolism: Aspirin, which has a half-life of about 15 minutes, is hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin may not be detectable 1 to 2 hours after dosing. Salicylic acid, which has a plasma half-life of approximately 6 hours, is conjugated in the liver to form salicyluric acid, salicyl phenolic glucuronide, salicyl acyl glucuronide, gentisic acid, and gentisuric acid. At higher serum concentrations of salicylic acid, the total clearance of salicylic acid decreases due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses of aspirin (e.g., > 10 grams), the plasma half-life of salicylic acid may be increased to over 20 hours. Elimination: The elimination of salicylic acid is constant in relation to the plasma salicylic acid concentration. Following therapeutic doses of aspirin, approximately 75, 10, 10, and 5 percent is found excreted in the urine as salicyluric acid, salicylic acid, a phenolic glucuronide of salicylic acid, and an acyl glucuronide of salicylic acid, 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda respectively. As the urinary pH rises above 6.5, the renal clearance of free salicylate increases from less than 5 percent to greater than 80 percent. Alkalinization of the urine is a key concept in the management of salicylate overdose (see OVERDOSAGE, Treatment of Overdosage). Clearance of salicylic acid is also reduced in patients with renal impairment. Codeine Phosphate: Absorption: Codeine is readily absorbed from the GI tract. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. Distribution: Codeine is rapidly distributed from the intravascular spaces to the tissues with preferential uptake by the liver, spleen, and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration of codeine does not correlate with brain concentration of codeine or the relief of pain. Metabolism: The plasma half-life of codeine is about 2.9 hours. Elimination: 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. INDICATIONS AND USAGE Soma Compound with Codeine is indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults. Soma Compound with Codeine should only be used for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use has not been established and because acute, painful musculoskeletal conditions are generally of short duration (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Soma Compound with Codeine is contraindicated in patients with a history of: • a serious GI complication (i.e., bleeding, perforations, obstruction) due to aspirin use • aspirin induced asthma (a symptom complex with occurs in patients who have asthma, rhinosinusitis, and nasal polyps who develop a severe, potentially fatal bronchospasm shortly after taking aspirin or other NSAIDs) • hypersensitivity reaction to carbamate such as meprobamate • acute intermittent prophyria 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Carisoprodol: Sedation Carisoprodol has may have sedative properties and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. There have been post-marketing reports of motor vehicle accidents associated with the use of carisoprodol. Since the sedative effects of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricylic antidepressants) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Drug Dependence, Withdrawal, and Abuse In post-marketing experience with carisoprodol, cases of dependence, withdrawal, and abuse have been reported with prolonged use. Most cases of dependence, withdrawal, and abuse occurred in patients who have had a history of addiction or who used carisoprodol in combination with other drugs with abuse potential. However, there have been post-marketing adverse event reports of carisoprodol-associated abuse when used without other drugs with abuse potential. Withdrawal symptoms have been reported following abrupt cessation after prolonged use. To reduce the chance of carisoprodol dependence, withdrawal, or abuse, carisoprodol should be used with caution in addiction prone patients and in patients taking other CNS depressants including alcohol, and carisoprodol should not be used more than two to three weeks for the relief of acute musculoskeletal discomfort. Although most reports of carisoprodol-associated abuse have been seen in patients receiving concomitant drugs with abuse potential, there have been post-marketing adverse event reports of carisoprodol-associated abuse when used without drugs with abuse potential. One of the metabolites of cCarisoprodol, and one of its metabolites, meprobamate (a controlled substance), may cause dependence (see CLINICAL PHARMACOLOGY). Aspirin: Serious Gastrointestinal Adverse Reactions Aspirin can cause serious gastrointestinal (GI) adverse reactions including bleeding, perforation, and obstruction of the stomach, small intestine, or large intestine, which can be fatal. Aspirin-associated serious GI adverse reactions can occur anywhere along the GI tract, at any time, with or without warning symptoms. Patients at higher risk of aspirin-associated serious upper GI adverse reactions include patients with a history of aspirin associated GI bleeding from ulcers (complicated ulcers), a history of aspirin- associated ulcers (uncomplicated ulcers), geriatric patients, patients with poor baseline health status, patients taking higher doses of aspirin, and patients taking concomitant anticoagulants, NSAIDs, and/or large amounts of alcohol. To minimize the risk for aspirin-associated GI serious adverse reactions, the lowest effective aspirin dose should be used for the shortest possible duration. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Anaphylaxis and Anaphylactoid Reactions Aspirin may cause an increased risk of serious anaphylaxis and anaphylactoid reactions, which can occur in patients without known prior exposure to aspirin (see CONTRAINDICATIONS). Patients with a serious anaphylaxis and anaphylactoid reaction should receive emergency care. Codeine Phosphate: Respiratory Depression Respiratory depression is a serious adverse reaction of opioid agonists, including codeine phosphate. Opioid-associated respiratory depression is more likely to occur in geriatric patients, debilitated patients, in non-tolerant patients who are given large initial doses of opioids, and in patients who are receiving concomitant respiratory depressants (e.g. other opioids, benzodiazepines, tricyclic antidepressants, phenothiazines, skeletal muscle relaxants, alcohol). In addition, patients with chronic obstructive pulmonary disease (COPD), restrictive lung disease, decreased respiratory drive, and/or respiratory depression are at a greater risk of opioid-associated respiratory depression. Opioid- associated respiratory depression may be increased in patients with increased intracranial pressure (e.g., patients with head trauma, intracranial lesions). Abuse and Diversion Codeine phosphate is a Schedule III controlled substance. Administration of opioids including codeine phosphate has been associated with abuse. Healthcare professionals should contact their State Professional Licensing Board or State Substances Authority for information on how to prevent or detect abuse or diversion of codeine phosphate. Dependence and Tolerance Use of opioids, including codeine phosphate, can result in psychological and/or physical dependence. Withdrawal symptoms associated with abrupt opioid discontinuation include restlessness, irritability, anxiety, lacrimation, rhinorrhea, sweating, chills, mydriasis, insomnia, diarrhea, tachypnea, tachycardia, and/or hypertension. The use of opioids, including codeine phosphate, use can result in tolerance – the need for increasing doses to maintain a desired effect in the absence of other factors (e.g., disease progression). Gastrointestinal Obstruction Opioids, including codeine phosphate, may cause gastrointestinal obstruction. Sedation Opioids, including codeine phosphate, may impair the mental and physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. Since the sedative effects of codeine phosphate and other CNS depressants (e.g., other opioids, benzodiazepines, tricyclic antidepressants, skeletal muscle relaxants, alcohol) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypotension The use of opioids, including codeine phosphate, may cause hypotension. Opioid- associated hypotension is more likely in patients with dehydration or with the concomitant use of drugs associated with hypotension. PRECAUTIONS Patients with impaired renal or hepatic function The safety and pharmacokinetics of Soma Compound with Codeine in patients with renal or hepatic impairment have not been evaluated. Carisoprodol: Since carisoprodol is excreted by the kidney and is metabolized in the liver, caution should be exercised if carisoprodol is administered to patients with impaired renal or hepatic function. Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis. Seizures There have been post-marketing reports of seizures in patients who received carisoprodol. Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol) (see OVERDOSAGE). Aspirin: Gastrointestinal Adverse Reactions In addition to serious gastrointestinal adverse reactions, the use of aspirin is also associated with gastritis, gastrointestinal erosions, abdominal pain, heartburn, vomiting, and nausea (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Codeine Phosphate: Obscuring Medical Conditions Opioids, including codeine phosphate, may obscure the clinical course of patients with head injuries because of the CNS depressive effects of opioids. In addition, opioids, including codeine phosphate, may obscure the symptoms and/or signs that are used for the diagnosis or for the monitoring of patients with acute abdominal conditions. Ultra-rapid Metabolizers of Codeine Some patients may be ultra-rapid metabolizers of codeine phosphate due to a specific CYP2D6*2x2 genotype. These patients convert codeine into its active metabolite, morphine, more rapidly and completely than patients who are normal metabolizers of codeine, resulting in higher than expected serum morphine levels. Even at labeled dosage regimens of codeine phosphate, patients who are ultra-rapid metabolizers may experience overdose symptoms such as respiratory depression, extreme sleepiness, or delirium. Toxic serum levels of morphine have been reported in infants of nursing mothers who may be ultra-rapid metabolizers (see PRECAUTIONS , Nursing Mothers). The prevalence of this CYP2D6 phenotype has been estimated at 16 to 28% in North Africans, Ethiopians, and Arabs; 1 to 10% in Caucasians; 3% in African 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Americans; and 0.5 to 1% in Chinese, Japanese, and Hispanics. Data is not available for other ethnic groups. When healthcare providers prescribe codeine-containing products, they should choose the lowest effective dose for the shortest period of time. Use in Patients with Pancreatic or Biliary Duct Disease Opioids, including codeine phosphate, should be used with caution in patients with pancreatic or biliary duct disease because opioids may cause spasm of the sphincter of Oddi and diminish pancreatic and/or biliary secretions. Information for Patients: Patients should be advised to contact their health care provider if they experience any adverse reactions to Soma Compound with Codeine. Carisoprodol: 1. Since Patients should be advised that carisoprodol may cause drowsiness and/or dizziness, and has been associated with motor vehicle accidents. pPatients should be advised to assess their individual response to avoid taking carisoprodol before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery (see WARNINGS, Sedation). 2. Patients should be advised to avoid alcoholic beverages while taking carisoprodol and to check with their doctor before taking other CNS depressants such as benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or other sedatives (see WARNINGS, Sedation). 3. Patients should be advised that treatment with carisoprodol should be limited to acute use (up to two or three weeks) for the relief of acute, musculoskeletal discomfort. In the post-marketing experience with carisoprodol, cases of dependence, withdrawal, and abuse have been reported with prolonged use. If the musculoskeletal symptoms still persist, patients should contact their healthcare provider for further evaluation. Aspirin: 4. Patients should be warned that aspirin can cause epigastric discomfort, gastric and duodenal ulcers, and serious GI adverse reactions, such as bleeding, perforations, and/or obstruction of the stomach or intestines, which may result in hospitalization and death. Although serious GI bleeding can occur without warning symptoms (e.g., hematemesis, melena, hematochezia), patients should be alert for these symptoms and should seek urgent medical care if any of these indicative symptoms occur (see WARNINGS, Serious Gastrointestinal Adverse Reactions). In addition, patients should be alert for symptoms of ulcers (e.g., night time epigastric discomfort, vomiting, weight loss) and should seek medical attention if these symptoms occur. Patients who consume three or more 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda alcoholic drinks a day should be counseled about the GI bleeding risks involved with the use of aspirin with alcohol. 5. Patients should be informed of the symptoms of an anaphylactoid reaction or anaphylaxis (e.g., hives, difficulty breathing, swelling of face or throat). If these symptoms occur, patients should be instructed to seek immediate emergency help. Codeine Phosphate: 6. Since codeine phosphate may cause drowsiness and/or dizziness, patients should be advised to assess their individual response to codeine phosphate before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery (see WARNING, Sedation). 7. Patients should be advised to avoid alcoholic beverages while taking codeine phosphate and to check with their doctor before taking other CNS depressants such as other opioids, benzodiazepines, tricyclic antidepressants, sedating antihistamines, or other sedatives (see WARNINGS, Respiratory Depression and Sedation). 8. Patients should be advised that codeine phosphate is a controlled substance. Codeine phosphate can result in psychological and physical dependence (see WARNING, Dependence and Tolerance). 9. Codeine phosphate tablets should be placed in a secure place out of the reach of children 10. Patients should be advised that opioids, including codeine phosphate, can cause constipation and appropriate measures should be taken to reduce the risk of constipation (e.g., dietary changes, laxatives). 11. Patients should be advised that opioids, including codeine phosphate, have been associated with hypotension and gastrointestinal obstruction (WARNINGS, Hypotension, Gastrointestinal Obstruction). 12. Patients should be advised that a subset of people who use codeine (ultra-rapid metabolizers) may convert codeine into its active metabolite, morphine, resulting that higher than expected exposure of morphine which can lead to increased opioid toxicity (see PRECAUTIONS, Ultra-rapid Metabolizers of Codeine). 13. Nursing mothers using codeine should be informed that a subset of people who use codeine (ultra-rapid metabolizers) may convert codeine into its active metabolite, morphine, resulting that higher than expected exposure of morphine which can lead to toxic serum levels of morphine in infants of nursing mothers. Nursing mothers should be informed how to recognize the symptoms of morphine toxicity in their infants, such as sedation, difficulty breastfeeding, breathing 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda difficulties, and decreased tone (see PRECAUTIONS, Ultra-rapid Metabolizers of Codeine). Drug Interactions Carisoprodol: The sedative effect of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Concomitant use of carisoprodol and meprobamate, a metabolite of carisoprodol, is not recommended (see WARNINGS, Sedation). Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see CLINICAL PHARMACOLOGY). Co-administration of CYP2C19 inhibitors, such as omeprazole or fluvoxamine, with carisoprodol could result in increased exposure of carisoprodol and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such as rifampin or St. John’s Wort, with carisoprodol could result in decreased exposure of carisoprodol and increased exposure of meprobamate. Low dose aspirin also showed an induction effect of CYP2C19. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown. Aspirin: Clinically important interactions may occur when certain drugs or alcohol are administered concomitantly with aspirin. Alcohol: Concomitant use of aspirin with ≥ 3 alcoholic drinks may increase the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Anticoagulants: Concomitant use of aspirin and anticoagulants (e.g., heparin, warfarin, clopidogrel) increase the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Additionally, aspirin can displace warfarin from protein binding sites, leading to prolongation of the international normalized ratio (INR). Antihypertensives: The concomitant administration of aspirin with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta- blockers, and diuretics may diminish the hypotensive effects of these anti-hypertensive products due to aspirin’s inhibition of renal prostaglandins, which may lead to decreased renal blood flow and increased sodium and fluid retention. Concomitant use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide due to competition at the renal tubule for secretion. Corticosteroids: Concomitant administration of aspirin and corticosteroids may decrease salicylate plasma levels. Methotrexate: Aspirin may enhance the toxicity of methotrexate due to displacement of methotrexate from its plasma protein binding sites and/or reduction of the renal clearance of methotrexate. 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nonsteroidal anti-inflammatory drugs (NSAIDs): The concurrent use of aspirin with selective and nonselective NSAIDs increases the risk of serious GI adverse reactions (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Products that effect urinary pH: Ammonium chloride and other drugs that acidify the urine can elevate plasma salicylate concentrations. In contrast, antacids, by alkalinizing the urine, may decrease plasma salicylate concentrations. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid and sulfinpyrazone. Codeine Phosphate: The sedative effects of codeine phosphate and other CNS depressants (e.g., alcohol, benzodiazepines, other opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously (see WARNINGS, Respiratory Depression and Sedation). Carcinogens, Mutagenesis, Impairments of Fertility: No long-term studies of carcinogens have been done with Soma Compound with Codeine. Carisoprodol: Long tern studies in animals have not been performed to evaluate the carcinogenic potential of carisoprodol. Carisoprodol was not formally evaluated for genotoxicity. In published studies, carisoprodol was mutagenic in the in vitro mouse lymphoma cell assay in the absence of metabolizing enzymes, but was not mutagenic in the presence of metabolizing enzymes. Carisoprodol was clastogenic in the in vitro chromosomal aberration assay using Chinese hamster ovary cells with or without the presence of metabolizing enzymes. Other types of genotoxic tests resulted in negative findings. Carisoprodol was not mutagenic in the Ames reverse mutation assay using S. typhimurium strains with or without metabolizing enzymes, and was not clastogenic in an in vitro mouse micronucleus assay of circulating blood cells. Carisoprodol was not formally evaluated for effects on fertility. Published reproductive studies of carisoprodol in mice found no alteration in fertility although an alteration in reproductive cycles characterized by a greater time spend in estrus was observed at a carisoprodol dose of 1200 mg/kg/day. In a 13-week toxicology study that did not determine fertility, mouse testes weight and sperm motility were reduced at a dose of 1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day, corresponding to approximately 2.6 times the human equivalent dosage of 350 mg four times a day, based on a body surface area comparison. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The significance of these findings for human fertility is not known. Aspirin: Administration of aspirin for 68 weeks in the feed of rats was not carcinogenic. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Aspirin has been shown to inhibit ovulation in rats (see Pregnancy). Pregnancy: Pregnancy Category D. It is not known whether Soma Compound with Codeine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adequate animal reproduction studies have not been conducted with Soma Compound with Codeine. Soma Compound with Codeine should be given to a pregnant woman only if clearly needed. Carisoprodol: There are no data on the use of carisoprodol during human pregnancy. Animal studies indicate that carisoprodol crosses the placenta and results in adverse effects on fetal growth and postnatal survival. The primary metabolite of carisoprodol, meprobamate, is an approved anxiolyic. Retrospective, post-marketing studies do not show a consistent association between maternal use of meprobamate and an increased risk for particular congenital malformations. Teratogenic effects: Animal studies have not adequately evaluated the teratogenic effects of carisoprodol. There was no increase in the incidence of congenital malformations noted in the reproductive studies in rats, rabbits, and mice treated with meprobamate. Retrospective, post-marketing studies of meprobamate during human pregnancy were equivocal for demonstrating an increased risk of congenital malformations following the first trimester exposure. Across studies that indicated an increased risk, the types of malformations were inconsistent. Nonteratogenic effects: In animal studies, carisoprodol reduced fetal weights, postnatal weight gain, and postnatal survival at maternal doses equivalent to 1 to 1.5 times the human dose (based on a body surface area comparison). Rats exposed to meprobamate in-utero showed behavioral alterations that persisted into adulthood. For children exposed to meprobamate in-utero, one study found no adverse effects on mental or motor development or IQ scores. Carisoprodol should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Aspirin: Teratogenic effects: Prior to 30 weeks gestation, aspirin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, aspirin should be avoided by pregnant women as premature closure of the fetal ductus arteriosus which may result in fetal pulmonary hypertension and fetal death. Salicylate products have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths, and neonatal death. Studies in 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda rodents have show salicylates to be teratogenic when given in early gestation, and embryocidal when given in later gestation in doses considerably greater than usual therapeutic doses in humans. Labor and Delivery Carisoprodol: There is no information about the effects of carisoprodol on the mother and the fetus during labor and delivery. Aspirin: Ingestion of aspirin within one week of delivery or during labor may prolong delivery or lead to excessive blood loss in the mother, fetus, or neonate. Prolonged labor due to prostaglandin inhibition has been reported with aspirin use. Codeine Phosphate: The use of codeine phosphate during labor may lead to respiratory depression in the neonate. Nursing Mothers Carisoprodol: Very limited data in humans show that carisoprodol is present in break milk and may reach concentrations two to four times the maternal plasma concentrations. In one case report, a breast-fed infant received about 4 to 6% of the maternal daily dose though breast milk and experienced no adverse effects. However, milk production was inadequate and the baby was supplemented with formula. In lactation studies in mice, female pup survival and pup weight at weaning was decreased. This information suggests that maternal use of carisoprodol may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when carisoprodol is administered to a nursing woman. Aspirin: Nursing mothers should avoid the use of aspirin because salicylate is excreted in breast milk which may lead to bleeding in the infant. Codeine Phosphate: 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. Despite the common use of codeine products to manage postpartum pain, reports of codeine-associated adverse reactions in nursing infants are rare. Nursing mothers who are ultra-rapid metabolizers of codeine have higher-than-expected levels of morphine (the active metabolite of codeine) in their blood, leading to higher levels of morphine in their breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, in nursing mothers who are ultra-rapid metabolizers of codeine, the maternal use of codeine can lead to serious adverse reactions, including death; in their nursing infants and in the nursing mothers (see PRECAUTIONS, Ultra- rapid Metabolizers of Codeine). Prior to prescribing nursing mothers codeine phosphate, 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 the infant. If a codeine containing product is 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. Pediatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound with Codeine in pediatric patients less than 16 years of age have not been established. Geriatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound with Codeine in pediatric patients over 65 years of age have not been established. ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions which have occurred with the administration of the individual products alone may also occur with the use of Soma Compound with Codeine. The following events have been reported during post-approval individual use of carisoprodol, aspirin, and codeine. 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. Carisoprodol: Cardiovascular: Tachycardia, postural hypotension, and facial flushing (see OVERDOSAGE). Central Nervous System: Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, insomnia, and seizures (see OVERDOSAGE). Gastrointestinal: Nausea, vomiting, and epigastric discomfort. Hematologic: Leukopenia, pancytopenia. Aspirin: The most common adverse reactions associated with the use of aspirin have been gastrointestinal, including both abdominal pain, anorexia, nausea, vomiting, gastritis, and occult bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions and PRECAUTIONS, Gastrointestinal Adverse Reactions). Other adverse reactions associated with the use of aspirin include elevated liver enzymes, rash, pruritus, purpura, intracranial hemorrhage, interstitial nephritis, acute renal failure, and tinnitus. Tinnitus may be a sign of high serum salicylate levels (see OVERDOSAGE). Codeine Phosphate: Nausea, vomiting, constipation, miosis, sedation, dizziness. DRUG ABUSE AND DEPENDENCE – Controlled Substance: Schedule C-III (see WARNINGS). 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Discontinuation of carisoprodol in animals or in humans after chronic administration can produce withdrawal signs, and there are published case reports of human carisoprodol dependence. In vitro studies demonstrate that carisoprodol elicits barbiturate-like effects. Animal behavioral studies indicate that carisoprodol produces rewarding effects. Monkeys self administer carisoprodol. Drug discrimination studies using rats indicate that carisoprodol has positive reinforcing and discriminating effects similar to barbital, meprobamate, and chlordiazepoxide. OVERDOSAGE Signs and Symptoms: Any of the following signs and symptoms which have been reported with overdose of the individual products may occur with overdose of Soma Compound with Codeine and may be modified to a varying degree by the effects of the other products present in Soma Compound with Codeine. Carisoprodol: Overdosage of carisoprodol commonly produces CNS depression. Death, coma, respiratory depression, hypotension, seizures, delirium, hallucinations, dystonic reactions, nystagmus, blurred vision, mydriasis, euphoria, muscular incoordination, rigidity, and/or headache have been reported with SOMA overdosage. Many of the carisoprodol overdoses have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol). The effects of an overdose of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) can be additive even when one of the drugs has been taken in the recommended dosage. Fatal accidental and non-accidental overdoses of carisoprodol have been reported alone or in combination with CNS depressants. Aspirin: Salicylate toxicity may result from an overdose of an acute ingestion or chronic intoxication. Mild to moderate salicylate poisoning is usually associated with plasma salicylic concentrations about 200 µg/mL and is characterized by tinnitus, hearing difficulty, headache, dim vision, dizziness, tachypnea, increased thirst, nausea, vomiting, sweating, and diarrhea. In the early stages of overdose, CNS stimulation and respiratory alkalosis can occur; however, in the later stages CNS depression and metabolic acidosis can occur. Symptoms and signs of severe salicylate poisoning, associated with plasma salicylic concentrations greater that 400 µg/mL, include hyperthermia, dehydration, delirium, GI hemorrhage, pulmonary edema, and CNS depression (e.g., coma). Death is usually due to respiratory failure or cardiovascular collapse. Overdose of aspirin in pediatric patients: Salicylate poisoning should be considered in pediatric patients with symptoms of vomiting, hyperpnea, and hyperthermia. Salicylate poisoning should be considered in infants with metabolic acidosis and all pediatric patients with severe salicylate poisoning. 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Codeine Phosphate: Acute overdose of opioids, including codeine phosphate, is characterized by CNS depression (somnolence progressing to coma), respiratory depression, hypotension, miosis, skeletal muscle flaccidity, and cold and clammy skin. Treatment of Overdosage: Provide symptomatic and supportive treatment, as indicated. For more information on the management of an overdose of Soma Compound with Codeine (carisoprodol, aspirin, and codeine phosphate, USP) tablets, contact a Poison Control Center. Carisoprodol: Basic life support measures should be instituted as dictated by the clinical presentation of the carisoprodol overdose. Induced emesis is not recommended due to the risk of CNS and respiratory depression, which may increase the risk of aspiration pneumonia. Gastric lavage should be considered soon after ingestion (within one hour). Circulatory support should be administered with volume infusion and vasopressor agents if needed. Seizures should be treated with intravenous benzodiazepines and the reoccurrence of seizures may be treated with phenobarbital. In cases of severe CNS depression, airway protective reflexes may be compromised and tracheal intubation should be considered for airway protection and respiratory support. The following types of treatment have been used successfully with an overdose of meprobamate, a metabolite of carisoprodol: activated charcoal (oral or via nasogastric tube), forced diuresis, peritoneal dialysis, and hemodialysis (carisoprodol is also dialyzable). Careful monitoring of urinary output is necessary and overhydration should be avoided. Observe for possible relapse due to incomplete gastric emptying and delayed absorption Aspirin: Since there are no specific antidotes for salicylate poisoning, the aim of the treatment is to enhance elimination of salicylate; reduce further salicylate absorption; correct fluid, electrolyte, or acid/base imbalances; and provide cardio-respiratory support. The acid-base status should be followed closely with serial serum pH determinations (using arterial blood gas). If acidosis is present, intravenous sodium bicarbonate should be given, along with adequate hydration, until salicylate levels decrease to within the therapeutic range. To enhance elimination, forced diuresis and alkalinization of the urine may be beneficial. Gastric emptying and/or lavage are recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal is beneficial, if less than 3 hours have passed since ingestion. Charcoal absorption should not be employed prior to emesis and lavage. In patients with renal insufficiency or in cases of life-threatening aspirin intoxication, hemodialysis or peritoneal dialysis is usually required. Additional treatment of aspirin overdose in pediatric patients: Pediatric patients should be sponged with tepid water. Infusion of glucose may be required to control hypoglycemia. Exchange transfusion may be indicated in infants and young children. Codeine Phosphate: After a severe opioid overdose, primary attention should be given to the need for re-establishment of a patent airway and institution of assisted ventilation. Elimination or evacuation of gastric contents may be necessary in order to eliminate unabsorbed drug. Before attempting treatment by gastric emptying or activated charcoal, care should be taken to secure the airway. Pure opioid antagonist (e.g., naloxone, nalmefene) are specific antidotes to severe respiratory and CNS depression resulting from 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda opioid overdose. If the response to these opioid antagonists is sub-optimal, additional antagonist should be administered. Since the duration of action of codeine may exceed that of the opioid antagonist, the patient’s respiratory status should be continuously monitored for the need for additional doses of antagonist to maintain adequate respiration. DOSAGE AND ADMINISTRATION The recommended daily dose of Soma Compound with Codeine is 1 or 2 tablets, four times daily in adults. One Soma Compound with Codeine tablet contains 200 mg of carisoprodol, 325 mg of aspirin, and 16 mg of codeine phosphate. The maximum daily dose (i.e., two tablets taken four times daily) will provide 1600 mg of carisoprodol, 2600 mg of aspirin, and 128 mg of codeine phosphate per day. The recommended maximum duration of Soma Compound with Codeine use is up to two or three weeks. HOW SUPPLIED Soma Compound with Codeine (carisoprodol 200 mg, aspirin 325 mg, and codeine phosphate, 16 mg) Tablets are oval, convex, two-layered, and inscribed on the white layer with SOMA CC and on the yellow layer with WALLACE 2403. The tablets are available in bottles of 100 (NDC 0037-2403-01). Storage: Store at controlled room temperature 15°-30°C (59°-86°F). Protect from moisture. Dispense in a tight, light-resistant container. To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Company logo ©2009 Meda Pharmaceuticals Inc. IN-095E2-15 Rev 10/09 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.127181	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/012366s032lbl.pdf', 'application_number': 12366, 'submission_type': 'SUPPL ', 'submission_number': 32}
10,807	Zarontin® (Ethosuximide Capsules, USP) DESCRIPTION Zarontin (ethosuximide) is an anticonvulsant succinimide, chemically designated as alpha-ethyl-alpha methyl-succinimide, with the following structural formula: structural formula Each Zarontin capsule contains 250 mg ethosuximide, USP. Also contains: polyethylene glycol 400, NF. The capsule contains D&C yellow No. 10; FD&C red No. 3; gelatin, NF; glycerin, USP; and sorbitol. CLINICAL PHARMACOLOGY Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. INDICATIONS AND USAGE Zarontin is indicated for the control of absence (petit mal) epilepsy. CONTRAINDICATION Ethosuximide should not be used in patients with a history of hypersensitivity to succinimides. WARNINGS Blood dyscrasias Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of ethosuximide; therefore, periodic blood counts should be performed. Should signs and/or symptoms of infection (eg, sore throat, fever) develop, blood counts should be considered at that point. Effects on Liver and Kidneys Ethosuximide is capable of producing morphological and functional changes in the animal liver. In humans, abnormal liver and renal function studies have been reported.Ethosuximide should be administered with extreme caution to patients with known liver or renal disease. Periodic urinalysis and liver function studies are advised for all patients receiving the drug. Systemic Lupus Erythematosus Cases of systemic lupus erythematosus have been reported with the use of ethosuximide. The physician should be alert to this possibility. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Zarontin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Zarontin or any other AED must balance the risk of suicidal thoughts and behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Usage in Pregnancy: Ethosuximide crosses the placenta. Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs. Cases of birth defects have been reported with ethosuximide. The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodological problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, eg, genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential. Ethosuximide is excreted in human breast milk. Because the effects of ethosuximide on the nursing infant are unknown, caution should be exercised when ethosuximide is administered to a nursing mother. Ethosuximide should be used in nursing mothers only if the benefits clearly outweigh the risks. PRECAUTIONS General: Ethosuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients. As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) status. Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Zarontin. Instruct patients to take Zarontin only as prescribed. Ethosuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a motor vehicle or other such activity requiring alertness; therefore, the patient should be cautioned accordingly. Patients taking ethosuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen. Patients should be instructed to promptly contact their physician if they develop signs and/or symptoms (eg, sore throat, fever), suggesting an infection. Patients, their caregivers, and families should be counseled that AEDs, including Zarontin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). Drug Interactions: Since Zarontin (ethosuximide) may interact with concurrently administered antiepileptic drugs, periodic 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda serum level determinations of these drugs may be necessary (eg, ethosuximide may elevate phenytoin serum levels and valproic acid has been reported to both increase and decrease ethosuximide levels). Pregnancy: To provide information regarding the effects of in utero exposure to Zarontin, physicians are advised to recommend that pregnant patients taking Zarontin enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website: http://www.aedpregnancyregistry.org/ See WARNINGS. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 3 years have not been established. (See DOSAGE AND ADMINISTRATION section.) ADVERSE REACTIONS Body As A Whole: Allergic reaction. Gastrointestinal System: Gastrointestinal symptoms occur frequently and include anorexia, vague gastric upset, nausea and vomiting, cramps, epigastric and abdominal pain, weight loss, and diarrhea. There have been reports of gum hypertrophy and swelling of the tongue. Hemopoietic System: Hemopoietic complications associated with the administration of ethosuximide have included leukopenia, agranulocytosis, pancytopenia, with or without bone marrow suppression, and eosinophilia. Nervous System: Neurologic and sensory reactions reported during therapy with ethosuximide have included drowsiness, headache, dizziness, euphoria, hiccups, irritability, hyperactivity, lethargy, fatigue, and ataxia. Psychiatric or psychological aberrations associated with ethosuximide administration have included disturbances of sleep, night terrors, inability to concentrate, and aggressiveness. These effects may be noted particularly in patients who have previously exhibited psychological abnormalities. There have been rare reports of paranoid psychosis, increased libido, and increased state of depression with overt suicidal intentions. Integumentary System: Dermatologic manifestations which have occurred with the administration of ethosuximide have included urticaria, Stevens-Johnson syndrome, systemic lupus erythematosus, pruritic erythematous rashes, and hirsutism. Special Senses: Myopia. Genitourinary System: Vaginal bleeding, microscopic hematuria. OVERDOSAGE Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. A relationship between ethosuximide toxicity and its plasma levels has not been established. The therapeutic range of serum levels is 40 mcg/mL to 100 mcg/mL, although levels as high as 150 mcg/mL have been reported without signs of toxicity. Treatment: Treatment should include emesis (unless the patient is or could rapidly become obtunded, comatose, or convulsing) or gastric lavage, activated charcoal, cathartics, and general supportive measures. Hemodialysis may be useful to treat ethosuximide overdose. Forced diuresis and exchange transfusions are ineffective. DOSAGE AND ADMINISTRATION Zarontin is administered by the oral route. The initial dose for patients 3 to 6 years of age is one capsule (250 mg) per day; for patients 6 years of age and older, 2 capsules (500 mg) per day. The dose thereafter 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda must be individualized according to the patient’s response. Dosage should be increased by small increments. One useful method is to increase the daily dose by 250 mg every four to seven days until control is achieved with minimal side effects. Dosages exceeding 1.5 g daily, in divided doses, should be administered only under the strictest supervision of the physician. The optimal dose for most pediatric patients is 20 mg/kg/day. This dose has given average plasma levels within the accepted therapeutic range of 40 to 100 mcg/mL. Subsequent dose schedules can be based on effectiveness and plasma level determinations. Zarontin may be administered in combination with other anticonvulsants when other forms of epilepsy coexist with absence (petit mal). The optimal dose for most pediatric patients is 20mg/kg/day. HOW SUPPLIED Zarontin is supplied as: N 0071-0237-24—Bottles of 100. Each capsule contains 250 mg ethosuximide. Store at 25 ° C (77 ° F); excursions permitted to 15-30 ° C (59-86 ° F) [see USP Controlled Room Temperature]. company logo LAB-0094-6.0 Revised August 2010 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE ZARONTIN, (Ză rŏn' tĭn) (ethosuximide) Capsules, Oral Solution Read this Medication Guide before you start taking ZARONTIN and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about ZARONTIN, ask your healthcare provider or pharmacist. What is the most important information I should know about ZARONTIN? Do not stop taking ZARONTIN without first talking to your healthcare provider. Stopping ZARONTIN suddenly can cause serious problems. ZARONTIN can cause serious side effects, including: 1. Rare but serious blood problems that may be life-threatening. Call your healthcare provider right away if you have: • fever, swollen glands, or sore throat that come and go or do not go away • frequent infections or an infection that does not go away • easy bruising • red or purple spots on your body • bleeding gums or nose bleeds • severe fatigue or weakness 2. Systematic Lupus Erythematosus. Call your healthcare provider right away if you have any of these symptoms: • joint pain and swelling • muscle pain • fatigue • low-grade fever • pain in the chest that is worse with breathing • unexplained skin rash 3. Like other antiepileptic drugs, ZARONTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • new or worse anxiety • feeling agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase activity and talking (mania) • other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop ZARONTIN without first talking to a healthcare provider. • Stopping ZARONTIN suddenly can cause serious problems. • Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. What is ZARONTIN? ZARONTIN is a prescription medicine used to treat absence (petit mal) seizures. Who should not take ZARONTIN? Do not take ZARONTIN if you are allergic to succinimides (methsuximide or ethosuximide), or any of the ingredients in ZARONTIN. See the end of this Medication Guide for a complete list of ingredients in ZARONTIN. What should I tell my healthcare provider before taking ZARONTIN? Before you take ZARONTIN, tell your healthcare provider if you: • have or had liver problems • have or have had depression, mood problems or suicidal thoughts or behavior • have any other medical conditions • are pregnant or plan to become pregnant. It is not known if ZARONTIN can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking ZARONTIN. You and your healthcare provider should decide if you should take ZARONTIN while you are pregnant. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda o If you become pregnant while taking ZARONTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. You can enroll in this registry by calling 1-888-233-2334. • are breast-feeding or plan to breast-feed. It is not known if ZARONTIN can pass into breast milk. You and your healthcare provider should decide how you will feed your baby while you take ZARONTIN. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking ZARONTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine. How should I take ZARONTIN? • Take ZARONTIN exactly as prescribed. Your healthcare provider will tell you how much ZARONTIN to take. • Your healthcare provider may change your dose. Do not change your dose of ZARONTIN without talking to your healthcare provider. • If you take too much ZARONTIN, call your healthcare provider or your local Poison Control Center right away. What should I avoid while taking ZARONTIN? • Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking ZARONTIN without first talking to your healthcare provider. ZARONTIN taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse. o Do not drive, operate heavy machinery, or do other dangerous activities until you know how ZARONTIN affects you. ZARONTIN can slow your thinking and motor skills. What are the possible side effects of ZARONTIN? • See “What is the most important information I should know about ZARONTIN?” ZARONTIN may cause other serious side effects, including: • Serious allergic reactions. Call your healthcare provider right away if you have any of these symptoms: • skin rash • hives • sores in your mouth • blistering or peeling skin 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Changes in thinking, mood, or behavior. Some patients may get abnormally suspicious thoughts, hallucinations (seeing or hearing things that are not there), or delusions (false thoughts or beliefs). • Grand mal seizures can happen more often or become worse Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of ZARONTIN include • nausea or vomiting • fatigue • indigestion, stomach pain • dizziness or lightheadedness • diarrhea • unsteadiness when walking • weight loss • headache • loss of appetite • loss of concentration • hiccups Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects with ZARONTIN. For more information, ask your healthcare provider or pharmacist. 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 ZARONTIN? • Store ZARONTIN capsules at room temperature, between 59°F to 86°F (15°C to 30°C). • Store ZARONTIN syrup (oral solution) at 20º-25ºC (68º-77ºF). Preserve in tight containers. Protect from freezing and light. Keep ZARONTIN and all medicines out of the reach of children. General information about ZARONTIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZARONTIN for a condition for which it was not prescribed. Do not give ZARONTIN to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about ZARONTIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ZARONTIN that is written for healthcare professionals. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For more information, go to www.pfizer.com or call 1-800-438-1985. What are the ingredients in ZARONTIN? Active ingredient: ethosuximide Capsules Inactive ingredients: Polyethylene glycol 400, NF; D&C yellow No. 10; FD&C red No.3; gelatin, NF; glycerin, USP; and sorbitol. Oral Solution Inactive ingredients: Each 5 ml (teaspoonful) of oral solution contains 250 mg ethosuximide in a raspberry flavored base. Also contains citric acid, anhydrous, USP; FD&C red No. 40; FD&C yellow No. 6; flavor; glycerin, USP; purified water, USP; saccharin sodium, USP; sodium benzoate, NF; Sodium Citrate, USP; sucrose, NF. This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo LAB-403-1.0 Revised August 2010 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.257811	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012380s032lbl.pdf', 'application_number': 12380, 'submission_type': 'SUPPL ', 'submission_number': 32}
10,806	SOMA® COMPOUND with CODEINE CIII (carisoprodol, aspirin and codeine phosphate, USP) Tablets for Oral Use Warning: May be habit-forming. WARNING: Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to CYP2D6 polymorphism (see WARNINGS – Codeine Phosphate-Death Related to Ultra-Rapid Metabolism of Codeine to Morphine). DESCRIPTION Soma Compound with Codeine (carisoprodol, aspirin, and codeine phosphate tablets, USP) is a fixed-dose combination product containing the following three products:  200 mg of carisoprodol, a centrally-acting muscle relaxant  325 mg of aspirin, an analgesic with antipyretic and anti-inflammatory properties  16 mg of codeine phosphate, a centrally-acting narcotic analgesic. It is available as a two-layered, white and yellow, oval-shaped tablet for oral administration. Carisoprodol: Chemically, carisoprodol is N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate and its molecular formula is C12H24N2O4, with a molecular weight of 260.33. The structural formula of carisoprodol is: structural formula Aspirin: Chemically, aspirin (acetylsalicyclic acid) is 2-(acetyloxy)-, benzoic acid and its molecular formula is C9H8O4, with a molecular weight of 180.16. The structural formula of aspirin is: 1 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Codeine Phosphate: Chemically, codeine phosphate is 7,8-Didehydro-4,5α-epoxy-3-methoxy 17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate and its molecular formula is C18H24NO7P, with a molecular weight of 406.37. The structural formula of codeine phosphate is: structural formula Other ingredients in the Soma Compound with Codeine drug product are croscarmellose sodium, D&C Yellow #10, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, sodium metabisulfite, starch, and stearic acid. CLINICAL PHARMACOLOGY Mechanism of Action Carisoprodol: The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified. In animal studies, muscle relaxation induced by carisoprodol is associated with altered interneuronal activity in the spinal cord and in the descending reticular formation of the brain. Aspirin: The mechanism of action of aspirin in relieving pain is by inhibition of the body’s production of prostaglandins, which are thought to cause pain sensations by stimulating muscle contractions and dilating blood vessels. Codeine Phosphate: The precise mechanism of action of codeine phosphate, an opioid agonist, in relieving pain has not been established. The binding of codeine phosphate to mu, delta, and kappa opioid receptors in the central nervous system (CNS) may change the perception of pain. The analgesic activity of codeine phosphate is probably due to its conversion to morphine. 2 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacodynamics Carisoprodol: Carisoprodol is a centrally-acting muscle relaxant that does not directly relax tense skeletal muscles. A metabolite of carisoprodol, meprobamate, has anxiolytic and sedative properties. The degree to which these properties of meprobamate contribute to the safety and efficacy of Soma Compound with Codeine is unknown. Aspirin: Aspirin is a non-narcotic analgesic with anti-inflammatory and anti-pyretic activity. Inhibition of prostaglandin biosynthesis appears to account for most of its anti-inflammatory and for at least part of its analgesic and antipyretic properties. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever. Aspirin can cause serious gastrointestinal injury including bleeding, obstruction, and perforations from ulcers possibly by inhibition of the production of prostaglandins, compromising the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing (see WARNINGS). Aspirin inhibits platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Codeine Phosphate: Codeine phosphate is a centrally-acting narcotic analgesic. Its actions are qualitatively similar to morphine, but its potency is substantially less. Opioids, including codeine phosphate have the following effects:  respiratory depression by a direct effect on the brainstem respiratory centers  depression of the cough reflex by direct effect on the cough center in the medulla  constriction of the pupils (i.e., miosis)  decreased gastric, biliary, and pancreatic secretions  reduction in the motility of the stomach and small and large intestine which results in constipation and delayed digestion  nausea and vomiting by directly stimulating the chemoreceptor trigger zone  increased biliary tract pressure as a result of spasm of the sphincter of Oddi  peripheral vasodilatation which may result in orthostatic hypotension  histamine release which may result in pruritus, flushing, and sweating  increased tone of the bladder detrusor muscle, ureters, and vesical sphincter which may result in urinary retention Pharmacokinetics Carisoprodol: The pharmacokinetics of carisoprodol and its metabolite meprobamate were studied in a study of 24 healthy subjects (12 male and 12 female) who received single doses of 350 mg of carisoprodol (see Table 1). The Cmax of meprobamate was 2.5 ± 0.5 μg/mL (mean ± SD) after administration of a single 350 mg dose of carisoprodol, which is approximately 30% of the Cmax of meprobamate (approximately 8 μg/mL) after administration of a single 400 mg dose of meprobamate. 3 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Pharmacokinetic Parameters of Carisoprodol and Meprobamate (Mean ± SD, n=24) Carisoprodol Meprobamate Cmax (μg/mL) 1.8 ± 1.0 2.5 ± 0.5 AUCinf (μg∙hour/mL) 7.0 ± 5.0 46 ± 9.0 Tmax (hour) 1.7 ± 0.8 4.5 ± 1.9 T1/2 (hour) 2.0 ± 0.5 9.6 ± 1.5 Absorption: Absolute bioavailability of carisoprodol has not been determined. After administration of a single dose of 350 mg of carisoprodol, the mean time to peak plasma concentrations (Tmax) of carisoprodol was approximately 1.5 to 2 hours. Co-administration of a high-fat meal with 350 mg of carisoprodol had no effect on the pharmacokinetics of carisoprodol. Metabolism: The major pathway of carisoprodol metabolism is via the liver by cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism (see Patients with Reduced CYP2C19 Activity below). Elimination: Carisoprodol is eliminated by both renal and non-renal routes with a terminal elimination half-life of approximately 2 hours after administration of a single dose of 350 mg of carisoprodol. The half-life of meprobamate is approximately 10 hours after administration of a single dose of 350 mg of carisoprodol. Gender: Exposure of carisoprodol is higher in females than in male subjects (approximately 30 to 50% on a weight adjusted basis). Overall exposure of meprobamate is comparable between female and male subjects. Patients with Reduced CYP2C19 Activity: Carisoprodol should be used with caution in patients with reduced CYP2C19 activity. Published studies indicate that patients who are poor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3 to 5% and in Asians is approximately 15 to 20%. Aspirin: Absorption: The rate of aspirin absorption from the gastrointestinal (GI) tract is dependent upon the presence or absence of food, gastric pH (the presence of absence of GI antacids), and other physiologic factors. Following absorption, aspirin is hydrolyzed to salicylic acid in the gut wall and during first-pass metabolism with peak plasma levels of salicylic acid occurring within 1 to 2 hours of dosing. 4 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distribution: Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, kidneys, heart, and lungs. The protein binding of salicylate is concentration dependent, i.e., nonlinear. At plasma concentrations of salicylic acid, < 100 μg/mL and > 400 μg/mL, approximately 90 and 76 percent of plasma salicylate is bound to albumin, respectively. Metabolism: Aspirin, which has a half-life of about 15 minutes, is hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin may not be detectable 1 to 2 hours after dosing. Salicylic acid, which has a plasma half-life of approximately 6 hours, is conjugated in the liver to form salicyluric acid, salicyl phenolic glucuronide, salicyl acyl glucuronide, gentisic acid, and gentisuric acid. At higher serum concentrations of salicylic acid, the total clearance of salicylic acid decreases due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses of aspirin (e.g., > 10 grams), the plasma half-life of salicylic acid may be increased to over 20 hours. Elimination: The elimination of salicylic acid is constant in relation to the plasma salicylic acid concentration. Following therapeutic doses of aspirin, approximately 75, 10, 10, and 5 percent is found excreted in the urine as salicyluric acid, salicylic acid, a phenolic glucuronide of salicylic acid, and an acyl glucuronide of salicylic acid, respectively. As the urinary pH rises above 6.5, the renal clearance of free salicylate increases from less than 5 percent to greater than 80 percent. Alkalinization of the urine is a key concept in the management of salicylate overdose (see OVERDOSAGE, Treatment of Overdosage). Clearance of salicylic acid is also reduced in patients with renal impairment. Codeine Phosphate: Absorption: Codeine is readily absorbed from the GI tract. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. Distribution: Codeine is rapidly distributed from the intravascular spaces to the tissues with preferential uptake by the liver, spleen, and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration of codeine does not correlate with brain concentration of codeine or the relief of pain. Metabolism: The plasma half-life of codeine is about 2.9 hours. Elimination: 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. INDICATIONS AND USAGE 5 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Soma Compound with Codeine is indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults. Soma Compound with Codeine should only be used for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use has not been established and because acute, painful musculoskeletal conditions are generally of short duration (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Soma Compound with Codeine is contraindicated in patients with a history of:  a serious GI complication (i.e., bleeding, perforations, obstruction) due to aspirin use  aspirin induced asthma (a symptom complex which occurs in patients who have asthma, rhinosinusitis, and nasal polyps who develop a severe, potentially fatal bronchospasm shortly after taking aspirin or other NSAIDs)  hypersensitivity reaction to carbamate such as meprobamate  acute intermittent porphyria  Codeine sulphate is contraindicated for postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy (see WARNINGS – Codeine Phosphate – Death Related to Ultra-Rapid Metabolism of Codeine to Morphine). WARNINGS Carisoprodol: Sedation Carisoprodol has sedative properties and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. There have been post-marketing reports of motor vehicle accidents associated with the use of carisoprodol. Since the sedative effects of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricylic antidepressants) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Drug Dependence, Withdrawal, and Abuse Carisoprodol, the active ingredient in SOMA, has been subject to abuse, dependence, withdrawal, misuse and criminal diversion (see DRUG ABUSE AND DEPENDENCE). Abuse of SOMA poses a risk of overdose which may lead to death, CNS and respiratory depression, hypotension, seizures and other disorders (see OVERDOSAGE). Post-marketing cases of carisoprodol, abuse and dependence have been reported in patients with prolonged use and a history of drug abuse. Although most of these patients took other drugs of abuse, some patients solely abused carisoprodol. Withdrawal symptoms have been reported following abrupt cessation of SOMA after prolonged use. Reported withdrawal symptoms included insomnia, vomiting, abdominal cramps, headache, tremors, muscle twitching, ataxia, 6 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hallucinations, and psychosis. One of carisoprodol’s metabolites, meprobamate, (a controlled substance), may also cause dependence (see CLINICAL PHARMACOLOGY). To reduce the risk of SOMA abuse, assess the risk of abuse prior to prescribing. After prescribing, limit the length of treatment to three weeks for the relief of acute muscolosketal discomfort, keep careful prescription records, monitor for signs of abuse and overdose, and educate patients and their families about abuse and on proper storage and disposal. Aspirin: Serious Gastrointestinal Adverse Reactions Aspirin can cause serious gastrointestinal (GI) adverse reactions including bleeding, perforation, and obstruction of the stomach, small intestine, or large intestine, which can be fatal. Aspirin- associated serious GI adverse reactions can occur anywhere along the GI tract, at any time, with or without warning symptoms. Patients at higher risk of aspirin-associated serious upper GI adverse reactions include patients with a history of aspirin associated GI bleeding from ulcers (complicated ulcers), a history of aspirin-associated ulcers (uncomplicated ulcers), geriatric patients, patients with poor baseline health status, patients taking higher doses of aspirin, and patients taking concomitant anticoagulants, NSAIDs, and/or large amounts of alcohol. To minimize the risk for aspirin-associated GI serious adverse reactions, the lowest effective aspirin dose should be used for the shortest possible duration. Anaphylaxis and Anaphylactoid Reactions Aspirin may cause an increased risk of serious anaphylaxis and anaphylactoid reactions, which can occur in patients without known prior exposure to aspirin (see CONTRAINDICATIONS). Patients with a serious anaphylaxis and anaphylactoid reaction should receive emergency care. Codeine Phosphate: Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory depression and death have occurred in children who received codeine in the post operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra- rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 [CYP2D6] or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra- rapid metabolizers of codeine (see PRECAUTIONS – Nursing Mothers). Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as 1/1xN or 1/2xN). 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 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. 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 have life-threatening or fatal 7 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) (see OVERDOSAGE). Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS). When prescribing codeine-containing drug, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose (see OVERDOSAGE). Respiratory Depression Respiratory depression is a serious adverse reaction of opioid agonists, including codeine phosphate. Opioid-associated respiratory depression is more likely to occur in geriatric patients, debilitated patients, in non-tolerant patients who are given large initial doses of opioids, and in patients who are receiving concomitant respiratory depressants (e.g. other opioids, benzodiazepines, tricyclic antidepressants, phenothiazines, skeletal muscle relaxants, alcohol). In addition, patients with chronic obstructive pulmonary disease (COPD), restrictive lung disease, decreased respiratory drive, and/or respiratory depression are at a greater risk of opioid- associated respiratory depression. Opioid-associated respiratory depression may be increased in patients with increased intracranial pressure (e.g., patients with head trauma, intracranial lesions). Abuse and Diversion Codeine phosphate is a Schedule III controlled substance. Administration of opioids including codeine phosphate has been associated with abuse. Healthcare professionals should contact their State Professional Licensing Board or State Substances Authority for information on how to prevent or detect abuse or diversion of codeine phosphate. Dependence and Tolerance Use of opioids, including codeine phosphate, can result in psychological and/or physical dependence. Withdrawal symptoms associated with abrupt opioid discontinuation include restlessness, irritability, anxiety, lacrimation, rhinorrhea, sweating, chills, mydriasis, insomnia, diarrhea, tachypnea, tachycardia, and/or hypertension. The use of opioids, including codeine phosphate, use can result in tolerance – the need for increasing doses to maintain a desired effect in the absence of other factors (e.g., disease progression). Gastrointestinal Obstruction Opioids, including codeine phosphate, may cause gastrointestinal obstruction. Sedation Opioids, including codeine phosphate, may impair the mental and physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery. Since the sedative effects of codeine phosphate and other CNS depressants (e.g., 8 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda other opioids, benzodiazepines, tricyclic antidepressants, skeletal muscle relaxants, alcohol) may be additive, appropriate caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Hypotension The use of opioids, including codeine phosphate, may cause hypotension. Opioid-associated hypotension is more likely in patients with dehydration or with the concomitant use of drugs associated with hypotension. PRECAUTIONS Patients with impaired renal or hepatic function The safety and pharmacokinetics of Soma Compound with Codeine in patients with renal or hepatic impairment have not been evaluated. Carisoprodol: Since carisoprodol is excreted by the kidney and is metabolized in the liver, caution should be exercised if carisoprodol is administered to patients with impaired renal or hepatic function. Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis. Seizures There have been post-marketing reports of seizures in patients who received carisoprodol. Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol) (see OVERDOSAGE). Aspirin: Gastrointestinal Adverse Reactions In addition to serious gastrointestinal adverse reactions, the use of aspirin is also associated with gastritis, gastrointestinal erosions, abdominal pain, heartburn, vomiting, and nausea (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Codeine Phosphate: Obscuring Medical Conditions Opioids, including codeine phosphate, may obscure the clinical course of patients with head injuries because of the CNS depressive effects of opioids. In addition, opioids, including codeine phosphate, may obscure the symptoms and/or signs that are used for the diagnosis or for the monitoring of patients with acute abdominal conditions. Use in Patients with Pancreatic or Biliary Duct Disease Opioids, including codeine phosphate, should be used with caution in patients with pancreatic or biliary duct disease because opioids may cause spasm of the sphincter of Oddi and diminish pancreatic and/or biliary secretions. 9 Reference ID: 3305983 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 advised to contact their health care provider if they experience any adverse reactions to Soma Compound with Codeine. Carisoprodol: 1. Patients should be advised that carisoprodol may cause drowsiness and/or dizziness, and has been associated with motor vehicle accidents. Patients should be advised to avoid taking carisoprodol before engaging in potentially hazardous activities such as driving a motor vehicle or operating machinery (see WARNINGS, Sedation). 2. Patients should be advised to avoid alcoholic beverages while taking carisoprodol and to check with their doctor before taking other CNS depressants such as benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or other sedatives (see WARNINGS, Sedation). 3. Patients should be advised that treatment with carisoprodol should be limited to acute use (up to two or three weeks) for the relief of acute, musculoskeletal discomfort. In the post-marketing experience with carisoprodol, cases of dependence, withdrawal, and abuse have been reported with prolonged use. If musculoskeletal symptoms still persist, patients should contact their healthcare provider for further evaluation. Aspirin: 1. Patients should be warned that aspirin can cause epigastric discomfort, gastric and duodenal ulcers, and serious GI adverse reactions, such as bleeding, perforations, and/or obstruction of the stomach or intestines, which may result in hospitalization and death. Although serious GI bleeding can occur without warning symptoms (e.g., hematemesis, melena, hematochezia), patients should be alert for these symptoms and should seek urgent medical care if any of these indicative symptoms occur (see WARNINGS, Serious Gastrointestinal Adverse Reactions). In addition, patients should be alert for symptoms of ulcers (e.g., night time epigastric discomfort, vomiting, weight loss) and should seek medical attention if these symptoms occur. Patients who consume three or more alcoholic drinks a day should be counseled about the GI bleeding risks involved with the use of aspirin with alcohol. 2. Patients should be informed of the symptoms of an anaphylactoid reaction or anaphylaxis (e.g., hives, difficulty breathing, swelling of face or throat). If these symptoms occur, patients should be instructed to seek immediate emergency help. Codeine Phosphate: 1. Since codeine phosphate may cause drowsiness and/or dizziness, patients should be advised to assess their individual response to codeine phosphate before engaging in 10 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda potentially hazardous activities such as driving a motor vehicle or operating machinery (see WARNINGS, Sedation). 2. Patients should be advised to avoid alcoholic beverages while taking codeine phosphate and to check with their doctor before taking other CNS depressants such as other opioids, benzodiazepines, tricyclic antidepressants, sedating antihistamines, or other sedatives (see WARNINGS, Respiratory Depression and Sedation). 3. Patients should be advised that codeine phosphate is a controlled substance. Codeine phosphate can result in psychological and physical dependence (see WARNINGS, Dependence and Tolerance). 4. Codeine phosphate tablets should be placed in a secure place out of the reach of children 5. Patients should be advised that opioids, including codeine phosphate, can cause constipation and appropriate measures should be taken to reduce the risk of constipation (e.g., dietary changes, laxatives). 6. Patients should be advised that opioids, including codeine phosphate, have been associated with hypotension and gastrointestinal obstruction (WARNINGS, Hypotension, Gastrointestinal Obstruction). 7. Advise patients that some people have a genetic variation that results in codeine changing into morphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid codeine metabolizer or not. These higher-than–normal levels of morphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. As a result, codeine is contraindicated in all children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving codeine for other reasons to monitor for signs of respiratory depression (see WARNINGS –Death Related to Ultra- Rapid Metabolism of Codeine to Morphine). 8. Nursing mothers using codeine should be informed that a subset of people who use codeine (ultra-rapid metabolizers) may convert codeine into its active metabolite, morphine, resulting in higher than expected exposure of morphine which can lead to toxic serum levels of morphine in infants of nursing mothers. Nursing mothers should be informed how to recognize the symptoms of morphine toxicity in their infants, such as sedation, difficulty breastfeeding, breathing difficulties, and decreased tone (see WARNINGS –Death Related to Ultra-Rapid Metabolism of Codeine to Morphine). Drug Interactions 11 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carisoprodol: The sedative effect of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Concomitant use of carisoprodol and meprobamate, a metabolite of carisoprodol, is not recommended (see WARNINGS, Sedation). Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see CLINICAL PHARMACOLOGY). Co-administration of CYP2C19 inhibitors, such as omeprazole or fluvoxamine, with carisoprodol could result in increased exposure of carisoprodol and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such as rifampin or St. John’s Wort, with carisoprodol could result in decreased exposure of carisoprodol and increased exposure of meprobamate. Low dose aspirin also showed an induction effect of CYP2C19. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown. Aspirin: Clinically important interactions may occur when certain drugs or alcohol are administered concomitantly with aspirin. Alcohol: Concomitant use of aspirin with ≥ 3 alcoholic drinks may increase the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Anticoagulants: Concomitant use of aspirin and anticoagulants (e.g., heparin, warfarin, clopidogrel) increase the risk of GI bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Additionally, aspirin can displace warfarin from protein binding sites, leading to prolongation of the international normalized ratio (INR). Antihypertensives: The concomitant administration of aspirin with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and diuretics may diminish the hypotensive effects of these anti-hypertensive products due to aspirin’s inhibition of renal prostaglandins, which may lead to decreased renal blood flow and increased sodium and fluid retention. Concomitant use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide due to competition at the renal tubule for secretion. Corticosteroids: Concomitant administration of aspirin and corticosteroids may decrease salicylate plasma levels. Methotrexate: Aspirin may enhance the toxicity of methotrexate due to displacement of methotrexate from its plasma protein binding sites and/or reduction of the renal clearance of methotrexate. Nonsteroidal anti-inflammatory drugs (NSAIDs): The concurrent use of aspirin with selective and nonselective NSAIDs increases the risk of serious GI adverse reactions (see WARNINGS, Serious Gastrointestinal Adverse Reactions). Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. 12 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Products that effect urinary pH: Ammonium chloride and other drugs that acidify the urine can elevate plasma salicylate concentrations. In contrast, antacids, by alkalinizing the urine, may decrease plasma salicylate concentrations. Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid and sulfinpyrazone. Codeine Phosphate: The sedative effects of codeine phosphate and other CNS depressants (e.g., alcohol, benzodiazepines, other opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously (see WARNINGS, Respiratory Depression and Sedation). Carcinogens, Mutagenesis, Impairments of Fertility: No long-term studies of carcinogens have been done with Soma Compound with Codeine. Carisoprodol: Long term studies in animals have not been performed to evaluate the carcinogenic potential of carisoprodol. Carisoprodol was not formally evaluated for genotoxicity. In published studies, carisoprodol was mutagenic in the in vitro mouse lymphoma cell assay in the absence of metabolizing enzymes, but was not mutagenic in the presence of metabolizing enzymes. Carisoprodol was clastogenic in the in vitro chromosomal aberration assay using Chinese hamster ovary cells with or without the presence of metabolizing enzymes. Other types of genotoxic tests resulted in negative findings. Carisoprodol was not mutagenic in the Ames reverse mutation assay using S. typhimurium strains with or without metabolizing enzymes, and was not clastogenic in an in vitro mouse micronucleus assay of circulating blood cells. Carisoprodol was not formally evaluated for effects on fertility. Published reproductive studies of carisoprodol in mice found no alteration in fertility although an alteration in reproductive cycles characterized by a greater time spend in estrus was observed at a carisoprodol dose of 1200 mg/kg/day. In a 13-week toxicology study that did not determine fertility, mouse testes weight and sperm motility were reduced at a dose of 1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day, corresponding to approximately 2.6 times the human equivalent dosage of 350 mg four times a day, based on a body surface area comparison. The significance of these findings for human fertility is not known. Aspirin: Administration of aspirin for 68 weeks in the feed of rats was not carcinogenic. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Aspirin has been shown to inhibit ovulation in rats (see Pregnancy). Pregnancy: Pregnancy Category D. It is not known whether Soma Compound with Codeine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adequate animal reproduction studies 13 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda have not been conducted with Soma Compound with Codeine. Soma Compound with Codeine should be given to a pregnant woman only if clearly needed. Carisoprodol: There are no data on the use of carisoprodol during human pregnancy. Animal studies indicate that carisoprodol crosses the placenta and results in adverse effects on fetal growth and postnatal survival. The primary metabolite of carisoprodol, meprobamate, is an approved anxiolyic. Retrospective, post-marketing studies do not show a consistent association between maternal use of meprobamate and an increased risk for particular congenital malformations. Teratogenic effects: Animal studies have not adequately evaluated the teratogenic effects of carisoprodol. There was no increase in the incidence of congenital malformations noted in the reproductive studies in rats, rabbits, and mice treated with meprobamate. Retrospective, post- marketing studies of meprobamate during human pregnancy were equivocal for demonstrating an increased risk of congenital malformations following the first trimester exposure. Across studies that indicated an increased risk, the types of malformations were inconsistent. Nonteratogenic effects: In animal studies, carisoprodol reduced fetal weights, postnatal weight gain, and postnatal survival at maternal doses equivalent to 1 to 1.5 times the human dose (based on a body surface area comparison). Rats exposed to meprobamate in-utero showed behavioral alterations that persisted into adulthood. For children exposed to meprobamate in-utero, one study found no adverse effects on mental or motor development or IQ scores. Carisoprodol should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Aspirin: Teratogenic effects: Prior to 30 weeks gestation, aspirin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, aspirin should be avoided by pregnant women as premature closure of the fetal ductus arteriosus which may result in fetal pulmonary hypertension and fetal death. Salicylate products have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths, and neonatal death. Studies in rodents have shown salicylates to be teratogenic when given in early gestation, and embryocidal when given in later gestation in doses considerably greater than usual therapeutic doses in humans. Labor and Delivery Carisoprodol: There is no information about the effects of carisoprodol on the mother and the fetus during labor and delivery. Aspirin: Ingestion of aspirin within one week of delivery or during labor may prolong delivery or lead to excessive blood loss in the mother, fetus, or neonate. Prolonged labor due to prostaglandin inhibition has been reported with aspirin use. Codeine Phosphate: The use of codeine phosphate during labor may lead to respiratory depression in the neonate. 14 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers Carisoprodol: Very limited data in humans show that carisoprodol is present in breast milk and may reach concentrations two to four times the maternal plasma concentrations. In one case report, a breast-fed infant received about 4 to 6% of the maternal daily dose though breast milk and experienced no adverse effects. However, milk production was inadequate and the baby was supplemented with formula. In lactation studies in mice, female pup survival and pup weight at weaning was decreased. This information suggests that maternal use of carisoprodol may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when carisoprodol is administered to a nursing woman. Aspirin: Nursing mothers should avoid the use of aspirin because salicylate is excreted in breast milk which may lead to bleeding in the infant. Codeine Phosphate: 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. Despite the common use of codeine products to manage postpartum pain, reports of codeine- associated adverse reactions in nursing infants are rare. Nursing mothers who are ultra-rapid metabolizers of codeine have higher-than-expected levels of morphine (the active metabolite of codeine) in their blood, leading to higher levels of morphine in their breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, in nursing mothers who are ultra-rapid metabolizers of codeine, the maternal use of codeine can lead to serious adverse reactions, including death, in their nursing infants and in the nursing mothers (see WARNINGS –Death Related to Ultra-Rapid Metabolism of Codeine to Morphine). Prior to prescribing nursing mothers codeine phosphate, 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 the infant. 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. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. Pediatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound with Codeine in pediatric patients less than 16 years of age have not been established. Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in these patients (see WARNINGS –Death Related to Ultra-Rapid Metabolism of Codeine to Morphine and CONTRAINDICATIONS). 15 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use: The efficacy, safety, and pharmacokinetics of Soma Compound with Codeine in geriatric patients over 65 years of age have not been established. ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions which have occurred with the administration of the individual products alone may also occur with the use of Soma Compound with Codeine. The following events have been reported during post-approval individual use of carisoprodol, aspirin, and codeine. 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. Carisoprodol: Cardiovascular: Tachycardia, postural hypotension, and facial flushing (see OVERDOSAGE). Central Nervous System: Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, insomnia, and seizures (see OVERDOSAGE). Gastrointestinal: Nausea, vomiting, and epigastric discomfort. Hematologic: Leukopenia, pancytopenia. Aspirin: The most common adverse reactions associated with the use of aspirin have been gastrointestinal, including both abdominal pain, anorexia, nausea, vomiting, gastritis, and occult bleeding (see WARNINGS, Serious Gastrointestinal Adverse Reactions and PRECAUTIONS, Gastrointestinal Adverse Reactions). Other adverse reactions associated with the use of aspirin include elevated liver enzymes, rash, pruritus, purpura, intracranial hemorrhage, interstitial nephritis, acute renal failure, and tinnitus. Tinnitus may be a sign of high serum salicylate levels (see OVERDOSAGE). Codeine Phosphate: Nausea, vomiting, constipation, miosis, sedation, dizziness. DRUG ABUSE AND DEPENDENCE – Controlled Substance: Schedule C-III (see WARNINGS). Controlled Substance SOMA contains carisoprodol, a Schedule IV controlled substance. Carisoprodol has been subject to abuse, misuse, and criminal diversion for nontherapeutic use (see WARNINGS). Abuse Abuse of carisoprodol poses a risk of overdosage which may lead to death, CNS and respiratory depression, hypotension, seizures and other disorders (see WARNINGS). Patients at high risk of 16 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SOMA abuse may include those with prolonged use of carisoprodol, with a history of drug abuse, or those who use SOMA in combination with other abused drugs. Prescription drug abuse is the intentional non-therapeutic use of a drug, even once, for its rewarding psychological or physiological effects. Drug addiction, which develops after repeated drug abuse, is characterized by a strong desire to take a drug despite harmful consequences, difficulty in controlling its use, giving a higher priority to drug use than to obligations, increased tolerance, and sometimes physical withdrawal. Drug abuse and drug addiction are separate and distinct from physical dependence and tolerance (for example, abuse or addiction may not be accompanied by tolerance or physical dependence) (see DEPENDENCE). Dependence Tolerance is when a patient’s reaction to a specific dosage and concentration is progressively reduced, in the absence of disease progression, requiring an increase in the dosage to maintain the same. Physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Both tolerance and physical dependence have been reported with prolonged use of SOMA. Reported withdrawal symptoms with SOMA include insomnia, vomiting, abdominal cramps, headache, tremors, muscle twitching, anxiety, ataxia, hallucinations, and psychosis. Instruct patients taking large doses of SOMA or those taking the drug for a prolonged time to not abruptly stop SOMA (see WARNINGS). OVERDOSAGE Signs and Symptoms: Any of the following signs and symptoms which have been reported with overdose of the individual products may occur with overdose of Soma Compound with Codeine and may be modified to a varying degree by the effects of the other products present in Soma Compound with Codeine. Carisoprodol: Overdosage of carisoprodol commonly produces CNS depression. Death, coma, respiratory depression, hypotension, seizures, delirium, hallucinations, dystonic reactions, nystagmus, blurred vision, mydriasis, euphoria, muscular incoordination, rigidity, and/or headache have been reported with SOMA overdosage. Serotonin syndrome has been reported with carisoprodol intoxication. Many of the carisoprodol overdoses have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol). The effects of an overdose of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) can be additive even when one of the drugs has been taken in the recommended dosage. Fatal accidental and non-accidental overdoses of carisoprodol have been reported alone or in combination with CNS depressants. Aspirin: Salicylate toxicity may result from an overdose of an acute ingestion or chronic intoxication. Mild to moderate salicylate poisoning is usually associated with plasma salicylic concentrations about 200 μg/mL and is characterized by tinnitus, hearing difficulty, headache, dim vision, dizziness, tachypnea, increased thirst, nausea, vomiting, sweating, and diarrhea. In 17 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the early stages of overdose, CNS stimulation and respiratory alkalosis can occur; however, in the later stages CNS depression and metabolic acidosis can occur. Symptoms and signs of severe salicylate poisoning, associated with plasma salicylic concentrations greater that 400 μg/mL, include hyperthermia, dehydration, delirium, GI hemorrhage, pulmonary edema, and CNS depression (e.g., coma). Death is usually due to respiratory failure or cardiovascular collapse. Overdose of aspirin in pediatric patients: Salicylate poisoning should be considered in pediatric patients with symptoms of vomiting, hyperpnea, and hyperthermia. Salicylate poisoning should be considered in infants with metabolic acidosis and all pediatric patients with severe salicylate poisoning. Codeine Phosphate: Acute overdose of opioids, including codeine phosphate, is characterized by CNS depression (somnolence progressing to coma), respiratory depression, hypotension, miosis, skeletal muscle flaccidity, and cold and clammy skin. Treatment of Overdosage: Provide symptomatic and supportive treatment, as indicated. For more information on the management of an overdose of Soma Compound with Codeine (carisoprodol, aspirin, and codeine phosphate, USP) tablets, contact a Poison Control Center. Carisoprodol: Basic life support measures should be instituted as dictated by the clinical presentation of the carisoprodol overdose. Vomiting should not be induced due to the risk of CNS and respiratory depression and subsequent aspiration. Gastric lavage should be considered soon after ingestion (within one hour). Circulatory support should be administered with volume infusion and vasopressor agents if needed. Seizures should be treated with intravenous benzodiazepines and the reoccurrence of seizures may be treated with phenobarbital. In cases of severe CNS depression, airway protective reflexes may be compromised and tracheal intubation should be considered for airway protection and respiratory support. For decontamination in cases of severe toxicity, activated charcoal should be considered in a hospital setting in patients with large overdoses who present early and are not demonstrating CNS depression and can protect their airway. Aspirin: Since there are no specific antidotes for salicylate poisoning, the aim of the treatment is to enhance elimination of salicylate; reduce further salicylate absorption; correct fluid, electrolyte, or acid/base imbalances; and provide cardio-respiratory support. The acid-base status should be followed closely with serial serum pH determinations (using arterial blood gas). If acidosis is present, intravenous sodium bicarbonate should be given, along with adequate hydration, until salicylate levels decrease to within the therapeutic range. To enhance elimination, forced diuresis and alkalinization of the urine may be beneficial. Gastric emptying and/or lavage are recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal is beneficial, if less than 3 hours have passed since ingestion. Charcoal absorption should not be employed prior to emesis and lavage. In patients with renal insufficiency or in cases of life- threatening aspirin intoxication, hemodialysis or peritoneal dialysis is usually required. 18 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Additional treatment of aspirin overdose in pediatric patients: Pediatric patients should be sponged with tepid water. Infusion of glucose may be required to control hypoglycemia. Exchange transfusion may be indicated in infants and young children. Codeine Phosphate: After a severe opioid overdose, primary attention should be given to the need for re-establishment of a patent airway and institution of assisted ventilation. Elimination or evacuation of gastric contents may be necessary in order to eliminate unabsorbed drug. Before attempting treatment by gastric emptying or activated charcoal, care should be taken to secure the airway. Pure opioid antagonist (e.g., naloxone, nalmefene) are specific antidotes to severe respiratory and CNS depression resulting from opioid overdose. If the response to these opioid antagonists is sub-optimal, additional antagonist should be administered. Since the duration of action of codeine may exceed that of the opioid antagonist, the patient’s respiratory status should be continuously monitored for the need for additional doses of antagonist to maintain adequate respiration. DOSAGE AND ADMINISTRATION The recommended daily dose of Soma Compound with Codeine is 1 or 2 tablets, four times daily in adults. One Soma Compound with Codeine tablet contains 200 mg of carisoprodol, 325 mg of aspirin, and 16 mg of codeine phosphate. The maximum daily dose (i.e., two tablets taken four times daily) will provide 1600 mg of carisoprodol, 2600 mg of aspirin, and 128 mg of codeine phosphate per day. The recommended maximum duration of Soma Compound with Codeine use is up to two or three weeks. HOW SUPPLIED Soma Compound with Codeine (carisoprodol 200 mg, aspirin 325 mg, and codeine phosphate, 16 mg) Tablets are oval, convex, two-layered, and inscribed on the white layer with SOMA CC and on the yellow layer with WALLACE 2403. The tablets are available in bottles of 100 (NDC 0037-2403-01). Storage: Store at controlled room temperature 15°-30°C (59°-86°F). Protect from moisture. Dispense in a tight, light-resistant container. company logo ©2013 Meda Pharmaceuticals Inc. IN-095E2-xx Rev 5/2013 19 Reference ID: 3305983 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.340369	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012366s034lbl.pdf', 'application_number': 12366, 'submission_type': 'SUPPL ', 'submission_number': 34}
10,809	---------- DIDREX - benzphetamine hydrochloride tablet Pharmacia and Upjohn Company Didrex CIII brand of benzphetamine hydrochloride tablets DESCRIPTION DIDREX Tablets contain the anorectic agent benzphetamine hydrochloride. Benzphetamine hydrochloride is a white crystalline powder readily soluble in water and 95% ethanol. The chemical name for benzphetamine hydrochloride is d-N,α-Dimethyl-N (phenylmethyl)-benzeneethanamine hydrochloride and its molecular weight is 275.82. The structural formula (dextro form) is represented below: Structural Formula Each DIDREX Tablet, for oral administration, contains 50 mg of benzphetamine hydrochloride. Inactive Ingredients: Calcium Stearate, Corn Starch, Erythrosine Sodium. FD & C Yellow No. 6, Lactose, Povidone, Sorbitol. CLINICAL PHARMACOLOGY Benzphetamine hydrochloride is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, the amphetamines. Actions include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for. Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics". It has not been established, however, that the action of such drugs in treating obesity is primarily one of appetite suppression. Other central nervous system actions, or metabolic effects, may be involved. Adult obese subjects instructed in dietary management and treated with "anorectic" drugs, lose more weight on the average than those treated with placebo and diet, as determined in relatively short-term clinical trials. The magnitude of increased weight loss of drug-treated patients over placebo-treated patients is only a fraction of a pound a week. The rate of weight loss is the greatest in the first weeks of therapy for both drug and placebo subjects and tends to decrease in succeeding weeks. The possible origins of the increased weight loss due to the various drug effects are not established. The amount of weight loss associated with the use of an "anorectic" drug varies from trial to trial, and the increased weight loss appears to be related in part to variables other than the drug prescribed, such as the physician-investigator, the population treated, and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non-drug factors on weight loss. The natural history of obesity is measured in years, whereas the studies cited are restricted to a few weeks duration; thus, the total impact of drug-induced weight loss over that of diet alone must be considered to be clinically limited. Pharmacokinetic data in humans are not available. INDICATIONS AND USAGE DIDREX Tablets are indicated in the management of exogenous obesity as a short term (a few weeks) adjunct in a regimen of weight reduction based on caloric restriction in patients with an initial body mass index (BMI) of 30 kg/m2 or higher who have not responded to appropriate weight reducing regimen (diet and/or exercise) alone. Below is a chart of Body Mass Index (BMI) based on various heights and weights. BMI is calculated by taking the patient's weight, in kilograms (kg), divided by the patient's height, in meters (m), squared. Metric conversions are as follows: pounds ÷2.2 = kg; inches × 0.0254 = meters. The limited usefulness of agents of this class (See CLINICAL PHARMACOLOGY) should be weighed against possible risks inherent in their use such as those described below. BODY MASS INDEX (BMI), kg/m2 Weight Height (feet, inches) (pounds) 5'0" 5'3" 5'6" 5'9" 6'0" 6'3" 140 27 25 23 21 19 18 150 29 27 24 22 20 19 160 31 28 26 24 22 20 170 33 30 28 25 23 21 180 35 32 29 27 25 23 190 37 34 31 28 26 24 200 39 36 32 30 27 25 210 41 37 34 31 29 26 220 43 39 36 33 30 28 page 1 of 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 230 45 41 37 34 31 29 240 47 43 39 36 33 30 250 49 44 40 37 34 31 DIDREX Tablets are indicated for use as monotherapy only. CONTRAINDICATIONS DIDREX Tablets are contraindicated in patients with advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to sympathomimetic amines, and glaucoma. Benzphetamine should not be given to patients who are in an agitated state or who have a history of drug abuse. Hypertensive crises have resulted when sympathomimetic amines have been used concomitantly or within 14 days following use of monoamine oxidase inhibitors. DIDREX should not be used concomitantly with other CNS stimulants. DIDREX may cause fetal harm when administered to a pregnant woman. Amphetamines have been shown to be teratogenic and embryotoxic in mammals at high multiples of the human dose. DIDREX is contraindicated in women who are or may become pregnant. 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 hazard to the fetus. WARNINGS DIDREX Tablets should not be used in combination with other anorectic agents, including prescribed drugs, over-the-counter preparations and herbal products. In a case-control epidemiological study, the use of anorectic agents was associated with an increased risk of developing pulmonary hypertension, a rare, but often fatal disorder. The use of anorectic agents for longer than three months was associated with a 23-fold increase in the risk of developing pulmonary hypertension. Increased risk of pulmonary hypertension with repeated courses of therapy cannot be excluded. It should be noted that benzphetamine was not specifically studied in this case-control study. The onset or aggravation of exertional dyspnea, or unexplained symptoms of angina pectoris, syncope, or lower extremity edema suggest the possibility of occurrence of pulmonary hypertension. Under these circumstances, DIDREX Tablets should be immediately discontinued, and the patient should be evaluated for the possible presence of pulmonary hypertension. Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine has been reported. Possible contributing factors include use for extended periods of time, higher than recommended dose, and/or use in combination with other anorectic drugs. However, no cases of this valvulopathy have been reported when benzphetamine has been used alone. The potential risk of possible serious adverse effects such as valvular heart disease and pulmonary hypertension should be assessed carefully against the potential benefit of weight loss. Baseline cardiac evaluation should be considered to detect pre-existing valvular heart diseases or pulmonary hypertension prior to initiation of benzphetamine treatment. DIDREX Tablets are not recommended in patients with known heart murmur or valvular heart disease. Echocardiogram during and after treatment could be useful for detecting any valvular disorders which may occur. To limit unwarranted exposure and risks, treatment with DIDREX Tablets should be continued only if the patient has satisfactory weight loss within the first 4 weeks of treatment (i.e., weight loss of at least 4 pounds, or as determined by the physician and patient). When tolerance to the anorectic effect develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued. DIDREX Tablets are not recommended for severely hypertensive patients or for patients with symptomatic cardiovascular disease including arrhythmias. DIDREX Tablets are not recommended for patients who used any anorectic agents within the prior year. PRECAUTIONS General Insulin requirements in diabetes mellitus may be altered in association with use of anorexigenic drugs and the concomitant dietary restrictions. Psychological disturbances have been reported in patients who receive an anorectic agent together with a restrictive dietary regime. Caution is to be exercised in prescribing amphetamines for patients with even mild hypertension. The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. Information for Patients Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; the patient should therefore be cautioned accordingly. Drug Interactions Efficacy of DIDREX Tablets in combination with other anorectic agents has not been studied and the combined use may have the potential for serious cardiac problems. page 2 of 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypertensive crises have resulted when sympathomimetic amines have been used concomitantly or within 14 days following use of monoamine oxidase inhibitors. DIDREX should not be used concomitantly with other CNS stimulants. Amphetamines may decrease the hypotensive effect of antihypertensives. Amphetamines may enhance the effects of tricyclic antidepressants. Urinary alkalinizing agents increase blood levels and decrease excretion of amphetamines. Urinary acidifying agents decrease blood levels and increase excretion of amphetamines. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies to evaluate the potential for carcinogenesis, mutagenesis or impairment of fertility have not been performed by Pharmacia & Upjohn Company. Pregnancy Pregnancy Category X (see CONTRAINDICATIONS section). Nursing Mothers Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Use of benzphetamine hydrochloride is not recommended in individuals under 12 years of age. Geriatric Use Clinical studies of DIDREX Tablets did not include sufficient numbers of subjects aged 65 and over to establish safety and efficacy in this population. 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 The following have been associated with the use of benzphetamine hydrochloride: Cardiovascular Palpitation, tachycardia, elevation of blood pressure. There have been isolated reports of cardiomyopathy and ischemic cardiac events associated with chronic amphetamine use. Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine, both independently and especially when used in combination with other anorectic drugs, have been reported. However, no cases of this valvulopathy have been reported when DIDREX Tablets have been used alone. CNS Overstimulation, restlessness, dizziness, insomnia, tremor, sweating, headache; rarely, psychotic episodes at recommended doses; depression following withdrawal of the drug. Gastrointestinal Dryness of the mouth, unpleasant taste, nausea, diarrhea, other gastrointestinal disturbances. Allergic Urticaria and other allergic reactions involving the skin. Endocrine Changes in libido. DRUG ABUSE AND DEPENDENCE Benzphetamine is a controlled substance under the Controlled Substance Act by the Drug Enforcement Administration and has been assigned to Schedule III. Benzphetamine hydrochloride is related chemically and pharmacologically to the amphetamines. Amphetamines and related stimulant drugs have been extensively abused, and the possibility of abuse of DIDREX Tablets should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. Abuse of amphetamines and related drugs may be associated with intense psychological dependence and severe social dysfunction. There are reports of patients who have increased the dosage to many times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. page 3 of 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE Manifestations of Overdosage Acute overdosage with amphetamines may result in restlessness, tremor, tachypnea, confusion, assaultiveness and panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Hyperpyrexia and rhabdomyolysis have been reported and can lead to a number of associated complications. Fatal poisoning is usually preceded by convulsions and coma. Treatment of Overdosage (See WARNINGS)— Information concerning the effects of overdosage with DIDREX Tablets is extremely limited. The following is based on experience with other anorexiants. Management of acute amphetamine intoxication is largely symptomatic and includes sedation with a barbiturate. If hypertension is marked, the use of a nitrite or rapidly acting alpha receptor blocking agent should be considered. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendations in this regard. Acidification of the urine increases amphetamine excretion. The oral LD50 is 174 mg/kg in mice and 104 mg/kg in rats. The intraperitoneal LD50 in mice is 153 mg/kg. DOSAGE AND ADMINISTRATION Dosage should be individualized according to the response of the patient. The suggested dosage ranges from 25 to 50 mg one to three times daily. Treatment should begin with 25 to 50 mg once daily with subsequent increase in individual dose or frequency according to response. A single daily dose is preferably given in mid-morning or mid-afternoon, according to the patient's eating habits. In an occasional patient it may be desirable to avoid late afternoon administration. Use of benzphetamine hydrochloride is not recommended in individuals under 12 years of age. HOW SUPPLIED DIDREX Tablets are supplied as follows: 50 mg (peach, round, imprinted with DIDREX 50, scored) Bottles of 100 NDC 0009-0024-01 Bottles of 500 NDC 0009-0024-02 Store at controlled room temperature 20° to 25° C (68° to 77° F). [see USP] Rx only Company logo Manufactured by: MOVA Pharmaceuticals Manati, PR 00674 LAB-0028-3.0 August 2009 page 4 of 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.466761	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012427s026lbl.pdf', 'application_number': 12427, 'submission_type': 'SUPPL ', 'submission_number': 26}
10,808	NDA 012380/S-034 FDA Approved Labeling Text dated 4/30/2012 Page 1 Zarontin® (Ethosuximide Capsules, USP) DESCRIPTION Zarontin (ethosuximide) is an anticonvulsant succinimide, chemically designated as alpha-ethyl-alpha methyl-succinimide, with the following structural formula: structural formula Each Zarontin capsule contains 250 mg ethosuximide, USP. Also contains: polyethylene glycol 400, NF. The capsule contains D&C yellow No. 10; FD&C red No. 3; gelatin, NF; glycerin, USP; and sorbitol. CLINICAL PHARMACOLOGY Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. INDICATIONS AND USAGE Zarontin is indicated for the control of absence (petit mal) epilepsy. CONTRAINDICATION Ethosuximide should not be used in patients with a history of hypersensitivity to succinimides. WARNINGS Blood dyscrasias Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of ethosuximide; therefore, periodic blood counts should be performed. Should signs and/or symptoms of infection (e.g., sore throat, fever) develop, blood counts should be considered at that point. Effects on Liver and Kidneys Ethosuximide is capable of producing morphological and functional changes in the animal liver. In humans, abnormal liver and renal function studies have been reported. Ethosuximide should be administered with extreme caution to patients with known liver or renal disease. Periodic urinalysis and liver function studies are advised for all patients receiving the drug. Systemic Lupus Erythematosus Cases of systemic lupus erythematosus have been reported with the use of ethosuximide. The physician should be alert to this possibility. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Zarontin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among Reference ID: 3124002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Indication Placebo Patients Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1000 Incidence of Events in Additional Drug 1000 Patients Patients Drug Patients with Events Patients/Incidence in Per 1000 Patients Placebo Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 NDA 012380/S-034 FDA Approved Labeling Text dated 4/30/2012 Page 2 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by indication for antiepileptic drugs in the pooled analysis The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Zarontin or any other AED must balance the risk of suicidal thoughts and behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Serious Dermatologic Reactions Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS), have been reported with ethosuximide treatment. SJS can be fatal. The onset of symptoms is usually within 28 days, but can occur later. Zarontin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS, use of this drug should not be resumed and alternative therapy should be considered. Reference ID: 3124002 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 012380/S-034 FDA Approved Labeling Text dated 4/30/2012 Page 3 Usage in Pregnancy: Ethosuximide crosses the placenta. Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs. Cases of birth defects have been reported with ethosuximide. The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodological problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential. Ethosuximide is excreted in human breast milk. Because the effects of ethosuximide on the nursing infant are unknown, caution should be exercised when ethosuximide is administered to a nursing mother. Ethosuximide should be used in nursing mothers only if the benefits clearly outweigh the risks. PRECAUTIONS General: Ethosuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients. As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) status. Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Zarontin. Instruct patients to take Zarontin only as prescribed. Ethosuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a motor vehicle or other such activity requiring alertness; therefore, the patient should be cautioned accordingly. Patients taking ethosuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen. Patients should be instructed to promptly contact their physician if they develop signs and/or symptoms (e.g., sore throat, fever), suggesting an infection. Patients, their caregivers, and families should be counseled that AEDs, including Zarontin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Reference ID: 3124002 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 012380/S-034 FDA Approved Labeling Text dated 4/30/2012 Page 4 Prior to initiation of treatment with Zarontin, the patient should be instructed that a rash may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section). Drug Interactions: Since Zarontin (ethosuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (e.g., ethosuximide may elevate phenytoin serum levels and valproic acid has been reported to both increase and decrease ethosuximide levels). Pregnancy: To provide information regarding the effects of in utero exposure to Zarontin, physicians are advised to recommend that pregnant patients taking Zarontin enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website: http://www.aedpregnancyregistry.org/ See WARNINGS. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 3 years have not been established. (See DOSAGE AND ADMINISTRATION section.) ADVERSE REACTIONS Body As A Whole: Allergic reaction. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Gastrointestinal System: Gastrointestinal symptoms occur frequently and include anorexia, vague gastric upset, nausea and vomiting, cramps, epigastric and abdominal pain, weight loss, and diarrhea. There have been reports of gum hypertrophy and swelling of the tongue. Hemopoietic System: Hemopoietic complications associated with the administration of ethosuximide have included leukopenia, agranulocytosis, pancytopenia, with or without bone marrow suppression, and eosinophilia. Nervous System: Neurologic and sensory reactions reported during therapy with ethosuximide have included drowsiness, headache, dizziness, euphoria, hiccups, irritability, hyperactivity, lethargy, fatigue, and ataxia. Psychiatric or psychological aberrations associated with ethosuximide administration have included disturbances of sleep, night terrors, inability to concentrate, and aggressiveness. These effects may be noted particularly in patients who have previously exhibited psychological abnormalities. There have been rare reports of paranoid psychosis, increased libido, and increased state of depression with overt suicidal intentions. Integumentary System: Dermatologic manifestations which have occurred with the administration of ethosuximide have included urticaria, pruritic erythematous rashes, and hirsutism. Special Senses: Myopia. Genitourinary System: Vaginal bleeding, microscopic hematuria. OVERDOSAGE Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. A relationship between ethosuximide toxicity and its plasma levels has not been established. Reference ID: 3124002 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 012380/S-034 FDA Approved Labeling Text dated 4/30/2012 Page 5 The therapeutic range of serum levels is 40 mcg/mL to 100 mcg/mL, although levels as high as 150 mcg/mL have been reported without signs of toxicity. Treatment: Treatment should include emesis (unless the patient is or could rapidly become obtunded, comatose, or convulsing) or gastric lavage, activated charcoal, cathartics, and general supportive measures. Hemodialysis may be useful to treat ethosuximide overdose. Forced diuresis and exchange transfusions are ineffective. DOSAGE AND ADMINISTRATION Zarontin is administered by the oral route. The initial dose for patients 3 to 6 years of age is one capsule (250 mg) per day; for patients 6 years of age and older, 2 capsules (500 mg) per day. The dose thereafter must be individualized according to the patient’s response. Dosage should be increased by small increments. One useful method is to increase the daily dose by 250 mg every four to seven days until control is achieved with minimal side effects. Dosages exceeding 1.5 g daily, in divided doses, should be administered only under the strictest supervision of the physician. The optimal dose for most pediatric patients is 20 mg/kg/day. This dose has given average plasma levels within the accepted therapeutic range of 40 to 100 mcg/mL. Subsequent dose schedules can be based on effectiveness and plasma level determinations. Zarontin may be administered in combination with other anticonvulsants when other forms of epilepsy coexist with absence (petit mal). The optimal dose for most pediatric patients is 20 mg/kg/day. HOW SUPPLIED Zarontin is supplied as: NDC 0071-0237-24:Bottles of 100. Each capsule contains 250 mg ethosuximide. Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F) [see USP Controlled Room Temperature]. company logo LAB-0094-8.0 Revised March 2012 Reference ID: 3124002 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.473685	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/012380s034lbl.pdf', 'application_number': 12380, 'submission_type': 'SUPPL ', 'submission_number': 34}
10,811	1 PRESCRIBING INFORMATION 1 2 TABLOID® 3 brand Thioguanine 4 40-mg Scored Tablets 5 CAUTION 6 TABLOID brand Thioguanine is a potent drug. It should not be used unless a diagnosis 7 of acute nonlymphocytic leukemia has been adequately established and the responsible 8 physician is knowledgeable in assessing response to chemotherapy. 9 DESCRIPTION 10 TABLOID brand Thioguanine was synthesized and developed by Hitchings, Elion, and 11 associates at the Wellcome Research Laboratories. It is one of a large series of purine analogues 12 which interfere with nucleic acid biosynthesis, and has been found active against selected human 13 neoplastic diseases. 14 Thioguanine, known chemically as 2-amino-1,7-dihydro-6H-purine-6-thione, is an analogue 15 of the nucleic acid constituent guanine, and is closely related structurally and functionally to 16 PURINETHOL® (mercaptopurine). Its structural formula is: 17 18 19 20 TABLOID brand Thioguanine is available in tablets for oral administration. Each scored 21 tablet contains 40 mg thioguanine and the inactive ingredients gum acacia, lactose, magnesium 22 stearate, potato starch, and stearic acid. 23 CLINICAL PHARMACOLOGY 24 Clinical studies have shown that the absorption of an oral dose of thioguanine in humans is 25 incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 26 46%). Following oral administration of 35S-6-thioguanine, total plasma radioactivity reached a 27 maximum at 8 hours and declined slowly thereafter. Parent drug represented only a very small 28 fraction of the total plasma radioactivity at any time, being virtually undetectable throughout the 29 period of measurements. 30 The oral administration of radiolabeled thioguanine revealed only trace quantities of parent 31 drug in the urine. However, a methylated metabolite, 2-amino-6-methylthiopurine (MTG), 32 appeared very early, rose to a maximum 6 to 8 hours after drug administration, and was still 33 being excreted after 12 to 22 hours. Radiolabeled sulfate appeared somewhat later than MTG but 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 was the principal metabolite after 8 hours. Thiouric acid and some unidentified products were 35 found in the urine in small amounts. Intravenous administration of 35S-6-thioguanine disclosed a 36 median plasma half-disappearance time of 80 minutes (range: 25 to 240 minutes) when the 37 compound was given in single doses of 65 to 300 mg/m2. Although initial plasma levels of 38 thioguanine did correlate with the dose level, there was no correlation between the plasma 39 half-disappearance time and the dose. 40 Thioguanine is incorporated into the DNA and the RNA of human bone marrow cells. Studies 41 with intravenous 35S-6-thioguanine have shown that the amount of thioguanine incorporated into 42 nucleic acids is more than 100 times higher after 5 daily doses than after a single dose. With the 43 5-dose schedule, from one-half to virtually all of the guanine in the residual DNA was replaced 44 by thioguanine. Tissue distribution studies of 35S-6-thioguanine in mice showed only traces of 45 radioactivity in brain after oral administration. No measurements have been made of thioguanine 46 concentrations in human cerebrospinal fluid (CSF), but observations on tissue distribution in 47 animals, together with the lack of CNS penetration by the closely related compound, 48 mercaptopurine, suggest that thioguanine does not reach therapeutic concentrations in the CSF. 49 Monitoring of plasma levels of thioguanine during therapy is of questionable value. There is 50 technical difficulty in determining plasma concentrations, which are seldom greater than 1 to 51 2 mcg/mL after a therapeutic oral dose. More significantly, thioguanine enters rapidly into the 52 anabolic and catabolic pathways for purines, and the active intracellular metabolites have 53 appreciably longer half-lives than the parent drug. The biochemical effects of a single dose of 54 thioguanine are evident long after the parent drug has disappeared from plasma. Because of this 55 rapid metabolism of thioguanine to active intracellular derivatives, hemodialysis would not be 56 expected to appreciably reduce toxicity of the drug. 57 Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine 58 phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanylic acid (TGMP). 59 This nucleotide reaches high intracellular concentrations at therapeutic doses. TGMP interferes 60 at several points with the synthesis of guanine nucleotides. It inhibits de novo purine 61 biosynthesis by pseudo-feedback inhibition of glutamine-5-phosphoribosylpyrophosphate 62 amidotransferase—the first enzyme unique to the de novo pathway for purine ribonucleotide 63 synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by 64 competition for the enzyme IMP dehydrogenase. At one time TGMP was felt to be a significant 65 inhibitor of ATP:GMP phosphotransferase (guanylate kinase), but recent results have shown this 66 not to be so. 67 Thioguanylic acid is further converted to the di- and tri-phosphates, thioguanosine 68 diphosphate (TGDP) and thioguanosine triphosphate (TGTP) (as well as their 2′-deoxyribosyl 69 analogues) by the same enzymes which metabolize guanine nucleotides. Thioguanine 70 nucleotides are incorporated into both the RNA and the DNA by phosphodiester linkages and it 71 has been argued that incorporation of such fraudulent bases contributes to the cytotoxicity of 72 thioguanine. 73 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Thus, thioguanine has multiple metabolic effects and at present it is not possible to designate 74 one major site of action. Its tumor inhibitory properties may be due to one or more of its effects 75 on (a) feedback inhibition of de novo purine synthesis; (b) inhibition of purine nucleotide 76 interconversions; or (c) incorporation into the DNA and the RNA. The net consequence of its 77 actions is a sequential blockade of the synthesis and utilization of the purine nucleotides. 78 The catabolism of thioguanine and its metabolites is complex and shows significant 79 differences between humans and the mouse. In both humans and mice, after oral administration 80 of 35S-6-thioguanine, urine contains virtually no detectable intact thioguanine. While 81 deamination and subsequent oxidation to thiouric acid occurs only to a small extent in humans, it 82 is the main pathway in mice. The product of deamination by guanase, 6-thioxanthine is inactive, 83 having negligible antitumor activity. This pathway of thioguanine inactivation is not dependent 84 on the action of xanthine oxidase, and an inhibitor of that enzyme (such as allopurinol) will not 85 block the detoxification of thioguanine even though the inactive 6-thioxanthine is normally 86 further oxidized by xanthine oxidase to thiouric acid before it is eliminated. In humans, 87 methylation of thioguanine is much more extensive than in the mouse. The product of 88 methylation, 2-amino-6-methylthiopurine, is also substantially less active and less toxic than 89 thioguanine and its formation is likewise unaffected by the presence of allopurinol. Appreciable 90 amounts of inorganic sulfate are also found in both murine and human urine, presumably arising 91 from further metabolism of the methylated derivatives. 92 In some animal tumors, resistance to the effect of thioguanine correlates with the loss of 93 HGPRTase activity and the resulting inability to convert thioguanine to thioguanylic acid. 94 However, other resistance mechanisms, such as increased catabolism of TGMP by a nonspecific 95 phosphatase, may be operative. Although not invariable, it is usual to find cross-resistance 96 between thioguanine and its close analogue, PURINETHOL (mercaptopurine). 97 INDICATIONS AND USAGE 98 a) Acute Nonlymphocytic Leukemias: TABLOID brand Thioguanine is indicated for 99 remission induction, remission consolidation, and maintenance therapy of acute 100 nonlymphocytic leukemias. The response to this agent depends upon the age of the patient 101 (younger patients faring better than older) and whether thioguanine is used in previously 102 treated or previously untreated patients. Reliance upon thioguanine alone is seldom justified 103 for initial remission induction of acute nonlymphocytic leukemias because combination 104 chemotherapy including thioguanine results in more frequent remission induction and longer 105 duration of remission than thioguanine alone. 106 b) Other Neoplasms: TABLOID brand Thioguanine is not effective in chronic lymphocytic 107 leukemia, Hodgkin’s lymphoma, multiple myeloma, or solid tumors. Although thioguanine is 108 one of several agents with activity in the treatment of the chronic phase of chronic 109 myelogenous leukemia, more objective responses are observed with MYLERAN® (busulfan), 110 and therefore busulfan is usually regarded as the preferred drug. 111 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 CONTRAINDICATIONS 112 Thioguanine should not be used in patients whose disease has demonstrated prior resistance to 113 this drug. In animals and humans, there is usually complete cross-resistance between 114 PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. 115 WARNINGS 116 SINCE DRUGS USED IN CANCER CHEMOTHERAPY ARE POTENTIALLY 117 HAZARDOUS, IT IS RECOMMENDED THAT ONLY PHYSICIANS EXPERIENCED WITH 118 THE RISKS OF THIOGUANINE AND KNOWLEDGEABLE IN THE NATURAL HISTORY 119 OF ACUTE NONLYMPHOCYTIC LEUKEMIAS ADMINISTER THIS DRUG. 120 The most consistent, dose-related toxicity is bone marrow suppression. This may be 121 manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Any one of 122 these findings may also reflect progression of the underlying disease. Since thioguanine may 123 have a delayed effect, it is important to withdraw the medication temporarily at the first sign of 124 an abnormally large fall in any of the formed elements of the blood. 125 There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase 126 (TPMT) who may be unusually sensitive to the myelosuppressive effects of thioguanine and 127 prone to developing rapid bone marrow suppression following the initiation of treatment. 128 Substantial dosage reductions may be required to avoid the development of life-threatening bone 129 marrow suppression in these patients. Prescribers should be aware that some laboratories offer 130 testing for TPMT deficiency. Since bone marrow suppression may be associated with factors 131 other than TPMT deficiency, TPMT testing may not identify all patients at risk for severe 132 toxicity. Therefore, close monitoring of clinical and hematologic parameters is important. Bone 133 marrow suppression could be exacerbated by coadministration with drugs that inhibit TPMT, 134 such as olsalazine, mesalazine, or sulphasalazine. 135 It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white 136 blood cell count and differential count, and quantitative platelet count be obtained frequently 137 while the patient is on thioguanine therapy. In cases where the cause of fluctuations in the 138 formed elements in the peripheral blood is obscure, bone marrow examination may be useful for 139 the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a 140 given dosage of thioguanine must be based not only on the absolute hematologic values, but also 141 upon the rapidity with which changes are occurring. In many instances, particularly during the 142 induction phase of acute leukemia, complete blood counts will need to be done more frequently 143 in order to evaluate the effect of the therapy. The dosage of thioguanine may need to be reduced 144 when this agent is combined with other drugs whose primary toxicity is myelosuppression. 145 Myelosuppression is often unavoidable during the induction phase of adult acute 146 nonlymphocytic leukemias if remission induction is to be successful. Whether or not this 147 demands modification or cessation of dosage depends both upon the response of the underlying 148 disease and a careful consideration of supportive facilities (granulocyte and platelet transfusions) 149 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 which may be available. Life-threatening infections and bleeding have been observed as 150 consequences of thioguanine-induced granulocytopenia and thrombocytopenia. 151 The effect of thioguanine on the immunocompetence of patients is unknown. 152 Pregnancy: Pregnancy Category D. Drugs such as thioguanine are potential mutagens and 153 teratogens. Thioguanine may cause fetal harm when administered to a pregnant woman. 154 Thioguanine has been shown to be teratogenic in rats when given in doses 5 times the human 155 dose. When given to the rat on the 4th and 5th days of gestation, 13% of surviving placentas did 156 not contain fetuses, and 19% of offspring were malformed or stunted. The malformations noted 157 included generalized edema, cranial defects, and general skeletal hypoplasia, hydrocephalus, 158 ventral hernia, situs inversus, and incomplete development of the limbs. There are no adequate 159 and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the 160 patient becomes pregnant while taking the drug, the patient should be apprised of the potential 161 hazard to the fetus. Women of childbearing potential should be advised to avoid becoming 162 pregnant. 163 PRECAUTIONS 164 General: Although the primary toxicity of thioguanine is myelosuppression, other toxicities 165 have occasionally been observed, particularly when thioguanine is used in combination with 166 other cancer chemotherapeutic agents. 167 A few cases of jaundice have been reported in patients with leukemia receiving thioguanine. 168 Among these were 2 adult male patients and 4 pediatric patients with acute myelogenous 169 leukemia and an adult male with acute lymphocytic leukemia who developed veno-occlusive 170 hepatic disease while receiving chemotherapy for their leukemia. Six patients had received 171 cytarabine prior to treatment with thioguanine, and some were receiving other chemotherapy in 172 addition to thioguanine when they became symptomatic. While veno-occlusive hepatic disease 173 has not been reported in patients treated with thioguanine alone, it is recommended that 174 thioguanine be withheld if there is evidence of toxic hepatitis or biliary stasis, and that 175 appropriate clinical and laboratory investigations be initiated to establish the etiology of the 176 hepatic dysfunction. Deterioration in liver function studies during thioguanine therapy should 177 prompt discontinuation of treatment and a search for an explanation of the hepatotoxicity. 178 Information for Patients: Patients should be informed that the major toxicities of thioguanine 179 are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Patients should 180 never be allowed to take the drug without medical supervision and should be advised to consult 181 their physician if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local 182 infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing 183 potential should be advised to avoid becoming pregnant. 184 Laboratory Tests: Prescribers should be aware that some laboratories offer testing for TPMT 185 deficiency (see WARNINGS). 186 It is advisable to monitor liver function tests (serum transaminases, alkaline phosphatase, 187 bilirubin) at weekly intervals when first beginning therapy and at monthly intervals thereafter. It 188 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 may be advisable to perform liver function tests more frequently in patients with known 189 pre-existing liver disease or in patients who are receiving thioguanine and other hepatotoxic 190 drugs. Patients should be instructed to discontinue thioguanine immediately if clinical jaundice is 191 detected (see WARNINGS). 192 Drug Interactions: There is usually complete cross-resistance between PURINETHOL 193 (mercaptopurine) and TABLOID brand Thioguanine. 194 In one study, 12 of approximately 330 patients receiving continuous busulfan and thioguanine 195 therapy for treatment of chronic myelogenous leukemia were found to have esophageal varices 196 associated with abnormal liver function tests. Subsequent liver biopsies were performed in 4 of 197 these patients, all of which showed evidence of nodular regenerative hyperplasia. Duration of 198 combination therapy prior to the appearance of esophageal varices ranged from 6 to 45 months. 199 With the present analysis of the data, no cases of hepatotoxicity have appeared in the 200 busulfan-alone arm of the study. Long-term continuous therapy with thioguanine and busulfan 201 should be used with caution. 202 As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or 203 sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients 204 receiving concurrent thioguanine therapy (see WARNINGS). 205 Carcinogenesis, Mutagenesis, Impairment of Fertility: In view of its action on cellular 206 DNA, thioguanine is potentially mutagenic and carcinogenic, and consideration should be given 207 to the theoretical risk of carcinogenesis when thioguanine is administered (see WARNINGS). 208 Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section. 209 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because of the 210 potential for tumorigenicity shown for thioguanine, a decision should be made whether to 211 discontinue nursing or to discontinue the drug, taking into account the importance of the drug to 212 the mother. 213 Pediatric Use: See DOSAGE AND ADMINISTRATION section. 214 Geriatric Use: Clinical studies of thioguanine did not include sufficient numbers of subjects 215 aged 65 and over to determine whether they respond differently from younger subjects. Other 216 reported clinical experience has not identified differences in responses between the elderly and 217 younger patients. In general, dose selection for an elderly patient should be cautious, usually 218 starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, 219 renal, or cardiac function, and of concomitant disease or other drug therapy. 220 ADVERSE REACTIONS 221 The most frequent adverse reaction to thioguanine is myelosuppression. The induction of 222 complete remission of acute myelogenous leukemia usually requires combination chemotherapy 223 in dosages which produce marrow hypoplasia. Since consolidation and maintenance of remission 224 are also effected by multiple-drug regimens whose component agents cause myelosuppression, 225 pancytopenia is observed in nearly all patients. Dosages and schedules must be adjusted to 226 prevent life-threatening cytopenias whenever these adverse reactions are observed. 227 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Hyperuricemia frequently occurs in patients receiving thioguanine as a consequence of rapid 228 cell lysis accompanying the antineoplastic effect. Adverse effects can be minimized by increased 229 hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase 230 inhibitor such as ZYLOPRIM® (allopurinol). Unlike PURINETHOL (mercaptopurine) and 231 IMURAN® (azathioprine), thioguanine may be continued in the usual dosage when allopurinol 232 is used conjointly to inhibit uric acid formation. 233 Less frequent adverse reactions include nausea, vomiting, anorexia, and stomatitis. Intestinal 234 necrosis and perforation have been reported in patients who received multiple-drug 235 chemotherapy including thioguanine. 236 Hepatic Effects: Liver enzyme and other liver function studies are occasionally abnormal. If 237 jaundice, hepatomegaly, or anorexia with tenderness in the right hypochondrium occurs, 238 thioguanine should be withheld until the exact etiology can be determined. There have been 239 reports of veno-occlusive liver disease occurring in patients who received combination 240 chemotherapy including thioguanine. Esophageal varices have been reported in patients 241 receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous 242 leukemia (see PRECAUTIONS: Drug Interactions). 243 OVERDOSAGE 244 Signs and symptoms of overdosage may be immediate, such as nausea, vomiting, malaise, 245 hypotension, and diaphoresis; or delayed, such as myelosuppression and azotemia. It is not 246 known whether thioguanine is dialyzable. Hemodialysis is thought to be of marginal use due to 247 the rapid intracellular incorporation of thioguanine into active metabolites with long persistence. 248 The oral LD50 of thioguanine was determined to be 823 mg/kg ± 50.73 mg/kg and 249 740 mg/kg ± 45.24 mg/kg for male and female rats, respectively. Symptoms of overdosage may 250 occur after a single dose of as little as 2.0 to 3.0 mg/kg thioguanine. As much as 35 mg/kg has 251 been given in a single oral dose with reversible myelosuppression observed. There is no known 252 pharmacologic antagonist of thioguanine. The drug should be discontinued immediately if 253 unintended toxicity occurs during treatment. Severe hematologic toxicity may require supportive 254 therapy with platelet transfusions for bleeding, and granulocyte transfusions and antibiotics if 255 sepsis is documented. If a patient is seen immediately following an accidental overdosage of the 256 drug, it may be useful to induce emesis. 257 DOSAGE AND ADMINISTRATION 258 TABLOID brand Thioguanine is administered orally. The dosage which will be tolerated and 259 effective varies according to the stage and type of neoplastic process being treated. Because the 260 usual therapies for adult and pediatric acute nonlymphocytic leukemias involve the use of 261 thioguanine with other agents in combination, physicians responsible for administering these 262 therapies should be experienced in the use of cancer chemotherapy and in the chosen protocol. 263 There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase 264 (TPMT) who may be unusually sensitive to the myelosuppressive effects of thioguanine and 265 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 prone to developing rapid bone marrow suppression following the initiation of treatment. 266 Substantial dosage reductions may be required to avoid the development of life-threatening bone 267 marrow suppression in these patients (see WARNINGS). Prescribers should be aware that some 268 laboratories offer testing for TPMT deficiency. 269 Ninety-six (59%) of 163 pediatric patients with previously untreated acute nonlymphocytic 270 leukemia obtained complete remission with a multiple-drug protocol including thioguanine, 271 prednisone, cytarabine, cyclophosphamide, and vincristine. Remission was maintained with daily 272 thioguanine, 4-day pulses of cytarabine and cyclophosphamide, and a single dose of vincristine 273 every 28 days. The median duration of remission was 11.5 months.8 274 Fifty-three percent of previously untreated adults with acute nonlymphocytic leukemias 275 attained remission following use of the combination of thioguanine and cytarabine according to a 276 protocol developed at The Memorial Sloan-Kettering Cancer Center. A median duration of 277 remission of 8.8 months was achieved with the multiple-drug maintenance regimen which 278 included thioguanine. 279 On those occasions when single-agent chemotherapy with thioguanine may be appropriate, 280 the usual initial dosage for pediatric patients and adults is approximately 2 mg/kg of body weight 281 per day. If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or 282 platelet depression, the dosage may be cautiously increased to 3 mg/kg/day. The total daily dose 283 may be given at one time. 284 The dosage of thioguanine used does not depend on whether or not the patient is receiving 285 ZYLOPRIM (allopurinol); this is in contradistinction to the dosage reduction which is 286 mandatory when PURINETHOL (mercaptopurine) or IMURAN (azathioprine) is given 287 simultaneously with allopurinol. 288 Procedures for proper handling and disposal of anticancer drugs should be considered. Several 289 guidelines on this subject have been published.1-8 290 There is no general agreement that all of the procedures recommended in the guidelines are 291 necessary or appropriate. 292 HOW SUPPLIED 293 Greenish-yellow, scored tablets containing 40 mg thioguanine, imprinted with 294 “WELLCOME” and “U3B” on each tablet; in bottles of 25 (NDC 0173-0880-25). 295 Store at 15° to 25°C (59° to 77°F) in a dry place. 296 REFERENCES 297 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations 298 for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41. 299 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: 300 Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, 301 National Institutes of Health and Human Services, 1992, US Dept of Health and Human 302 Services, Public Health Service publication NIH 92-2621. 303 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. 304 JAMA. 1985;253:1590-1591. 305 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling 306 cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study 307 Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health 308 Sciences, 179 Longwood Avenue, Boston, MA 02115. 309 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling 310 of antineoplastic agents. Med J Australia. 1983;1:426-428. 311 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the 312 Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263. 313 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling 314 cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 315 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) 316 Am J Health-Syst Pharm. 1996;53:1669-1685. 317 318 319 320 Manufactured by 321 DSM Pharmaceuticals, Inc. 322 Greenville, NC 27834 323 for GlaxoSmithKline 324 Research Triangle Park, NC 27709 325 326 2003, GlaxoSmithKline. All rights reserved. 327 328 Date of Issue RL- 329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.686659	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/12429slr021_tabloid_lbl.pdf', 'application_number': 12429, 'submission_type': 'SUPPL ', 'submission_number': 21}
10,813	Depo-Provera® medroxyprogesterone acetate injectable suspension, USP DESCRIPTION DEPO-PROVERA Sterile Aqueous Suspension contains medroxyprogesterone acetate, which is a derivative of progesterone and is active by the parenteral and oral routes of administration. It is a white to off-white, odorless crystalline powder, stable in air, melting between 200° and 210° C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether and insoluble in water. The chemical name for medroxyprogesterone acetate is Pregn-4-ene-3, 20-dione, 17 (acetyloxy)-6-methyl-, (6α)-. The structural formula is: structural formula DEPO-PROVERA for intramuscular injection is available as 400 mg/mL medroxyprogesterone acetate. Each mL of the 400 mg/mL suspension contains: Medroxyprogesterone acetate .............400 mg Polyethylene glycol 3350....................20.3 mg Sodium sulfate anhydrous .....................11 mg with Myristyl-gamma-picolinium chloride ............................................1.69 mg added as preservative When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. 1 Reference ID: 3943732 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ACTIONS Medroxyprogesterone acetate, administered parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative endometrium into secretory endometrium. Medroxyprogesterone acetate inhibits (in the usual dose range) the secretion of pituitary gonadotropin which, in turn, prevents follicular maturation and ovulation. Because of its prolonged action and the resulting difficulty in predicting the time of withdrawal bleeding following injection, medroxyprogesterone acetate is not recommended in secondary amenorrhea or dysfunctional uterine bleeding. In these conditions oral therapy is recommended. INDICATIONS AND USES Adjunctive therapy and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal carcinoma. CONTRAINDICATIONS 1. Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease 2. Known sensitivity to DEPO-PROVERA (medroxyprogesterone acetate or any of its other ingredients). WARNINGS 1. Thromboembolic Disorders The physician should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, cerebrovascular disorder, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately. 2. Ocular Disorders Medication should be discontinued pending examination if there is a sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn. 3. Multi-dose Use Multi-dose use of DEPO-PROVERA Sterile Aqueous Suspension from a single vial requires special care to avoid contamination. Although initially sterile, any multi-dose use of vials may lead to contamination unless strict aseptic technique is observed. PRECAUTIONS 1. Physical Examination It is good medical practice for all women to have annual history and physical examinations, including women using DEPO-PROVERA Sterile Aqueous Suspension. The physical examination, however, may be deferred until after initiation of DEPO 2 Reference ID: 3943732 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PROVERA if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. 2. Breast Cancer Women who have or have had a history of breast cancer should be advised against the use of DEPO-PROVERA, as breast cancer may be hormonally sensitive. Women with a strong family history of breast cancer should be monitored with particular care. 3. Fluid Retention Because progestational drugs may cause some degree of fluid retention, conditions which might be influenced by this condition, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation. 4.Vaginal Bleeding In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind and adequate diagnostic measures undertaken. 5. Depression Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree. 6.Masking of Climacteric The age of the patient constitutes no absolute limiting factor although treatment with progestin may mask the onset of the climacteric. 7. Use with Estrogen Studies of the addition of a progestin product to an estrogen replacement regimen for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of endometrial suggest that 10–13 days of a progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established. There are possible risks which may be associated with the inclusion of progestin in estrogen replacement regimen, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving such therapy. 3 Reference ID: 3943732 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8. Hepatic Dysfunction Monitor patients for hepatic dysfunction periodically and temporarily interrupt DEPO PROVERA Sterile Aqueous Suspension use if the patient develops hepatic dysfunction. Do not resume use until markers of liver function return to normal. 9. Decrease in Bone Mineral Density Medroxyprogesterone acetate given as 150 mg intramuscularly every three months reduces serum estrogen levels and is associated with loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of Depo-Provera by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. An evaluation of BMD may be appropriate in some patients who use higher doses of medroxyprogesterone acetate for long-term treatment of endometrial or renal carcinoma. 10. Effects on the Hypothalmic-Pituitary-Adrenal Axis Some patients receiving medroxyprogesterone acetate may exhibit suppressed adrenal function. Medroxyprogesterone acetate may have cortisol-like glucocorticoid activity and provide negative feedback to the hypothalamus or pituitary. This may result in decreased plasma cortisol levels, decreased cortisol secretion, and low plasma ACTH levels. The use of DEPO-PROVERA Sterile Aqueous Suspension may, due to its cortisol-like glucocorticoid activity, also produce Cushingoid symptoms such as weight gain, edema/fluid retention, and facial swelling. 11. Prolonged Use The effect of prolonged use of DEPO-PROVERA Sterile Aqueous Suspension at the recommended doses on pituitary, ovarian, adrenal, hepatic, and uterine function is not known. 12. Interference with Laboratory Tests The use of DEPO-PROVERA Sterile Aqueous Suspension may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. [See LABORATORY TEST INTERACTIONS]. 13. Multi-dose Use When multi-dose vials are used, special care to prevent contamination of the contents is essential. There is some evidence that benzalkonium chloride is not an adequate antiseptic for sterilizing DEPO-PROVERA Sterile Aqueous Suspension multi-dose vials. A povidone-iodine solution or similar product is recommended to cleanse the vial top prior to aspiration of contents. [See WARNINGS]. 14. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term intramuscular administration of Medroxyprogesterone acetate (MPA) has been shown to produce mammary tumors in beagle dogs. There is no evidence of a carcinogenic effect associated with the oral administration of MPA to rats and mice. 4 Reference ID: 3943732 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Medroxyprogesterone acetate at high doses is an anti-fertility drug and return to ovulation and fertility may be delayed after stopping treatment. 15. Pregnancy Teratogenic effects It is not known whether medroxyprogesterone acetate can cause fetal harm when administered to a pregnant woman. Medroxyprogesterone acetate should be given to a pregnant woman only if clearly needed. 16. Nursing Mothers Published studies report the presence of medroxyprogesterone acetate in human milk. Caution should be exercised when medroxyprogesterone acetate is administered to a nursing woman. 17. Pediatric Use Safety and efficacy of DEPO- PROVERA for endometrial and renal carcinoma have not been established in pediatric patients. Depo-Provera is associated with loss of BMD which is of particular concern during adolescence and early adulthood, a critical period of bone accretion. (See PRECAUTIONS: Decrease in Bone Mineral Density) DRUG INTERACTIONS Aminoglutethimide administered concomitantly with DEPO-PROVERA Sterile Aqueous Suspension may significantly depress the serum concentrations of medroxyprogesterone acetate. DEPO-PROVERA users should be warned of the possibility of decreased efficacy with the use of this or any related drugs. In vitro Medroxyprogesterone acetate is metabolized primarily by hydroxylation via the CYP3A4. Though no formal drug interaction trials have been conducted, concomitant administration of strong CYP3A inhibitors is expected to increase concentrations of medroxyprogesterone acetate, whereas the concomitant administration of strong CYP3A inducers is expected to decrease medroxyprogesterone acetate concentrations. Therefore, coadministration with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort) should be avoided. LABORATORY TEST INTERACTIONS The pathologist should be advised of progestin therapy when relevant specimens are submitted. The following laboratory tests may be affected by progestins including DEPO PROVERA Sterile Aqueous Suspension: 5 Reference ID: 3943732 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda a) Plasma and urinary steroid levels are decreased (e.g. progesterone, estradiol, pregnanediol, testosterone, cortisol). b) Gonadotropin levels are decreased. c) Sex-hormone binding globulin concentrations are decreased. d) Protein bound iodine and butanol extractable protein bound iodine may increase. T3 uptake values may decrease. e) Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase. f) Sulfobromophthalein and other liver function test values may be increased. g) The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies. ADVERSE REACTIONS – See PRECAUTIONS for possible adverse effects on the fetus Reproductive System and Breast Disorders –breakthrough bleeding –spotting –change in menstrual flow –amenorrhea –changes in cervical erosion and cervical secretions –breast tenderness and galactorrhea –erectile dysfunction Nervous System Disorders –headache –dizziness –somnolence –convulsions Psychiatric Disorders –nervousness –euphoria –mental depression –insomnia General Disorders and Administration Site Conditions –edema –pyrexia –fatigue –malaise –injection site reaction, injection site pain/tenderness, injection site persistent atrophy/indentation/dimpling, lipodystrophy acquired, injection site nodule/lump 6 Reference ID: 3943732 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In a few instances there have been undesirable sequelae at the site of injection, such as residual lump, change in color of skin, or sterile abscess. Investigations –change in weight (increase or decrease) Hepatobiliary Disorders –cholestatic jaundice, including neonatal jaundice Skin and Subcutaneous Tissue Disorders –skin sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash –acne, alopecia and hirsutism –rash (allergic) with and without pruritis Immune System Disorders –anaphylactoid reactions and anaphylaxis –angioedema Gastrointestinal Disorders –nausea Endocrine Disorders –corticoid-like effects (e.g., Cushingoid syndrome) Metabolism and Nutrition Disorders –hypercalcemia A statistically significant association has been demonstrated between use of estrogen-pro gestin combination drugs and pulmonary embolism and cerebral thrombosis and embolism. For this reason patients on progestin therapy should be carefully observed. There is also evidence suggestive of an association with neuro-ocular lesions, e.g. retinal thrombosis and optic neuritis. The following adverse reactions have been observed in patients receiving estrogen progestin combination drugs: –rise in blood pressure in susceptible individuals –premenstrual syndrome –changes in libido –changes in appetite –cystitis-like syndrome –headache –nervousness –fatigue –backache –hirsutism 7 Reference ID: 3943732 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda –loss of scalp hair –erythema multiforma –erythema nodosum –hemorrhagic eruption –itching –dizziness The following laboratory results may be altered by the use of estrogen-progestin combination drugs: –increased sulfobromophthalein retention and other hepatic function tests –coagulation tests: increase in prothrombin factors VII, VIII, IX, and X –metyrapone test –pregnanediol determinations –thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values DOSAGE AND ADMINISTRATION The suspension is intended for intramuscular administration only. When multi-dose vials are used, special care to prevent contamination of the contents is essential [see WARNINGS and PRECAUTIONS]. Endometrial or Renal Carcinoma Doses of 400 mg to 1000 mg of DEPO-PROVERA Sterile Aqueous Suspension per week are recommended initially. If improvement is noted within a few weeks or months and the disease appears stabilized, it may be possible to maintain improvement with as little as 400 mg per month. Medroxyprogesterone acetate is not recommended as primary therapy, but as adjunctive and palliative treatment in advanced inoperable cases including those with recurrent or metastatic disease. Geriatric Use Renal Carcinoma Of the 349 subjects in a clinical study of Depo Provera in renal carcinoma, 30 percent were 65 and over, while 5 percent were 75 and over. 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. Endometrial Carcinoma This product has been used primarily in post-menopausal women for the treatment of endometrial carcinoma. Clinical experience has not identified differences in safety or effectiveness between elderly and younger patients. 8 Reference ID: 3943732 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatic Impairment DEPO-PROVERA Sterile Aqueous Suspension should not be used by women with significant liver disease and should be discontinued if jaundice or disturbances of liver function occur [see PRECAUTIONS]. Renal Impairment The effect of renal impairment on DEPO-PROVERA pharmacokinetics has not been studied. HOW SUPPLIED DEPO-PROVERA Sterile Aqueous Suspension is available as 400 mg/mL in 2.5 mL vials. NDC 0009-0626-01 2.5ml vial Rx only company logo LAB-0143-5.1 Revised June 2016 9 Reference ID: 3943732 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.725602	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012541s084lbl.pdf', 'application_number': 12541, 'submission_type': 'SUPPL ', 'submission_number': 84}
10,810	1 PRESCRIBING INFORMATION TABLOID® BRAND THIOGUANINE 40-mg Scored Tablets CAUTION TABLOID brand Thioguanine is a potent drug. It should not be used unless a diagnosis of acute nonlymphocytic leukemia has been adequately established and the responsible physician is knowledgeable in assessing response to chemotherapy. DESCRIPTION TABLOID brand Thioguanine was synthesized and developed by Hitchings, Elion, and associates at the Wellcome Research Laboratories. It is one of a large series of purine analogues which interfere with nucleic acid biosynthesis, and has been found active against selected human neoplastic diseases.1 Thioguanine, known chemically as 2-amino-1,7-dihydro-6H-purine-6-thione, is an analogue of the nucleic acid constituent guanine, and is closely related structurally and functionally to PURINETHOL® (mercaptopurine). Its structural formula is: TABLOID brand Thioguanine is available in tablets for oral administration. Each scored tablet contains 40 mg thioguanine and the inactive ingredients gum acacia, lactose, magnesium stearate, potato starch, and stearic acid. CLINICAL PHARMACOLOGY Clinical studies have shown that the absorption of an oral dose of thioguanine in humans is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%).2,3 Following oral administration of 35S-6-thioguanine, total plasma radioactivity reached a maximum at 8 hours and declined slowly thereafter. Parent drug represented only a very small This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda fraction of the total plasma radioactivity at any time, being virtually undetectable throughout the period of measurements. The oral administration of radiolabeled thioguanine revealed only trace quantities of parent drug in the urine. However, a methylated metabolite, 2-amino-6-methylthiopurine (MTG), appeared very early, rose to a maximum 6 to 8 hours after drug administration, and was still being excreted after 12 to 22 hours. Radiolabeled sulfate appeared somewhat later than MTG but was the principal metabolite after 8 hours. Thiouric acid and some unidentified products were found in the urine in small amounts.3 Intravenous administration of 35S-6-thioguanine disclosed a median plasma half-disappearance time of 80 minutes (range: 25 to 240 minutes) when the compound was given in single doses of 65 to 300 mg/m2. Although initial plasma levels of thioguanine did correlate with the dose level, there was no correlation between the plasma half-disappearance time and the dose.2 Thioguanine is incorporated into the DNA and the RNA of human bone marrow cells. Studies with intravenous 35S-6-thioguanine have shown that the amount of thioguanine incorporated into nucleic acids is more than 100 times higher after 5 daily doses than after a single dose. With the 5-dose schedule, from one-half to virtually all of the guanine in the residual DNA was replaced by thioguanine.2 Tissue distribution studies of 35S-6-thioguanine in mice showed only traces of radioactivity in brain after oral administration. No measurements have been made of thioguanine concentrations in human cerebrospinal fluid (CSF), but observations on tissue distribution in animals, together with the lack of CNS penetration by the closely related compound, mercaptopurine, suggest that thioguanine does not reach therapeutic concentrations in the CSF. Monitoring of plasma levels of thioguanine during therapy is of questionable value.3 There is technical difficulty in determining plasma concentrations, which are seldom greater than 1 to 2 mcg/mL after a therapeutic oral dose. More significantly, thioguanine enters rapidly into the anabolic and catabolic pathways for purines, and the active intracellular metabolites have appreciably longer half-lives than the parent drug. The biochemical effects of a single dose of thioguanine are evident long after the parent drug has disappeared from plasma. Because of this rapid metabolism of thioguanine to active intracellular derivatives, hemodialysis would not be expected to appreciably reduce toxicity of the drug. Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanylic acid (TGMP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This nucleotide reaches high intracellular concentrations at therapeutic doses. TGMP interferes at several points with the synthesis of guanine nucleotides. It inhibits de novo purine biosynthesis by pseudo-feedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase—the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. At one time TGMP was felt to be a significant inhibitor of ATP:GMP phosphotransferase (guanylate kinase),4 but recent results have shown this not to be so.5 Thioguanylic acid is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) (as well as their 2′-deoxyribosyl analogues) by the same enzymes which metabolize guanine nucleotides.6 Thioguanine nucleotides are incorporated into both the RNA and the DNA by phosphodiester linkages2 and it has been argued that incorporation of such fraudulent bases contributes to the cytotoxicity of thioguanine. Thus, thioguanine has multiple metabolic effects and at present it is not possible to designate one major site of action. Its tumor inhibitory properties may be due to one or more of its effects on (a) feedback inhibition of de novo purine synthesis; (b) inhibition of purine nucleotide interconversions; or (c) incorporation into the DNA and the RNA. The net consequence of its actions is a sequential blockade of the synthesis and utilization of the purine nucleotides.4,6,7 The catabolism of thioguanine and its metabolites is complex and shows significant differences between humans and the mouse.2,3 In both humans and mice, after oral administration of 35S-6-thioguanine, urine contains virtually no detectable intact thioguanine. While deamination and subsequent oxidation to thiouric acid occurs only to a small extent in humans, it is the main pathway in mice. The product of deamination by guanase, 6-thioxanthine is inactive, having negligible antitumor activity. This pathway of thioguanine inactivation is not dependent on the action of xanthine oxidase, and an inhibitor of that enzyme (such as allopurinol) will not block the detoxification of thioguanine even though the inactive 6-thioxanthine is normally further oxidized by xanthine oxidase to thiouric acid before it is eliminated. In humans, methylation of thioguanine is much more extensive than in the mouse. The product of methylation, 2-amino-6-methylthiopurine, is also substantially less active and less toxic than thioguanine and its formation is likewise unaffected by the presence of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda allopurinol. Appreciable amounts of inorganic sulfate are also found in both murine and human urine, presumably arising from further metabolism of the methylated derivatives. In some animal tumors, resistance to the effect of thioguanine correlates with the loss of HGPRTase activity and the resulting inability to convert thioguanine to thioguanylic acid. However, other resistance mechanisms, such as increased catabolism of TGMP by a nonspecific phosphatase, may be operative. Although not invariable, it is usual to find cross-resistance between thioguanine and its close analogue, PURINETHOL (mercaptopurine). INDICATIONS AND USAGE a) Acute Nonlymphocytic Leukemias: TABLOID brand Thioguanine is indicated for remission induction, remission consolidation, and maintenance therapy of acute nonlymphocytic leukemias.8,9 The response to this agent depends upon the age of the patient (younger patients faring better than older) and whether thioguanine is used in previously treated or previously untreated patients. Reliance upon thioguanine alone is seldom justified for initial remission induction of acute nonlymphocytic leukemias because combination chemotherapy including thioguanine results in more frequent remission induction and longer duration of remission than thioguanine alone. b) Other Neoplasms: TABLOID brand Thioguanine is not effective in chronic lymphocytic leukemia, Hodgkin’s lymphoma, multiple myeloma, or solid tumors. Although thioguanine is one of several agents with activity in the treatment of the chronic phase of chronic myelogenous leukemia, more objective responses are observed with MYLERAN® (busulfan), and therefore busulfan is usually regarded as the preferred drug. CONTRAINDICATIONS Thioguanine should not be used in patients whose disease has demonstrated prior resistance to this drug. In animals and humans, there is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. WARNINGS SINCE DRUGS USED IN CANCER CHEMOTHERAPY ARE POTENTIALLY HAZARDOUS, IT IS RECOMMENDED THAT ONLY PHYSICIANS EXPERIENCED WITH THE RISKS OF THIOGUANINE AND KNOWLEDGEABLE IN THE NATURAL HISTORY OF ACUTE NONLYMPHOCYTIC LEUKEMIAS ADMINISTER THIS DRUG. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The most consistent, dose-related toxicity is bone marrow suppression. This may be manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Any one of these findings may also reflect progression of the underlying disease. Since thioguanine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in any of the formed elements of the blood. There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effects of mercaptopurine and prone to developing rapid bone marrow suppression following the initiation of treatment. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine. It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained frequently while the patient is on thioguanine therapy. In cases where the cause of fluctuations in the formed elements in the peripheral blood is obscure, bone marrow examination may be useful for the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a given dosage of thioguanine must be based not only on the absolute hematologic values, but also upon the rapidity with which changes are occurring. In many instances, particularly during the induction phase of acute leukemia, complete blood counts will need to be done more frequently in order to evaluate the effect of the therapy. The dosage of thioguanine may need to be reduced when this agent is combined with other drugs whose primary toxicity is myelosuppression. Myelosuppression is often unavoidable during the induction phase of adult acute nonlymphocytic leukemias if remission induction is to be successful. Whether or not this demands modification or cessation of dosage depends both upon the response of the underlying disease and a careful consideration of supportive facilities (granulocyte and platelet transfusions) which may be available. Life-threatening infections and bleeding have been observed as consequences of thioguanine-induced granulocytopenia and thrombocytopenia. The effect of thioguanine on the immunocompetence of patients is unknown. Pregnancy: Pregnancy Category D. Drugs such as thioguanine are potential mutagens and teratogens. Thioguanine may cause fetal harm when administered to a pregnant woman. Thioguanine has been shown to be teratogenic in rats when given in doses 5 times the human dose. When given to the rat on the 4th and 5th days of gestation, 13% of surviving placentas did This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda not contain fetuses, and 19% of offspring were malformed or stunted. The malformations noted included generalized edema, cranial defects, and general skeletal hypoplasia, hydrocephalus, ventral hernia, situs inversus, and incomplete development of the limbs.10 There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. PRECAUTIONS General: Although the primary toxicity of thioguanine is myelosuppression, other toxicities have occasionally been observed, particularly when thioguanine is used in combination with other cancer chemotherapeutic agents. A few cases of jaundice have been reported in patients with leukemia receiving thioguanine. Among these were 2 adult male patients and 4 pediatric patients with acute myelogenous leukemia and an adult male with acute lymphocytic leukemia who developed veno-occlusive hepatic disease while receiving chemotherapy for their leukemia.11,12 Six patients had received cytarabine prior to treatment with thioguanine, and some were receiving other chemotherapy in addition to thioguanine when they became symptomatic. While veno-occlusive hepatic disease has not been reported in patients treated with thioguanine alone, it is recommended that thioguanine be withheld if there is evidence of toxic hepatitis or biliary stasis, and that appropriate clinical and laboratory investigations be initiated to establish the etiology of the hepatic dysfunction. Deterioration in liver function studies during thioguanine therapy should prompt discontinuation of treatment and a search for an explanation of the hepatotoxicity. Information for Patients: Patients should be informed that the major toxicities of thioguanine are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Patients should never be allowed to take the drug without medical supervision and should be advised to consult their physician if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing potential should be advised to avoid becoming pregnant. Laboratory Tests: It is advisable to monitor liver function tests (serum transaminases, alkaline phosphatase, bilirubin) at weekly intervals when first beginning therapy and at monthly intervals thereafter. It may be advisable to perform liver function tests more frequently in patients with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda known pre-existing liver disease or in patients who are receiving thioguanine and other hepatotoxic drugs. Patients should be instructed to discontinue thioguanine immediately if clinical jaundice is detected (see WARNINGS). Drug Interactions: There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. In one study, 12 of approximately 330 patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia were found to have esophageal varices associated with abnormal liver function tests.13 Subsequent liver biopsies were performed in 4 of these patients, all of which showed evidence of nodular regenerative hyperplasia. Duration of combination therapy prior to the appearance of esophageal varices ranged from 6 to 45 months. With the present analysis of the data, no cases of hepatotoxicity have appeared in the busulfan-alone arm of the study. Long-term continuous therapy with thioguanine and busulfan should be used with caution. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy (see WARNINGS). Carcinogenesis, Mutagenesis, Impairment of Fertility: In view of its action on cellular DNA, thioguanine is potentially mutagenic and carcinogenic, and consideration should be given to the theoretical risk of carcinogenesis when thioguanine is administered (see WARNINGS). Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for thioguanine, 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: See DOSAGE AND ADMINISTRATION section. Geriatric Use: Clinical studies of thioguanine 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 ADVERSE REACTIONS The most frequent adverse reaction to thioguanine is myelosuppression. The induction of complete remission of acute myelogenous leukemia usually requires combination chemotherapy in dosages which produce marrow hypoplasia.14 Since consolidation and maintenance of remission are also effected by multiple-drug regimens whose component agents cause myelosuppression, pancytopenia is observed in nearly all patients. Dosages and schedules must be adjusted to prevent life-threatening cytopenias whenever these adverse reactions are observed. Hyperuricemia frequently occurs in patients receiving thioguanine as a consequence of rapid cell lysis accompanying the antineoplastic effect. Adverse effects can be minimized by increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such as ZYLOPRIM® (allopurinol). Unlike PURINETHOL (mercaptopurine) and IMURAN® (azathioprine), thioguanine may be continued in the usual dosage when allopurinol is used conjointly to inhibit uric acid formation. Less frequent adverse reactions include nausea, vomiting, anorexia, and stomatitis. Intestinal necrosis and perforation have been reported in patients who received multiple-drug chemotherapy including thioguanine. Hepatic Effects: Liver enzyme and other liver function studies are occasionally abnormal. If jaundice, hepatomegaly, or anorexia with tenderness in the right hypochondrium occurs, thioguanine should be withheld until the exact etiology can be determined. There have been reports of veno-occlusive liver disease occurring in patients who received combination chemotherapy including thioguanine.11,12 Esophageal varices have been reported in patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia (see PRECAUTIONS: Drug Interactions). OVERDOSAGE Signs and symptoms of overdosage may be immediate, such as nausea, vomiting, malaise, hypertension, and diaphoresis; or delayed, such as myelosuppression and azotemia.15 It is not known whether thioguanine is dialyzable. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of thioguanine into active metabolites with long persistence. The oral LD50 of thioguanine was determined to be 823 mg/kg ± 50.73 mg/kg and 740 mg/kg ± 45.24 mg/kg for male and female rats, respectively.16 Symptoms of overdosage may occur after a single dose of as little as 2.0 to 3.0 mg/kg thioguanine. As much as 35 mg/kg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda has been given in a single oral dose with reversible myelosuppression observed. There is no known pharmacologic antagonist of thioguanine. The drug should be discontinued immediately if unintended toxicity occurs during treatment. Severe hematologic toxicity may require supportive therapy with platelet transfusions for bleeding, and granulocyte transfusions and antibiotics if sepsis is documented. If a patient is seen immediately following an accidental overdosage of the drug, it may be useful to induce emesis. DOSAGE AND ADMINISTRATION TABLOID brand Thioguanine is administered orally. The dosage which will be tolerated and effective varies according to the stage and type of neoplastic process being treated. Because the usual therapies for adult and pediatric acute nonlymphocytic leukemias involve the use of thioguanine with other agents in combination, physicians responsible for administering these therapies should be experienced in the use of cancer chemotherapy and in the chosen protocol. Ninety-six (59%) of 163 pediatric patients with previously untreated acute nonlymphocytic leukemia obtained complete remission with a multiple-drug protocol including thioguanine, prednisone, cytarabine, cyclophosphamide, and vincristine. Remission was maintained with daily thioguanine, 4-day pulses of cytarabine and cyclophosphamide, and a single dose of vincristine every 28 days. The median duration of remission was 11.5 months.8 Fifty-three percent of previously untreated adults with acute nonlymphocytic leukemias attained remission following use of the combination of thioguanine and cytarabine according to a protocol developed at The Memorial Sloan-Kettering Cancer Center. A median duration of remission of 8.8 months was achieved with the multiple-drug maintenance regimen which included thioguanine.9 On those occasions when single-agent chemotherapy with thioguanine may be appropriate, the usual initial dosage for pediatric patients and adults is approximately 2 mg/kg of body weight per day. If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or platelet depression, the dosage may be cautiously increased to 3 mg/kg/day. The total daily dose may be given at one time. The dosage of thioguanine used does not depend on whether or not the patient is receiving ZYLOPRIM (allopurinol); this is in contradistinction to the dosage reduction which is mandatory when PURINETHOL (mercaptopurine) or IMURAN (azathioprine) is given simultaneously with allopurinol. 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.17-23 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. HOW SUPPLIED Greenish-yellow, scored tablets containing 40 mg thioguanine, imprinted with “WELLCOME” and “U3B” on each tablet; in bottle of 25 (NDC 0173-0880-25). Store at 15° to 25°C (59° to 77°F) in a dry place. REFERENCES 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41. 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health and Human Services, 1992, US Dept of Health and Human Services, Public Health Service publication NIH 92-2621. 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591. 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983; 1:426-428. 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983; 33:258-263. 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049. 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.). Am J Health-SystPharm. 1996;53-1669-1685 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Manufactured by DSM Pharmaceuticals, Inc. Greenville, NC 27834 for GlaxoSmithKline Research Triangle Park, NC 27709 , GlaxoSmithKline. All rights reserved. Date of Issue RL-no. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.818820	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/12429slr019_tabloid_lbl.pdf', 'application_number': 12429, 'submission_type': 'SUPPL ', 'submission_number': 19}
10,812	1 PRESCRIBING INFORMATION 1 TABLOID® 2 brand Thioguanine 3 40-mg Scored Tablets 4 CAUTION 5 TABLOID brand Thioguanine is a potent drug. It should not be used unless a diagnosis 6 of acute nonlymphocytic leukemia has been adequately established and the responsible 7 physician is knowledgeable in assessing response to chemotherapy. 8 DESCRIPTION 9 TABLOID brand Thioguanine was synthesized and developed by Hitchings, Elion, and 10 associates at the Wellcome Research Laboratories. It is one of a large series of purine analogues 11 which interfere with nucleic acid biosynthesis, and has been found active against selected human 12 neoplastic diseases. 13 Thioguanine, known chemically as 2-amino-1,7-dihydro-6H-purine-6-thione, is an analogue 14 of the nucleic acid constituent guanine, and is closely related structurally and functionally to 15 PURINETHOL® (mercaptopurine). Its structural formula is: 16 17 18 19 TABLOID brand Thioguanine is available in tablets for oral administration. Each scored 20 tablet contains 40 mg thioguanine and the inactive ingredients gum acacia, lactose, magnesium 21 stearate, potato starch, and stearic acid. 22 CLINICAL PHARMACOLOGY 23 Clinical studies have shown that the absorption of an oral dose of thioguanine in humans is 24 incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 25 46%). Following oral administration of 35S-6-thioguanine, total plasma radioactivity reached a 26 maximum at 8 hours and declined slowly thereafter. Parent drug represented only a very small 27 fraction of the total plasma radioactivity at any time, being virtually undetectable throughout the 28 period of measurements. 29 The oral administration of radiolabeled thioguanine revealed only trace quantities of parent 30 drug in the urine. However, a methylated metabolite, 2-amino-6-methylthiopurine (MTG), 31 appeared very early, rose to a maximum 6 to 8 hours after drug administration, and was still 32 being excreted after 12 to 22 hours. Radiolabeled sulfate appeared somewhat later than MTG but 33 was the principal metabolite after 8 hours. Thiouric acid and some unidentified products were 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 found in the urine in small amounts. Intravenous administration of 35S-6-thioguanine disclosed a 35 median plasma half-disappearance time of 80 minutes (range: 25 to 240 minutes) when the 36 compound was given in single doses of 65 to 300 mg/m2. Although initial plasma levels of 37 thioguanine did correlate with the dose level, there was no correlation between the plasma 38 half-disappearance time and the dose. 39 Thioguanine is incorporated into the DNA and the RNA of human bone marrow cells. Studies 40 with intravenous 35S-6-thioguanine have shown that the amount of thioguanine incorporated into 41 nucleic acids is more than 100 times higher after 5 daily doses than after a single dose. With the 42 5-dose schedule, from one-half to virtually all of the guanine in the residual DNA was replaced 43 by thioguanine. Tissue distribution studies of 35S-6-thioguanine in mice showed only traces of 44 radioactivity in brain after oral administration. No measurements have been made of thioguanine 45 concentrations in human cerebrospinal fluid (CSF), but observations on tissue distribution in 46 animals, together with the lack of CNS penetration by the closely related compound, 47 mercaptopurine, suggest that thioguanine does not reach therapeutic concentrations in the CSF. 48 Monitoring of plasma levels of thioguanine during therapy is of questionable value. There is 49 technical difficulty in determining plasma concentrations, which are seldom greater than 1 to 50 2 mcg/mL after a therapeutic oral dose. More significantly, thioguanine enters rapidly into the 51 anabolic and catabolic pathways for purines, and the active intracellular metabolites have 52 appreciably longer half-lives than the parent drug. The biochemical effects of a single dose of 53 thioguanine are evident long after the parent drug has disappeared from plasma. Because of this 54 rapid metabolism of thioguanine to active intracellular derivatives, hemodialysis would not be 55 expected to appreciably reduce toxicity of the drug. 56 Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine 57 phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanylic acid (TGMP). 58 This nucleotide reaches high intracellular concentrations at therapeutic doses. TGMP interferes 59 at several points with the synthesis of guanine nucleotides. It inhibits de novo purine 60 biosynthesis by pseudo-feedback inhibition of glutamine-5-phosphoribosylpyrophosphate 61 amidotransferase—the first enzyme unique to the de novo pathway for purine ribonucleotide 62 synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by 63 competition for the enzyme IMP dehydrogenase. At one time TGMP was felt to be a significant 64 inhibitor of ATP:GMP phosphotransferase (guanylate kinase), but recent results have shown this 65 not to be so. 66 Thioguanylic acid is further converted to the di- and tri-phosphates, thioguanosine 67 diphosphate (TGDP) and thioguanosine triphosphate (TGTP) (as well as their 2′-deoxyribosyl 68 analogues) by the same enzymes which metabolize guanine nucleotides. Thioguanine 69 nucleotides are incorporated into both the RNA and the DNA by phosphodiester linkages and it 70 has been argued that incorporation of such fraudulent bases contributes to the cytotoxicity of 71 thioguanine. 72 Thus, thioguanine has multiple metabolic effects and at present it is not possible to designate 73 one major site of action. Its tumor inhibitory properties may be due to one or more of its effects 74 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 on (a) feedback inhibition of de novo purine synthesis; (b) inhibition of purine nucleotide 75 interconversions; or (c) incorporation into the DNA and the RNA. The net consequence of its 76 actions is a sequential blockade of the synthesis and utilization of the purine nucleotides. 77 The catabolism of thioguanine and its metabolites is complex and shows significant 78 differences between humans and the mouse. In both humans and mice, after oral administration 79 of 35S-6-thioguanine, urine contains virtually no detectable intact thioguanine. While 80 deamination and subsequent oxidation to thiouric acid occurs only to a small extent in humans, it 81 is the main pathway in mice. The product of deamination by guanase, 6-thioxanthine is inactive, 82 having negligible antitumor activity. This pathway of thioguanine inactivation is not dependent 83 on the action of xanthine oxidase, and an inhibitor of that enzyme (such as allopurinol) will not 84 block the detoxification of thioguanine even though the inactive 6-thioxanthine is normally 85 further oxidized by xanthine oxidase to thiouric acid before it is eliminated. In humans, 86 methylation of thioguanine is much more extensive than in the mouse. The product of 87 methylation, 2-amino-6-methylthiopurine, is also substantially less active and less toxic than 88 thioguanine and its formation is likewise unaffected by the presence of allopurinol. Appreciable 89 amounts of inorganic sulfate are also found in both murine and human urine, presumably arising 90 from further metabolism of the methylated derivatives. 91 In some animal tumors, resistance to the effect of thioguanine correlates with the loss of 92 HGPRTase activity and the resulting inability to convert thioguanine to thioguanylic acid. 93 However, other resistance mechanisms, such as increased catabolism of TGMP by a nonspecific 94 phosphatase, may be operative. Although not invariable, it is usual to find cross-resistance 95 between thioguanine and its close analogue, PURINETHOL (mercaptopurine). 96 INDICATIONS AND USAGE 97 a) Acute Nonlymphocytic Leukemias: TABLOID brand Thioguanine is indicated for 98 remission induction and remission consolidation treatment of acute nonlymphocytic 99 leukemias. However, it is not recommended for use during maintenance therapy or similar 100 long term continuous treatments due to the high risk of liver toxicity (see WARNINGS and 101 ADVERSE REACTIONS). 102 The response to this agent depends upon the age of the patient (younger patients faring 103 better than older) and whether thioguanine is used in previously treated or previously 104 untreated patients. Reliance upon thioguanine alone is seldom justified for initial remission 105 induction of acute nonlymphocytic leukemias because combination chemotherapy including 106 thioguanine results in more frequent remission induction and longer duration of remission 107 than thioguanine alone. 108 b) Other Neoplasms: TABLOID brand Thioguanine is not effective in chronic lymphocytic 109 leukemia, Hodgkin’s lymphoma, multiple myeloma, or solid tumors. Although thioguanine is 110 one of several agents with activity in the treatment of the chronic phase of chronic 111 myelogenous leukemia, more objective responses are observed with MYLERAN® (busulfan), 112 and therefore busulfan is usually regarded as the preferred drug. 113 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 CONTRAINDICATIONS 114 Thioguanine should not be used in patients whose disease has demonstrated prior resistance to 115 this drug. In animals and humans, there is usually complete cross-resistance between 116 PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. 117 WARNINGS 118 SINCE DRUGS USED IN CANCER CHEMOTHERAPY ARE POTENTIALLY 119 HAZARDOUS, IT IS RECOMMENDED THAT ONLY PHYSICIANS EXPERIENCED WITH 120 THE RISKS OF THIOGUANINE AND KNOWLEDGEABLE IN THE NATURAL HISTORY 121 OF ACUTE NONLYMPHOCYTIC LEUKEMIAS ADMINISTER THIS DRUG. 122 THIOGUANINE IS NOT RECOMMENDED FOR MAINTENANCE THERAPY OR 123 SIMILAR LONG TERM CONTINUOUS TREATMENTS DUE TO THE HIGH RISK OF 124 LIVER TOXICITY ASSOCIATED WITH VASCULAR ENDOTHELIAL DAMAGE (see 125 DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS). This liver toxicity has 126 been observed in a high proportion of children receiving thioguanine as part of maintenance 127 therapy for acute lymphoblastic leukaemia and in other conditions associated with continuous 128 use of thioguanine. This liver toxicity is particularly prevalent in males. Liver toxicity usually 129 presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinaemia, tender 130 hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal 131 hypertension (splenomegaly, thrombocytopenia, and oesophageal varices). Histopathological 132 features associated with this toxicity include hepatoportal sclerosis, nodular regenerative 133 hyperplasia, peliosis hepatis, and periportal fibrosis. 134 Thioguanine therapy should be discontinued in patients with evidence of liver toxicity as 135 reversal of signs and symptoms of liver toxicity have been reported upon withdrawal. 136 Patients must be carefully monitored (see PRECAUTIONS, Laboratory Tests). Early 137 indications of liver toxicity are signs associated with portal hypertension such as 138 thrombocytopenia out of proportion with neutropenia and splenomegaly. Elevations of liver 139 enzymes have also been reported in association with liver toxicity but do not always occur. 140 The most consistent, dose-related toxicity is bone marrow suppression. This may be 141 manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Any one of 142 these findings may also reflect progression of the underlying disease. Since thioguanine may 143 have a delayed effect, it is important to withdraw the medication temporarily at the first sign of 144 an abnormally large fall in any of the formed elements of the blood. 145 There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase 146 (TPMT) who may be unusually sensitive to the myelosuppressive effects of thioguanine and 147 prone to developing rapid bone marrow suppression following the initiation of treatment. 148 Substantial dosage reductions may be required to avoid the development of life-threatening bone 149 marrow suppression in these patients. Prescribers should be aware that some laboratories offer 150 testing for TPMT deficiency. Since bone marrow suppression may be associated with factors 151 other than TPMT deficiency, TPMT testing may not identify all patients at risk for severe 152 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 toxicity. Therefore, close monitoring of clinical and hematologic parameters is important. Bone 153 marrow suppression could be exacerbated by coadministration with drugs that inhibit TPMT, 154 such as olsalazine, mesalazine, or sulphasalazine. 155 It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white 156 blood cell count and differential count, and quantitative platelet count be obtained frequently 157 while the patient is on thioguanine therapy. In cases where the cause of fluctuations in the 158 formed elements in the peripheral blood is obscure, bone marrow examination may be useful for 159 the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a 160 given dosage of thioguanine must be based not only on the absolute hematologic values, but also 161 upon the rapidity with which changes are occurring. In many instances, particularly during the 162 induction phase of acute leukemia, complete blood counts will need to be done more frequently 163 in order to evaluate the effect of the therapy. The dosage of thioguanine may need to be reduced 164 when this agent is combined with other drugs whose primary toxicity is myelosuppression. 165 Myelosuppression is often unavoidable during the induction phase of adult acute 166 nonlymphocytic leukemias if remission induction is to be successful. Whether or not this 167 demands modification or cessation of dosage depends both upon the response of the underlying 168 disease and a careful consideration of supportive facilities (granulocyte and platelet transfusions) 169 which may be available. Life-threatening infections and bleeding have been observed as 170 consequences of thioguanine-induced granulocytopenia and thrombocytopenia. 171 The effect of thioguanine on the immunocompetence of patients is unknown. 172 Pregnancy: Pregnancy Category D. Drugs such as thioguanine are potential mutagens and 173 teratogens. Thioguanine may cause fetal harm when administered to a pregnant woman. 174 Thioguanine has been shown to be teratogenic in rats when given in doses 5 times the human 175 dose. When given to the rat on the 4th and 5th days of gestation, 13% of surviving placentas did 176 not contain fetuses, and 19% of offspring were malformed or stunted. The malformations noted 177 included generalized edema, cranial defects, and general skeletal hypoplasia, hydrocephalus, 178 ventral hernia, situs inversus, and incomplete development of the limbs. There are no adequate 179 and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the 180 patient becomes pregnant while taking the drug, the patient should be apprised of the potential 181 hazard to the fetus. Women of childbearing potential should be advised to avoid becoming 182 pregnant. 183 PRECAUTIONS 184 General: Although the primary toxicity of thioguanine is myelosuppression, other toxicities 185 have occasionally been observed, particularly when thioguanine is used in combination with 186 other cancer chemotherapeutic agents. 187 A few cases of jaundice have been reported in patients with leukemia receiving thioguanine. 188 Among these were 2 adult male patients and 4 pediatric patients with acute myelogenous 189 leukemia and an adult male with acute lymphocytic leukemia who developed hepatic 190 veno-occlusive disease while receiving chemotherapy for their leukemia. Six patients had 191 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 received cytarabine prior to treatment with thioguanine, and some were receiving other 192 chemotherapy in addition to thioguanine when they became symptomatic. While hepatic 193 veno-occlusive disease has not been reported in patients treated with thioguanine alone, it is 194 recommended that thioguanine be withheld if there is evidence of toxic hepatitis or biliary stasis, 195 and that appropriate clinical and laboratory investigations be initiated to establish the etiology of 196 the hepatic dysfunction. Deterioration in liver function studies during thioguanine therapy should 197 prompt discontinuation of treatment and a search for an explanation of the hepatotoxicity. 198 Information for Patients: Patients should be informed that the major toxicities of thioguanine 199 are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Patients should 200 never be allowed to take the drug without medical supervision and should be advised to consult 201 their physician if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local 202 infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing 203 potential should be advised to avoid becoming pregnant. 204 Laboratory Tests: Prescribers should be aware that some laboratories offer testing for TPMT 205 deficiency (see WARNINGS). 206 It is advisable to monitor liver function tests (serum transaminases, alkaline phosphatase, 207 bilirubin) at weekly intervals when first beginning therapy and at monthly intervals thereafter. It 208 may be advisable to perform liver function tests more frequently in patients with known 209 pre-existing liver disease or in patients who are receiving thioguanine and other hepatotoxic 210 drugs. Patients should be instructed to discontinue thioguanine immediately if clinical jaundice is 211 detected (see WARNINGS). 212 Drug Interactions: There is usually complete cross-resistance between PURINETHOL 213 (mercaptopurine) and TABLOID brand Thioguanine. 214 As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or 215 sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients 216 receiving concurrent thioguanine therapy (see WARNINGS). 217 Carcinogenesis, Mutagenesis, Impairment of Fertility: In view of its action on cellular 218 DNA, thioguanine is potentially mutagenic and carcinogenic, and consideration should be given 219 to the theoretical risk of carcinogenesis when thioguanine is administered (see WARNINGS). 220 Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section. 221 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because of the 222 potential for tumorigenicity shown for thioguanine, a decision should be made whether to 223 discontinue nursing or to discontinue the drug, taking into account the importance of the drug to 224 the mother. 225 Pediatric Use: See DOSAGE AND ADMINISTRATION section. 226 Geriatric Use: Clinical studies of thioguanine did not include sufficient numbers of subjects 227 aged 65 and over to determine whether they respond differently from younger subjects. Other 228 reported clinical experience has not identified differences in responses between the elderly and 229 younger patients. In general, dose selection for an elderly patient should be cautious, usually 230 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, 231 renal, or cardiac function, and of concomitant disease or other drug therapy. 232 ADVERSE REACTIONS 233 The most frequent adverse reaction to thioguanine is myelosuppression. The induction of 234 complete remission of acute myelogenous leukemia usually requires combination chemotherapy 235 in dosages which produce marrow hypoplasia. Since consolidation and maintenance of remission 236 are also effected by multiple-drug regimens whose component agents cause myelosuppression, 237 pancytopenia is observed in nearly all patients. Dosages and schedules must be adjusted to 238 prevent life-threatening cytopenias whenever these adverse reactions are observed. 239 Hyperuricemia frequently occurs in patients receiving thioguanine as a consequence of rapid 240 cell lysis accompanying the antineoplastic effect. Adverse effects can be minimized by increased 241 hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase 242 inhibitor such as ZYLOPRIM® (allopurinol). Unlike PURINETHOL (mercaptopurine) and 243 IMURAN® (azathioprine), thioguanine may be continued in the usual dosage when allopurinol is 244 used conjointly to inhibit uric acid formation. 245 Less frequent adverse reactions include nausea, vomiting, anorexia, and stomatitis. Intestinal 246 necrosis and perforation have been reported in patients who received multiple-drug 247 chemotherapy including thioguanine. 248 Hepatic Effects: Liver toxicity associated with vascular endothelial damage has been reported 249 when thioguanine is used in maintenance or similar long term continuous therapy which is not 250 recommended (see WARNINGS and DOSAGE AND ADMINISTRATION). This usually 251 presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinaemia, tender 252 hepatomegaly, weight gain due to fluid retention, and ascites) or signs and symptoms of portal 253 hypertension (splenomegaly, thrombocytopenia, and esophageal varices). Elevation of liver 254 transaminases, alkaline phosphatase, and gamma glutamyl transferase and jaundice may also 255 occur. Histopathological features associated with this toxicity include hepatoportal sclerosis, 256 nodular regenerative hyperplasia, peliosis hepatis, and periportal fibrosis. 257 Liver toxicity during short term cyclical therapy presents as veno-occlusive disease. Reversal 258 of signs and symptoms of this liver toxicity has been reported upon withdrawal of short term or 259 long term continuous therapy. 260 Centrilobular hepatic necrosis has been reported in a few cases; however, the reports are 261 confounded by the use of high doses of thioguanine, other chemotherapeutic agents, and oral 262 contraceptives and chronic alcohol abuse. 263 OVERDOSAGE 264 Signs and symptoms of overdosage may be immediate, such as nausea, vomiting, malaise, 265 hypotension, and diaphoresis; or delayed, such as myelosuppression and azotemia. It is not 266 known whether thioguanine is dialyzable. Hemodialysis is thought to be of marginal use due to 267 the rapid intracellular incorporation of thioguanine into active metabolites with long persistence. 268 The oral LD50 of thioguanine was determined to be 823 mg/kg ± 50.73 mg/kg and 269 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 740 mg/kg ± 45.24 mg/kg for male and female rats, respectively. Symptoms of overdosage may 270 occur after a single dose of as little as 2.0 to 3.0 mg/kg thioguanine. As much as 35 mg/kg has 271 been given in a single oral dose with reversible myelosuppression observed. There is no known 272 pharmacologic antagonist of thioguanine. The drug should be discontinued immediately if 273 unintended toxicity occurs during treatment. Severe hematologic toxicity may require supportive 274 therapy with platelet transfusions for bleeding, and granulocyte transfusions and antibiotics if 275 sepsis is documented. If a patient is seen immediately following an accidental overdosage of the 276 drug, it may be useful to induce emesis. 277 DOSAGE AND ADMINISTRATION 278 TABLOID brand Thioguanine is administered orally. The dosage which will be tolerated and 279 effective varies according to the stage and type of neoplastic process being treated. Because the 280 usual therapies for adult and pediatric acute nonlymphocytic leukemias involve the use of 281 thioguanine with other agents in combination, physicians responsible for administering these 282 therapies should be experienced in the use of cancer chemotherapy and in the chosen protocol. 283 There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase 284 (TPMT) who may be unusually sensitive to the myelosuppressive effects of thioguanine and 285 prone to developing rapid bone marrow suppression following the initiation of treatment. 286 Substantial dosage reductions may be required to avoid the development of life-threatening bone 287 marrow suppression in these patients (see WARNINGS). Prescribers should be aware that some 288 laboratories offer testing for TPMT deficiency. 289 Ninety-six (59%) of 163 pediatric patients with previously untreated acute nonlymphocytic 290 leukemia obtained complete remission with a multiple-drug protocol including thioguanine, 291 prednisone, cytarabine, cyclophosphamide, and vincristine. Remission was maintained with daily 292 thioguanine, 4-day pulses of cytarabine and cyclophosphamide, and a single dose of vincristine 293 every 28 days. The median duration of remission was 11.5 months.8 294 Fifty-three percent of previously untreated adults with acute nonlymphocytic leukemias 295 attained remission following use of the combination of thioguanine and cytarabine according to a 296 protocol developed at The Memorial Sloan-Kettering Cancer Center. A median duration of 297 remission of 8.8 months was achieved with the multiple-drug maintenance regimen which 298 included thioguanine. 299 On those occasions when single-agent chemotherapy with thioguanine may be appropriate, 300 the usual initial dosage for pediatric patients and adults is approximately 2 mg/kg of body weight 301 per day. If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or 302 platelet depression, the dosage may be cautiously increased to 3 mg/kg/day. The total daily dose 303 may be given at one time. 304 The dosage of thioguanine used does not depend on whether or not the patient is receiving 305 ZYLOPRIM (allopurinol); this is in contradistinction to the dosage reduction which is 306 mandatory when PURINETHOL (mercaptopurine) or IMURAN (azathioprine) is given 307 simultaneously with allopurinol. 308 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Procedures for proper handling and disposal of anticancer drugs should be considered. Several 309 guidelines on this subject have been published.1-8 310 There is no general agreement that all of the procedures recommended in the guidelines are 311 necessary or appropriate. 312 HOW SUPPLIED 313 Greenish-yellow, scored tablets containing 40 mg thioguanine, imprinted with 314 “WELLCOME” and “U3B” on each tablet; in bottles of 25 (NDC 0173-0880-25). 315 Store at 15° to 25°C (59° to 77°F) in a dry place. 316 REFERENCES 317 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations 318 for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41. 319 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: 320 Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, 321 National Institutes of Health and Human Services, 1992, US Dept of Health and Human 322 Services, Public Health Service publication NIH 92-2621. 323 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. 324 JAMA. 1985;253:1590-1591. 325 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling 326 cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study 327 Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health 328 Sciences, 179 Longwood Avenue, Boston, MA 02115. 329 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling 330 of antineoplastic agents. Med J Australia. 1983;1:426-428. 331 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the 332 Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263. 333 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling 334 cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 335 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) 336 Am J Health-Syst Pharm. 1996;53:1669-1685. 337 338 339 340 Manufactured by 341 DSM Pharmaceuticals, Inc. 342 Greenville, NC 27834 343 for GlaxoSmithKline 344 Research Triangle Park, NC 27709 345 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 346 YEAR, GlaxoSmithKline. All rights reserved. 347 348 Month YEAR RL-XXX 349 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.871236	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/12429s022lbl.pdf', 'application_number': 12429, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,814	Page 1 Rev. November 2003 TENUATE® IV (diethylpropion hydrochloride USP) immediate-release 25 mg tablets TENUATE® DOSPAN® IV (diethylpropion hydrochloride USP) controlled-release 75 mg tablets DESCRIPTION TENUATE® is available for oral administration in immediate-release tablets containing 25 mg diethylpropion hydrochloride and in controlled-release tablets containing 75 mg diethylpropion hydrochloride. The inactive ingredients in each immediate-release tablet are: corn starch, lactose, magnesium stearate, pregelatinized corn starch, talc, and tartaric acid. The inactive ingredients in each controlled-release tablet are: carbomer 934P, mannitol, povidone, tartaric acid, zinc stearate. Diethylpropion hydrochloride is a sympathomimetic agent. The chemical name for diethylpropion hydrochloride is 1-phenyl-2-diethyl-amino-1-propanone hydrochloride. Its chemical structure is: In TENUATE DOSPAN tablets, diethylpropion hydrochloride is dispersed in a hydrophilic matrix. On exposure to water, the diethylpropion hydrochloride is released at a relatively uniform rate as a result of slow hydration of the matrix. The result is controlled release of the anorectic agent. CLINICAL PHARMACOLOGY Diethylpropion hydrochloride is a sympathomimetic amine with some pharmacologic activity similar to that of the prototype drugs of this class used in obesity, the amphetamines. Actions include some central nervous system stimulation and elevation of blood pressure. Tolerance has been demonstrated with all drugs of this class in which these phenomena have been looked for. Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." It has not been established, however, that the action of such drugs in treating obesity is primarily one of appetite suppression. For example, other central nervous system actions or metabolic effects may be involved. Adult obese subjects instructed in dietary management and treated with "anorectic" drugs lose more weight on the average than those treated with placebo and diet, as determined in relatively short-term clinical trials. The magnitude of increased weight loss of drug-treated patients over placebo-treated patients averages some fraction of a pound a week. However, individual weight loss may vary substantially from patient to patient. The rate of weight loss is greatest in the first weeks of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 therapy for both drug and placebo subjects and tends to decrease in succeeding weeks. The possible origins of the increased weight loss due to the various drug effects are not established. The amount of weight loss associated with the use of an "anorectic" drug varies from trial to trial, and the increased weight loss appears to be related in part to variables other than the drug prescribed, such as the physician/investigator relationship, the population treated, and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non- drug factors on weight loss. The natural history of obesity is measured in years, whereas most studies cited are restricted to a few weeks duration; thus, the total impact of drug-induced weight loss over that of diet alone is unknown. Diethylpropion is rapidly absorbed from the GI tract after oral administration and is extensively metabolized through a complex pathway of biotransformation involving N-dealkylation and reduction. Many of these metabolites are biologically active and may participate in the therapeutic action of TENUATE or TENUATE DOSPAN. Due to the varying lipid solubilities of these metabolites, their circulating levels are affected by urinary pH. Diethylpropion and/or its active metabolites are believed to cross the blood-brain barrier and the placenta. Diethylpropion and its metabolites are excreted mainly by the kidney. It has been reported that between 75-106% of the dose is recovered in the urine within 48 hours after dosing. Using a phosphorescence assay that is specific for basic compounds containing benzoyl group, the plasma half-life of the aminoketone metabolites is estimated to be between 4 to 6 hours. The controlled-release characteristics of TENUATE DOSPAN have been demonstrated by studies in humans in which plasma levels of diethylpropion-related materials were measured by phosphorescence analysis. Plasma levels obtained with the 75 mg TENUATE DOSPAN formulation administered once daily indicated a more gradual release than the immediate-release formulation (three 25 mg tablets given in a single dose). TENUATE DOSPAN has not been shown superior in effectiveness to the same dosage of the immediate-release formulation (one 25 mg tablet three times daily). After administration of a single dose of TENUATE DOSPAN (one 75 mg controlled-release tablet) or diethylpropion hydrochloride solution (75 mg dose) in a cross-over study using normal human subjects, the amount of parent compound and its active metabolites recovered in the urine within 48 hours for the two dosage forms were not statistically different. INDICATIONS AND USAGE TENUATE and TENUATE DOSPAN are indicated in the management of exogenous obesity as a short-term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction in patients with an initial body mass index (BMI) of 30 kg/m2 or higher and who have not responded to appropriate weight reducing regimen (diet and/or exercise) alone. Below is a chart of BMI based on various heights and weights. BMI is calculated by taking the patients weight, in kilograms (kg), divided by the patient’s height, in meters (m), squared. Metric conversions are as follows: pounds divided by 2.2 = kg; inches x 0.0254 = meters. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 Body Mass Index (BMI), kg/m2 Weight (pounds) Height (feet, inches) 5’0” 5’3” 5’6” 5’9” 6’0” 6’3” 140 27 25 23 21 19 18 150 29 27 24 22 20 19 160 31 28 26 24 22 20 170 33 30 28 25 23 21 180 35 32 29 27 25 23 190 37 34 31 28 26 24 200 39 36 32 30 27 25 210 41 37 34 31 29 26 220 43 39 36 33 30 28 230 45 41 37 34 31 29 240 47 43 39 36 33 30 250 49 44 40 37 34 31 The usefulness of agents of this class (see CLINICAL PHARMACOLOGY) should be measured against possible risk factors inherent in their use such as those described below. TENUATE and TENUATE DOSPAN are indicated for use as monotherapy only. CONTRAINDICATIONS Pulmonary hypertension, advanced arteriosclerosis, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma, severe hypertension. (See PRECAUTIONS.) Agitated states. Patients with a history of drug abuse. Use in combination with other anorectic agents is contraindicated. During or within 14 days following the administration of monoamine oxidase inhibitors, hypertensive crises may result. WARNINGS TENUATE and TENUATE DOSPAN should not be used in combination with other anorectic agents, including prescribed drugs, over-the-counter preparations, and herbal products. In a case-control epidemiological study, the use of anorectic agents, including diethylpropion, was associated with an increased risk of developing pulmonary hypertension, a rare, but often fatal disorder. The use of anorectic agents for longer than 3 months was associated with a 23-fold increase in the risk of developing pulmonary hypertension. Increased risk of pulmonary hypertension with repeated courses of therapy cannot be excluded. The onset or aggravation of exertional dyspnea, or unexplained symptoms of angina pectoris, syncope, or lower extremity edema suggest the possibility of occurrence of pulmonary hypertension. Under these circumstances, TENUATE or TENUATE DOSPAN should be immediately discontinued, and the patient should be evaluated for the possible presence of pulmonary hypertension. Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine has been reported. Possible contributing factors include use for extended periods of time, higher than recommended dose, and/or use in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 combination with other anorectic drugs. Valvulopathy has been very rarely reported with TENUATE and TENUATE DOSPAN monotherapy, but the causal relationship remains uncertain. The potential risk of possible serious adverse effects such as valvular heart disease and pulmonary hypertension should be assessed carefully against the potential benefit of weight loss. Baseline cardiac evaluation should be considered to detect preexisting valvular heart diseases or pulmonary hypertension prior to initiation of TENUATE or TENUATE DOSPAN treatment. TENUATE and TENUATE DOSPAN are not recommended in patients with known heart murmur or valvular heart disease. Echocardiogram during and after treatment could be useful for detecting any valvular disorders which may occur. To limit unwarranted exposure and risks, treatment with TENUATE or TENUATE DOSPAN should be continued only if the patient has satisfactory weight loss within the first 4 weeks of treatment (e.g., weight loss of at least 4 pounds, or as determined by the physician and patient). TENUATE and TENUATE DOSPAN are not recommended for patients who used any anorectic agents within the prior year. If tolerance develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued. TENUATE or TENUATE DOSPAN may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; the patient should therefore be cautioned accordingly. Prolonged use of diethylpropion hydrochloride may induce dependence with withdrawal syndrome on cessation of therapy. Hallucinations have occurred rarely following high doses of the drug. Several cases of toxic psychosis have been reported following the excessive use of the drug and some have been reported in which the recommended dose appears not to have been exceeded. Psychosis abated after the drug was discontinued. When central nervous system active agents are used, consideration must always be given to the possibility of adverse interactions with alcohol. PRECAUTIONS General Caution is to be exercised in prescribing TENUATE or TENUATE DOSPAN for patients with hypertension or with symptomatic cardiovascular disease, including arrhythmias. TENUATE or TENUATE DOSPAN should not be administered to patients with severe hypertension. Reports suggest that diethylpropion hydrochloride may increase convulsions in some epileptics. Therefore, epileptics receiving TENUATE or TENUATE DOSPAN should be carefully monitored. Titration of dose or discontinuance of TENUATE or TENUATE DOSPAN may be necessary. The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. Information for Patient The patient should be cautioned about concomitant use of alcohol or other CNS-active drugs and TENUATE or TENUATE DOSPAN. (See WARNINGS.) The patient should be advised to observe caution when driving or engaging in any potentially hazardous activity. Laboratory Tests None This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 Drug Interactions Because TENUATE and TENUATE DOSPAN are monoamines, hypertension may result when either agent is used with monoamine oxidase (MAO) inhibitors (See CONTRAINDICATIONS). Efficacy of diethylpropion with other anorectic agents has not been studied and the combined use may have the potential for serious cardiac problems; therefore, the concomitant use with other anorectic agents is contraindicated. Antidiabetic drug requirements (i.e., insulin) may be altered. Concurrent use with general anesthetics may result in arrhythmias. The pressor effects of diethylpropion and those of other drugs may be additive when the drugs are used concomitantly; conversely, diethylpropion may interfere with antihypertensive drugs (i.e., guanethidine, a-methyldopa). Concurrent use of phenothiazines may antagonize the anorectic effect of diethylpropion. Carcinogenesis, Mutagenesis, and Impairment of Fertility No long-term animal studies have been done to evaluate diethylpropion hydrochloride for carcinogenicity. Mutagenicity studies have not been conducted. Animal reproduction studies have revealed no evidence of impairment of fertility (see Pregnancy). Pregnancy Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 1.6 times the human dose (based on mg/m2) and have revealed no evidence of impaired fertility or harm to the fetus due to diethylpropion hydrochloride. 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. Spontaneous reports of congenital malformations have been recorded in humans, but no causal relationship to diethylpropion has been established. Non-Teratogenic Effects. Abuse with diethylpropion hydrochloride during pregnancy may result in withdrawal symptoms in the human neonate. Nursing Mothers Since diethylpropion hydrochloride and/or its metabolites have been shown to be excreted in human milk, caution should be exercised when TENUATE or TENUATE DOSPAN is administered to a nursing woman. Geriatric Use Clinical studies of TENUATE or TENUATE DOSPAN 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 in 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 Page 6 Pediatric Use Since safety and effectiveness in pediatric patients below the age of 16 have not been established, TENUATE or TENUATE DOSPAN is not recommended for use in pediatric patients 16 years of age and under. ADVERSE REACTIONS Cardiovascular: Precordial pain, arrhythmia (including ventricular), ECG changes, tachycardia, elevation of blood pressure, palpitation and rare reports of pulmonary hypertension. Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine, both independently and especially when used in combination, have been reported. Valvulopathy has been very rarely reported with TENUATE or TENUATE DOSPAN monotherapy, but the causal relationship remains uncertain. Central Nervous System: In a few epileptics an increase in convulsive episodes has been reported; rarely psychotic episodes at recommended doses; dyskinesia, blurred vision, overstimulation, nervousness, restlessness, dizziness, jitteriness, insomnia, anxiety, euphoria, depression, dysphoria, tremor, mydriasis, drowsiness, malaise, headache, and cerebrovascular accident Gastrointestinal: Vomiting, diarrhea, abdominal discomfort, dryness of the mouth, unpleasant taste, nausea, constipation, other gastrointestinal disturbances Allergic: Urticaria, rash, ecchymosis, erythema Endocrine: Impotence, changes in libido, gynecomastia, menstrual upset Hematopoietic System: Bone marrow depression, agranulocytosis, leukopenia Miscellaneous: A variety of miscellaneous adverse reactions has been reported by physicians. These include complaints such as dysuria, dyspnea, hair loss, muscle pain, increased sweating, and polyuria. DRUG ABUSE AND DEPENDENCE TENUATE and TENUATE DOSPAN are schedule IV controlled substances. Diethylpropion hydrochloride has some chemical and pharmacologic similarities to the amphetamines and other related stimulant drugs that have been extensively abused. There have been reports of subjects becoming psychologically dependent on diethylpropion. The possibility of abuse should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. Abuse of amphetamines and related drugs may be associated with varying degrees of psychologic dependence and social dysfunction which, in the case of certain drugs, may be severe. There are reports of patients who have increased the dosage to many times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. OVERDOSAGE Manifestations of acute overdosage include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, and mydriasis. Fatigue and depression usually follow the central stimulation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 Cardiovascular effects include tachycardia, arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Overdose of pharmacologically similar compounds has resulted in convulsions, coma and death. The reported oral LD50 for mice is 600 mg/kg, for rats is 250 mg/kg and for dogs is 225 mg/kg. Management of acute diethylpropion hydrochloride intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Intravenous phentolamine (Regitine®) has been suggested on pharmacologic grounds for possible acute, severe hypertension, if this complicates TENUATE or TENUATE DOSPAN overdosage. DOSAGE AND ADMINISTRATION TENUATE (diethylpropion hydrochloride) immediate-release: One immediate-release 25 mg tablet three times daily, one hour before meals, and in midevening if desired to overcome night hunger. TENUATE DOSPAN (diethylpropion hydrochloride) controlled-release: One controlled-release 75 mg tablet daily, swallowed whole, in midmorning. Geriatric use: This drug in 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 PRECAUTIONS, Geriatric Use.) HOW SUPPLIED NDC 0068-0697-61 25 mg immediate-release tablets in bottles of 100 Each white, round tablet is debossed TENUATE 25 or MERRELL 697 Keep tightly closed, store at room temperature, preferably below 86°F. Protect from excessive heat. NDC 0068-0698-61 75 mg controlled-release tablets in bottles of 100 NDC 0068-0698-62 75 mg controlled-release tablets in bottles of 250 Each white, capsule-shaped tablet is debossed TENUATE 75 or MERRELL 698 Keep tightly closed. Store at room temperature, below 86°F. Rx only Rev. November 2003 Manufactured by: Patheon Pharmaceuticals Inc. Cincinnati, OH 45215 USA Manufactured for: Merrell Pharmaceuticals Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 An Aventis Pharmaceuticals Company Bridgewater, NJ 08807 USA www.aventis-us.com ©2003 Aventis Pharmaceuticals Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.905046	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/11722s029,12546s032lbl.pdf', 'application_number': 12546, 'submission_type': 'SUPPL ', 'submission_number': 32}
10,815	NDA 12-583/S-037 Page 3 [Company Logo] OPHTHETIC® (proparacaine HCl ophthalmic solution) 0.5% DESCRIPTION OPHTHETIC® (proparacaine HCl ophthalmic solution) 0.5% is a topical local anesthetic for ophthalmic use. Structural Formula: [structure] Chemical Name: Benzoic acid, 3-amino-4-propoxy-, 2-(diethylamino)ethyl ester, monohydrochloride. Contains: Active: proparacaine HCl 0.5% Preservative: benzalkonium chloride (0.01%). Inactives: glycerin; sodium chloride; and purified water. The pH may be adjusted with hydrochloric acid and/or sodium hydroxide. CLINICAL PHARMACOLOGY OPHTHETIC® ophthalmic solution is a rapidly-acting topical anesthetic, with induced anesthesia lasting approximately 10-20 minutes. INDICATIONS AND USAGE OPHTHETIC® ophthalmic solution is indicated for procedures in which a topical ophthalmic anesthetic is indicated: corneal anesthesia of short duration, e.g. tonometry, gonioscopy, removal of corneal foreign bodies, and for short corneal and conjunctival procedures. NDA 12-583/S-028 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-583/S-037 Page 4 CONTRAINDICATIONS OPHTHETIC® ophthalmic solution should be considered contraindicated in patients with known hypersensitivity to any of the ingredients of this preparation. WARNINGS Prolonged use of a topical ocular anesthetic is not recommended. It may produce permanent corneal opacification with accompanying visual loss. PRECAUTIONS Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate carcinogenic potential, mutagenicity, or possible impairment of fertility in males or females. Pregnancy: Pregnancy Category C: Animal reproduction studies have not been conducted with OPHTHETIC® (proparacaine hydrochloride ophthalmic solution) 0.5%. It is also not known whether proparacaine hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Proparacaine hydrochloride should be administered 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 proparacaine hydrochloride is administered to a nursing mother. Pediatric Use: Safety and effectiveness of proparacaine HCl Ophthalmic Solution in pediatric patients have been established. Use of proparacaine HCl is supported by evidence from adequate and well- controlled studies in adults and children over the age of twelve, and safety information in neonates and other pediatric patients. Geriatric use: No overall clinical differences in safety or effectiveness have been observed between the elderly and other adult patients. NDA 12-583/S-028 NDA 12-583/S-037 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 ADVERSE REACTIONS Occasional temporary stinging, burning and conjunctival redness may occur with the use of proparacaine. A rare, severe, immediate-type, apparently hyperallergic corneal reaction characterized by acute, intense and diffuse epithelial keratitis, a gray, ground glass appearance, sloughing of large areas of necrotic epithelium, corneal filaments and, sometimes, iritis with descemetitis has been reported. Allergic contact dermatitis from proparacaine with drying and fissuring of the fingertips has also been reported. DOSAGE AND ADMINISTRATION Usual Dosage: Removal of foreign bodies and sutures, and for tonometry: 1 to 2 drops (in single instillations) in each eye before operating. Short corneal and conjunctival procedures: 1 drop in each eye every 5 to 10 minutes for 5 to 7 doses. Note: OPHTHETIC® should be clear to straw-color. If the solution becomes darker, discard the solution. HOW SUPPLIED OPHTHETIC® (proparacaine hydrochloride ophthalmic solution) 0.5% is supplied in plastic dropper bottles in the following size: 15 mL – NDC 11980-048-15 Bottle must be stored in unit carton to protect contents from light. Store bottles under refrigeration at 2° to 8°C (36° to 46°F). Rx Only NDA 12-583/S-028 NDA 12-583/S-037 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 Allergan, Inc. Irvine, CA 92612, U.S.A. ©2000 Allergan, Inc. ©Registered trademarks of Allergan, Inc. R424X 71430US10H This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-583/S-028 NDA 12-583/S-037 Page 7 Carton, 15 mL, 0.5% 63095US10H Lot No: Exp: 011269 [Company logo]® No 0048 ALLERGAN 4424X NDC 11980-048-15 15 mL OPHTHETIC® (proparacaine HCl ophthalmic solution) 0.5% Sterile [Company logo]® ALLERGAN NDC 11980-048-15 15 mL OPHTHETIC® (proparacaine HCl ophthalmic solution) 0.5% Sterile Rx Only [Company logo]® ALLERGAN NDC 11980-048-15 15 mL OPHTHETIC® (proparacaine HCl ophthalmic solution) 0.5% Sterile Rx Only Bar code CONTAINS: Active: proparacaine HCl 0.5%. Preservative: benzalkonium chloride (0.01%). Inactivies: glycerin; sodium chloride; and purified water. The pH may be adjusted with hydrochloric acid and/or sodium hydroxide. USUAL DOSAGE: Refer to accompanying literature. Note: Bottle must be stored in unit carton to protect contents from light. Store bottles under refrigeration 2° to 8°C (36° to 46°F). OPHTHETIC® should be clear to straw-color. If the solution becomes darker, discard the solution. NOT FOR INJECTION. Allergan Inc., Irvine, CA 92612, U.S.A. ©2000 Allergan, Inc. ®Registered trademarks of Allergan, Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-583/S-028 NDA 12-583/S-037 Page 8 Container Label Bottles, 15 mL, 0.5% CONTAINS: Active: proparacaine HCl 0.5%. Preservative: benzalkonium chloride (0.01%). Inactivies: glycerin; sodium chloride; and purified water. The pH may be adjusted with hydrochloric acid and/or sodium hydroxide. USUAL DOSAGE: Refer to accompanying literature. Note: Bottle must be stored in unit carton to protect contents from light. Store bottles under refrigeration 2° to 8°C (36° to 46°F). OPHTHETIC® should be clear to straw-color. If the solution becomes darker, discard the solution. NOT FOR INJECTION. Allergan Inc., Irvine, CA 92612, U.S.A. ©2000 Allergan, Inc. ®Registered trademarks of Allergan, Inc. [Company logo]® ALLERGAN NDC 11980-048-15 15 mL OPHTHETIC® (proparacaine HCl ophthalmic solution) 0.5% Sterile Rx Only 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 6/20/02 11:03:40 AM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:49.967631	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/12583s037lbl.pdf', 'application_number': 12583, 'submission_type': 'SUPPL ', 'submission_number': 28}
10,816	Aldactazide® spironolactone and hydrochlorothiazide tablets WARNING Spironolactone, an ingredient of ALDACTAZIDE, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). ALDACTAZIDE should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided. Fixed-dose combination drugs are not indicated for initial therapy of edema or hypertension. Edema or hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension and edema is not static but must be reevaluated as conditions in each patient warrant. DESCRIPTION ALDACTAZIDE oral tablets contain: spironolactone . . . . . . . . . . . . . . . . . . . . 25 mg hydrochlorothiazide . . . . . . . . . . . . . . . . 25 mg or spironolactone . . . . . . . . . . . . . . . . . . . . 50 mg hydrochlorothiazide . . . . . . . . . . . . . . . . 50 mg Spironolactone (ALDACTONE®), an aldosterone antagonist, is 17-hydroxy-7α mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate and has the following structural formula: structural formula Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Hydrochlorothiazide, a diuretic and antihypertensive, is 6-chloro-3,4-dihydro-2H-1,2,4 benzothiadiazine-7-sulfonamide 1,1-dioxide and has the following structural formula: Reference ID: 2949073 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution. Inactive ingredients include calcium sulfate, corn starch, flavor, hydroxypropyl cellulose, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. ACTIONS / CLINICAL PHARMACOLOGY Mechanism of action: ALDACTAZIDE is a combination of two diuretic agents with different but complementary mechanisms and sites of action, thereby providing additive diuretic and antihypertensive effects. Additionally, the spironolactone component helps to minimize the potassium loss characteristically induced by the thiazide component. The diuretic effect of spironolactone is mediated through its action as a specific pharmacologic antagonist of aldosterone, primarily by competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Hydrochlorothiazide promotes the excretion of sodium and water primarily by inhibiting their reabsorption in the cortical diluting segment of the distal renal tubule. ALDACTAZIDE is effective in significantly lowering the systolic and diastolic blood pressure in many patients with essential hypertension, even when aldosterone secretion is within normal limits. Both spironolactone and hydrochlorothiazide reduce exchangeable sodium, plasma volume, body weight, and blood pressure. The diuretic and antihypertensive effects of the individual components are potentiated when spironolactone and hydrochlorothiazide are given concurrently. Pharmacokinetics: Spironolactone is rapidly and extensively metabolized. Sulfur- containing products are the predominant metabolites and are thought to be primarily responsible, together with spironolactone, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (ALDACTONE film-coated tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a lowfat breakfast and blood was drawn thereafter. Accumulation Factor: Reference ID: 2949073 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7-α-(thiomethyl) spirolactone (TMS) AUC (0–24 hr, day 15)/AUC (0–24 hr, day 1) 1.25 Mean Peak Serum Concentration 391 ng/mL at 3.2 hr Mean (SD) Post-Steady State Half-Life 13.8 hr (6.4) (terminal) 6-ß-hydroxy-7-α- (thiomethyl) spirolactone (HTMS) 1.50 125 ng/mL at 5.1 hr 15.0 hr (4.0) (terminal) Canrenone (C) 1.41 181 ng/mL at 4.3 hr 16.5 hr (6.3) (terminal) Spironolactone 1.30 80 ng/mL at 2.6 hr Approximately 1.4 hr (0.5) (ß half-life) The pharmacological activity of spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively. In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile. The effect of food on spironolactone absorption (two 100 mg ALDACTONE tablets) was assessed in a single dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known. Hydrochlorothiazide is rapidly absorbed following oral administration. Onset of action of hydrochlorothiazide is observed within one hour and persists for 6 to 12 hours. Hydrochlorothiazide plasma concentrations attain peak levels at one to two hours and decline with a half-life of four to five hours. Hydrochlorothiazide undergoes only slight metabolic alteration and is excreted in urine. It is distributed throughout the extracellular space, with essentially no tissue accumulation except in the kidney. INDICATIONS AND USAGE Spironolactone, an ingredient of ALDACTAZIDE, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions section). ALDACTAZIDE should be 3 Reference ID: 2949073 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda used only in those conditions described below. Unnecessary use of this drug should be avoided. ALDACTAZIDE is indicated for: Edematous conditions for patients with: Congestive heart failure: • For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures; • The treatment of diuretic-induced hypokalemia in patients with congestive heart failure when other measures are considered inappropriate; • The treatment of patients with congestive heart failure taking digitalis when other therapies are considered inadequate or inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: • Aldosterone levels may be exceptionally high in this condition. ALDACTAZIDE is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. The nephrotic syndrome: • For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension: • For patients with essential hypertension in whom other measures are considered inadequate or inappropriate; • In hypertensive patients for the treatment of a diuretic-induced hypokalemia when other measures are considered inappropriate. Usage in Pregnancy. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. ALDACTAZIDE is indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Precautions: Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme Reference ID: 2949073 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda discomfort that is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate. CONTRAINDICATIONS ALDACTAZIDE is contraindicated in patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, or hyperkalemia, and in patients who are allergic to thiazide diuretics or to other sulfonamide-derived drugs. ALDACTAZIDE may also be contraindicated in acute or severe hepatic failure. WARNINGS Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with ALDACTAZIDE therapy. Excessive potassium intake may cause hyperkalemia in patients receiving ALDACTAZIDE (see Precautions: General). ALDACTAZIDE should not be administered concurrently with other potassium-sparing diuretics. Spironolactone, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when ALDACTAZIDE is given concomitantly with these drugs (see Precautions: Drug interactions). ALDACTAZIDE should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Lithium generally should not be given with diuretics (see Precautions: Drug interactions). 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 may add to or potentiate the action of other antihypertensive drugs. Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma. Sulfonamide derivatives, including thiazides, have been reported to exacerbate or activate systemic lupus erythematosus. 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 5 Reference ID: 2949073 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. PRECAUTIONS General: All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance, e.g., hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hypokalemia or hyperkalemia. 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 the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal. Consequently, no potassium supplement should ordinarily be given with ALDACTAZIDE. Concomitant administration of potassium-sparing diuretics and ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin, has been associated with severe hyperkalemia. If hyperkalemia is suspected (warning signs include paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock), an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes. If hyperkalemia is present, ALDACTAZIDE should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. Hypokalemia may develop as a result of profound diuresis, particularly when ALDACTAZIDE is used concomitantly with loop diuretics, glucocorticoids, or ACTH, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmias and may exaggerate the effects of digitalis therapy. Potassium depletion may induce signs of digitalis intoxication at previously tolerated dosage levels. 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. ALDACTAZIDE therapy may cause a transient elevation of BUN. This appears to represent a concentration phenomenon rather than renal toxicity, since the BUN level 6 Reference ID: 2949073 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda returns to normal after use of ALDACTAZIDE is discontinued. Progressive elevation of BUN is suggestive of the presence of preexisting renal impairment. Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function. Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be induced, especially when ALDACTAZIDE is administered in combination with other diuretics, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening. A true low-salt syndrome may rarely develop with ALDACTAZIDE therapy and may be manifested by increasing mental confusion similar to that observed with hepatic coma. This syndrome is differentiated from dilutional hyponatremia in that it does not occur with obvious fluid retention. Its treatment requires that diuretic therapy be discontinued and sodium administered. Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic 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 ALDACTAZIDE may be enhanced in the post sympathetectomy patient. If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy. 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. Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in patients on prolonged thiazide therapy. Gynecomastia may develop in association with the use of spironolactone; physicians should be alert to its possible onset. The development of gynecomastia appears to be related to both dosage level and duration of therapy and is normally reversible when ALDACTAZIDE is discontinued. In rare instances, some breast enlargement may persist when ALDACTAZIDE is discontinued. 7 Reference ID: 2949073 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 who receive ALDACTAZIDE should be advised to avoid potassium supplements and foods containing high levels of potassium including salt substitutes. Laboratory tests: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments. Drug interactions: ACE inhibitors: Concomitant administration of ACE inhibitors with potassium-sparing diuretics has been associated with severe hyperkalemia. Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Antidiabetic drugs (e.g., oral agents, insulin): Dosage adjustment of the antidiabetic drug may be required. Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur. Pressor amines (e.g., norepinephrine): Both spironolactone and hydrochlorothiazide reduce the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with ALDACTAZIDE. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant may result. Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Combination of NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when ALDACTAZIDE and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Digoxin: Spironolactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. It may be necessary to reduce the maintenance and digitalization doses when spironolactone is administered, and the patient should be carefully monitored to avoid over- or underdigitalization. 8 Reference ID: 2949073 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug/Laboratory test interactions: Thiazides should be discontinued before carrying out tests for parathyroid function (see Precautions: General). Thiazides may also decrease serum PBI levels without evidence of alteration of thyroid function. Several reports of possible interference with digoxin radioimmunoassays by spironolactone or its metabolites have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay specific) has been fully established. Carcinogenesis, mutagenesis, impairment of fertility: Spironolactone: Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150, and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, 100, and 150 mg spironolactone/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females. A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) for a period of one year. In two year studies in the rat, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors. Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone has been reported to be negative in some mammalian mutagenicity tests in vitro and inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others. In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg spironolactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), spironolactone was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two week posttreatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating 9 Reference ID: 2949073 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda estrogen levels, which would be expected to impair mating, fertility, and fecundity. Spironolactone (100 mg/kg/day), administered i.p. to female mice during a two week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating. 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 of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo 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. Pregnancy: Teratogenic effects. Pregnancy Category C. 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 hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Spironolactone: Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryo- toxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 Reference ID: 2949073 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well-controlled studies with ALDACTAZIDE in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of ALDACTAZIDE in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus. Non-teratogenic effects Spironolactone or its metabolites may, and hydrochlorothiazide does, cross the placental barrier and appear in cord blood. Therefore, the use of ALDACTAZIDE in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. The hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. Nursing mothers: Canrenone, a major (and active) metabolite of spironolactone, appears in human breast milk. Because spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted. Pediatric use: Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity. Hydrochlorothiazide: Body as a whole: Weakness. Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics, or antihypertensive drugs). Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialoadenitis, cramping, constipation, gastric irritation, nausea, anorexia. Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia. Hypersensitivity: Anaphylactic reactions, necrotizing angitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura. 11 Reference ID: 2949073 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolic: Electrolyte imbalance (see Precautions), hyperglycemia, glycosuria, hyperuricemia. Musculoskeletal: Muscle spasm. Nervous system/psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness. Renal: Renal failure, renal dysfunction, interstitial nephritis (see Warnings). Skin: Erythema multiforme, pruritus. Special senses: Transient blurred vision, xanthopsia. Spironolactone: Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting. Endocrine: Gynecomastia (see Precautions), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding. Carcinoma of the breast has been reported in patients taking spironolactone but a cause and effect relationship has not been established. Hematologic: Agranulocytosis. Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis. Nervous system/psychiatric: Mental confusion, ataxia, headache, drowsiness, lethargy. Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration. Renal: Renal dysfunction (including renal failure). OVERDOSAGE The oral LD50 of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats. Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia (less commonly seen with ALDACTAZIDE because the hydrochlorothiazide component tends to produce hypokalemia), or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. 12 Reference ID: 2949073 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda However, because ALDACTAZIDE contains both spironolactone and hydrochlorothiazide, the toxic effects may be intensified, and signs of thiazide overdosage may be present. These include electrolyte imbalance such as hypokalemia and/or hyponatremia. The potassium-sparing action of spironolactone may predominate and hyperkalemia may occur, especially in patients with impaired renal function. BUN determinations have been reported to rise transiently with hydrochlorothiazide. There may be CNS depression with lethargy or even coma. Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, ALDACTAZIDE should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. DOSAGE AND ADMINISTRATION Optimal dosage should be established by individual titration of the components (see boxed Warning). Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). The usual maintenance dose of ALDACTAZIDE is 100 mg each of spironolactone and hydrochlorothiazide daily, administered in a single dose or in divided doses, but may range from 25 mg to 200 mg of each component daily depending on the response to the initial titration. In some instances it may be desirable to administer separate tablets of either ALDACTONE (spironolactone) or hydrochlorothiazide in addition to ALDACTAZIDE in order to provide optimal individual therapy. The onset of diuresis with ALDACTAZIDE occurs promptly and, due to prolonged effect of the spironolactone component, persists for two to three days after ALDACTAZIDE is discontinued. Essential hypertension. Although the dosage will vary depending on the results of titration of the individual ingredients, many patients will be found to have an optimal response to 50 mg to 100 mg each of spironolactone and hydrochlorothiazide daily, given in a single dose or in divided doses. Concurrent potassium supplementation is not recommended when ALDACTAZIDE is used in the long-term management of hypertension or in the treatment of most edematous conditions, since the spironolactone content of ALDACTAZIDE is usually sufficient to minimize loss induced by the hydrochlorothiazide component. 13 Reference ID: 2949073 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED ALDACTAZIDE tablets containing 25 mg of spironolactone (ALDACTONE) and 25 mg of hydrochlorothiazide are round, tan, film coated, with SEARLE and 1011 debossed on one side and ALDACTAZIDE and 25 on the other side, supplied as: NDC Number Size 0025-1011-31 bottle of 100 ALDACTAZIDE tablets containing 50 mg of spironolactone (ALDACTONE) and 50 mg of hydrochlorothiazide are oblong, tan, scored, film coated, with SEARLE and 1021 debossed on the scored side and ALDACTAZIDE and 50 on the other side, supplied as: NDC Number 0025-1021-31 Size bottle of 100 Store below 77°F (25°C). Rx only company logo LAB-0233-4.0 Revised March 2011 Reference ID: 2949073 14 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/ MARY R SOUTHWORTH 05/19/2011 Reference ID: 2949073 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.078655	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/012616s068lbl.pdf', 'application_number': 12616, 'submission_type': 'SUPPL ', 'submission_number': 68}
10,817	Aldactazide® spironolactone and hydrochlorothiazide tablets WARNING Spironolactone, an ingredient of ALDACTAZIDE, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). ALDACTAZIDE should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided. Fixed-dose combination drugs are not indicated for initial therapy of edema or hypertension. Edema or hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension and edema is not static but must be reevaluated as conditions in each patient warrant. DESCRIPTION ALDACTAZIDE oral tablets contain: spironolactone . . . . . . . . . . . . . . . . . . . . 25 mg hydrochlorothiazide . . . . . . . . . . . . . . . . 25 mg or spironolactone . . . . . . . . . . . . . . . . . . . . 50 mg hydrochlorothiazide . . . . . . . . . . . . . . . . 50 mg Spironolactone (ALDACTONE®), an aldosterone antagonist, is 17-hydroxy-7α mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate and has the following structural formula: structural formula Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Hydrochlorothiazide, a diuretic and antihypertensive, is 6-chloro-3,4-dihydro-2H-1,2,4 benzothiadiazine-7-sulfonamide 1,1-dioxide and has the following structural formula: Reference ID: 3323478 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution. Inactive ingredients include calcium sulfate, corn starch, flavor, hydroxypropyl cellulose, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. ACTIONS / CLINICAL PHARMACOLOGY Mechanism of action: ALDACTAZIDE is a combination of two diuretic agents with different but complementary mechanisms and sites of action, thereby providing additive diuretic and antihypertensive effects. Additionally, the spironolactone component helps to minimize the potassium loss characteristically induced by the thiazide component. The diuretic effect of spironolactone is mediated through its action as a specific pharmacologic antagonist of aldosterone, primarily by competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Hydrochlorothiazide promotes the excretion of sodium and water primarily by inhibiting their reabsorption in the cortical diluting segment of the distal renal tubule. ALDACTAZIDE is effective in significantly lowering the systolic and diastolic blood pressure in many patients with essential hypertension, even when aldosterone secretion is within normal limits. Both spironolactone and hydrochlorothiazide reduce exchangeable sodium, plasma volume, body weight, and blood pressure. The diuretic and antihypertensive effects of the individual components are potentiated when spironolactone and hydrochlorothiazide are given concurrently. Pharmacokinetics: Spironolactone is rapidly and extensively metabolized. Sulfur- containing products are the predominant metabolites and are thought to be primarily responsible, together with spironolactone, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (ALDACTONE film-coated tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a lowfat breakfast and blood was drawn thereafter. Accumulation Factor: Reference ID: 3323478 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda AUC (0–24 hr, Mean Peak Mean (SD) day 15)/AUC Serum Post-Steady (0–24 hr, day 1) Concentration State Half-Life 7-α-(thiomethyl) 1.25 391 ng/mL 13.8 hr (6.4) spirolactone (TMS) at 3.2 hr (terminal) 6-ß-hydroxy-7-α- (thiomethyl) spirolactone (HTMS) 1.50 125 ng/mL at 5.1 hr 15.0 hr (4.0) (terminal) Canrenone (C) 1.41 181 ng/mL at 4.3 hr 16.5 hr (6.3) (terminal) Spironolactone 1.30 80 ng/mL at 2.6 hr Approximately 1.4 hr (0.5) (ß half-life) The pharmacological activity of spironolactone metabolites in man is not known. HHHowever, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively. In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile. The effect of food on spironolactone absorption (two 100 mg ALDACTONE tablets) was assessed in a single dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known. Hydrochlorothiazide is rapidly absorbed following oral administration. Onset of action of hydrochlorothiazide is observed within one hour and persists for 6 to 12 hours. Hydrochlorothiazide plasma concentrations attain peak levels at one to two hours and decline with a half-life of four to five hours. Hydrochlorothiazide undergoes only slight metabolic alteration and is excreted in urine. It is distributed throughout the extracellular space, with essentially no tissue accumulation except in the kidney. INDICATIONS AND USAGE Spironolactone, an ingredient of ALDACTAZIDE, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions section). ALDACTAZIDE should be Reference ID: 3323478 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda used only in those conditions described below. Unnecessary use of this drug should be avoided. ALDACTAZIDE is indicated for: Edematous conditions for patients with: Congestive heart failure: • For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures; • The treatment of diuretic-induced hypokalemia in patients with congestive heart failure when other measures are considered inappropriate; • The treatment of patients with congestive heart failure taking digitalis when other therapies are considered inadequate or inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: • Aldosterone levels may be exceptionally high in this condition. ALDACTAZIDE is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. The nephrotic syndrome: • For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension: • For patients with essential hypertension in whom other measures are considered inadequate or inappropriate; • In hypertensive patients for the treatment of a diuretic-induced hypokalemia when other measures are considered inappropriate. Usage in Pregnancy. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. ALDACTAZIDE is indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Precautions: Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased Reference ID: 3323478 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort that is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate. CONTRAINDICATIONS ALDACTAZIDE is contraindicated in patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, hypercalcemia, hyperkalemia, Addison’s disease or other conditions associated with hyperkalemia, and in patients who are allergic to thiazide diuretics or to other sulfonamide-derived drugs. ALDACTAZIDE may also be contraindicated in acute or severe hepatic failure. WARNINGS Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with ALDACTAZIDE therapy. Excessive potassium intake may cause hyperkalemia in patients receiving ALDACTAZIDE (see Precautions: General). Concomitant administration of ALDACTAZIDE with the following drugs or potassium sources may lead to severe hyperkalemia: • other potassium-sparing diuretics • ACE inhibitors • angiotensin II receptor antagonists • aldosterone blockers • non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin • heparin and low molecular weight heparin • other drugs known to cause hyperkalemia • potassium supplements • diet rich in potassium • salt substitutes containing potassium ALDACTAZIDE should not be administered concurrently with other potassium-sparing diuretics. Spironolactone, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when ALDACTAZIDE is given concomitantly with these drugs (see Precautions: Drug interactions). ALDACTAZIDE should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Lithium generally should not be given with diuretics (see Precautions: Drug interactions). 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. Reference ID: 3323478 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thiazides may add to or potentiate the action of other antihypertensive drugs. Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma. Sulfonamide derivatives, including thiazides, have been reported to exacerbate or activate systemic lupus erythematosus. 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. PRECAUTIONS General: All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance, e.g., hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hypokalemia or hyperkalemia. 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 the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal. Consequently, no potassium supplement should ordinarily be given with ALDACTAZIDE. If hyperkalemia is suspected (warning signs include paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock), an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes. If hyperkalemia is present, ALDACTAZIDE should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. Reference ID: 3323478 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypokalemia may develop as a result of profound diuresis, particularly when ALDACTAZIDE is used concomitantly with loop diuretics, glucocorticoids, or ACTH, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmias and may exaggerate the effects of digitalis therapy. Potassium depletion may induce signs of digitalis intoxication at previously tolerated dosage levels. 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. ALDACTAZIDE therapy may cause a transient elevation of BUN. This appears to represent a concentration phenomenon rather than renal toxicity, since the BUN level returns to normal after use of ALDACTAZIDE is discontinued. Progressive elevation of BUN is suggestive of the presence of preexisting renal impairment. Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function. Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be induced, especially when ALDACTAZIDE is administered in combination with other diuretics, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening. A true low-salt syndrome may rarely develop with ALDACTAZIDE therapy and may be manifested by increasing mental confusion similar to that observed with hepatic coma. This syndrome is differentiated from dilutional hyponatremia in that it does not occur with obvious fluid retention. Its treatment requires that diuretic therapy be discontinued and sodium administered. Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic 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 ALDACTAZIDE may be enhanced in the post sympathetectomy patient. If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy. 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. Reference ID: 3323478 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thiazides should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in patients on prolonged thiazide therapy. Gynecomastia may develop in association with the use of spironolactone; physicians should be alert to its possible onset. The development of gynecomastia appears to be related to both dosage level and duration of therapy and is normally reversible when ALDACTAZIDE is discontinued. In rare instances, some breast enlargement may persist when ALDACTAZIDE is discontinued. Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined. Information for patients: Patients who receive ALDACTAZIDE should be advised to avoid potassium supplements and foods containing high levels of potassium including salt substitutes. Laboratory tests: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments. Drug interactions: ACE inhibitors: Concomitant administration of ACE inhibitors with potassium-sparing diuretics has been associated with severe hyperkalemia. Angiotensin II receptor antagonists, aldosterone blockers, heparin, low molecular weight heparin, and other drugs known to cause hyperkalemia: Concomitant administration may lead to severe hyperkalemia. Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Antidiabetic drugs (e.g., oral agents, insulin): Dosage adjustment of the antidiabetic drug may be required. Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur. Pressor amines (e.g., norepinephrine): Both spironolactone and hydrochlorothiazide reduce the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with ALDACTAZIDE. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant may result. Reference ID: 3323478 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Combination of NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when ALDACTAZIDE and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Digoxin: Spironolactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. It may be necessary to reduce the maintenance and digitalization doses when spironolactone is administered, and the patient should be carefully monitored to avoid over- or underdigitalization. Cholestyramine: Hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine. Drug/Laboratory test interactions: Thiazides should be discontinued before carrying out tests for parathyroid function (see Precautions: General). Thiazides may also decrease serum PBI levels without evidence of alteration of thyroid function. Several reports of possible interference with digoxin radioimmunoassays by spironolactone or its metabolites have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay specific) has been fully established. Carcinogenesis, mutagenesis, impairment of fertility: Spironolactone: Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150, and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30 and 100 mg spironolactone/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females. A dose-related (above 30 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) for a period of one year. In two year studies in the rat, oral Reference ID: 3323478 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors. Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone has been reported to be negative in some mammalian mutagenicity tests in vitro and inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others. In a three-litter reproduction study in which female rats received dietary doses of 15 and 500 mg spironolactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 500 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), spironolactone was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two week posttreatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility, and fecundity. Spironolactone (100 mg/kg/day), administered i.p. to female mice during a two week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating. 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 of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo 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. Reference ID: 3323478 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. Pregnancy: Teratogenic effects. Pregnancy Category C. 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 hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Spironolactone: Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryo- toxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well-controlled studies with ALDACTAZIDE in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of ALDACTAZIDE in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus. Non-teratogenic effects Spironolactone or its metabolites may, and hydrochlorothiazide does, cross the placental barrier and appear in cord blood. Therefore, the use of ALDACTAZIDE in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. The hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. Nursing mothers: Canrenone, a major (and active) metabolite of spironolactone, appears in human breast milk. Because spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted. Reference ID: 3323478 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thiazides are excreted in human milk in small amounts. Thiazides when given at high doses can cause intense diuresis which can in turn inhibit milk production. The use of ALDACTAZIDE during breast feeding is not recommended. If ALDACTAZIDE is used during breast feeding, doses should be kept as low as possible. Pediatric use: Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity. Hydrochlorothiazide: Body as a whole: Weakness. Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics, or antihypertensive drugs). Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialoadenitis, cramping, constipation, gastric irritation, nausea, anorexia. Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia. Hypersensitivity: Anaphylactic reactions, necrotizing angitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura. Metabolic: Electrolyte imbalance (see Precautions), hyperglycemia, glycosuria, hyperuricemia. Musculoskeletal: Muscle spasm. Nervous system/psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness. Renal: Renal failure, renal dysfunction, interstitial nephritis (see Warnings). Skin: Erythema multiforme, pruritus. Special senses: Transient blurred vision, xanthopsia. Spironolactone: Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting. Reproductive: Gynecomastia (see Precautions), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast pain. Carcinoma of the Reference ID: 3323478 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda breast has been reported in patients taking spironolactone but a cause and effect relationship has not been established. Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia. Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis. Metabolism: Hyperkalemia, electrolyte disturbances (see Warnings and Precautions). Musculoskeletal: Leg cramps. Nervous system/psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness. Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration. Renal: Renal dysfunction (including renal failure). Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritus. OVERDOSAGE The oral LD50 of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats. Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia (less commonly seen with ALDACTAZIDE because the hydrochlorothiazide component tends to produce hypokalemia), or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. However, because ALDACTAZIDE contains both spironolactone and hydrochlorothiazide, the toxic effects may be intensified, and signs of thiazide overdosage may be present. These include electrolyte imbalance such as hypokalemia and/or hyponatremia. The potassium-sparing action of spironolactone may predominate and hyperkalemia may occur, especially in patients with impaired renal function. BUN determinations have been reported to rise transiently with hydrochlorothiazide. There may be CNS depression with lethargy or even coma. Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Reference ID: 3323478 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, ALDACTAZIDE should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. DOSAGE AND ADMINISTRATION Optimal dosage should be established by individual titration of the components (see boxed Warning). Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). The usual maintenance dose of ALDACTAZIDE is 100 mg each of spironolactone and hydrochlorothiazide daily, administered in a single dose or in divided doses, but may range from 25 mg to 200 mg of each component daily depending on the response to the initial titration. In some instances it may be desirable to administer separate tablets of either ALDACTONE (spironolactone) or hydrochlorothiazide in addition to ALDACTAZIDE in order to provide optimal individual therapy. The onset of diuresis with ALDACTAZIDE occurs promptly and, due to prolonged effect of the spironolactone component, persists for two to three days after ALDACTAZIDE is discontinued. Essential hypertension. Although the dosage will vary depending on the results of titration of the individual ingredients, many patients will be found to have an optimal response to 50 mg to 100 mg each of spironolactone and hydrochlorothiazide daily, given in a single dose or in divided doses. Concurrent potassium supplementation is not recommended when ALDACTAZIDE is used in the long-term management of hypertension or in the treatment of most edematous conditions, since the spironolactone content of ALDACTAZIDE is usually sufficient to minimize loss induced by the hydrochlorothiazide component. HOW SUPPLIED ALDACTAZIDE tablets containing 25 mg of spironolactone (ALDACTONE) and 25 mg of hydrochlorothiazide are round, tan, film coated, with SEARLE and 1011 debossed on one side and ALDACTAZIDE and 25 on the other side, supplied as: NDC Number Size 0025-1011-31 bottle of 100 ALDACTAZIDE tablets containing 50 mg of spironolactone (ALDACTONE) and 50 mg of hydrochlorothiazide are oblong, tan, scored, film coated, with SEARLE and 1021 debossed on the scored side and ALDACTAZIDE and 50 on the other side, supplied as: Reference ID: 3323478 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC Number Size 0025-1021-31 bottle of 100 Store below 77°F (25°C). company logo LAB-0233-6.0 Revised June 2013 Reference ID: 3323478 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.263511	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012616s073lbl.pdf', 'application_number': 12616, 'submission_type': 'SUPPL ', 'submission_number': 73}
10,819	SEARLE Flagyl® (metronidazole) WARNING Metronidazole has been shown to be carcinogenic in mice and rats. (See PRECAUTIONS.) Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the Indications and Usage section below. DESCRIPTION Flagyl (metronidazole) is an oral synthetic antiprotozoal and antibacterial agent, 1-(β-hydroxyethyl)-2- methyl-5-nitroimidazole, which has the following structural formula: N CH2CH2OH O2N CH3 N Flagyl tablets contain 250 mg or 500 mg of metronidazole. Inactive ingredients include cellulose, FD&C Blue No. 2 Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, stearic acid, and titanium dioxide. CLINICAL PHARMACOLOGY Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms, with an average elimination half-life in healthy humans of eight hours. The major route of elimination of metronidazole and its metabolites is via the urine (60 to 80% of the dose), with fecal excretion accounting for 6 to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(β-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73m2. Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2-hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Both the parent compound and the metabolite possess in vitro bactericidal activity against most strains of anaerobic bacteria and in vitro trichomonacidal activity. Metronidazole appears in cerebrospinal fluid, saliva, and human milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between one and two hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose. Oral administration of 250 mg, 500 mg, or 2,000 mg produced peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively. Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma levels in males are generally lower. Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole is decreased in patients with decreased liver function. Microbiology: Trichomonas vaginalis, Entamoeba histolytica. Flagyl (metronidazole) possesses direct trichomonacidal and amebacidal activity against T. vaginalis and E. histolytica. The in vitro minimal inhibitory concentration (MIC) for most strains of these organisms is 1 mcg/mL or less. Anaerobic Bacteria. Metronidazole is active in vitro against most obligate anaerobes but does not appear to possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Against susceptible organisms, metronidazole is generally bactericidal at concentrations equal to or slightly higher than the minimal inhibitory concentrations. Metronidazole has been shown to have in vitro and clinical activity against the following organisms: Anaerobic gram-negative bacilli, including: Bacteroides species including the Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus) Fusobacterium species Anaerobic gram-positive bacilli, including: Clostridium species and susceptible strains of Eubacterium Anaerobic gram-positive cocci, including: Peptococcus niger Peptostreptococcus species Susceptibility Tests: Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to metronidazole; however, the rapid, routine susceptibility testing of individual isolates of anaerobic bacteria is not always practical, and therapy may be started while awaiting these results. Quantitative methods give the most precise estimates of susceptibility to antibacterial drugs. A standardized agar dilution method and a broth microdilution method are recommended.1 Control strains are recommended for standardized susceptibility testing. Each time the test is performed, one or more of the following strains should be included: Clostridium perfringens ATCC 13124, Bacteroides fragilis ATCC 25285, and Bacteroides thetaiotaomicron ATCC 29741. The mode metronidazole MICs for those three strains are reported to be 0.25, 0.25, and 0.5 mcg/mL, respectively. A clinical laboratory is considered under acceptable control if the results of the control strains are within one doubling dilution of the mode MICs reported for metronidazole. A bacterial isolate may be considered susceptible if the MIC value for metronidazole is not more than 16 mcg/mL. An organism is considered resistant if the MIC is greater than 16 mcg/mL. A report of “resistant” from the laboratory indicates that the infecting organism is not likely to respond to therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Symptomatic Trichomoniasis. Flagyl is indicated for the treatment of symptomatic trichomoniasis in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures). Asymptomatic Trichomoniasis. Flagyl is indicated in the treatment of asymptomatic females when the organism is associated with endocervicitis, cervicitis, or cervical erosion. Since there is evidence that presence of the trichomonad can interfere with accurate assessment of abnormal cytological smears, additional smears should be performed after eradication of the parasite. Treatment of Asymptomatic Consorts. T. vaginalis infection is a venereal disease. Therefore, asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has been found to be present, in order to prevent reinfection of the partner. The decision as to whether to treat an asymptomatic male partner who has a negative culture or one for whom no culture has been attempted is an individual one. In making this decision, it should be noted that there is evidence that a woman may become reinfected if her consort is not treated. Also, since there can be considerable difficulty in isolating the organism from the asymptomatic male carrier, negative smears and cultures cannot be relied upon in this regard. In any event, the consort should be treated with Flagyl in cases of reinfection. Amebiasis. Flagyl is indicated in the treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess. In amebic liver abscess, Flagyl therapy does not obviate the need for aspiration or drainage of pus. Anaerobic Bacterial Infections. Flagyl is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with Flagyl therapy. In a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to Flagyl. In the treatment of most serious anaerobic infections, Flagyl I.V. (metronidazole hydrochloride) is usually administered initially. This may be followed by oral therapy with Flagyl (metronidazole) at the discretion of the physician. INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species, Peptococcus niger, and Peptostreptococcus species. SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus niger, Peptostreptococcus species, and Fusobacterium species. GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus niger, and Peptostreptococcus species. BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group, and Clostridium species. BONE AND JOINT INFECTIONS, as adjunctive therapy, caused by Bacteroides species including the B. fragilis group. CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group. LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group. ENDOCARDITIS caused by Bacteroides species including the B. fragilis group. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Flagyl is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. In patients with trichomoniasis, Flagyl is contraindicated during the first trimester of pregnancy. (See Warnings.) WARNINGS Convulsive Seizures and Peripheral Neuropathy: Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with metronidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of Flagyl (metronidazole) therapy. Flagyl should be administered with caution to patients with central nervous system diseases. PRECAUTIONS General: Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously. Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with Flagyl (metronidazole) and requires treatment with a candidacidal agent. Information for patients: Alcoholic beverages should be avoided while taking Flagyl and for at least one day afterward. See Drug interactions. Laboratory tests: Flagyl (metronidazole) is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy for trichomoniasis and amebiasis, especially if a second course of therapy is necessary, and before and after therapy for anaerobic infections. Drug interactions: Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when Flagyl (metronidazole) is prescribed for patients on this type of anticoagulant therapy. The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported. The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. In patients stabilized on relatively high doses of lithium, short-term Flagyl therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication. Alcoholic beverages should not be consumed during Flagyl therapy and for at least one day afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug/Laboratory test interactions: Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD+ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7. Carcinogenesis, mutagenesis, impairment of fertility: Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats. Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels (approx. 500 mg/kg/day which is approximately 33 times the most frequently recommended human dose for a 50 kg adult based on mg/kg body weight) there was a statistically significant increase in the incidence of malignant liver tumors in males. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Several long-term, oral-dosing studies in the rat have been completed. There were statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage. Fertility studies have been performed in mice at doses up to six times the maximum recommended human dose based on mg/m2 and have revealed no evidence of impaired fertility. Pregnancy: Teratogenic Effects-Pregnancy Category B. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Reproduction studies have been performed in rats at doses up to five times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to metronidazole. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 20 mg/kg/day, approximately one and a half times the most frequently recommended human dose (750 mg/day) based on mg/kg body weight; however in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because metronidazole is a carcinogen in rodents, this drug should be used during pregnancy only if clearly needed. Use of Flagyl for trichomoniasis during pregnancy should be restricted to those in whom alternative treatment has been inadequate. Use of Flagyl (metronidazole) for trichomoniasis in pregnancy should be carefully evaluated because metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known (see above). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing mothers: Because of the potential for tumorigenicity, shown for metronidazole in mouse and rat studies, 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. Metronidazole is secreted in human milk in concentrations similar to those found in plasma. Geriatric use: No overall differences have been reported in safety and effectiveness between younger and older individuals, but greater sensitivity of some older individuals cannot be ruled out. Systemic exposure to the active metabolite, 2-hydroxymethyl metronidazole, is higher in the elderly. Metronidazole 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. Although decreased renal function does not alter the single dose pharmacokinetics of metronidazole, 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. Plasma clearance of metronidazole is decreased in patients with decreased liver function. Therefore, in elderly patients, monitoring of serum levels may be necessary to adjust the metronidazole dose accordingly. Pediatric use: Safety and effectiveness in pediatric patients have not been established, except for the treatment of amebiasis. ADVERSE REACTIONS Two serious adverse reactions reported in patients treated with Flagyl (metronidazole) have been convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of Flagyl, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur. The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea reported by about 12% of patients, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping. Constipation has also been reported. The following reactions have also been reported during treatment with Flagyl (metronidazole): Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy. Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia. Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings. Central Nervous System: Convulsive seizures, peripheral neuropathy, dizziness, vertigo, incoordination, ataxia, confusion, irritability, depression, weakness, and insomnia. Hypersensitivity: Urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever. Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling ìserum sickness.î If patients receiving Flagyl drink alcoholic beverages, they may experience abdominal distress, nausea, vomiting, flushing, or headache. A modification of the taste of alcoholic beverages has also been reported. Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported. Crohn’s disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established. Crohn’s disease is not an approved indication for Flagyl. OVERDOSAGE Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day. Treatment: There is no specific antidote for Flagyl overdose; therefore, management of the patient should consist of symptomatic and supportive therapy. DOSAGE AND ADMINISTRATION In elderly patients, the pharmacokinetics of metronidazole may be altered, and, therefore, monitoring of serum levels may be necessary to adjust the metronidazole dosage accordingly. Trichomoniasis: In the Female: One-day treatmentótwo grams of Flagyl, given either as a single dose or in two divided doses of one gram each given in the same day. Seven-day course of treatmentó250 mg three times daily for seven consecutive days. There is some indication from controlled comparative studies that cure rates as determined by vaginal smears, signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen. The dosage regimen should be individualized. Single-dose treatment can assure compliance, especially if administered under supervision, in those patients who cannot be relied on to continue the seven-day regimen. A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain appropriate treatment. Further, some patients may tolerate one treatment regimen better than the other. Pregnant patients should not be treated during the first trimester. (See Contraindications.) In pregnant patients in whom alternative treatment has been inadequate, the one-day course of therapy should not be used, as it results in higher serum levels which can reach the fetal circulation (see PRECAUTIONS, Pregnancy). When repeat courses of the drug are required, it is recommended that an interval of four to six weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measures. Total and differential leukocyte counts should be made before and after re- treatment. In the Male: Treatment should be individualized as for the female. Amebiasis: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adults: For acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times daily for 5 to 10 days. For amebic liver abscess: 500 mg or 750 mg orally three times daily for 5 to 10 days. Pediatric patients: 35 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days. Anaerobic Bacterial Infections: In the treatment of most serious anaerobic infections, Flagyl I.V. (metronidazole hydrochloride) is usually administered initially. The usual adult oral dosage is 7.5 mg/kg every six hours (approx. 500 mg for a 70-kg adult). A maximum of 4 g should not be exceeded during a 24-hour period. The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment. Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously. Close monitoring of plasma metronidazole levels2 and toxicity is recommended. The dose of Flagyl should not be specifically reduced in anuric patients since accumulated metabolites may be rapidly removed by dialysis. HOW SUPPLIED Flagyl 250-mg tablets are round, blue, film coated, with SEARLE and 1831 debossed on one side and FLAGYL and 250 on the other side; bottles of 50, 100, and 2,500. Flagyl 500-mg tablets are oblong, blue, film coated, with FLAGYL debossed on one side and 500 on the other side; bottles of 50, 100, and 500. Storage and Stability: Store below 77 °F (25 °C) and protect from light. 1. Proposed standard: PSM-11óProposed Reference Dilution Procedure for Antimicrobic Susceptibility Testing of Anaerobic Bacteria, National Committee for Clinical Laboratory Standards; and Sutter, et al.: Collaborative Evaluation of a Proposed Reference Dilution Method of Susceptibility Testing of Anaerobic Bacteria, Antimicrob. Agents Chemother. 16:495ñ502 (Oct.) 1979; and Tally, et al.: In Vitro Activity of Thienamycin, Antimicrob. Agents Chemother. 14:436ñ438 (Sept.) 1978. 2. Ralph, E.D., and Kirby, W.M.M.: Bioassay of Metronidazole With Either Anaerobic or Aerobic Incubation, J. Infect. Dis. 132:587ñ591 (Nov.) 1975; or Gulaid, et al.: Determination of Metronidazole and Its Major Metabolites in Biological Fluids by High Pressure Liquid Chromatography, Br. J. Clin. Pharmacol. 6:430ñ432, 1978. Rx only 5/5/99 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda G.D. Searle & Co. Box 5110, Chicago IL 60680 USA Address medical inquiries to: G.D. Searle & Co. Healthcare Information Services 5200 Old Orchard Road Skokie IL 60077 SEARLE ©1999, G.D. Searle & Co. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.301052	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/12623slr058_flagyl_lbl.pdf', 'application_number': 12623, 'submission_type': 'SUPPL ', 'submission_number': 58}
10,820	FLAGYL® (metronidazole) tablets To reduce the development of drug-resistant bacteria and maintain the effectiveness of FLAGYL® and other antibacterial drugs, FLAGYL® should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. WARNING Metronidazole has been shown to be carcinogenic in mice and rats (see PRECAUTIONS). Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the INDICATIONS AND USAGE section below. DESCRIPTION FLAGYL (metronidazole) tablets, 250 mg or 500 mg is an oral formulation of the synthetic nitroimidazole antimicrobial, 2-methyl-5-nitro-1H-imidazole-1-ethanol, which has the following structural formula: structural formula FLAGYL (metronidazole) tablets contain 250 mg or 500 mg of metronidazole. Inactive ingredients include cellulose, FD&C Blue No. 2 Lake, hydroxypropyl cellulose, hypromellose, polyethylene glycol, stearic acid, and titanium dioxide. CLINICAL PHARMACOLOGY Absorption Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms. Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between one and two hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose. Oral administration of 250 mg, 500 mg, or 2,000 mg produced peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively. Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma levels in males are generally lower. Reference ID: 3358531 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distribution Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses. Metabolism/Excretion The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(ß hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2. The average elimination half-life of metronidazole in healthy subjects is eight hours. Renal Impairment Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. Subjects with end-stage renal disease (ESRD; CLCR= 8.1±9.1 mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher Cmax of hydroxy-metronidazole and 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CLCR= 126±16 mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS). Effect of Dialysis Following a single intravenous infusion or oral dose of metronidazole 500 mg, the clearance of metronidazole was investigated in ESRD subjects undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A hemodialysis session lasting for 4 to 8 hours removed 40% to 65% of the administered metronidazole dose, depending on the type of dialyzer membrane used and the duration of the dialysis session. If the administration of metronidazole cannot be separated from the dialysis session, supplementation of metronidazole dose following hemodialysis should be considered (see DOSAGE AND ADMINISTRATION). A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD. Reference ID: 3358531 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatic Impairment Following a single intravenous infusion of 500 mg metronidazole, the mean AUC24 of metronidazole was higher by 114% in patients with severe (Child-Pugh C) hepatic impairment, and by 54% and 53% in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to healthy control subjects. There were no significant changes in the AUC24 of hydroxyl-metronidazole in these hepatically impaired patients. A reduction in metronidazole dosage by 50% is recommended in patients with severe (Child-Pugh C) hepatic impairment (see DOSAGE AND ADMINISTRATION). No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Geriatric Patients Following a single 500 mg oral or IV dose of metronidazole, subjects >70 years old with no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxy-metronidazole (active metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared to young healthy controls <40 years old. In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS). Pediatric Patients In one study, newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured during the first 3 days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding elimination half-lives ranged from 109 to 22.5 hours. Microbiology Mechanism of Action Metronidazole exerts antibacterial effects in an anaerobic environment by the following possible mechanism: Once metronidazole enters the organism, the drug is reduced by intracellular electron transport proteins. Because of this alteration to the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of the bacteria. Metronidazole is active against most obligate anaerobes, but does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Reference ID: 3358531 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Activity In Vitro and In Vivo Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive anaerobes Clostridium species Eubacterium species Peptococcus species Peptostreptococcus species Gram-negative anaerobes Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B.vulgatus) Fusobacterium species Protozoal parasites Entamoeba histolytica Trichomonas vaginalis The following in vitro data are available, but their clinical significance is unknown: Metronidazole exhibits in vitro minimum inhibitory concentrations (MIC’s) of <8 mcg/mL or less against most (≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. Gram-negative anaerobes Bacteroides fragilis group (B. caccae, B. uniformis) Prevotella species (P. bivia, P. buccae, P. disiens) Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Anaerobic Techniques Quantitative methods are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria susceptibility to metronidazole can be determined by the reference Reference ID: 3358531 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda broth or agar dilution method1,2. The MIC values obtained should be interpreted according to the following criteria: Susceptibility Test Interpretive Criteria for Metronidazole MIC (mcg/mL) Interpretation ≤ 8 Susceptible (S) 16 Intermediate (I) ≥ 32 Resistant (R) For protozoal parasites: Standardized tests do not exist for use in clinical microbiology laboratories. A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. 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 a high dosage of the drug product is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2 Standard metronidazole powder should provide a value within the MIC ranges noted in the following table: Agar and Broth Acceptable Quality Control Ranges for Metronidazole Acceptable Quality Control Ranges for Metronidazole Minimum Inhibitory QC Strain Concentration (mcg/mL) Agar Broth Bacteroides fragilis ATCC 25285 0.25–1.0 0.25-2.0 Bacteroides thetaiotaomicron ATCC 29741 0.5–2.0 0.5-4.0 Reference ID: 3358531 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Symptomatic Trichomoniasis. FLAGYL is indicated for the treatment of T. vaginalis infection in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures). Asymptomatic Trichomoniasis. FLAGYL is indicated in the treatment of asymptomatic T. vaginalis infection in females when the organism is associated with endocervicitis, cervicitis, or cervical erosion. Since there is evidence that presence of the trichomonad can interfere with accurate assessment of abnormal cytological smears, additional smears should be performed after eradication of the parasite. Treatment of Asymptomatic Sexual Partners. T. vaginalis infection is a venereal disease. Therefore, asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has been found to be present, in order to prevent reinfection of the partner. The decision as to whether to treat an asymptomatic male partner who has a negative culture or one for whom no culture has been attempted is an individual one. In making this decision, it should be noted that there is evidence that a woman may become reinfected if her sexual partner is not treated. Also, since there can be considerable difficulty in isolating the organism from the asymptomatic male carrier, negative smears and cultures cannot be relied upon in this regard. In any event, the sexual partner should be treated with FLAGYL in cases of reinfection. Amebiasis. FLAGYL is indicated in the treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess. In amebic liver abscess, FLAGYL therapy does not obviate the need for aspiration or drainage of pus. Anaerobic Bacterial Infections. FLAGYL is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with FLAGYL therapy. In a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to FLAGYL. INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species, Peptococcus species, and Peptostreptococcus species. SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species. Reference ID: 3358531 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species. BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group and Clostridium species. BONE AND JOINT INFECTIONS, (as adjunctive therapy), caused by Bacteroides species including the B. fragilis group. CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group. LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group. ENDOCARDITIS caused by Bacteroides species including the B. fragilis group. To reduce the development of drug-resistant bacteria and maintain the effectiveness of FLAGYL and other antibacterial drugs, FLAGYL 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 Hypersensitivity FLAGYL Tablets is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. In patients with trichomoniasis, FLAGYL Tablets is contraindicated during the first trimester of pregnancy (see PRECAUTIONS). Psychotic Reaction with Disulfiram Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks (see PRECAUTIONS, Drug Interactions). Interaction with Alcohol Reference ID: 3358531 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole (see PRECAUTIONS, Drug Interactions). WARNINGS Central and Peripheral Nervous System Effects Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Convulsive seizures have been reported in patients treated with metronidazole. Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS). PRECAUTIONS General Hepatic Impairment Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment (Child-Pugh C), a reduced dose of FLAGYL is recommended. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Renal Impairment Reference ID: 3358531 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY). Fungal Superinfections Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with FLAGYL and requires treatment with a candidacidal agent. Use in Patients with Blood Dyscrasias Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy. Drug-Resistant Bacteria and Parasites Prescribing FLAGYL in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria and parasites. Information for Patients Interaction with Alcohol Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking FLAGYL and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions). Treatment of Bacterial and Parasitic Infections Patients should be counseled that FLAGYL should only be used to treat bacterial and parasitic infections. FLAGYL does not treat viral infections (e.g., the common cold). When FLAGYL 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 FLAGYL in the future. Reference ID: 3358531 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks (see CONTRAINDICATIONS). Alcoholic Beverages Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy (see CONTRAINDICATIONS). Warfarin and other Oral Anticoagulants Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When FLAGYL is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored. Lithium In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication. Busulfan Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly. Drugs that Inhibit CYP450 Enzymes The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. Reference ID: 3358531 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drugs that Induce CYP450 Enzymes The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported. Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD+ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7. Carcinogenesis, Mutagenesis, Impairment of Fertility Tumors affecting the liver, lungs, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters. Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m2 (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage. Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up at 400 mg/kg/day (similar to the maximum recommended clinical dose, based on body surface area comparisons) for 28 days. However, rats treated at the same dose for 6 weeks or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight week, drug-free recovery period. Reference ID: 3358531 11 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 B There are no adequate and well controlled studies of FLAGYL in pregnant women. There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole. Nursing Mothers Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, 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. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula. Geriatric Use In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY, PRECAUTIONS). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see DOSAGE AND ADMINISTRATION). Reference ID: 3358531 12 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 in pediatric patients have not been established, except for the treatment of amebiasis. ADVERSE REACTIONS The following reactions have been reported during treatment with metronidazole: Central Nervous System: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur. In addition, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia (see WARNINGS). Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation. Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy. Dermatologic: Erythematous rash and pruritus. Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia. Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings. Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever. Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance. Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported. Reference ID: 3358531 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established. Crohn’s disease is not an approved indication for FLAGYL tablets. OVERDOSAGE Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day. Treatment of Overdosage: There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy. DOSAGE AND ADMINISTRATION Trichomoniasis: In the Female: One-day treatment − two grams of FLAGYL, given either as a single dose or in two divided doses of one gram each, given in the same day. Seven-day course of treatment − 250 mg three times daily for seven consecutive days. There is some indication from controlled comparative studies that cure rates as determined by vaginal smears and signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen. The dosage regimen should be individualized. Single-dose treatment can assure compliance, especially if administered under supervision, in those patients who cannot be relied on to continue the seven-day regimen. A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain appropriate treatment. Further, some patients may tolerate one treatment regimen better than the other. Pregnant patients should not be treated during the first trimester (see CONTRAINDICATIONS). In pregnant patients for whom alternative treatment has been inadequate, the one-day course of therapy should not be used, as it results in higher serum levels which can reach the fetal circulation (see PRECAUTIONS, Pregnancy). Reference ID: 3358531 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda When repeat courses of the drug are required, it is recommended that an interval of four to six weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measures. Total and differential leukocyte counts should be made before and after re-treatment. In the Male: Treatment should be individualized as it is for the female. Amebiasis Adults: For acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times daily for 5 to 10 days. For amebic liver abscess: 500 mg or 750 mg orally three times daily for 5 to 10 days. Pediatric patients: 35 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days. Anaerobic Bacterial Infections In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially. The usual adult oral dosage is 7.5 mg/kg every six hours (approx. 500 mg for a 70-kg adult). A maximum of 4 g should not be exceeded during a 24-hour period. The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment. Dosage Adjustments Patients with Severe Hepatic Impairment For patients with severe hepatic impairment (Child-Pugh C), the dose of FLAGYL should be reduced by 50% (see CLINICAL PHARMACOLOGY and PRECAUTIONS). Patients Undergoing Hemodialysis: Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of metronidazole cannot be separated from the hemodialysis session, supplementation of metronidazole dosage following the hemodialysis session should be considered, depending on the patient’s clinical situation (see CLINICAL PHARMACOLOGY). Reference ID: 3358531 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED FLAGYL 250-mg tablets are round, blue, film coated, with SEARLE and 1831 debossed on one side and FLAGYL and 250 on the other side; supplied as bottles of 50 and 100. NDC Number Size 25-1831-50 bottle of 50 25-1831-31 bottle of 100 FLAGYL 500-mg tablets are oblong, blue, film coated, with FLAGYL debossed on one side and 500 on the other side; bottles of 50 and 100. NDC Number Size 25-1821-50 bottle of 50 25-1821-31 bottle of 100 Storage and Stability: Store below 77°F (25°C) and protect from light. REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012. 2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013. Rx only company logo LAB-0162-6.2 Revised June 2013 Reference ID: 3358531 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.373870	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012623s065lbl.pdf', 'application_number': 12623, 'submission_type': 'SUPPL ', 'submission_number': 65}
10,818	Aldactazide® spironolactone and hydrochlorothiazide tablets WARNING Spironolactone, an ingredient of ALDACTAZIDE, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). ALDACTAZIDE should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided. Fixed-dose combination drugs are not indicated for initial therapy of edema or hypertension. Edema or hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension and edema is not static but must be reevaluated as conditions in each patient warrant. DESCRIPTION ALDACTAZIDE oral tablets contain: spironolactone . . . . . . . . . . . . . . . . . . . . 25 mg hydrochlorothiazide . . . . . . . . . . . . . . . . 25 mg or spironolactone . . . . . . . . . . . . . . . . . . . . 50 mg hydrochlorothiazide . . . . . . . . . . . . . . . . 50 mg Spironolactone (ALDACTONE®), an aldosterone antagonist, is 17-hydroxy-7α mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate and has the following structural formula: structural formula Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Hydrochlorothiazide, a diuretic and antihypertensive, is 6-chloro-3,4-dihydro-2H-1,2,4 benzothiadiazine-7-sulfonamide 1,1-dioxide and has the following structural formula: Reference ID: 3647004 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution. Inactive ingredients include calcium sulfate, corn starch, flavor, hydroxypropyl cellulose, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. ACTIONS / CLINICAL PHARMACOLOGY Mechanism of action: ALDACTAZIDE is a combination of two diuretic agents with different but complementary mechanisms and sites of action, thereby providing additive diuretic and antihypertensive effects. Additionally, the spironolactone component helps to minimize the potassium loss characteristically induced by the thiazide component. The diuretic effect of spironolactone is mediated through its action as a specific pharmacologic antagonist of aldosterone, primarily by competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Hydrochlorothiazide promotes the excretion of sodium and water primarily by inhibiting their reabsorption in the cortical diluting segment of the distal renal tubule. ALDACTAZIDE is effective in significantly lowering the systolic and diastolic blood pressure in many patients with essential hypertension, even when aldosterone secretion is within normal limits. Both spironolactone and hydrochlorothiazide reduce exchangeable sodium, plasma volume, body weight, and blood pressure. The diuretic and antihypertensive effects of the individual components are potentiated when spironolactone and hydrochlorothiazide are given concurrently. Pharmacokinetics: Spironolactone is rapidly and extensively metabolized. Sulfur- containing products are the predominant metabolites and are thought to be primarily responsible, together with spironolactone, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (ALDACTONE film-coated tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a lowfat breakfast and blood was drawn thereafter. Reference ID: 3647004 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Accumulation Factor: AUC (0–24 hr, Mean Peak Mean (SD) day 15)/AUC Serum Post-Steady (0–24 hr, day 1) Concentration State Half-Life 7-α-(thiomethyl) 1.25 391 ng/mL 13.8 hr (6.4) spirolactone (TMS) at 3.2 hr (terminal) 6-ß-hydroxy-7-α (thiomethyl) spirolactone (HTMS) 1.50 125 ng/mL at 5.1 hr 15.0 hr (4.0) (terminal) Canrenone (C) 1.41 181 ng/mL at 4.3 hr 16.5 hr (6.3) (terminal) Spironolactone 1.30 80 ng/mL at 2.6 hr Approximately 1.4 hr (0.5) (ß half-life) The pharmacological activity of spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively. In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile. The effect of food on spironolactone absorption (two 100 mg ALDACTONE tablets) was assessed in a single dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known. Hydrochlorothiazide is rapidly absorbed following oral administration. Onset of action of hydrochlorothiazide is observed within one hour and persists for 6 to 12 hours. Hydrochlorothiazide plasma concentrations attain peak levels at one to two hours and decline with a half-life of four to five hours. Hydrochlorothiazide undergoes only slight metabolic alteration and is excreted in urine. It is distributed throughout the extracellular space, with essentially no tissue accumulation except in the kidney. Reference ID: 3647004 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Spironolactone, an ingredient of ALDACTAZIDE, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions section). ALDACTAZIDE should be used only in those conditions described below. Unnecessary use of this drug should be avoided. ALDACTAZIDE is indicated for: Edematous conditions for patients with: Congestive heart failure: • For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures; • The treatment of diuretic-induced hypokalemia in patients with congestive heart failure when other measures are considered inappropriate; • The treatment of patients with congestive heart failure taking digitalis when other therapies are considered inadequate or inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: • Aldosterone levels may be exceptionally high in this condition. ALDACTAZIDE is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. The nephrotic syndrome: • For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension: • For patients with essential hypertension in whom other measures are considered inadequate or inappropriate; • In hypertensive patients for the treatment of a diuretic-induced hypokalemia when other measures are considered inappropriate; • ALDACTAZIDE 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 the classes to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with ALDACTAZIDE. 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 Reference ID: 3647004 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 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. Usage in Pregnancy. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. ALDACTAZIDE is indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Precautions: Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort that is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate. Reference ID: 3647004 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS ALDACTAZIDE is contraindicated in patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, hypercalcemia, hyperkalemia, Addison’s disease, and in patients who are allergic to thiazide diuretics or to other sulfonamide-derived drugs. ALDACTAZIDE may also be contraindicated in acute or severe hepatic failure. WARNINGS Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with ALDACTAZIDE therapy. Excessive potassium intake may cause hyperkalemia in patients receiving ALDACTAZIDE (see Precautions: General). Concomitant administration of ALDACTAZIDE with the following drugs or potassium sources may lead to severe hyperkalemia: • other potassium-sparing diuretics • ACE inhibitors • angiotensin II receptor antagonists • aldosterone blockers • non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin • heparin and low molecular weight heparin • other drugs or conditions known to cause hyperkalemia • potassium supplements • diet rich in potassium • salt substitutes containing potassium ALDACTAZIDE should not be administered concurrently with other potassium-sparing diuretics. Spironolactone, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when ALDACTAZIDE is given concomitantly with these drugs (see Precautions: Drug interactions). ALDACTAZIDE should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Lithium generally should not be given with diuretics (see Precautions: Drug interactions). 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 may add to or potentiate the action of other antihypertensive drugs. Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma. Reference ID: 3647004 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sulfonamide derivatives, including thiazides, have been reported to exacerbate or activate systemic lupus erythematosus. 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. PRECAUTIONS General: Serum Electrolyte Abnormalities: Spironolactone can cause hyperkalemia. The risk of hyperkalemia may be increased in patients with renal insufficiency, diabetes mellitus or with concomitant use of drugs that raise serum potassium (see Drug Interactions). Hydrochlorothiazide can cause hypokalemia and hyponatremia. The risk of hypokalemia may be increased in patients with cirrhosis, brisk diuresis, or with concomitant use of drugs that lower serum potassium. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Monitor serum electrolytes periodically. Other Metabolic Disturbances: Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving ALDACTAZIDE. Gynecomastia: Gynecomastia may develop in association with the use of spironolactone; physicians should be alert to its possible onset. The development of gynecomastia appears to be related to both dosage level and duration of therapy and is normally reversible when ALDACTAZIDE is discontinued. In rare instances, some breast enlargement may persist when ALDACTAZIDE is discontinued. Somnolence: Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined. Reference ID: 3647004 7 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 who receive ALDACTAZIDE should be advised to avoid potassium supplements and foods containing high levels of potassium including salt substitutes. Laboratory tests: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments. Drug interactions: ACE inhibitors, Angiotensin II receptor antagonists, aldosterone blockers, potassium supplements, heparin, low molecular weight heparin, and other drugs known to cause hyperkalemia: Concomitant administration may lead to severe hyperkalemia. Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Antidiabetic drugs (e.g., oral agents, insulin): Dosage adjustment of the antidiabetic drug may be required (see Precautions). Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur. Pressor amines (e.g., norepinephrine): Both spironolactone and hydrochlorothiazide reduce the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with ALDACTAZIDE. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant may result. Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Combination of NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when ALDACTAZIDE and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Digoxin: Spironolactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. Monitor serum digoxin levels and adjust dose accordingly. Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (see Precautions). Reference ID: 3647004 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cholestyramine: Hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine. Drug/Laboratory test interactions: Thiazides should be discontinued before carrying out tests for parathyroid function (see Precautions: General). Thiazides may also decrease serum PBI levels without evidence of alteration of thyroid function. Several reports of possible interference with digoxin radioimmunoassays by spironolactone or its metabolites have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay specific) has been fully established. Carcinogenesis, mutagenesis, impairment of fertility: Spironolactone: Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150, and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30 and 100 mg spironolactone/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females. A dose-related (above 30 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) for a period of one year. In two year studies in the rat, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors. Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone has been reported to be negative in some mammalian mutagenicity tests in vitro and inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others. In a three-litter reproduction study in which female rats received dietary doses of 15 and 500 mg spironolactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 500 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), spironolactone was found to increase the Reference ID: 3647004 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two week posttreatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility, and fecundity. Spironolactone (100 mg/kg/day), administered i.p. to female mice during a two week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating. 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 of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo 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. Pregnancy: Teratogenic effects. Pregnancy Category C. 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 hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Spironolactone: Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryo- toxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic Reference ID: 3647004 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well-controlled studies with ALDACTAZIDE in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of ALDACTAZIDE in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus. Non-teratogenic effects Spironolactone or its metabolites may, and hydrochlorothiazide does, cross the placental barrier and appear in cord blood. Therefore, the use of ALDACTAZIDE in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. The hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. Nursing mothers: Canrenone, a major (and active) metabolite of spironolactone, appears in human breast milk. Because spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted. Thiazides are excreted in human milk in small amounts. Thiazides when given at high doses can cause intense diuresis which can in turn inhibit milk production. The use of ALDACTAZIDE during breast feeding is not recommended. If ALDACTAZIDE is used during breast feeding, doses should be kept as low as possible. Pediatric use: Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity. Hydrochlorothiazide: Body as a whole: Weakness. Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics, or antihypertensive drugs). Reference ID: 3647004 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialoadenitis, cramping, constipation, gastric irritation, nausea, anorexia. Eye Disorders: acute myopia and acute angle closure glaucoma (see Warnings). Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia. Hypersensitivity: Anaphylactic reactions, necrotizing angitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura. Metabolic: Electrolyte imbalance (see Precautions), hyperglycemia, glycosuria, hyperuricemia. Musculoskeletal: Muscle spasm. Nervous system/psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness. Renal: Renal failure, renal dysfunction, interstitial nephritis (see Warnings). Skin: Erythema multiforme, pruritus. Special senses: Transient blurred vision, xanthopsia. Spironolactone: Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting. Reproductive: Gynecomastia (see Precautions), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast pain. Carcinoma of the breast has been reported in patients taking spironolactone but a cause and effect relationship has not been established. Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia. Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis. Metabolism: Hyperkalemia, electrolyte disturbances (see Warnings and Precautions). Musculoskeletal: Leg cramps. Nervous system/psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness. Reference ID: 3647004 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration. Renal: Renal dysfunction (including renal failure). Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritus. OVERDOSAGE The oral LD50 of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats. Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia (less commonly seen with ALDACTAZIDE because the hydrochlorothiazide component tends to produce hypokalemia), or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. However, because ALDACTAZIDE contains both spironolactone and hydrochlorothiazide, the toxic effects may be intensified, and signs of thiazide overdosage may be present. These include electrolyte imbalance such as hypokalemia and/or hyponatremia. The potassium-sparing action of spironolactone may predominate and hyperkalemia may occur, especially in patients with impaired renal function. BUN determinations have been reported to rise transiently with hydrochlorothiazide. There may be CNS depression with lethargy or even coma. Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, ALDACTAZIDE should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. DOSAGE AND ADMINISTRATION Optimal dosage should be established by individual titration of the components (see boxed Warning). Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). The usual maintenance dose of ALDACTAZIDE is 100 mg each of Reference ID: 3647004 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda spironolactone and hydrochlorothiazide daily, administered in a single dose or in divided doses, but may range from 25 mg to 200 mg of each component daily depending on the response to the initial titration. In some instances it may be desirable to administer separate tablets of either ALDACTONE (spironolactone) or hydrochlorothiazide in addition to ALDACTAZIDE in order to provide optimal individual therapy. The onset of diuresis with ALDACTAZIDE occurs promptly and, due to prolonged effect of the spironolactone component, persists for two to three days after ALDACTAZIDE is discontinued. Essential hypertension. Although the dosage will vary depending on the results of titration of the individual ingredients, many patients will be found to have an optimal response to 50 mg to 100 mg each of spironolactone and hydrochlorothiazide daily, given in a single dose or in divided doses. Concurrent potassium supplementation is not recommended when ALDACTAZIDE is used in the long-term management of hypertension or in the treatment of most edematous conditions, since the spironolactone content of ALDACTAZIDE is usually sufficient to minimize loss induced by the hydrochlorothiazide component. HOW SUPPLIED ALDACTAZIDE tablets containing 25 mg of spironolactone (ALDACTONE) and 25 mg of hydrochlorothiazide are round, tan, film coated, with SEARLE and 1011 debossed on one side and ALDACTAZIDE and 25 on the other side, supplied as: NDC Number Size 0025-1011-31 bottle of 100 ALDACTAZIDE tablets containing 50 mg of spironolactone (ALDACTONE) and 50 mg of hydrochlorothiazide are oblong, tan, scored, film coated, with SEARLE and 1021 debossed on the scored side and ALDACTAZIDE and 50 on the other side, supplied as: NDC Number Size 0025-1021-31 bottle of 100 Store below 77°F (25°C). company logo LAB-0233-8.x Revised Month 2014 Reference ID: 3647004 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.439639	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/012616s076lbl.pdf', 'application_number': 12616, 'submission_type': 'SUPPL ', 'submission_number': 76}
10,822	SYNALAR® (fluocinolone acetonide) Ointment 0.025% Rx Only DESCRIPTION SYNALAR® (fluocinolone acetonide) Ointment 0.025% is intended for topical administration. The active component is the corticosteroid fluocinolone acetonide, which has the chemical name pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21- dihydroxy-16,17-[(1-methylethylidene)bis (oxy)]-,(6α,11β,16α)-. It has the following chemical structure: CH3 HO CH3 CH3 O CH3 O O C F F C=O CH2OH SYNALAR® Ointment contains fluocinolone acetonide 0.25 mg/g in a white petrolatum USP vehicle. 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 vasocon- strictor 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. 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. 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 SYNALAR® Ointment is indicated for the relief of the inflammatory and pruritic manifestations of corticosteriod-responsive dermatoses. CONTRAINDICATIONS Topical corticosteroids 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 suppression 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. 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. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short-term use. 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 that for which it was prescribed. IP029 SYN Ointment PI-301.indd 1 7/18/12 11:41 AM Reference ID: 3284596 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. 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 adminis- tered 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 terato- genic effects from topically applied corticosteroids. Therefore, topical corticoste- roids 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 administered corticosteroids are secreted into breast milk in quanti- ties 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 Pediatric patients may demonstrate greater susceptibility to topical corticosteroid- induced hypothalmic-pituitary-adrenal (HPA) axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. 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, head- aches, 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 cortico- steroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: Burning Hypertrichosis Maceration of the skin Itching Acneiform eruptions Secondary infection Irritation Hypopigmentation Skin atrophy Dryness Perioral dermatitis Striae Folliculitis Allergic contact dermatitis Miliaria OVERDOSAGE Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS). DOSAGE AND ADMINISTRATION SYNALAR® Ointment is generally applied to the affected area as a thin film from two to four times daily depending on the severity of the condition. In hairy sites, the hair should be parted to allow direct contact with the lesion. Occlusive dressing may be used for the management of psoriasis or recalcitrant conditions. Some plastic films may be flammable and due care should be exer- cised in their use. Similarly, caution should be employed when such films are used on children or left in their proximity, to avoid the possibility of accidental suffocation. If an infection develops, the use of the occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted. HOW SUPPLIED SYNALAR® (fluocinolone acetonide) Ointment 0.025% is supplied in 60 g Tube – NDC 43538-910-60 120 g Tube – NDC 43538-910-12 STORAGE Store at room temperature 15-25°C (59-77°F); avoid freezing and excessive heat above 40°C (104°F). Manufactured for: 363 Route 46 West, Fairfield, NJ 07004-2402 USA www.medimetriks.com Manufactured by: IGI Laboratories, Inc., Buena, NJ 08310 IP029 Iss. 8/12 IP029 SYN Ointment PI-301.indd 2 7/18/12 11:41 AM Reference ID: 3284596 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.551148	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012787s071lbl.pdf', 'application_number': 12787, 'submission_type': 'SUPPL ', 'submission_number': 71}
10,821	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	2025-02-12T13:43:50.563124	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1997/012770s024lbl.pdf', 'application_number': 12770, 'submission_type': 'SUPPL ', 'submission_number': 24}
10,824	Cordran® SP Cream and Cordran® Ointment Flurandrenolide, USP DESCRIPTION Cordran® (flurandrenolide, USP) is a potent corticosteroid intended for topical use. Flurandrenolide occurs as white to off-white, fluffy, crystalline powder and is odorless. Flurandrenolide is practically insoluble in water and in ether. One gram of flurandrenolide dissolves in 72 mL of alcohol and in 10 mL of chloroform. The molecular weight of flurandrenolide is 436.52. The chemical name of flurandrenolide is Pregn-4-ene-3,20-dione, 6-fluoro-11,21-dihydroxy 16,17-[(1-methylethylidene)bis (oxy)]-, (6α, 11β, 16α)-; its empirical formula is C24H33FO6. The structure is as follows: structural formula Each gram of Cordran® SP Cream (flurandrenolide Cream, USP) contains 0.5 mg (1.145 µmol; 0.05%) or 0.25 mg (0.57 µmol; 0.025%) flurandrenolide in an emulsified base composed of cetyl alcohol, citric acid, mineral oil, polyoxyl 40 stearate, propylene glycol, sodium citrate, stearic acid, and purified water. Each gram of Cordran® Ointment (flurandrenolide Ointment, USP) contains 0.5 mg (1.145 µmol; 0.05%) or 0.25 mg (0.57 µmol; 0.025%) flurandrenolide in a base composed of white wax, cetyl alcohol, sorbitan sesquioleate, and white petrolatum. CLINICAL PHARMACOLOGY Cordran is primarily effective because of its anti-inflammatory, antipruritic, and vasoconstrictive actions. The mechanism of the anti-inflammatory effect of topical corticosteroids is not completely understood. Corticosteroids with anti-inflammatory activity may stabilize cellular and lysosomal membranes. There is also the suggestion that the effect on the membranes of lysosomes prevents the release of proteolytic enzymes and, thus, plays a part in reducing inflammation. 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. Reference ID: 3344685 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. 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 then excreted in the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. INDICATIONS AND USAGE Cordran® (flurandrenolide, USP) is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. CONTRAINDICATIONS Topical corticosteroids are contraindicated in patients with a history of hypersensitivity to any of the components of these preparations. 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 that augment systemic absorption include 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 suppression using 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, so that supplemental systemic corticosteroids are required. Pediatric patients may absorb proportionately larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see Pediatric Use under PRECAUTIONS). If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. In the presence of dermatologic infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, Cordran 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 that for which it was prescribed. Reference ID: 3344685 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. The treated skin area should not be bandaged or otherwise covered or wrapped in order to be occlusive unless the patient is directed to do so 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 patient being treated in the diaper area, because these garments may constitute occlusive dressings. 6. Do not use Cordran on the face, underarms, or groin areas unless directed by your physician. 7. If no improvement is seen within 2 weeks, contact your physician. 8. Do not use other corticosteroid-containing products while using Cordran without first consulting your physician. 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. Usage in Pregnancy — Pregnancy Category C—Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corti-costeroids 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 for pregnant patients or 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 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 a nursing woman. Pediatric Use—Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing’s syndrome than do mature patients because of a larger skin surface area to body weight ratio. Hypothalamic-pituitary-adrenal (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. Reference ID: 3344685 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Administration of topical corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of pediatric patients. 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 Acneform eruptions Hypopigmentation Perioral dermatitis Allergic contact dermatitis The following may occur more frequently with occlusive dressings: Maceration of the skin Secondary infection Skin atrophy Striae Miliaria Postmarketing Adverse Reactions The following adverse reactions have been identified during post approval use of flurandrenolide, USP. 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. Skin: skin striae, hypersensitivity, skin atrophy, contact dermatitis and skin discoloration. OVERDOSAGE Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS). DOSAGE AND ADMINISTRATION For moist lesions, a small quantity of the cream should be rubbed gently into the affected areas 2 or 3 times a day. For dry, scaly lesions, the ointment is applied as a thin film to affected areas 2 or 3 times daily. Therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary. Cordran® (flurandrenolide, USP) should not be used with occlusive dressings unless directed by a physician. Tight-fitting diapers or plastic pants may constitute occlusive dressings. Reference ID: 3344685 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Cordran® SP Cream is supplied in aluminum tubes as follows: Cordran® SP Cream, 0.025%: 30 g (NDC 16110-034-30) 60 g (NDC 16110-034-60) 120 g (NDC 16110-034-12) Cordran® SP Cream, 0.05%: 15 g (NDC 16110-035-15) 30 g (NDC 16110-035-30) 60 g (NDC 16110-035-60) 120 g (NDC 16110-035-12) Cordran® Ointment is supplied in aluminum tubes as follows: Cordran® Ointment, 0.05% 15 g (NDC 16110-026-15) 30 g (NDC 16110-026-30) 60 g (NDC 16110-026-60) Keep out of reach of children. Storage Keep tightly closed. Protect from light. Store at 20° to 25°C (68° to 77°F) with excursions permitted to 15° to 30°C (59° to 86°F) [See USP controlled room temperature.]. Rx Only Revision: 07/2013 company logo Manufactured by DPT Laboratories, San Antonio, TX 78215 For Aqua Pharmaceuticals, West Chester, PA 19380 Reference ID: 3344685 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.736947	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012806s037lbl.pdf', 'application_number': 12806, 'submission_type': 'SUPPL ', 'submission_number': 37}
10,823	s truc tura l for m ula 6<1$/$5p ȵXRFLQRORQHDFHWRQLGH &UHDP for initiation of therapy in inﬂammatory dermatoses. Rx Only DESCRIPTION SYNALAR® (ﬂuocinolone acetonide) Cream 0.025% is intended for topical administration. The active component is the corticosteroid ﬂuocinolone aceton ide, which has the chemical name pregna-1,4-diene-3,20-dione,6,9-diﬂuoro-11,21 dihydroxy-16,17-[(1-methylethylidene)bis (oxy)]-,(6α,11β,16α)-. It has the following chemical structure: CH OH SYNALAR® Cream contains ﬂuocinolone acetonide 0.25 mg/g in a water-washable aqueous base of butylated hydroxytoluene, cetyl alcohol, citric acid, edetate diso dium, methylparaben and propylparaben (preservatives), mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, simethicone, stearyl alcohol, water (puriﬁed) and white beeswax. 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 vasocon strictor 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. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses (see DOSAGE AND ADMINISTRATION). Reference ID: 3289131 ,36<1&UHDP3,LQGG 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 SYNALAR® Cream is indicated for the relief of the inﬂammatory and pruritic mani festations of corticosteriod-responsive dermatoses. CONTRAINDICATIONS Topical corticosteroids 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 periodi cally for evidence of HPA axis suppression 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 substi tute 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. 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. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or ﬂexor areas, or on the face, this may occur even with short-term use. 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. $0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Patients should be advised not to use this medication for an y 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 adver se 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. 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 adminis tered 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 corti costeroids 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 administered corticosteroids are secreted into breast milk in quanti ties 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 Pediatric patients may demonstrate greater susceptibility to topical corticosteroid- induced hypothalmic-pituitary-adrenal (HPA) axis suppression and Cushing’ s syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in children receiving topical cor ticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimula tion. Manifestations of intracranial hyper tension include bulging fontanelles, headaches, and bilateral papilledema. Reference ID: 3289131 ,36<1&UHDP3,LQGG 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 cortico steroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: Burning Hypertrichosis Maceration of the skin Itching Acneiform eruptions Secondary infection Irritation Hypopigmentation Skin atrophy Dryness Perioral dermatitis Striae Folliculitis Allergic contact dermatitis Miliaria OVERDOSAGE Topically applied corticosteroids can be absorbed in suf ﬁcient amounts to produce systemic effects (see PRECAUTIONS). DOSAGE AND ADMINISTRATION SYNALAR® Cream is generally applied to the affected area as a thin ﬁlm from two to four times daily depending on the severity of the condition. In hairy sites, the hair should be parted to allow direct contact with the lesion. Occlusive dressing may be used for the management of psoriasis or recalcitrant conditions. Some plastic ﬁlms may be ﬂammable and due care should be exer cised in their use. Similarly, caution should be employed when such ﬁlms are used on children or left in their proximity, to avoid the possibility of accidental suffocation. If an infection develops, the use of the occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted. HOW SUPPLIED SYNALAR® (ﬂuocinolone acetonide) Cream 0.025% is supplied in 60 g Tube – NDC 43538-900-60 120 g Tube – NDC 43538-900-12 STORAGE Store at room temperature 15-25°C (59-77°F); avoid freezing and excessive heat above 40°C (104°F). Manufactured for: company logo 363 Route 46 West, Fairﬁeld, NJ 07004-2402 USA www.medimetriks.com Manufactured by: IGI Laboratories, Inc., Buena, NJ 08310 IP027 Iss. 8/12 $0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.767358	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012787s071lblrev.pdf', 'application_number': 12787, 'submission_type': 'SUPPL ', 'submission_number': 71}
10,825	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.817177	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/012892Orig1s015s016lbl.pdf', 'application_number': 12892, 'submission_type': 'SUPPL ', 'submission_number': 15}
10,826	Novartis Metopirone® metyrapone USP Capsules Diagnostic Test of Pituitary Adrenocorticotropic Function Prescribing Information DESCRIPTION Metopirone, metyrapone USP, is an inhibitor of endogenous adrenal corticosteroid synthesis, available as 250-mg capsules for oral administration. Its chemical name is 2-methyl-1, chemical name Metyrapone USP is a white to light amber, fine, crystalline powder, having a characteristic odor. It is sparingly soluble in water, and soluble in methanol and in chloroform. It forms water-soluble salts with acids. Its molecular weight is 226.28. Inactive Ingredients. Polyethylene glycol, glycerine, gelatin, sodium ethyl hydroxybenzoate, sodium propyl hydroxybenzoate, ethyl vanillin, 4-methoxyacetophenone, titanium dioxide, brown ink. CLINICAL PHARMACOLOGY Pharmacodynamics The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-β-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary. With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine. These metabolites are readily determined by measuring urinary 17-hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Reference ID: 2859992 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Because of these actions, Metopirone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis. Pharmacokinetics The response to Metopirone does not occur immediately. Following oral administration, peak steroid excretion occurs during the subsequent 24-hour period. Absorption Metopirone is absorbed rapidly and well when administered orally as prescribed. Peak plasma concentrations are usually reached 1 hour after administration. After administration of 750 mg, mean peak plasma concentrations are 3.7 µg/mL, falling to 0.5 µg/mL 4 hours after administration. Following a single 2000-mg dose, mean peak plasma concentrations of metyrapone in plasma are 7.3 µg/mL. Metabolism The major biotransformation is reduction of the ketone to metyrapol, an active alcohol metabolite. Eight hours after a single oral dose, the ratio of metyrapone to metyrapol in the plasma is 1:1.5. Metyrapone and metyrapol are both conjugated with glucuronide. Excretion Metyrapone is rapidly eliminated from the plasma. The mean ± SD terminal elimination half-life is 1.9 ± 0.7 hours. Metyrapol takes about twice as long as metyrapone to be eliminated from the plasma. After administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% as glucuronide) and 38.5% in the form of metyrapol (8.1% free and 91.9% as glucuronide) within 72 hours after the first dose was given. INDICATIONS AND USAGE Metopirone is a diagnostic drug for testing hypothalamic-pituitary ACTH function. CONTRAINDICATIONS Metopirone is contraindicated in patients with adrenal cortical insufficiency, or hypersensitivity to Metopirone or to any of its excipients. WARNINGS Metopirone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity. PRECAUTIONS General Ability of adrenals to respond to exogenous ACTH should be demonstrated before Metopirone is employed as a test. In the presence of hypo- or hyperthyroidism, response to the Metopirone test may be subnormal. Since Metopirone may cause dizziness and sedation, patients should exercise caution when driving or operating machinery. Reference ID: 2859992 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests See INTERPRETATION. Drug Interactions Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone. The metabolism of Metopirone is accelerated by phenytoin; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. A subnormal response may occur in patients on estrogen therapy. Metopirone inhibits the glucuronidation of acetaminophen and could possibly potentiate acetaminophen toxicity. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity and reproduction studies in animals have not been conducted. Metopirone was not mutagenic with or without metabolic activation in three strains of bacteria. Pregnancy Category C A subnormal response to Metopirone may occur in pregnant women. Animal reproduction studies have not been conducted with Metopirone. The Metopirone test was administered to 20 pregnant women in their second and third trimester of pregnancy and evidence was found that the fetal pituitary responded to the enzymatic block. It is not known if Metopirone can affect reproduction capacity. Metopirone should be given to a pregnant woman only if needed. Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with Metopirone. 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 Metopirone is administered to a nursing woman. Pediatric Use See DOSAGE AND ADMINISTRATION. Geriatric Use Clinical studies of Metopirone did not include sufficient numbers of subjects aged 65 years 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Cardiovascular System: Hypotension Gastrointestinal System: Nausea, vomiting, abdominal discomfort or pain. Central Nervous System: Headache, dizziness, sedation. Reference ID: 2859992 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dermatologic System: Allergic rash. Hematologic System: Rarely, decreased white blood cell count or bone marrow depression. OVERDOSAGE Acute Toxicity One case has been recorded in which a 6-year-old girl died after two doses of Metopirone, 2 g. Oral LD50 in animals (mg/kg): rats, 521; maximum tolerated intravenous dose in one dog, 300. Signs and Symptoms The clinical picture of poisoning with Metopirone is characterized by gastrointestinal symptoms and by signs of acute adrenocortical insufficiency. Cardiovascular System: Cardiac arrhythmias, hypotension, dehydration. Nervous System and Muscles: Anxiety, confusion, weakness, impairment of consciousness. Gastrointestinal System: Nausea, vomiting, epigastric pain, diarrhea. Laboratory Findings: Hyponatremia, hypochloremia, hyperkalemia. Combined Poisoning In patients under treatment with insulin or oral antidiabetics, the signs and symptoms of acute poisoning with Metopirone may be aggravated or modified. Treatment There is no specific antidote. Besides general measures to eliminate the drug and reduce its absorption, a large dose of hydrocortisone should be administered at once, together with saline and glucose infusions. Surveillance: For a few days blood pressure and fluid and electrolyte balance should be monitored. DOSAGE AND ADMINISTRATION Single-Dose Short Test This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate. Interpretation Normal values will depend on the method used to determine ACTH and 11-desoxycortisol levels. An intact ACTH reserve is generally indicated by an increase in plasma ACTH to at least 44 pmol/L (200 ng/L) or by an increase in 11-desoxycortisol to over 0.2 µmol/L (70 µg/L). Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure. Reference ID: 2859992 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Multiple-Dose Test Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS. Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed. Day 3-4: Rest period. Day 5: Administration of Metopirone: Recommended with milk or snack. Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg. Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended. Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect. Interpretation ACTH Test The normal 24-hour urinary excretion of 17-OHCS ranges from 3 to 12 mg. Following continuous intravenous infusion of 50 units ACTH over a period of 8 hours, 17-OHCS excretion increases to 15 to 45 mg per 24 hours. Metopirone Normal response: In patients with a normally functioning pituitary, administration of Metopirone is followed by a two- to four-fold increase of 17-OHCS excretion or doubling of 17-KGS excretion. Subnormal response: Subnormal response in patients without adrenal insufficiency is indicative of some degree of impairment of pituitary function, either panhypopituitarism or partial hypopituitarism (limited pituitary reserve). 1. Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids. 2. Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Reference ID: 2859992 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17 KGS). The response, however, to Metopirone is subnormal; that is, no significant increase in 17-OHCS or 17-KGS excretion occurs. This failure to respond to metyrapone may be interpreted as evidence of impaired pituitary-adrenal reserve. In view of the normal response to exogenous ACTH, the failure to respond to metyrapone is inferred to be related to a defect in the CNS-pituitary mechanisms which normally regulate ACTH secretions. Presumably the ACTH secreting mechanisms of these individuals are already working at their maximal rates to meet everyday conditions and possess limited “reserve” capacities to secrete additional ACTH either in response to stress or to decreased cortisol levels occurring as a result of metyrapone administration. Subnormal response in patients with Cushing’s syndrome is suggestive of either autonomous adrenal tumors that suppress the ACTH-releasing capacity of the pituitary or nonendocrine ACTH- secreting tumors. Excessive response: An excessive excretion of 17-OHCS or 17-KGS after administration of Metopirone is suggestive of Cushing’s syndrome associated with adrenal hyperplasia. These patients have an elevated excretion of urinary corticosteroids under basal conditions and will often, but not invariably, show a “supernormal” response to ACTH and also to Metopirone, excreting more than 35 mg per 24 hours of either 17-OHCS or 17-KGS. HOW SUPPLIED Capsules 250 mg -- soft gelatin, white to yellowish-white, oblong, opaque, imprinted CIBA on one side and LN on the other side in brown ink. Bottles of 18………………………………………………………………NDC 0078-0455-17 Do not store above 30ºC (86ºF). Protect from moisture and heat. Dispense in tight container (USP). T20 REV: Manufactured by: R.P. Scherer GmbH Eberbach/Baden, Germany Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis Reference ID: 2859992 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.881618	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012911s026lbl.pdf', 'application_number': 12911, 'submission_type': 'SUPPL ', 'submission_number': 26}
10,827	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metopirone® (Metyrapone Capsules) 250 mg Diagnostic Test of Pituitary Adrenocorticotropic Function Rx only Prescribing Information DESCRIPTION Metopirone (metyrapone Capsules) 250 mg is an inhibitor of endogenous adrenal corticosteroid synthesis, available as 250‑mg capsules for oral administration. Its chemical name is 2‑methyl‑1, 2‑di‑3‑pyridyl‑1‑propanone, and its structural formula is structural formula Metyrapone is a white to light amber, fine, crystalline powder, having a characteristic odor. It is sparingly soluble in water, and soluble in methanol and in chloroform. It forms water‑soluble salts with acids. Its molecular weight is 226.28. Inactive Ingredients. Polyethylene glycol, glycerin, gelatin, sodium ethyl hydroxybenzoate, sodium propyl hydroxybenzoate, ethyl vanillin, 4‑methoxyacetophenone, titanium dioxide, red ink. CLINICAL PHARMACOLOGY Pharmacodynamics The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-beta hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary. With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine. These metabolites are readily determined by measuring urinary 17 ‑hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Because of these actions, Metopirone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis. Pharmacokinetics The response to Metopirone does not occur immediately. Following oral administration, peak steroid excretion occurs during the subsequent 24-hour period. Absorption Metopirone is absorbed rapidly and well when administered orally as prescribed. Peak plasma concentrations are usually reached 1 hour after administration. After administration of 750 mg, mean peak plasma concentrations are 3.7 μg/mL, falling to 0.5 μg/mL 4 hours after administration. Following a single 2000-mg dose, mean peak plasma concentrations of metyrapone in plasma are 7.3 μg/mL. Metabolism Reference ID: 3368742 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The major biotransformation is reduction of the ketone to metyrapol, an active alcohol metabolite. Eight hours after a single oral dose, the ratio of metyrapone to metyrapol in the plasma is 1:1.5. Metyrapone and metyrapol are both conjugated with glucuronide. Excretion Metyrapone is rapidly eliminated from the plasma. The mean ± SD terminal elimination half‑life is 1.9 ± 0.7 hours. Metyrapol takes about twice as long as metyrapone to be eliminated from the plasma. After administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% as glucuronide) and 38.5% in the form of metyrapol (8.1% free and 91.9% as glucuronide) within 72 hours after the first dose was given. INDICATIONS AND USAGE Metopirone is a diagnostic drug for testing hypothalamic‑pituitary ACTH function. CONTRAINDICATIONS Metopirone is contraindicated in patients with adrenal cortical insufficiency, or hypersensitivity to Metopirone or to any of its excipients. WARNINGS Metopirone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity. PRECAUTIONS General Ability of adrenals to respond to exogenous ACTH should be demonstrated before Metopirone is employed as a test. In the presence of hypo‑ or hyperthyroidism, response to the Metopirone test may be subnormal. Since Metopirone may cause dizziness and sedation, patients should exercise caution when driving or operating machinery. Laboratory Tests See INTERPRETATION. Drug Interactions Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone. The metabolism of Metopirone is accelerated by phenytoin; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. A subnormal response may occur in patients on estrogen therapy. Metopirone inhibits the glucuronidation of acetaminophen and could possibly potentiate acetaminophen toxicity. Carcinogenesis, Mutagenesis, Impairment of Fertility Long‑term carcinogenicity and reproduction studies in animals have not been conducted. Metopirone was not mutagenic with or without metabolic activation in three strains of bacteria. Pregnancy Category C A subnormal response to Metopirone may occur in pregnant women. Animal reproduction studies have not been conducted with Metopirone. The Metopirone test was administered to 20 pregnant women in their second and third trimester of pregnancy and evidence was found that the fetal pituitary responded to the enzymatic block. It is not known if Metopirone can affect reproduction capacity. Metopirone should be given to a pregnant woman only if clearly needed. Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with Metopirone. Reference ID: 3368742 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 this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Metopirone is administered to a nursing woman. Pediatric Use See DOSAGE AND ADMINISTRATION. Geriatric Use Clinical studies of Metopirone did not include sufficient numbers of subjects aged 65 years 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Cardiovascular System: Hypotension. Gastrointestinal System: Nausea, vomiting, abdominal discomfort or pain. Central Nervous System: Headache, dizziness, sedation. Dermatologic System: Allergic rash. Hematologic System: Rarely, decreased white blood cell count or bone marrow depression. OVERDOSAGE Acute Toxicity One case has been recorded in which a 6‑year‑old girl died after two doses of Metopirone, 2 g. Oral LD50 in animals (mg/kg): rats, 521; maximum tolerated intravenous dose in one dog, 300. Signs and Symptoms The clinical picture of poisoning with Metopirone is characterized by gastrointestinal symptoms and by signs of acute adrenocortical insufficiency. Cardiovascular System: Cardiac arrhythmias, hypotension, dehydration. Nervous System and Muscles: Anxiety, confusion, weakness, impairment of consciousness. Gastrointestinal System: Nausea, vomiting, epigastric pain, diarrhea. Laboratory Findings: Hyponatremia, hypochloremia, hyperkalemia. Combined Poisoning In patients under treatment with insulin or oral antidiabetics, the signs and symptoms of acute poisoning with Metopirone may be aggravated or modified. Treatment There is no specific antidote. Besides general measures to eliminate the drug and reduce its absorption, a large dose of hydrocortisone should be administered at once, together with saline and glucose infusions. Surveillance: For a few days blood pressure and fluid and electrolyte balance should be monitored. DOSAGE AND ADMINISTRATION Single‑Dose Short Test This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate. Reference ID: 3368742 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Interpretation Normal values will depend on the method used to determine ACTH and 11‑desoxycortisol levels. An intact ACTH reserve is generally indicated by an increase in plasma ACTH to at least 44 pmol/L (200 ng/L) or by an increase in 11‑desoxycortisol to over 0.2 μ mol/L (70 μ g/L). Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure. Multiple-Dose Test Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS. Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed. Day 3-4: Rest period. Day 5: Administration of Metopirone: Recommended with milk or snack. Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg. Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended. Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect. Interpretation ACTH Test The normal 24-hour urinary excretion of 17-OHCS ranges from 3 to 12 mg. Following continuous intravenous infusion of 50 units ACTH over a period of 8 hours, 17-OHCS excretion increases to 15 to 45 mg per 24 hours. Metopirone Normal response: In patients with a normally functioning pituitary, administration of Metopirone is followed by a two‑ to four‑fold increase of 17-OHCS excretion or doubling of 17-KGS excretion. Subnormal response: Subnormal response in patients without adrenal insufficiency is indicative of some degree of impairment of pituitary function, either panhypopituitarism or partial hypopituitarism (limited pituitary reserve). 1. Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids. 2. Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17-KGS). The response, however, to Metopirone is subnormal; that is, no significant increase in 17‑OHCS or 17‑KGS excretion occurs. This failure to respond to metyrapone may be interpreted as evidence of impaired pituitary‑adrenal reserve. In view of the normal response to exogenous ACTH, the failure to respond to metyrapone is inferred to be related to a defect in the CNS‑ pituitary mechanisms which normally regulate ACTH secretions. Presumably the ACTH secreting mechanisms of these individuals are already working at their maximal rates to meet everyday conditions and possess limited “reserve” capacities to secrete additional ACTH either in response to stress or to decreased cortisol levels occurring as a result of metyrapone administration. Subnormal response in patients with Cushing’s syndrome is suggestive of either autonomous adrenal tumors that suppress the ACTH-releasing capacity of the pituitary or nonendocrine ACTH-secreting tumors. Excessive response: An excessive excretion of 17-OHCS or 17-KGS after administration of Metopirone is suggestive of Cushing’s syndrome associated with adrenal hyperplasia. These patients have an elevated excretion of urinary corticosteroids Reference ID: 3368742 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda under basal conditions and will often, but not invariably, show a “supernormal” response to ACTH and also to Metopirone, excreting more than 35 mg per 24 hours of either 17-OHCS or 17-KGS. HOW SUPPLIED Capsules 250 mg -- soft gelatin, white to yellowish‑white, oblong, opaque, imprinted HRA on one side in red ink. Bottles of 18...................................................................................................................NDC 76336-455-17 Do not store above 30 oC (86 oF). Protect from moisture and heat. Dispense in tight container (USP). 5003157 Address medical inquiries to: Direct Success Inc. 1710 Hwy 34 Farmingdale, NJ 07727 (855) 674-7663 (855) M-Pirone Fax: (855) 674-6767 company logo Manufactured by: R.P. Scherer Eberbach, Germany For: Laboratoire HRA Pharma Paris, France REV: AUGUST 2013 Reference ID: 3368742 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/ RAMESH RAGHAVACHARI 09/05/2013 Reference ID: 3368742 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:50.980867	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012911Orig1s033lbl.pdf', 'application_number': 12911, 'submission_type': 'SUPPL ', 'submission_number': 33}
10,828	NDA 12-945/S-037 & S-038 Page 3 DIAMOX® SEQUELS® (Acetazolamide Extended-Release Capsules) Rx only DESCRIPTION DIAMOX SEQUELS (Acetazolamide Extended-Release Capsules) are an inhibitor of the enzyme carbonic anhydrase. DIAMOX is a white to faintly yellowish white crystalline, odorless powder, weakly acidic, very slightly soluble in water and slightly soluble in alcohol. The chemical name for DIAMOX is N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide and has the following chemical structure: [structure] MW 222.24 C4H6N403S2 DIAMOX SEQUELS are extended-release capsules, for oral administration, each containing 500 mg of acetazolamide and the following inactive ingredients: Microcrystalline cellulose, sodium lauryl sulfate and talc. The ingredients in the capsule shell are D&C red no. 28, D&C yellow no. 10, FD&C red no. 40, gelatin and titanium dioxide. The ingredients in the imprinting ink are D&C yellow no. 10 aluminum lake, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, pharmaceutical glaze, propylene glycol and synthetic iron oxide. CLINICAL PHARMACOLOGY DIAMOX is a potent carbonic anhydrase inhibitor, effective in the control of fluid secretion (e.g., some types of glaucoma), in the treatment of certain convulsive disorders (e.g., epilepsy) and in the promotion of diuresis in instances of abnormal fluid retention (e.g., cardiac edema). DIAMOX is not a mercurial diuretic. Rather, it is a non-bacteriostatic sulfonamide possessing a chemical structure and pharmacological activity distinctly different from the bacteriostatic sulfonamides. DIAMOX is an enzyme inhibitor that acts specifically on carbonic anhydrase, the enzyme that catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In the eye, this inhibitory action of acetazolamide decreases the secretion of aqueous humor and results in a drop in intraocular pressure, a reaction considered desirable in cases of glaucoma and even in certain non-glaucomatous conditions. Evidence seems to indicate that DIAMOX has utility as an adjuvant in treatment of certain dysfunctions of the central nervous system (e.g., epilepsy). Inhibition of carbonic anhydrase in this area appears to retard abnormal, paroxysmal, excessive discharge from central nervous system neurons. The diuretic effect of DIAMOX is due to its action in the kidney on the reversible reaction involving hydration of carbon dioxide and dehydration of carbonic acid. The result is renal loss of HCO3 ion, which carries out sodium, water, and potassium. Alkalinization of the urine and promotion of diuresis are thus affected. Alteration in ammonia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-945/S-037 & S-038 Page 4 metabolism occurs due to increased reabsorption of ammonia by the renal tubules as a result of urinary alkalinization. DIAMOX SEQUELS provide prolonged action to inhibit aqueous humor secretion for 18 to 24 hours after each dose, whereas tablets act for only eight to 12 hours. The prolonged continuous effect of SEQUELS permits a reduction in dosage frequency. Plasma concentrations of acetazolamide peak from three to six hours after administration of DIAMOX SEQUELS, compared to one to four hours with tablets. Food does not affect bioavailability of DIAMOX SEQUELS. Placebo-controlled clinical trials have shown that prophylactic administration of DIAMOX at a dose of 250 mg every eight to 12 hours (or a 500 mg controlled-release capsule once daily) before and during rapid ascent to altitude results in fewer and/or less severe symptoms of acute mountain sickness (AMS) such as headache, nausea, shortness of breath, dizziness, drowsiness, and fatigue. Pulmonary function (e.g., minute ventilation, expired vital capacity, and peak flow) is greater in the DIAMOX treated group, both in subjects with AMS and asymptomatic subjects. The DIAMOX treated climbers also had less difficulty in sleeping. INDICATIONS AND USAGE For adjunctive treatment of: chronic simple (open-angle) glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure. DIAMOX is also indicated for the prevention or amelioration of symptoms associated with acute mountain sickness despite gradual ascent. CONTRAINDICATIONS Hypersensitivity to acetazolamide or any excipients in the formulation. Since acetazolamide is a sulfonamide derivative, cross sensitivity between acetazolamide, sulfonamides and other sulfonamide derivatives is possible. Acetazolamide therapy is contraindicated in situations in which sodium and/or potassium blood serum levels are depressed, in cases of marked kidney and liver disease or dysfunction, in suprarenal gland failure, and in hyperchloremic acidosis. It is contraindicated in patients with cirrhosis because of the risk of development of hepatic encephalopathy. Long-term administration of DIAMOX is contraindicated in patients with chronic non-congestive angle-closure glaucoma since it may permit organic closure of the angle to occur while the worsening glaucoma is masked by lowered intraocular pressure. WARNINGS Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens- Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitizations may recur when a sulfonamide is readministered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue use of this drug. Caution is advised for patients receiving concomitant high-dose aspirin and DIAMOX, as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-945/S-037 & S-038 Page 5 PRECAUTIONS General Increasing the dose does not increase the diuresis and may increase the incidence of drowsiness and/or paresthesia. Increasing the dose often results in a decrease in diuresis. Under certain circumstances, however, very large doses have been given in conjunction with other diuretics in order to secure diuresis in complete refractory failure. Information for Patients Adverse reactions common to all sulfonamide derivatives may occur: anaphylaxis, fever, rash (including erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis), crystalluria, renal calculus, bone marrow depression, thrombocytopenic purpura, hemolytic anemia, leukopenia, pancytopenia, and agranulocytosis. Caution is advised for early detection of such reactions and the drug should be discontinued and appropriate therapy instituted. In patients with pulmonary obstruction or emphysema where alveolar ventilation may be impaired, DIAMOX which may precipitate or aggravate acidosis should be used with caution. Gradual ascent is desirable to try to avoid acute mountain sickness. If rapid ascent is undertaken and DIAMOX is used, it should be noted that such use does not obviate the need for prompt descent if severe forms of high altitude sickness occur, i.e., high altitude pulmonary edema (HAPE) or high altitude cerebral edema. Caution is advised for patients receiving concomitant high-dose aspirin and DIAMOX, as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported (see WARNINGS). Both increases and decreases in blood glucose have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus. Acetazolamide treatment may cause electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis. Therefore, periodic monitoring of serum electrolytes is recommended. Particular caution is recommended in patients with conditions that are associated with, or predispose a patient to, electrolyte and acid/base imbalances, such as patients with impaired renal function (including elderly patients; see PRECAUTIONS, Geriatric Use), patients with diabetes mellitus, and patients with impaired alveolar ventilation. Some adverse reactions to acetazolamide, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery. Laboratory Tests To monitor for hematologic reactions common to all sulfonamides, it is recommended that a baseline CBC and platelet count be obtained on patients prior to initiating DIAMOX therapy and at regular intervals during therapy. If significant changes occur, early discontinuance and institution of appropriate therapy are important. Periodic monitoring of serum electrolytes is recommended. Drug Interactions Aspirin- See WARNINGS DIAMOX modifies phenytoin metabolism with increased serum levels of phenytoin. This may increase or enhance the occurrence of osteomalacia in some patients receiving chronic phenytoin therapy. Caution is advised in patients receiving chronic concomitant therapy. By decreasing the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-945/S-037 & S-038 Page 6 gastrointestinal absorption of primidone, DIAMOX may decrease serum concentrations of primidone and its metabolites, with a consequent possible decrease in anticonvulsant effect. Caution is advised when beginning, discontinuing, or changing the dose of DIAMOX in patients receiving primidone. Because of possible additive effects with other carbonic anhydrase inhibitors, concomitant use is not advisable. Acetazolamide may increase the effects of other folic acid antagonists. Acetazolamide decreases urinary excretion of amphetamine and may enhance the magnitude and duration of their effect. Acetazolamide reduces urinary excretion of quinidine and may enhance its effect. Acetazolamide may prevent the urinary antiseptic effect of methenamine. Acetazolamide increases lithium excretion and the lithium may be decreased. Acetazolamide and sodium bicarbonate used concurrently increases the risk of renal calculus formation. Acetazolamide may elevate cyclosporine levels. Drug/laboratory test interactions Sulfonamides may give false negative or decreased values for urinary phenolsulfonphthalein and phenol red elimination values for urinary protein, serum non-protein, and serum uric acid. Acetazolamide may produce an increased level of crystals in the urine. Acetazolamide interferes with the HPLC method of assay for theophylline. Interference with the theophylline assay by acetazolamide depends on the solvent used in the extraction; acetazolamide may not interfere with other assay methods for theophylline. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential of DIAMOX have not been conducted. In a bacterial mutagenicity assay, DIAMOX was not mutagenic when evaluated with and without metabolic activation. The drug had no effect on fertility when administered in the diet to male and female rats at a daily intake of up to 4 times the recommended human dose of 1000 mg in a 50 kg individual. Pregnancy: Teratogenic effects: Pregnancy Category C Acetazolamide, administered orally or parenterally, has been shown to be teratogenic (defects of the limbs) in mice, rats, hamsters, and rabbits. There are no adequate and well-controlled studies in pregnant women. Acetazolamide should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Because of the potential for serious adverse reactions in nursing infants from DIAMOX, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-945/S-037 & S-038 Page 7 importance of the drug to the mother. Acetazolamide should only be used by nursing women if the potential benefit justifies the potential risk to the child. Pediatric Use The safety and effectiveness of DIAMOX SEQUELS in pediatric patients below the age of 12 years have not been established. Growth retardation has been reported in children receiving long-term therapy, believed secondary to chronic acidosis. Geriatric Use Metabolic acidosis, which can be severe, may occur in the elderly with reduced renal function. 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 other drug therapy. ADVERSE REACTIONS Body as a whole: Headache, malaise, fatigue, fever, pain at injection site, flushing, growth retardation in children, flaccid paralysis, anaphylaxis. Digestive: Gastrointestinal disturbances such as nausea, vomiting, diarrhea. Hematological/Lymphatic: Blood dyscrasias such as aplastic anemia, agranulocytosis, leukopenia, thrombocytopenic purpura, melena. Hepato-biliary disorders: Abnormal liver function, cholestatic jaundice, hepatic insufficiency, fulminant hepatic necrosis Metabolic/Nutritional: Metabolic acidosis, electrolyte imbalance, including hypokalemia, hyponatremia, osteomalacia with long-term phenytoin therapy, loss of appetite, taste alteration, hyper/hypoglycemia Nervous: Drowsiness, paresthesia (including numbness and tingling of extremities and face), depression, excitement, ataxia, confusion, convulsions dizziness Skin: Allergic skin reactions including urticaria, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis Special senses: Hearing disturbances, tinnitus, transient myopia Urogenital: Crystalluria, increased risk of nephrolithiasis with long-term therapy, hematuria, glycosuria, renal failure polyuria OVERDOSAGE No specific antidote is known. Treatment should be symptomatic and supportive. Electrolyte imbalance, development of an acidotic state, and central nervous system effects might be expected to occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-945/S-037 & S-038 Page 8 Supportive measures are required to restore electrolyte and pH balance. The acidotic state can usually be corrected by the administration of bicarbonate. Despite its high intraerythrocytic distribution and plasma protein binding properties, DIAMOX may be dialyzable. This may be particularly important in the management of DIAMOX overdosage when complicated by the presence of renal failure. DOSAGE AND ADMINISTRATION Glaucoma: The recommended dosage is 1 capsule (500 mg) two times a day. Usually 1 capsule is administered in the morning and 1 capsule in the evening. It may be necessary to adjust the dose, but it has usually been found that dosage in excess of 2 capsules (1 g) does not produce an increased effect. The dosage should be adjusted with careful individual attention both to symptomatology and intraocular tension. In all cases, continuous supervision by a physician is advisable. In those unusual instances where adequate control is not obtained by the twice-a-day administration of DIAMOX SEQUELS, the desired control may be established by means of DIAMOX (tablets or parenteral). Use tablets or parenteral in accordance with the more frequent dosage schedules recommended for these dosage forms, such as 250 mg every four hours, or an initial dose of 500 mg followed by 250 mg or 125 mg every four hours, depending on the case in question. Acute Mountain Sickness: Dosage is 500 mg to 1000 mg daily, in divided doses using tablets or extended-release capsules as appropriate. In circumstances of rapid ascent, such as in rescue or military operations, the higher dose level of 1000 mg is recommended. It is preferable to initiate dosing 24 to 48 hours before ascent and to continue for 48 hours while at high altitude, or longer as necessary to control symptoms. HOW SUPPLIED DIAMOX® SEQUELS® (Acetazolamide Extended-Release Capsules) are available as 500 mg: Orange opaque cap and orange opaque body filled with white to off-white pellets. Imprinted in black ink, Barr 699. Available in bottles of: 100 NDC 51285-754-02 Store at controlled room temperature 20° to 25°C (68° to 77°F). DURAMED PHARMACEUTICALS, INC. Subsidiary of BarrPharmaceuticals, Inc. Pomona, New York 10970 Revised NOVEMBER 2004 BR-754 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-945/S-037 & S-038 Page 9 Container Label This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:51.058056	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/12945s037,038lbl.pdf', 'application_number': 12945, 'submission_type': 'SUPPL ', 'submission_number': 37}
10,830	Norflex (orphenadrine citrate) Injection [Graceway Pharmaceuticals, LLC] Effective Date: 10/01/2007 DESCRIPTION: Orphenadrine citrate is the citrate salt of orphenadrine (2-dimethylaminoethyl 2- methylbenzhydryl ether citrate). It occurs as a white, crystalline powder having a bitter taste. It is practically odorless; sparingly soluble in water, slightly soluble in alcohol. Norflex Injection contains 60 mg of orphenadrine citrate in aqueous solution in each ampul. Norflex Injection also contains: sodium bisulfite NF, 2.0 mg; sodium chloride USP, 5.8 mg; sodium hydroxide, to adjust pH; and water for injection USP, q.s. to 2 mL. CLINICAL PHARMACOLOGY: the mode of therapeutic action has not been clearly identified, but may be related to its analgesic properties. Orphenadrine citrate does not directly relax tense muscles in man. Orphenadrine citrate also possesses anti-cholinergic actions. INDICATIONS AND USAGE: Orphenadrine citrate is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculo skeletal conditions. CONTRAINDICATIONS: Contraindicated in patients with glaucoma, pyloric or duodenal obstruction, stenosing peptic ulcers, prostatic hypertrophy or obstruction of the bladder neck, cardio-spasm (megaesophagus) and myasthenia gravis. Contraindicated in patients who have demonstrated a previous hypersensitivity to the drug. WARNINGS: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Some patients may experience transient episodes of light-headedness, dizziness or syncope. Norflex may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; ambulatory patients should therefore be cautioned accordingly. Norflex Injection contains sodium bisulfite, 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 nonasthmatic people. PRECAUTIONS: Confusion, anxiety and tremors have been reported in few patients receiving propoxyphene and orphenadrine concomitantly. As these symptoms may be simply due to an additive effect, reduction of dosage and/or discontinuation of one or both agents is recommended in such cases. Orphenadrine citrate should be used with caution in patients with tachycardia, cardiac decompensation, coronary insufficiency, cardiac arrhythmias. Safety of continuous long-term therapy with orphenadrine has not been established. Therefore, if orphenadrine is prescribed for prolonged use, periodic monitoring of blood, urine and liver function values is recommended. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted with Norflex. It is also not know whether Norflex can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Norflex should be given to a pregnant woman only if clearly needed. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse reactions of orphenadrine are mainly due to the mild anti-cholinergic action of orphenadrine, and are usually associated with higher dosage. Dryness of the mouth is usually the first adverse effect to appear. When the daily dose is increased, possible adverse effects include: tachycardia, palpitation, urinary hesitancy or retention, blurred vision, dilatation of pupils, increased ocular tension, weakness, nausea, vomiting, headache, dizziness, constipation, drowsiness, hypersensitivity reactions, pruritus, hallucinations, agitation, tremor, gastric irritation, and rarely urticaria and other dermatoses. Infrequently, an elderly patient may experience some degree of mental confusion. These adverse reactions can usually be eliminated by reduction in dosage. Very rare cases of aplastic anemia associated with the use of orphenadrine tablets have been reported. No causal relationship has been established. Rare instances of anaphylactic reaction have been reported associated with the intramuscular injection of Norflex Injection. DRUG ABUSE AND DEPENDENCE: Orphenadrine has been chronically abused for its euphoric effects. The mood elevating effects may occur at therapeutic doses of orphenadrine. OVERDOSAGE: Orphenadrine is toxic when overdosed and typically induces anticholinergic effects. In a review of orphenadrine toxicity, the minimum lethal dose was found to be 2-3 grams for adults; however, the range of toxicity is variable and unpredictable. Treatment for orphenadrine overdose is evacuation of stomach contents (when necessary), charcoal at repeated doses, intensive monitoring, and appropriate supportive treatment of any emergent anticholinergic effects. DOSAGE AND ADMINISTRATION: INJECTION: Adults - One 2 mL ampul (60 mg) intravenously or intramuscularly; may be repeated every 12 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED: INJECTION: Boxes of 6 (NDC 0089-0540-06 ) 2 mL ampuls, each ampul containing 60 mg of orphenadrine citrate in aqueous solution. Store at controlled room temperature 15°-30°C (59°-86°F). Rx only September 2007 Manufactured for Graceway Pharmaceuticals, LLC Bristol, TN 37620 By Hospira, Inc. Lake Forest, IL 60045 Effective Date: 10/01/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:51.095565	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf', 'application_number': 13055, 'submission_type': 'SUPPL ', 'submission_number': 21}
10,829	Trecator (ethionamide tablets, USP) Tablets only DESCRIPTION Trecator (ethionamide tablets, USP) is used in the treatment of tuberculosis. The chemical name for ethionamide is 2-ethylthioisonicotinamide with the following structural formula: C8H10N2S M.W. 166.24 Ethionamide is a yellow crystalline, nonhygroscopic compound with a faint to moderate sulfide odor and a melting point of 162°C. It is practically insoluble in water and ether, but soluble in methanol and ethanol. It has a partition coefficient (octanol/water) Log P value of 0.3699. Trecator tablets contain 250 mg of ethionamide. The inactive ingredients present are croscarmellose sodium, FD&C Yellow #6, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, silicon dioxide, talc, and titanium dioxide. CLINICAL PHARMACOLOGY Absorption Ethionamide is essentially completely absorbed following oral administration and is not subjected to any appreciable first pass metabolism. Ethionamide tablets may be administered without regard to the timing of meals. The pharmacokinetic parameters of ethionamide following single oral-dose administration of 250 mg of Trecator film-coated tablets under fasted conditions to 40 healthy adult volunteers are provided in Table 1. Table 1: Mean (SD) Pharmacokinetic Parameters for Ethionamide Following Single-dose Administration of 250 mg Trecator Film-Coated Tablets to Healthy Adult Volunteers Cmax (µg/mL) Tmax (hrs) AUC (µg h/mL Film-Coated Tablet 2.16 (0.61) 1.02 (0.55) 7.67 (1.69) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. The Cmax for the film-coated tablets (2.16 µg/mL) was significantly higher than that of sugar-coated tablets (1.48 µg/mL) (see DOSAGE AND ADMINISTRATION). Distribution Ethionamide is rapidly and widely distributed into body tissues and fluids following administration of a sugar-coated tablet, with concentrations in plasma and various organs being approximately equal. Significant concentrations are also present in cerebrospinal fluid following administration of a sugar- coated tablet. Distribution of ethionamide into the same body tissues and fluids, including cerebrospinal fluid following administration of the film-coated tablet, has not been studied, but is not expected to differ significantly from that of the sugar-coated tablet. The drug is approximately 30% bound to proteins. The mean (SD) apparent oral volume of distribution observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 93.5 (19.2) L. Metabolism Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl- dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso- nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis. Elimination The mean (SD) half-life observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 1.92 (0.27) hours. Less than 1% of the oral dose is excreted as ethionamide in urine. Mechanism of Action Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The exact mechanism of action of ethionamide has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms. Microbiology In Vitro Activity Ethionamide exhibits bacteriostatic activity against extracellular and intracellular Mycobacterium tuberculosis organisms. The development of ethionamide resistant M. tuberculosis isolates can be obtained by repeated subculturing in liquid or on solid media containing increasing concentrations of ethionamide. Multi-drug resistant strains of M. tuberculosis may have acquired resistance to both isoniazid and ethionamide. However, the majority of M. tuberculosis isolates that are resistant to one are usually susceptible to the other. There is no evidence of cross-resistance between ethionamide and para-aminosalicylic acid (PAS), streptomycin, or cycloserine. However, limited data suggest that cross-resistance may exist between ethionamide and thiosemicarbazones (i.e., thiacetazone) as well as isoniazid. In Vivo Activity Ethionamide administered orally initially decreased the number of culturable Mycobacterium tuberculosis organisms from the lungs of H37Rv infected mice. Drug resistance developed with continued ethionamide monotherapy, but did not occur when mice received ethionamide in combination with streptomycin or isoniazid. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SUSCEPTIBILITY TESTING Ethionamide susceptibility testing should only be performed by qualified or reference laboratories. Two standardized in vitro susceptibility methods are available for testing ethionamide against M. tuberculosis organisms. The modified proportion method (CDC or NCCLS M24-P) utilizes Middlebrook and Cohn 7H10 agar medium impregnated with ethionamide at a final concentration of 5.0 µg/mL. After 2 to 3 weeks of incubation, MIC99 values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug, of at least 1% of the growth in the control culture, indicates resistance. The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 5.0 µg/mL of ethionamide. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay. Susceptibility test results obtained by these two different methods cannot be compared unless equivalent drug concentrations are evaluated. The clinical relevance of in vitro susceptibility test results for mycobacterial species other than M. tuberculosis using either the radiometric or the proportion method has not been determined. INDICATIONS AND USAGE Trecator is primarily indicated for the treatment of active tuberculosis in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance on the part of the patient to other drugs. Its use alone in the treatment of tuberculosis results in the rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility tests. If the susceptibility tests indicate that the patient's organism is resistant to one of the first-line antituberculosis drugs (i.e., isoniazid or rifampin) yet susceptible to ethionamide, ethionamide should be accompanied by at least one drug to which the M. tuberculosis isolate is known to be susceptible.3 If the tuberculosis is resistant to both isoniazid and rifampin, yet susceptible to ethionamide, ethionamide should be accompanied by at least two other drugs to which the M. tuberculosis isolate is known to be susceptible.3 Patient nonadherence to prescribed treatment can result in treatment failure and in the development of drug-resistant tuberculosis, which can be life-threatening and lead to other serious health risks. It is, therefore, essential that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended for all patients receiving treatment for tuberculosis. Patients in whom drug-resistant M. tuberculosis organisms are isolated should be managed in consultation with an expert in the treatment of drug-resistant tuberculosis. CONTRAINDICATIONS Ethionamide is contraindicated in patients with severe hepatic impairment and in patients who are hypersensitive to the drug. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS The use of Trecator alone in the treatment of tuberculosis results in rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility testing. However, therapy may be initiated prior to receiving the results of susceptibility tests as deemed appropriate by the physician. Ethionamide should be administered with at least one, sometimes two, other drugs to which the organism is known to be susceptible (see INDICATIONS AND USAGE). Drugs which have been used as companion agents are rifampin, ethambutol, pyrazinamide, cycloserine, kanamycin, streptomycin, and isoniazid. The usual warnings, precautions, and dosage regimens for these companion drugs should be observed. Patient compliance is essential to the success of the antituberculosis therapy and to prevent the emergence of drug-resistant organisms. Therefore, patients should adhere to the drug regimen for the full duration of treatment. It is recommended that directly observed therapy be practiced when patients are receiving antituberculous medication. Additional consultation from experts in the treatment of drug-resistant tuberculosis is recommended when patients develop drug-resistant organisms. PRECAUTIONS General Ethionamide may potentiate the adverse effects of the other antituberculous drugs administered concomitantly (see Drug Interactions). Ophthalmologic examinations (including ophthalmoscopy) should be performed before and periodically during therapy with Trecator. Information For Patients Patients should be advised to consult their physician should blurred vision or any loss of vision, with or without eye pain, occur during treatment. Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported. Laboratory Tests Determination of serum transaminases (SGOT, SGPT) should be made prior to initiation of therapy and should be monitored monthly. If serum transaminases become elevated during therapy, ethionamide and the companion antituberculosis drug or drugs may be discontinued temporarily until the laboratory abnormalities have resolved. Ethionamide and the companion antituberculosis medication(s) then should be reintroduced sequentially to determine which drug (or drugs) is (are) responsible for the hepatotoxicity. Blood glucose determinations should be made prior to and periodically throughout therapy with Trecator. Diabetic patients should be particularly alert for episodes of hypoglycemia. Periodic monitoring of thyroid function tests is recommended as hypothyroidism, with or without goiter, has been reported with ethionamide therapy. Drug Interactions Trecator has been found to temporarily raise serum concentrations of isoniazid. Trecator may potentiate the adverse effects of other antituberculous drugs administered concomitantly. In particular, convulsions have been reported when ethionamide is administered with cycloserine and special care should be taken when the treatment regimen includes both of these drugs. Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported. 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 Teratogenic Effects: Pregnancy Category C Animal studies conducted with Trecator indicate that the drug has teratogenic potential in rabbits and rats. The doses used in these studies on a mg/kg basis were considerably in excess of those recommended in humans. There are no adequate and well-controlled studies in pregnant women. Because of these animal studies, however, it must be recommended that Trecator be withheld from women who are pregnant, or who are likely to become pregnant while under therapy, unless the prescribing physician considers it to be an essential part of the treatment. Labor and Delivery The effect of Trecator on labor and delivery in pregnant women is unknown. Nursing Mothers Because no information is available on the excretion of ethionamide in human milk, Trecator should be administered to nursing mothers only if the benefits outweigh the risks. Newborns who are breast-fed by mothers who are taking Trecator should be monitored for adverse effects. Pediatric Use Due to the fact that pulmonary tuberculosis resistant to primary therapy is rarely found in neonates, infants, and children, investigations have been limited in these age groups. At present, the drug should not be used in pediatric patients under 12 years of age except when the organisms are definitely resistant to primary therapy and systemic dissemination of the disease, or other life-threatening complications of tuberculosis, is judged to be imminent. ADVERSE REACTIONS Gastrointestinal: The most common side effects of ethionamide are gastrointestinal disturbances including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia and weight loss. Adverse gastrointestinal effects appear to be dose related, with approximately 50% of patients unable to tolerate 1 gm as a single dose. Gastrointestinal effects may be minimized by decreasing dosage, by changing the time of drug administration, or by the concurrent administration of an antiemetic agent. Nervous System: Psychotic disturbances (including mental depression), drowsiness, dizziness, restlessness, headache, and postural hypotension have been reported with ethionamide. Rare reports of peripheral neuritis, optic neuritis, diplopia, blurred vision, and a pellagra-like syndrome also have been reported. Concurrent administration of pyridoxine has been recommended to prevent or relieve neurotoxic effects. Hepatic: Transient increases in serum bilirubin, SGOT, SGPT; Hepatitis (with or without jaundice). Other: Hypersensitivity reactions including rash, photosensitivity, thrombocytopenia and purpura have been reported rarely. Hypoglycemia, gynecomastia, impotence, and acne also have occurred. The management of patients with diabetes mellitus may become more difficult in those receiving ethionamide. OVERDOSAGE No specific information is available on the treatment of overdosage with Trecator. If it should occur, standard procedures to evacuate gastric contents and to support vital functions should be employed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION In the treatment of tuberculosis, a major cause of the emergence of drug-resistant organisms, and thus treatment failure, is patient nonadherence to prescribed treatment. Treatment failure and drug-resistant organisms can be life-threatening and may result in other serious health risks. It is, therefore, important that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended when patients are receiving treatment for tuberculosis. Consultation with an expert in the treatment of drug-resistant tuberculosis is advised for patients in whom drug-resistant tuberculosis is suspected or likely. Ethionamide should be administered with at least one, sometimes two, other drugs to which the organism is known to be susceptible (see INDICATIONS AND USAGE). Trecator is administered orally. The usual adult dose is 15 to 20 mg/kg/day, administered once daily or, if patient exhibits poor gastrointestinal tolerance, in divided doses, with a maximum daily dosage of 1 gram. Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. Patients should be monitored and have their dosage retitrated when switching from the sugar-coated tablet to the film-coated tablet (see CLINICAL PHARMACOLOGY). Therapy should be initiated at a dose of 250 mg daily, with gradual titration to optimal doses as tolerated by the patient. A regimen of 250 mg daily for 1 or 2 days, followed by 250 mg twice daily for 1 or 2 days with a subsequent increase to 1 gm in 3 or 4 divided doses has been reported.4,5 Thus far, there is insufficient evidence to indicate the lowest effective dosage levels. Therefore, in order to minimize the risk of resistance developing to the drug or to the companion drug, the principle of giving the highest tolerated dose (based on gastrointestinal intolerance) has been followed. In the adult this would seem to be between 0.5 and 1.0 gm daily, with an average of 0.75 gm daily. The optimum dosage for pediatric patients has not been established. However, pediatric dosages of 10 to 20mg/kg p.o. daily in 2 or 3 divided doses given after meals or 15mg/kg/24 hrs as a single daily dose have been recommended.1,2 As with adults, ethionamide may be administered to pediatric patients once daily. It should be noted that in patients with concomitant tuberculosis and HIV infection, malabsorption syndrome may be present. Drug malabsorption should be suspected in patients who adhere to therapy, but who fail to respond appropriately. In such cases, consideration should be given to therapeutic drug monitoring (see CLINICAL PHARMACOLOGY). The best times of administration are those which the individual patient finds most suitable in order to avoid or minimize gastrointestinal intolerance, which is usually at mealtimes. Every effort should be made to encourage patients to persevere with treatment when gastrointestinal side effects appear, since they may diminish in severity as treatment proceeds. Concomitant administration of pyridoxine is recommended. Duration of treatment should be based on individual clinical response. In general, continue therapy until bacteriological conversion has become permanent and maximal clinical improvement has occurred. HOW SUPPLIED Trecator (ethionamide tablets, USP) are supplied in bottles of 100 tablets as follows: 250 mg, orange film-coated tablet marked “W” on one side and “4117” on reverse side, NDC 0008- 4117-01. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Store at controlled room temperature 20° to 25°C (68° to 77°F). Dispense in a tight container. REFERENCES 1) Feign, R.D., and Cherry, J.D.: Textbook of Pediatric Infectious Diseases, 2nd Edition. Philadelphia, W.B. Saunders Co., 1987, pp. 1371-1372. 2) Nelson, W.E., Behrman, R.E., Vaughan, V.C. (eds.): Nelson Textbook of Pediatrics, 13th edition. Philadelphia, W.B. Saunders Co., 1987, p.636. 3) Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children, Am. J Respiratory and Critical Care Medicine, 149: 1359, 1994. 4) Peloquin, CA: Pharmacology of the Antimycobacterial Drugs, Med Clin North Am 77(6): 1230- 1262, 1993. 5) American Thoracic Society. Am J Respir Crit Care Med 1997;156:S1-S25. Manufactured for Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 By OSG Norwich Pharmaceuticals Inc. Norwich, New York 13815 Revised October 12, 2004 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:51.152818	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/13026s022,023lbl.pdf', 'application_number': 13026, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,832	Company Logo VALIUM® brand of diazepam TABLETS Rx Only DESCRIPTION Valium (diazepam) is a benzodiazepine derivative. The chemical name of diazepam is 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin 2-one. It is a colorless to light yellow crystalline compound, insoluble in water. The empirical formula is C16H13ClN2O and the molecular weight is 284.75. The structural formula is as follows: Chemical Structure Valium is available for oral administration as tablets containing 2 mg, 5 mg or 10 mg diazepam. In addition to the active ingredient diazepam, each tablet contains the following inactive ingredients: anhydrous lactose, corn starch, pregelatinized starch and calcium stearate with the following dyes: 5-mg tablets contain FD&C Yellow No. 6 and D&C Yellow No. 10; 10-mg tablets contain FD&C Blue No. 1. Valium 2-mg tablets contain no dye. CLINICAL PHARMACOLOGY Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle- relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system. Pharmacokinetics Absorption After oral administration >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25 to 2.5 hours. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food mean lag times are approximately This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 45 minutes as compared with 15 minutes when fasting. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. This results in an average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food. Distribution Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%). Diazepam and its metabolites cross the blood-brain and placental barriers and are also found in breast milk in concentrations approximately one tenth of those in maternal plasma (days 3 to 9 post-partum). In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg. The decline in the plasma concentration-time profile after oral administration is biphasic. The initial distribution phase has a half-life of approximately 1 hour, although it may range up to >3 hours. Metabolism Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are largely eliminated by glucuronidation. Elimination The initial distribution phase is followed by a prolonged terminal elimination phase (half-life up to 48 hours). The terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/min in young adults. Diazepam accumulates upon multiple dosing and there is some evidence that the terminal elimination half-life is slightly prolonged. Pharmacokinetics in Special Populations Children In children 3 - 8 years old the mean half-life of diazepam has been reported to be 18 hours. Newborns In full term infants, elimination half-lives around 30 hours have been reported, with a longer average half-life of 54 hours reported in premature infants of 28 - 34 weeks gestational age and 8 - 81 days post-partum. In both premature and full term infants the active metabolite desmethyldiazepam shows evidence of continued accumulation compared to children. Longer half-lives in infants may be due to incomplete maturation of metabolic pathways. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Elimination half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age. This appears to be due to an increase in volume of distribution with age and a decrease in clearance. Consequently, the elderly may have lower peak concentrations, and on multiple dosing higher trough concentrations. It will also take longer to reach steady-state. Conflicting information has been published on changes of plasma protein binding in the elderly. Reported changes in free drug may be due to significant decreases in plasma proteins due to causes other than simply aging. Hepatic Insufficiency In mild and moderate cirrhosis, average half-life is increased. The average increase has been variously reported from 2-fold to 5-fold, with individual half-lives over 500 hours reported. There is also an increase in volume of distribution, and average clearance decreases by almost half. Mean half-life is also prolonged with hepatic fibrosis to 90 hours (range 66 - 104 hours), with chronic active hepatitis to 60 hours (range 26 - 76 hours), and with acute viral hepatitis to 74 hours (range 49 - 129). In chronic active hepatitis, clearance is decreased by almost half. INDICATIONS Valium is indicated for the management of anxiety disorders or for the short- term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. In acute alcohol withdrawal, Valium may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. Valium is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, and stiff-man syndrome. Oral Valium may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy. The effectiveness of Valium in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient. CONTRAINDICATIONS Valium is contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. Valium is also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda insufficiency, and sleep apnea syndrome. It may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow-angle glaucoma. WARNINGS Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since Valium has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS- depressant drugs during Valium therapy. As with other agents that have anticonvulsant activity, when Valium is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication. Abrupt withdrawal of Valium in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures. Pregnancy An increased risk of congenital malformations and other developmental abnormalities associated with the use of benzodiazepine drugs during pregnancy has been suggested. There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines on a regular basis late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period. Diazepam has been shown to be teratogenic in mice and hamsters when given orally at daily doses of 100 mg/kg or greater (approximately eight times the maximum recommended human dose [MRHD=1 mg/kg/day] or greater on a mg/m2 basis). Cleft palate and encephalopathy are the most common and consistently reported malformations produced in these species by administration of high, maternally toxic doses of diazepam during organogenesis. Rodent studies have indicated that prenatal exposure to diazepam doses similar to those used clinically can produce long-term changes in cellular immune responses, brain neurochemistry, and behavior. In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. 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 hazard to the fetus. Patients should also be advised that if they 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug. Labor and Delivery Special care must be taken when Valium is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants). Nursing Mothers Diazepam passes into breast milk. Breastfeeding is therefore not recommended in patients receiving Valium. PRECAUTIONS General If Valium is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed - particularly with known compounds that may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants (see Drug Interactions). The usual precautions are indicated for severely depressed patients or those in whom there is any evidence of latent depression or anxiety associated with depression, particularly the recognition that suicidal tendencies may be present and protective measures may be necessary. Psychiatric and paradoxical reactions are known to occur when using benzodiazepines (see ADVERSE REACTIONS). Should this occur, use of the drug should be discontinued. These reactions are more likely to occur in children and the elderly. A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression. Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (see DRUG ABUSE AND DEPENDENCE). In debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially, to be increased gradually as needed and tolerated). 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Some loss of response to the effects of benzodiazepines may develop after repeated use of Valium for a prolonged time. Information for Patients To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug. The risk of dependence increases with duration of treatment; it is also greater in patients with a history of alcohol or drug abuse. Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during Valium therapy. As is true of most CNS- acting drugs, patients receiving Valium should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle. Drug Interactions Centrally Acting Agents If Valium is to be combined with other centrally acting agents, careful consideration should be given to the pharmacology of the agents employed particularly with compounds that may potentiate or be potentiated by the action of Valium, such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants. Alcohol Concomitant use with alcohol is not recommended due to enhancement of the sedative effect. Antacids Diazepam peak concentrations are 30% lower when antacids are administered concurrently. However, there is no effect on the extent of absorption. The lower peak concentrations appear due to a slower rate of absorption, with the time required to achieve peak concentrations on average 20 - 25 minutes greater in the presence of antacids. However, this difference was not statistically significant. Compounds Which Inhibit Certain Hepatic Enzymes There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation. At present, this 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole. Phenytoin There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam. Carcinogenesis, Mutagenesis, Impairment of Fertility In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximately 6 and 12 times, respectively, the maximum recommended human dose [MRHD=1 mg/kg/day] on a mg/m2 basis) for 80 and 104 weeks, respectively, an increased incidence of liver tumors was observed in males of both species. The data currently available are inadequate to determine the mutagenic potential of diazepam. Reproduction studies in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of an oral dose of 100 mg/kg/day (approximately 16 times the MRHD on a mg/m2 basis) prior to and during mating and throughout gestation and lactation. No adverse effects on fertility or offspring viability were noted at a dose of 80 mg/kg/day (approximately 13 times the MRHD on a mg/m2 basis). Pregnancy Category D (see WARNINGS: Pregnancy). Pediatric Use Safety and effectiveness in pediatric patients below the age of 6 months have not been established. Geriatric Use In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated). Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions 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. Hepatic Insufficiency Decreases in clearance and protein binding, and increases in volume of distribution and half-life has been reported in patients with cirrhosis. In such 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients, a 2- to 5- fold increase in mean half-life has been reported. Delayed elimination has also been reported for the active metabolite desmethyldiazepam. Benzodiazepines are commonly implicated in hepatic encephalopathy. Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations: Hepatic Insufficiency). ADVERSE REACTIONS Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported: Central Nervous System: confusion, depression, dysarthria, headache, slurred speech, tremor, vertigo Gastrointestinal System: constipation, nausea, gastrointestinal disturbances Special Senses: blurred vision, diplopia, dizziness Cardiovascular System: hypotension Psychiatric and Paradoxical Reactions: stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, delusions, increased muscle spasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly. Urogenital System: incontinence, changes in libido, urinary retention Skin and Appendages: skin reactions Laboratories: elevated transaminases and alkaline phosphatase Other: changes in salivation, including dry mouth, hypersalivation Antegrade amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior. Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after Valium therapy and are of no known significance. Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DRUG ABUSE AND DEPENDENCE Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970. Abuse and dependence of benzodiazepines have been reported. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving diazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence. Once physical dependence to benzodiazepines has developed, termination of treatment will be accompanied by withdrawal symptoms. The risk is more pronounced in patients on long-term therapy. Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuance of diazepam. These withdrawal symptoms may consist of tremor, abdominal and muscle cramps, vomiting, sweating, headache, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Chronic use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena. Rebound Anxiety: A transient syndrome whereby the symptoms that led to treatment with Valium recur in an enhanced form. This may occur upon discontinuation of treatment. It may be accompanied by other reactions including mood changes, anxiety, and restlessness. Since the risk of withdrawal phenomena and rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually. OVERDOSAGE Overdose of benzodiazepines is usually manifested by central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, confusion, and lethargy. In more serious cases, symptoms may include ataxia, diminished reflexes, hypotonia, hypotension, respiratory depression, coma (rarely), and death (very rarely). Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Management of Overdosage Following overdose with oral benzodiazepines, general supportive measures should be employed including the monitoring of respiration, pulse, and blood pressure. Vomiting should be induced (within 1 hour) if the patient is conscious. Gastric lavage should be undertaken with the airway protected if the patient is unconscious. Intravenous fluids should be administered. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiac function in intensive care. General supportive measures should be employed, along with intravenous fluids, and an adequate airway maintained. Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, if indicated, and other appropriate countermeasures. Dialysis is of limited value. As with the management of intentional overdosage with any drug, it should be considered that multiple agents may have been ingested. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. Caution should be observed in the use of flumazenil in epileptic patients treated with benzodiazepines. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, should be consulted prior to use. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE). DOSAGE AND ADMINISTRATION Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses. In such cases dosage should be increased cautiously to avoid adverse effects. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADULTS: USUAL DAILY DOSE: Management of Anxiety Disorders and Relief Depending upon severity of symptoms—2 mg of Symptoms of Anxiety. to 10 mg, 2 to 4 times daily Symptomatic Relief in Acute Alcohol 10 mg, 3 or 4 times during the first 24 hours, Withdrawal. reducing to 5 mg, 3 or 4 times daily as needed Adjunctively for Relief of Skeletal Muscle 2 mg to 10 mg, 3 or 4 times daily Spasm. Adjunctively in Convulsive Disorders. 2 mg to 10 mg, 2 to 4 times daily Geriatric Patients, or in the presence of 2 mg to 2.5 mg, 1 or 2 times daily initially; debilitating disease. increase gradually as needed and tolerated PEDIATRIC PATIENTS: Because of varied responses to CNS-acting 1 mg to 2.5 mg, 3 or 4 times daily initially; drugs, initiate therapy with lowest dose and increase gradually as needed and tolerated increase as required. Not for use in pediatric patients under 6 months. HOW SUPPLIED For oral administration, Valium is supplied as round, flat-faced scored tablets with V-shaped perforation and beveled edges. Valium is available as follows: 2 mg, white - bottles of 100 (NDC 0140-0004-01); 5 mg, yellow - bottles of 100 (NDC 0140-0005-01) and 500 (NDC 0140-0005-14); 10 mg, blue - bottles of 100 (NDC 0140-0006-01) and 500 (NDC 0140-0006-14). Engraved on tablets: 2 mg—2 VALIUM® (front) ROCHE (twice on scored side) 5 mg—5 VALIUM® (front) ROCHE (twice on scored side) 10 mg—10 VALIUM® (front) ROCHE (twice on scored side) STORAGE Store at room temperature 59º to 86ºF (15º to 30ºC). Dispense in tight, light- resistant containers as defined in USP/NF. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distributed by: Company logo and Address for Roche Products Inc. 27899464 Revised: January 2008 Printed in USA Copyright © 1987-2008 by Roche Products Inc. All rights reserved. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:51.303253	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013263s083lbl.pdf', 'application_number': 13263, 'submission_type': 'SUPPL ', 'submission_number': 83}
10,836	NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 PROTOPAM Chloride (pralidoxime chloride) for Injection Rx only DESCRIPTION Chemical name: 2-formyl-1-methylpyridinium chloride oxime. Available in the United States as PROTOPAM Chloride for Injection (PROTOPAM), pralidoxime chloride is frequently referred to as 2-PAM Chloride. Structural formula: structural formula C7H9CIN2O M.W. 172.61 Pralidoxime chloride occurs as an odorless, white, nonhygroscopic, crystalline powder which is soluble in water. Stable in air, it melts between 215º and 225º C, with decomposition. The specific activity of the drug resides in the 2-formyl-1-methylpyridinium ion and is independent of the particular salt employed. The chloride is preferred because of physiologic compatibility, excellent water solubility at all temperatures, and high potency per gram, due to its low molecular weight. Pralidoxime chloride is a cholinesterase reactivator. PROTOPAM for intravenous injection or infusion is prepared by cryo-desiccation. Each vial contains 1000 mg of sterile pralidoxime chloride, and sodium hydroxide to adjust pH, to be reconstituted with 20 mL of Sterile Water for Injection, USP. The pH of the 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 reconstituted solution is 3.5 to 4.5. Intramuscular or subcutaneous injection may be used when intravenous injection is not feasible. CLINICAL PHARMACOLOGY The principal action of pralidoxime chloride is to reactivate cholinesterase (mainly outside of the central nervous system) which has been inactivated by phosphorylation due to an organophosphate pesticide or related compound. The destruction of accumulated acetylcholine can then proceed, and neuromuscular junctions will again function normally. Pralidoxime chloride also slows the process of “aging” of phosphorylated cholinesterase to a nonreactivatable form, and detoxifies certain organophosphates by direct chemical reaction. The drug has its most critical effect in relieving paralysis of the muscles of respiration. Because pralidoxime chloride is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Pralidoxime chloride relieves muscarinic signs and symptoms, salivation, bronchospasm, etc., but this action is relatively unimportant since atropine is adequate for this purpose. Pralidoxime chloride has been studied in animals as an antidote against numerous organophosphate pesticides, chemicals, and drugs (see Animal Pharmacology and Toxicology). Regardless of whether or not animal studies suggest that the organophosphate poison to which a particular patient has been exposed is amenable to treatment with pralidoxime chloride, the use of pralidoxime chloride should, nevertheless, be considered in any life-threatening situation resulting from poisoning by these compounds, since the limited and arbitrary conditions of pharmacologic screening do not always accurately reflect the usefulness of pralidoxime chloride in the clinical situation. CLINICAL STUDIES There are no adequate and well controlled clinical studies that establish the effectiveness of pralidoxime chloride as a treatment for poisoning with organophosphates having anticholinesterase activity. However, its use has been considered to be successful against poisoning with numerous pesticides, chemicals, and drugs. Pharmacokinetics Animal studies suggest that the minimum therapeutic concentration of pralidoxime in plasma is 4 μg/mL; this level is reached in about 16 minutes after a single injection of 600 mg pralidoxime chloride. In one study of healthy adult volunteers and patients self- poisoned with organophosphate compounds, a single intramuscular injection of 1000 mg 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 of pralidoxime chloride resulted in mean peak plasma levels of 7.5 ± 1.7 μg/mL and 9.9 ± 2.4 μg/mL, respectively. Time to reach the mean peak plasma levels in both groups was similar, 34 minutes in healthy adults and 33 minutes in poisoned patients. Mean half-life was about 3 hours in both groups. Some evidence suggests that a loading dose followed by continuous intravenous infusion of pralidoxime chloride may maintain therapeutic levels longer than short intermittent infusion therapy. In a cross-over study of seven healthy adults (18 – 50 years) a short intravenous infusion dose of 16 mg/kg over 30 minutes was compared to an intravenous loading dose of 4 mg/kg over 15 minutes, followed by 3.2 mg/kg/hr for 3.75 hours (for a total dose of 16 mg/kg). Results showed that the mean time over which plasma levels were maintained above 4 μg/mL was prolonged in the volunteers who received a loading dose followed by continuous infusion as compared to those who received short infusion therapy (257.5 ± 50.5 min vs. 118.0 ± 52.1 min). Use of continuous intravenous infusion in adult patients with organophosphate poisoning has been described in several case reports, with and without loading doses. Infusion rates ranged from 400 – 600 mg/hr. In one case the blood levels were 11.6 – 13.7 μg/mL when given 400 mg/hr over 5 days (measured at 5, 10 and 18 hours). In another case following an initial loading dose of 1000 mg, blood levels were 11.79 μg/mL when given 500 mg/hr and 17.26 μg/mL when given 600 mg/hr. In the latter case the pralidoxime elimination half-life was 4 hours. In two other cases blood levels were not measured. Pralidoxime chloride is distributed throughout the extracellular water; its apparent volume of distribution at steady state has been reported to range from 0.60 to 2.7 L/kg. Pralidoxime chloride is not bound to plasma protein. Pralidoxime chloride is relatively short acting and repeated doses may be needed, unless continuous intravenous infusion is selected. Simulations suggest that after a dose of 1000 mg given intravenously, concentrations fall below 4 μg/mL in about 1.5 hours. The short duration of action of pralidoxime chloride and the necessity for repeated doses should be considered especially where there is any evidence of continuing absorption of the poison. The apparent half-life of pralidoxime is 74 to 77 minutes. The drug is rapidly excreted in the urine by renal tubular secretion, partly unchanged, and partly as a metabolite produced by the liver. After intramuscular administration of 1000 mg of pralidoxime chloride, the renal clearance has been reported to be 7.2 ± 2.9 mL/min/kg in healthy volunteers and 3.6 ± 1.5 mL/min/kg in organophosphate-poisoned patients. In one study of 11 organophosphate-poisoned pediatric patients (age, 0.8 to 18 years), an intravenous loading dose of 15-50 mg/kg (mean 29 mg/kg) of pralidoxime chloride 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 followed by a continuous infusion of 10-16 mg/kg/hr (mean 14 mg/kg/hr) over 12 to 43 hours (mean 27 ± 8 hours) resulted in an average steady state plasma concentration of 22.2 mg/L (6.9 to 47.4 mg/L) and an average body clearance of 0.88 L/kg/hr (0.28 to 2.20 L/kg/hr). After the continuous infusion was discontinued, determinations of the apparent volume of distribution and half-life ranged from 1.7 to 13.8 L/kg and from 2.4 to 5.3 hours, respectively. INDICATIONS AND USAGE PROTOPAM is indicated as an antidote: (1) In the treatment of poisoning due to those pesticides and chemicals (e.g., nerve agents) of the organophosphate class which have anticholinesterase activity and (2) In the control of overdosage by anticholinesterase drugs used in the treatment of myasthenia gravis. The principal indications for the use of PROTOPAM are muscle weakness and respiratory depression. In severe poisoning, respiratory depression may be due to muscle weakness. CONTRAINDICATIONS There are no known absolute contraindications for the use of PROTOPAM (see PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION). Relative contraindications include known hypersensitivity to the drug and other situations in which the risk of its use clearly outweighs possible benefit. WARNINGS PROTOPAM is not effective in the treatment of poisoning due to phosphorus, inorganic phosphates, or organophosphates not having anticholinesterase activity. PROTOPAM is not indicated as an antidote for intoxication by pesticides of the carbamate class since it may increase the toxicity of carbaryl. PRECAUTIONS General PROTOPAM has been well tolerated in most cases, but it must be remembered that the desperate condition of the organophosphate-poisoned patient will generally mask such minor signs and symptoms as have been noted in normal subjects. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 Intravenous administration of PROTOPAM should be carried out slowly and, preferably, by continuous or intermittent infusion, since temporary worsening of cholinergic manifestations (i.e. tachycardia, cardiac arrest, laryngospasm, and muscle rigidity or paralysis) may occur if PROTOPAM is infused too rapidly. The intermittent infusion rate should not exceed 200 mg/minute. If intravenous administration is not feasible, intramuscular or subcutaneous injection should be used (see DOSAGE AND ADMINISTRATION). PROTOPAM should be used with great caution in treating organophosphate overdosage in cases of myasthenia gravis since it may precipitate a myasthenic crisis. Because pralidoxime is excreted in the urine, a decrease in renal function will result in increased blood levels of the drug. Thus, the dosage of PROTOPAM should be reduced in the presence of renal insufficiency. Laboratory Tests Treatment of organophosphate poisoning should be instituted without waiting for the results of laboratory tests. Red blood cell, plasma cholinesterase, and urinary paranitrophenol measurements (in the case of parathion exposure) may be helpful in confirming the diagnosis and following the course of the illness, although such tests may be normal in the face of clinically significant organophosphate poisoning. A reduction in red blood cell cholinesterase concentration to below 50% of normal has been seen only with organophosphate ester poisoning. Drug Interactions When atropine and pralidoxime chloride are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime chloride has been delayed. The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime chloride: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. Prolonged paralysis has been reported in patients when succinylcholine is given with drugs having anticholinesterase activity; therefore, it should be used with caution. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 Carcinogenesis, Mutagenesis, Impairment of Fertility Because pralidoxime chloride is indicated for short-term emergency use only, no investigations of its potential for carcinogenesis, mutagenesis, or impairment of fertility have been conducted by the manufacturer, or reported in the literature. Pregnancy Teratogenic Effects—Pregnancy Category C Animal reproduction studies have not been conducted with pralidoxime chloride. It is also not known whether pralidoxime chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pralidoxime chloride 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 pralidoxime chloride is administered to a nursing woman. Pediatric Use There are no adequate and well-controlled clinical trials that establish the effectiveness of pralidoxime chloride in pediatric patients. Efficacy has been extrapolated from the adult population and is supported by nonclinical studies, pharmacokinetic studies in adults and experience in the pediatric population (see DOSAGE AND ADMINISTRATION). As in adults, laryngospasm, cardiac arrest, tachycardia, and muscle rigidity or paralysis have been reported following rapid intravenous injection. Muscle fasciculations, apnea, and convulsions have also been reported. Geriatric Use Clinical studies of PROTOPAM 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. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 ADVERSE REACTIONS Forty to 60 minutes after intramuscular injection, mild to moderate pain may be experienced at the site of injection. Pralidoxime chloride may cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure, hyperventilation, and muscular weakness when given parenterally to normal volunteers who have not been exposed to anticholinesterase poisons. In patients, it is very difficult to differentiate the toxic effects produced by atropine or the organophosphate compounds from those of the drug. Elevations in SGOT and/or SGPT enzyme levels were observed in 1 of 6 normal volunteers given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6 volunteers given 1800 mg intramuscularly. Levels returned to normal in about 2 weeks. Transient elevations in creatine phosphokinase were observed in all normal volunteers given the drug. When atropine and pralidoxime chloride are used together, the signs of atropinization may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime chloride has been delayed. Excitement and manic behavior immediately following recovery of consciousness have been reported in several cases. However, similar behavior has occurred in cases of organophosphate poisoning that were not treated with pralidoxime chloride. DRUG ABUSE AND DEPENDENCE PROTOPAM is not subject to abuse and possesses no known potential for dependence. OVERDOSAGE Manifestations of Overdosage Observed in normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In therapy it has been difficult to differentiate side effects due to the drug from those due to the effects of the poison. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 DOSAGE AND ADMINISTRATION Organophosphate Poisoning Treatment should include general supportive care, atropinization, and decontamination, in addition to the use of PROTOPAM. Treatment is most effective if initiated immediately after poisoning. Administration of PROTOPAM should be carried out slowly and, preferably, by infusion. If intravenous administration is not feasible, intramuscular or subcutaneous injection should be used. Generally, little is accomplished if PROTOPAM is given more than 36 hours after termination of exposure to the poison. When the poison has been ingested, it is particularly important to take into account the likelihood of continuing absorption from the lower bowel since this constitutes new exposure and fatal relapses have been reported after initial improvement. In such cases, additional doses of PROTOPAM may be needed every three to eight hours. In effect, the patient should be “titrated” with PROTOPAM as long as signs of poisoning recur. As in all cases of organophosphate poisoning, care should be taken to keep the patient under observation for at least 48 to 72 hours. If dermal exposure has occurred, clothing should be removed and the hair and skin washed thoroughly with sodium bicarbonate or alcohol as soon as possible. Supportive care, including airway management, respiratory and cardiovascular support, correction of metabolic abnormalities, and seizure control, may be necessary in cases of severe organophosphate poisoning. Atropine should be given as soon as possible after hypoxemia is improved. Atropine should not be given in the presence of significant hypoxia due to the risk of atropine- induced ventricular fibrillation. In adults, atropine may be given intravenously in doses of 2 to 4 mg. This should be repeated at 5- to 10-minute intervals until full atropinization (secretions are inhibited) or signs of atropine toxicity appear (delirium, hyperthermia, muscle twitching). Some degree of atropinization should be maintained for at least 48 hours, and until any depressed blood cholinesterase activity is reversed. Use of morphine, theophylline, aminophylline, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning (see PRECAUTIONS, Drug Interactions). Prolonged paralysis has been reported in patients when succinylcholine is given with drugs having anticholinesterase activity; therefore, it should be used with caution. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 After the effects of atropine become apparent, PROTOPAM may be administered. Symptoms Of Nerve Agent And Insecticide Poisoning PROTOPAM dosing is based, in part, on the severity of symptoms of nerve agent intoxication. These symptoms include the following: MILD symptoms: • Blurred vision and sore eyes • Teary eyes* • Runny nose* • Increased salivation such as sudden drooling* • Chest tightness or difficulty breathing • Tremors throughout the body or muscular twitching • Nausea and vomiting • Involuntary respiratory secretions SEVERE symptoms: • Strange or confused behavior • Severe difficulty breathing or respiratory secretions • Severe muscular twitching and general weakness** • Involuntary urination and defecation* • Convulsions • Unconsciousness Symptoms in INFANTS AND YOUNG CHILDREN: * These symptoms are sometimes observed in healthy infants and young children. In this age group, these symptoms are less reliable than other symptoms listed. Symptoms must be considered collectively when nerve agent or pesticide exposure is known or suspected. ** Infants may become drowsy or unconscious, with muscle floppiness rather than muscle twitching, soon after exposure to nerve agents or pesticides. ADULT DOSING ADULT INTRAVENOUS DOSING: Refer to the Preparation for Administration section for instructions on reconstitution and dilution of PROTOPAM that result in a 10-20 mg/mL solution for intravenous infusion. Inject an initial dose of 1000 to 2000 mg of PROTOPAM, preferably as an infusion in 100 mL of normal saline, over a 15- to 30-minute period. If this is not practical or if pulmonary edema is present, the dose should be given slowly (over not less than five 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 minutes) by intravenous injection, as a 50 mg/mL solution in water (e.g., 1000 mg in 20 mL). A second dose of 1000 to 2000 mg may be indicated after about one hour if muscle weakness has not been relieved. Additional doses may be given every 10-12 hours if muscle weakness persists. Intravenous administration of PROTOPAM should be carried out slowly and, preferably, by continuous or intermittent infusion, since temporary worsening of cholinergic manifestations (i.e. tachycardia, cardiac arrest, laryngospasm, and muscle rigidity or paralysis) may occur if PROTOPAM is infused too rapidly. The intermittent infusion rate should not exceed 200 mg/minute. If intravenous administration is not feasible, intramuscular or subcutaneous injection should be used. Evidence suggests that a loading dose followed by continuous intravenous infusion of PROTOPAM may maintain therapeutic levels longer than traditional short intermittent infusion therapy (see Pharmacokinetics). ADULT INTRAMUSCULAR DOSING: Refer to the Preparation for Administration section for instructions on reconstitution of PROTOPAM that result in an approximate 300 mg/mL solution for intramuscular administration. Intramuscular dosing in adults should be based on the severity of clinical symptoms. MILD SYMPTOMS • For treatment of mild symptoms, administer a 600 mg (2 mL) intramuscular dose of PROTOPAM. Wait 15 minutes for PROTOPAM to take effect. • If, after 15 minutes, mild symptoms persist, then administer a second 600 mg (2 mL) intramuscular dose of PROTOPAM. • If, after an additional 15 minutes, mild symptoms continue to persist, a third 600 mg (2 mL) intramuscular dose of PROTOPAM may be administered for a total cumulative dose of 1800 mg. • If at any time after the first dose, the patient develops severe symptoms, administer two additional 600 mg intramuscular doses in rapid succession for a total cumulative dose of 1800 mg of PROTOPAM. SEVERE SYMPTOMS 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 • For treatment of severe symptoms, administer three 600 mg intramuscular doses (3 doses of 2 mL each) in rapid succession for a total dose of 1800 mg of PROTOPAM. PERSISTENT SYMPTOMS • If symptoms persist after administering the complete 1800 mg regimen (3 injections of 600 mg each), the series may be repeated beginning approximately 1 hour after administration of the last injection. PEDIATRIC DOSING (FOR PATIENTS 16 YEARS AND UNDER) PEDIATRIC INTRAVENOUS DOSING: Refer to the Preparation for Administration section for instructions on reconstitution and dilution of PROTOPAM that result in a 10-20 mg/mL solution for intravenous infusion. PROTOPAM can be given as intermittent intravenous infusions or as a loading dose followed by continuous intravenous infusion, depending upon the patient’s clinical condition. The specific dose given should depend upon the severity of the symptoms. Loading Dose Followed By Continuous Infusion Administer a loading dose of 20-50 mg/kg (not to exceed 2000 mg/dose) over 15-30 minutes followed by a continuous infusion of 10-20 mg/kg/hour. Intermittent Infusion Dosing Administer an initial intermittent infusion of 20-50 mg/kg (not to exceed 2000 mg/dose) over 15-30 minutes. A second dose of 20-50 mg/kg may be indicated after about one hour if muscle weakness has not been relieved. Repeat dosing is permissible every 10-12 hours as needed. If it is not practical to administer intermittent or continuous intravenous infusions, or if pulmonary edema is present, the 20-50 mg/kg dose should be given slowly (over not less than five minutes) by intravenous injection as a 50 mg/mL solution in water (see Preparation for Administration section). Additional doses may be given every 10-12 hours if muscle weakness persists. PEDIATRIC INTRAMUSCULAR DOSING: 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 Refer to the Preparation for Administration section for instructions on reconstitution of PROTOPAM that result in an approximate 300 mg/mL solution for intramuscular administration. Intramuscular injections in children should be administered in the anterolateral aspect of the thigh to avoid the nerve, artery and vein, as well as the femur. Pharmacokinetic modeling using published data from the scientific literature was conducted to derive intramuscular dosing recommendations in the pediatric population. The specific intramuscular dose of PROTOPAM should depend upon the severity of the symptoms. MILD SYMPTOMS • For treatment of mild symptoms, administer a weight-appropriate intramuscular dose (see Table 1 below) of PROTOPAM. Wait 15 minutes for PROTOPAM to take effect. • If, after 15 minutes, mild symptoms persist, then administer a second weight- appropriate intramuscular dose of PROTOPAM. • If after an additional 15 minutes, mild symptoms continue to persist, a third weight-appropriate intramuscular dose of PROTOPAM may be administered. • The three PROTOPAM injections together are considered a single course of treatment, and the total amount of PROTOPAM administered per course of treatment (i.e., 3 weight-appropriate injections) should not exceed the total amounts listed in Table 1 below. • If at any time after the first dose, the patient develops severe symptoms, administer two additional weight-appropriate intramuscular doses of PROTOPAM in rapid succession. SEVERE SYMPTOMS • For treatment of severe symptoms, administer the weight-appropriate intramuscular dose (see Table 1 below) of PROTOPAM as three injections, in rapid succession, into the patient’s anterolateral thigh (see Table 1 below). PERSISTENT SYMPTOMS • If symptoms persist after administering a complete course (3 injections of the weight-appropriate dose each), the series may be repeated beginning approximately 1 hour after administration of the last injection. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 Table 1: Pediatric Intramuscular Dosing Recommendations1 Weight in kg Dose Per Injection2 Total Dose per Three- Injection Course3 < 40kg 15 mg/kg 45 mg/kg ≥ 40 kg4 Use Adult Dosing Recommendations5 Use Adult Dosing Recommendations 1 Dosing is based on an approximate 300 mg/mL solution. 2 During the treatment for mild symptoms, if at any time after the first dose, the patient develops severe symptoms, administer two additional weight- appropriate intramuscular doses of PROTOPAM in rapid succession. 3 Additional courses of PROTOPAM may be administered beginning one hour after the last injection. A single course consists of three separate, weight-appropriate injections, administered either with 15 minute inter-injection observation periods for patients with mild symptoms, or all in rapid succession for patients with severe symptoms. 4 Weight of 40 kg corresponds to approximately the 50th percentile for a 12 year old child per the weight-for-age percentile growth charts published by the Centers for Disease Control and Prevention in 2000. 5 Adult Dose Per Injection is 600 mg; Total Adult Dose per Three-Injection Course is 1800 mg. Anticholinesterase Overdosage As an antagonist to such anticholinesterases as neostigmine, pyridostigmine, and ambenonium, which are used in the treatment of myasthenia gravis, PROTOPAM may be given in a dosage of 1000 to 2000 mg intravenously followed by increments of 250 mg every five minutes. Preparation for Administration PROTOPAM is supplied as 1000 mg single-dose vials for injection. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 For INTRAVENOUS infusion: Reconstitute a single PROTOPAM 1000 mg vial by adding 20 mL of Sterile Water for Injection, USP, which results in a 50 mg/mL concentration. The solution should be further diluted with Normal Saline for Injection, USP to achieve a concentration of 10 to 20 mg/mL (e.g. 1000 mg in 100 mL or 2000 mg in 100 mL). For fluid restricted patients or for rapid administration (over at least 5 min), a maximum concentration of 50 mg/mL may be used. For INTRAMUSCULAR injection: Reconstitute a single PROTOPAM 1000 mg vial by adding 3.3 mL of Sterile Water for Injection, USP for an approximate concentration of 300 mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard unused solution after a dose has been withdrawn. HOW SUPPLIED NDC 60977-141-01—Hospital Package: This contains six 20 mL vials of 1 g each of sterile PROTOPAM Chloride (pralidoxime chloride) for Injection white to off-white porous cake, without diluent or syringe. When necessary, sodium hydroxide is added during processing to adjust the pH. Storage Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. ANIMAL PHARMACOLOGY AND TOXICOLOGY The following table lists chemical and trade or generic names of pesticides, chemicals, and drugs against which PROTOPAM (usually administered in conjunction with atropine) has been found to have antidotal activity on the basis of animal experiments. All compounds listed are organophosphates having anticholinesterase activity. A great many additional substances are in industrial use but have been omitted because of lack of specific information. AAT—see PARATHION 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 AFLIX® —see FORMOTHION ALKRON® —see PARATHION AMERICAN CYANAMID 3422—see PARATHION AMITON—diethyl-S-(2-diethylaminoethyl)phosphorothiolate ANTHIO® —see FORMOTHION APHAMITE—see PARATHION ARMIN—ethyl-4-nitrophenylethylphosphonate AZINPHOS-METHYL—dimethyl-S-[(4-oxo-1,2,3,-benzotriazin-3(4 H)-yl)methyl] phosphorodithioate MORPHOTHION—dimethyl-S-2-keto-2-(N-morpholyl)ethylphosphorodithioate NEGUVON® —see TRICHLOROFON NIRAN® —see PARATHION NITROSTIGMINE—see PARATHION O,O-DIETHYL-O-p-NITROPHENYL PHOSPHOROTHIOATE—see PARATHION O,O-DIETHYL-O-p-NITROPHENYLTHIO PHOSPHATE—see PARATHION OR 1191—see PHOSPHAMIDON OS 1836—see VINYLPHOS OXYDEMETONMETHYL—dimethyl-S-2-(ethylsulfinyl) ethyl phosphorothiolate PARAOXON—diethyl (4-nitrophenyl) phosphate PARATHION—diethyl (4-nitrophenyl) phosphorothionate PENPHOS—see PARATHION PHENCAPTON—diethyl-S-(2,5-dichlorophenylmercaptomethyl) phosphorodithioate PHOSDRIN® —see MEVINPHOS PHOS-KIL—see PARATHION PHOSPHAMIDON—1-chloro-1-diethylcarbamoyl-1-propen-2-yl-dimethylphosphate PHOSPHOLINE IODIDE® —see echothiophate iodide PHOSPHOROTHIOIC ACID, O,O-DIETHYL-O-p-NITROPHENYL ESTER—see PARATHION PLANTHION—see PARATHION QUELETOX—see FENTHION RHODIATOX® —see PARATHION RUELENE® —4-tert-butyl-2-chlorophenylmethyl-N-methylphosphoroamidate SARIN—isopropyl-methylphosphonofluoridate SHELL OS 1836—see VINYLPHOS SHELL 2046—see MEVINPHOS SNP—see PARATHION 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 014134/S-022 FDA Approved Labeling Text dated September 8, 2010 SOMAN—pinacolyl-methylphosphonofluoridate SYSTOX® —diethyl-(2-ethylmercaptoethyl) phosphorothionate TEP—see TEPP TEPP—tetraethylpyro phosphate THIOPHOS® —see PARATHION TIGUVON—see FENTHION TRICHLOROFON—dimethyl-1-hydroxy-2,2,2-trichloroethylphosphonate VAPONA® —see DICHLORVOS VAPOPHOS—see PARATHION VINYLPHOS—diethyl-2-chloro-vinylphosphate PROTOPAM appears to be ineffective, or marginally effective, against poisoning by: CIODRIN® (alpha-methylbenzyl-3-[dimethoxyphosphinyloxy]-ciscrotonate) DIMEFOX (tetramethylphosphorodiamidic fluoride) DIMETHOATE (dimethyl-S-[N-methylcarbamoylmethyl] phosphorodithioate) METHYL DIAZINON (dimethyl-[2-isopropyl-4-methylpyrimidyl]-phosphorothionate) METHYL PHENCAPTON (dimethyl-S-[2,5 dichlorophenylmercaptomethyl]phosphorodithioate) PHORATE (diethyl-S-ethylmercaptomethylphosphorodithioate) SCHRADAN (octamethylpyrophosphoramide) WEPSYN® (5-amino-1-[bis-(dimethylamino) phosphinyl]-3-phenyl-1,2,4-triazole). Baxter and PROTOPAM are trademarks of Baxter International, Inc., or its subsidiaries. company logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USA By: Baxter Pharmaceutical Solutions LLC Bloomington, IN 47403 For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT00067,B 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:51.395433	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/014134s022lbl.pdf', 'application_number': 14134, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,831	NDA 13-217/S-036 Page 3 SKELAXIN® (Metaxalone) DESCRIPTION SKELAXIN® (metaxalone) has the following chemical structure and name: 5-[(3,5-dimethylphenoxy) methyl]-2-oxazolidinone SKELAXIN (metaxalone) is available as a 400 mg round, pale rose tablet and an 800 mg oval, pink scored tablet. CLINICAL PHARMACOLOGY The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. It has no direct action on the contractile mechanism of striated muscle, the motor end plate or the nerve fiber. Pharmacokinetics: In a single center randomized, two-period crossover study in 42 healthy volunteers (31 males, 11 females), a single 400 mg SKELAXIN (metaxalone) tablet was administered under both fasted and fed conditions. Under fasted conditions, mean peak plasma concentrations (Cmax) of 865.3 ng/mL were achieved within 3.3 +/- 1.2 hours (S.D.) after dosing (Tmax). Metaxalone concentrations declined with a mean terminal half-life (t1/2) of 9.2 +/- 4.8 hours. The mean apparent oral clearance (CL/F) of metaxalone was 68 +/- 34 L/h. In the same study, following a standardized high fat meal, food statistically significantly increased the rate (Cmax) and extent of absorption (AUC(0-t), AUCinf) of metaxalone from SKELAXIN tablets. Relative to the fasted treatment the observed increases were 177.5%, 123.5%, and 115.4%, respectively. The mean Tmax was also increased to 4.3 +/- 2.3 hours, whereas the mean t1/2 was decreased to 2.4 +/- 1.2 hours. This decrease in half-life over that seen in the fasted subjects is felt to be due to the more complete absorption of metaxalone in the presence of a meal resulting in a better estimate of half-life. The mean apparent oral clearance (CL/F) of metaxalone was relatively unchanged relative to fasted administration (59 +/- 29 L/hr). Although a higher Cmax and AUC were observed This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-217/S-036 Page 4 after the administration of SKELAXIN (metaxalone) with a standardized high fat meal, the clinical relevance of these effects is unknown. In another single center, randomized four-period crossover study in 59 healthy volunteers (37 males, 22 females), the rate and extent of metaxalone absorption were determined after the administration of SKELAXIN tablets under both fasted and fed conditions. Under fasted conditions, the administration of two SKELAXIN 400 mg tablets produced peak plasma metaxalone concentrations (Cmax) of 1653 ng/mL 3.0 + 1.2 hours after dosing (Tmax). Metaxalone concentrations declined with mean terminal half-life (t½) of 8.0 + 4.6 hours. The mean apparent oral clearance (CL/F) of metaxalone was 66 + 34 L/hr. Except for a 17% decrease in mean Cmax, these values were not statistically different from those after the administration of one SKELAXIN 800 mg tablet. In the same study, the administration of two SKELAXIN 400 mg tablets following a standardized high fat meal showed an increase in the mean Cmax, and the area under the curve (AUC0-inf) of metaxalone by 194% and 142%, respectively. A high fat meal also increased the mean Tmax to 4.9 +/- 2.3 hours but decreased the mean t½ to 4.2 + 2.5 hr. The effect of a high fat meal on the absorption of metaxalone from one SKELAXIN 800 mg tablet was very similar to that on the absorption from two SKELAXIN 400 mg tablets in quality and quantity. The clinical relevance of these effects is unknown. The absolute bioavailability of metaxalone from SKELAXIN tablets is not known. Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites. The impact of age, gender, hepatic, and renal disease on the pharmacokinetics of SKELAXIN (metaxalone) has not been determined. In the absence of such information, SKELAXIN should be used with caution in patients with hepatic and/or renal impairment and in the elderly. INDICATIONS AND USAGE SKELAXIN (metaxalone) is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Metaxalone does not directly relax tense skeletal muscles in man. CONTRAINDICATIONS Known hypersensitivity to any components of this product. Known tendency to drug induced, hemolytic, or other anemias. Significantly impaired renal or hepatic function. WARNINGS SKELAXIN may enhance the effects of alcohol and other CNS depressants. PRECAUTIONS Metaxalone should be administered with great care to patients with pre-existing liver damage. Serial This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-217/S-036 Page 5 liver function studies should be performed in these patients. False-positive Benedict’s tests, due to an unknown reducing substance, have been noted. A glucose- specific test will differentiate findings. Information for Patients SKELAXIN may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle, especially when used with alcohol or other CNS depressants. Drug Interactions SKELAXIN may enhance the effects of alcohol, barbiturates and other CNS depressants. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of metaxalone has not been determined. Pregnancy Reproduction studies in rats have not revealed evidence of impaired fertility or harm to the fetus due to metaxalone. Post marketing experience has not revealed evidence of fetal injury, but such experience cannot exclude the possibility of infrequent or subtle damage to the human fetus. Safe use of metaxalone has not been established with regard to possible adverse effects upon fetal development. Therefore, metaxalone tablets should not be used in women who are or may become pregnant and particularly during early pregnancy unless in the judgement of the physician the potential benefits outweigh the possible hazards. Nursing Mothers It is not known whether this drug is secreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk. Pediatric Use Safety and effectiveness in children 12 years of age and below have not been established. ADVERSE REACTIONS The most frequent reactions to metaxalone include: CNS: drowsiness, dizziness, headache, and nervousness or “irritability;” Digestive: nausea, vomiting, gastrointestinal upset; Immune system: hypersensitivity reaction, rash with or without pruritus; Hematologic: leukopenia, hemolytic anemia; Hepatobiliary: jaundice. Though rare, anaphylactoid reactions have been reported with metaxalone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-217/S-036 Page 6 OVERDOSAGE Deaths by deliberate or accidental overdose have occurred with this class of drugs, particularly in combination with antidepressants and/or alcohol. When determining the LD50 in rats and mice, progressive sedation, hypnosis and finally respiratory failure were noted as the dosage increased. In dogs, no LD50 could be determined as the higher doses produced an emetic action in 15 to 30 minutes. Treatment - Gastric lavage and supportive therapy. Consultation with a regional poison control center is recommended. DOSAGE AND ADMINISTRATION The recommended dose for adults and children over 12 years of age is two 400 mg tablets (800 mg) or one 800 mg tablet three to four times a day. HOW SUPPLIED SKELAXIN (metaxalone) is available as a 400 mg pale rose tablet, inscribed with 8662 on the scored side and “C” on the other. Available in bottles of 100 (NDC 0086-0062-10) and in bottles of 500 (NDC 0086-0062-50). SKELAXIN (metaxalone) is also available as an 800 mg oval, scored pink tablet inscribed with 8667 on the scored side and “S” on the other. Available in bottles of 100 (NDC 59075-068-10) and in bottles of 500 (NDC 59075-068-50). Store at Controlled Room Temperature, between 15˚ C and 30˚ C (59˚ F and 86˚ F). Rx Only Revised: August, 2002 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/ --------------------- Lawrence Goldkind 8/30/02 04:27:00 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:51.448120	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/13217s036lbl.pdf', 'application_number': 13217, 'submission_type': 'SUPPL ', 'submission_number': 36}
10,837	NDA 14-214/S-053, S-055, S-056 Page 7 NSW-6 I (O) NegGram ® Caplets2 NALIDIXIC ACID, USP To reduce the development of drug-resistant bacteria and maintain the effectiveness of NegGram (nalidixic acid, USP) and other antibacterial drugs, NegGram should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NegGram®, brand of nalidixic acid, is a quinolone antibacterial agent for oral administration. Nalidixic acid is 1- ethyl-1, 4-dihydro-7-methyl-4-oxo-1, 8-naphthyridine-3-carboxylic acid. It is a pale yellow, crystalline substance and a very weak organic acid. Nalidixic acid has the following structural formula: Inactive Ingredients— Hydrogenated Vegetable Oil, Methylcellulose, Microcrystalline Cellulose, Sodium Lauryl Sulfate, Yellow Ferric Oxide. CLINICAL PHARMACOLOGY Following oral administration, NegGram is rapidly absorbed from the gastrointestinal tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Unchanged nalidixic acid appears in the urine along with an active metabolite, hydroxynalidixic acid, which has antibacterial activity similar to that of nalidixic acid. Other metabolites include glucuronic acid conjugates of nalidixic acid and hydroxy nalidixic acid, and the dicarboxylic acid derivative. The hydroxy metabolite represents 30 percent of the biologically active drug in the blood and 85 percent in the urine. Peak serum levels of active drug average approximately 20 mcg to 40 mcg per mL (90 percent protein bound), one to two hours after administration of a 1 g dose to a fasting normal individual, with a half-life of about 90 minutes. Peak urine levels of active drug average approximately 150 mcg to 200 mcg per mL, three to four hours after administration, with a half-life of about six hours. Approximately four percent of NegGram is excreted in the feces. Traces of nalidixic acid were found in blood and urine of an infant whose mother had received the drug during the last trimester of pregnancy. (See PRECAUTIONS—Drug Interactions.) Microbiology NegGram has marked antibacterial activity against gram-negative bacteria including Enterobacter species, Escherichia coli, Morganella Morganii; Proteus Mirabilis, Proteus vulgaris, and Providencia rettgeri. Pseudomonas species are generally resistant to the drug. NegGram is bactericidal and is effective over the entire urinary pH range. Conventional chromosomal resistance to NegGram taken in full dosage has been reported to emerge in approximately 2 to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 14-214/S-053, S-055, S-056 Page 8 14 percent of patients during treatment; however, bacterial resistance to NegGram has not been shown to be transferable via R factor. Susceptibility Test Diffusion Techniques: Quantitative methods that require measurement of zone diameters give the most precise estimates of antibacterial susceptibility. One such procedure recommended for use with a disc containing 30 mcg of nalidixic acid is the National Committee for Clinical Laboratory Standards (NCCLS) approved procedure. Only organisms from urinary tract infections should be tested. Results of laboratory tests using 30 mcg nalidixic acid discs should be interpreted using the following criteria: Zone Diameter (mm) Interpretation ≥19 (S) Susceptible 14-18 (I) Intermediate ≤13 (R) Resistant Dilution Techniques: Broth and agar dilution methods, such as those recommended by the NCCLS, may be used to determine the minimum inhibitory concentration (MIC) of nalidixic acid. MIC test results should be interpreted according to the following criteria: MIC (mcg/mL) Interpretation ≤16 (S) Susceptible ≥32 (R) Resistant For any susceptibility test, a report of "susceptible" indicates that the pathogen is likely to respond to nalidixic acid therapy. A report of "resistant" indicates that the pathogen is not likely to respond. A report of "intermediate" generally indicates that the test result is equivocal. The Quality Control strains should have the following assigned daily ranges for nalidixic acid: QC Strains E. Coli (ATCC 25922) Disc Zone Diameter 22-28 MIC (mcg/mL) 1.0-4.0 INDICATIONS AND USAGE NegGram (nalidixic acid, USP) is indicated for the treatment of urinary tract infections caused by susceptible gram-negative microorganisms, including the majority of E. Coli, Enterobacter species, Klebsiella species, and Proteus species. Disc susceptibility testing with the 30 mcg disc should be performed prior to administration of the drug, and during treatment if clinical response warrants. To reduce the development of drug-resistant bacteria and maintain effectiveness of NegGram and other antibacterial drugs, NegGram 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 when 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 NegGram is contraindicated in patients with known hypersensitivity to nalidixic acid or to related compounds, infants less than three months of age, and in patients with porphyria or a history of convulsive disorders. NegGram is contraindicated in patients undergoing concomitant therapy with melphalan or other related cancer chemotherapeutic alkylating agents because of serious gastrointestinal toxicity such as hemorrhagic ulcerative colitis or intestinal necrosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 14-214/S-053, S-055, S-056 Page 9 WARNINGS Central Nervous System (CNS) effects including convulsions, increased intracranial pressure, and toxic psychosis have been reported with nalidixic acid therapy. Convulsive seizures have been reported with other drugs in this class. Quinolones may also cause CNS stimulation which may lead to tremor, restlessness, lightheadedness, confusion, and hallucinations. Therefore, nalidixic acid should be used with caution in patients with known or suspected CNS disorders, such as, cerebral arteriosclerosis or epilepsy, or other factors which predispose seizures. (See ADVERSE REACTIONS.) If these reactions occur in patients receiving nalidixic acid, the drug should be discontinued and appropriate measures instituted. Serious and occasionally fatal hypersensitivity (anaphylactoid) 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. Serious anaphylactoid reactions required immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated. Nalidixic acid and other members of the quinolone drug class have been shown to cause arthropathy in juvenile animals. (See PRECAUTIONS and ANIMAL PHARMACOLOGY.) Pseudomembranous colitis has been reported with nearly all antibacterial agents, including quinolones, 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. 3 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 nalidixic acid. Nalidixic acid 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 tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including nalidixic acid. Post- marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. Nalidixic acid 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 tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including nalidixic acid. PRECAUTIONS General Blood counts and renal and liver function tests should be performed periodically if treatment is continued for more than two weeks. NegGram should be used with caution in patients with liver disease, epilepsy, or severe cerebral arteriosclerosis. (See WARNINGS.) While caution should be used in patients with severe renal failure, therapeutic concentrations of NegGram in the urine, without increased toxicity due to drug accumulation in the blood, have been observed in patients on full dosage with creatinine clearances as low as 2 mL/minute to 8 mL/minute. Moderate to severe phototoxicity reactions have been observed in patients who are exposed to direct sunlight while receiving NegGram or other members of this drug class. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs. If bacterial resistance to NegGram emerges during treatment, it usually does so within 48 hours, permitting rapid change to another antimicrobial. Therefore, if the clinical response is unsatisfactory or if relapse occurs, cultures and sensitivity tests should be repeated. Underdosage with NegGram during initial treatment (with less than 4 g per day for adults) may predispose to emergence of bacterial resistance. (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 14-214/S-053, S-055, S-056 Page 10 Cross-resistance between nalidixic acid and other quinolone derivatives such as oxolinic acid and cinoxacin has been observed. Caution should be observed in patients with glucose-6-phosphate dehydrogenase deficiency. (See ADVERSE REACTIONS). Prescribing NegGram 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 NegGram may be taken with or without meals. Patients should be advised to drink fluids liberally and not take antacids. Patients should be advised that quinolones may be associated with hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash or other allergic reactions. Quinolones may cause dizziness and light-headedness, therefore, patients should know how they react to NegGram before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination. Patients should be advised that quinolones may increase the effects of theophylline and caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones. Patients should be advised to avoid excessive sunlight or artificial ultraviolet light while receiving nalidixic acid and to discontinue therapy if phototoxicity occurs. Patients should be advised that convulsions have been reported in patients taking quinolones, including nalidixic acid, and to notify their physician before taking this drug if there is a history of this condition. Patients should be advised that mineral supplements, vitamins with iron or minerals, calcium-, aluminum-, magnesium-based antacids, sucralfate or Videx® , (didanosine), chewable/buffered tablets of the pediatric powder for oral solution should not be taken within the two-hour period before or within the two-hour period after taking nalidixic acid (see Drug Interactions). Patients should be advised: − that nalidixic acid may cause changes in the electrocardiogram (QTc interval prolongation) − that nalidixic acid should be avoided in patients receiving class IA (e.g. quinidine, Procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents − that nalidixic acid 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 nalidixic acid use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. Patients should be counseled that antibacterial drugs including NegGram should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NegGram 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 NegGram or other antibacterial drugs in the future. 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 quinolones and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted, as required. Quinolones have been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and the prolongation of its plasma half-life. Quinolones, including nalidixic acid, may enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation test should be closely monitored. Since active proliferation of organisms is a necessary condition for its antibacterial activity, the action of nalidixic acid may be inhibited by the presence of other antibacterial substances, especially bacteriostatic agents such as tetracycline, chloramphenicol, or nitrofurantoin, which is antagonistic to nalidixic acid in vitro. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 14-214/S-053, S-055, S-056 Page 11 Probenecid inhibits the tubular secretion of nalidixic acid and may reduce its efficacy in the treatment of urinary tract infections while increasing the risk of systemic side effects. Serious gastrointestinal toxicity has been associated with the concomitant use of nalidixic acid and the anti-cancer drug melphalan. (see CONTRAINDICATIONS) Antacids containing magnesium, aluminum, or calcium; sucralfate or divalent or trivalent cations such as iron; multivitamins containing zinc; and Videx®, (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution may substantially interfere with the absorption of quinolones, resulting in systemic levels considerably lower than desired. These agents should not be taken within the two-hour period before or within the two-hour period after nalidixic acid administration. Elevated serum levels of cyclosporine have been reported with the concomitant use of some quinolones and cyclosporine. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Drug Laboratory Test Interactions When Benedict's or Fehling's solution or Clinitest® Reagent Tablets are used to test the urine of patients taking NegGram, a false-positive reaction for glucose may be obtained, due to the liberation of glucuronic acid from the metabolites excreted. However, a colorimetric test for glucose based on an enzyme reaction (e.g., with Clinistix® Reagent Strips or Tes-Tape® ) does not give a false-positive reaction to the liberated glucuronic acid. Incorrect values may be obtained for urinary 17-keto and ketogenic steroids in patients receiving NegGram, because of an interaction between the drug and the m-dinitrobenzene used in the usual assay method. In such cases, the Porter-Silber test for 17-hydroxycorticoids may be used. Carcinogenesis, Mutagenesis, Impairment of Fertility In lifetime studies in the rat given nalidixic acid in the diet, there was an increased incidence of preputial gland neoplasms in the treated males and clitoral gland neoplasms in the treated females. Studies in mice in which nalidixic acid was administered in the feed for two years, or was given in the feed for 76 weeks followed by no treatment for 9 weeks, gave equivocal evidence of carcinogenic activity. Nalidixic acid was tested in the Ames bacterial mutagenicity test (maximum dose 33 mcg/plate) and the mouse lymphoma assay (L5178Y/TK; maximum dose 100 mcg/mL) with and without metabolic activation, and results were negative. Pregnancy: Teratogenic Effects. Pregnancy Category C NegGram has been shown to be teratogenic and embryocidal in rats when given in oral doses six times the human dose. NegGram also prolonged the duration of pregnancy especially at four times the clinical dose. There are no adequate and well-controlled studies in pregnant women. Since nalidixic acid, like other drugs in this class, causes arthropathy in immature animals, NegGram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See WARNINGS and ANIMAL PHARMACOLOGY.) Nursing Mothers Since nalidixic acid is excreted in breast milk, it is contraindicated during lactation.4 Pediatric Use Safety and effectiveness in infants below the age of three months have not been established. Usage in Patients Under 18 Years of Age Toxicological studies have shown that nalidixic acid and related drugs can produce erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of most species tested. No such joint lesions have been reported in humans to date. Nevertheless, until the significance of this finding is clarified, this drug should only be used in patients under 18 years of age when the potential benefit justifies the potential risk. If arthralgia occurs, treatment with nalidixic acid should be stopped. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Clinical studies of NegGram® 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. Caution should therefore be observed in using nalidixic acid in elderly patients. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 14-214/S-053, S-055, S-056 Page 12 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 PRECAUTIONS, General.) ADVERSE REACTIONS Reactions reported after oral administration of NegGram include the following. CNS effects: drowsiness, weakness, headache, dizziness and vertigo. Reversible subjective visual disturbances without objective findings have occurred infrequently (generally with each dose during the first few days of treatment). These reactions include overbrightness of lights, change in color perception, difficulty in focusing, decrease in visual acuity, and double vision. They usually disappeared promptly when dosage was reduced or therapy was discontinued. Toxic psychosis or brief convulsions have been reported rarely, usually following excessive doses. In general, the convulsions have occurred in patients with predisposing factors such as epilepsy or cerebral arteriosclerosis. In infants and children receiving therapeutic doses of NegGram, increased intracranial pressure with bulging anterior fontanel, papilledema, and headache has occasionally been observed. A few cases of 6th cranial nerve palsy have been reported. Although the mechanisms of these reactions are unknown, the signs and symptoms usually disappeared rapidly with no sequelae when treatment was discontinued. Gastrointestinal: abdominal pain, nausea, vomiting, and diarrhea. Allergic: rash, pruritus, urticaria, angioedema, eosinophilia, arthralgia with joint stiffness and swelling, and anaphylactoid reaction, including anaphylactic shock. Erythema Multiforme and Stevens-Johnson syndrome have been reported with nalidixic acid and other drugs in this class. Rash was the most frequently reported adverse reaction. Photosensitivity reactions consisting of erythema and bullae on exposed skin surfaces usually resolve completely in 2 weeks to 2 months after NegGram is discontinued; however, bullae may continue to appear with successive exposures to sunlight or with mild skin trauma for up to 3 months after discontinuation of drug. (See PRECAUTIONS.) Other: rarely, cholestasis, paresthesia, metabolic acidosis, thrombocytopenia, leukopenia, or hemolytic anemia, sometimes associated with glucose 6-phosphate dehydrogenase deficiency and peripheral neuropathy. OVERDOSAGE Manifestations: Toxic psychosis, convulsions, increased intracranial pressure, or metabolic acidosis may occur in patients taking more than the recommended dosage. Vomiting, nausea, and lethargy may also occur following overdosage. Treatment: Reactions are short-lived (two to three hours) because the drug is rapidly excreted. If absorption has occurred, increased fluid administration is advisable and supportive measures such as oxygen and means of artificial respiration should be available. Although anticonvulsant therapy has not been used in the few instances of overdosage reported, it may be indicated in a severe case. DOSAGE AND ADMINISTRATION Antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent cations such as iron; multivitamins containing zinc; or Videx® (Didanosine), chewable/buffered tablets of the pediatric powder for oral solution should not be taken within the two-hour period before or within the two-hour period after taking nalidixic acid. Adults. The recommended dosage for initial therapy in adults is 1 g administered four times daily for one or two weeks (total daily dose, 4 g). For prolonged therapy, the total daily dose may be reduced to 2 g after the initial treatment period. Underdosage during initial treatment may predispose to emergence of bacterial resistance. Pediatric Patients. Until further experience is gained, NegGram should not be administered to infants younger than three months. Dosage in pediatric patients 12 years of age and under should be calculated on the basis of body weight. The recommended total daily dosage for initial therapy is 25 mg/lb/day (55 mg/kg/day), administered in four equally divided doses. For prolonged therapy, the total daily dose may be reduced to 15 mg/lb/day (33 mg/kg/day). NegGram Caplets of 250 mg may be used. HOW SUPPLIED NegGram (nalidixic acid, USP) is supplied as: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 14-214/S-053, S-055, S-056 Page 13 Caplets of 500 mg, light buff-colored capsule-shaped tablets, bottles of 56 (NDC 0024-1322-03) Store at room temperature, up to 30° C (86° F). ANIMAL PHARMACOLOGY NegGram (nalidixic acid) and related drugs have been shown to cause arthropathy in juvenile animals of most species tested. (See WARNINGS.) Long-term administration of nalidixic acid to rats resulted in retinal degeneration and cataracts. Hydroxynalidixic acid, the principal metabolite of NegGram, did not produce any oculotoxic effects at any dosage level in seven species of animals including three primate species. However, oral administration of this metabolite in high doses has been shown to have oculotoxic potential, namely in dogs and cats where it produced retinal degeneration upon prolonged administration leading, in some cases, to blindness. In experiments with NegGram itself, little if any such activity could be elicited in either dogs or cats. Sensitivity to CNS side effects in these species limited the doses of NegGram that could be used; this factor, together with a low conversion rate to the hydroxy metabolite in these species, may explain the absence of these effects. Distributed by Sanofi-Synthelabo Inc. New York, NY 10016 Copyright, Sanofi-Synthelabo Inc. 1973, 2004 Revised June 2004 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:51.751379	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/14214s053,055,056lbl.pdf', 'application_number': 14214, 'submission_type': 'SUPPL ', 'submission_number': 55}
10,838	NegGram® Caplets (nalidixic acid, USP) To reduce the development of drug-resistant bacteria and maintain the effectiveness of NegGram (nalidixic acid, USP) and other antibacterial drugs, NegGram should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NegGram®, brand of nalidixic acid, is a quinolone antibacterial agent for oral administration. Nalidixic acid is 1-ethyl-1, 4-dihydro-7-methyl-4-oxo-1, 8-naphthyridine-3-carboxylic acid. It is a pale yellow, crystalline substance and a very weak organic acid. Nalidixic acid has the following structural formula: Inactive Ingredients - Hydrogenated Vegetable Oil, Methylcellulose, Microcrystalline Cellulose, Sodium Lauryl Sulfate, Yellow Ferric Oxide. CLINICAL PHARMACOLOGY Following oral administration, NegGram is rapidly absorbed from the gastrointestinal tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Unchanged nalidixic acid appears in the urine along with an active metabolite, hydroxynalidixic acid, which has antibacterial activity similar to that of nalidixic acid. Other metabolites include glucuronic acid conjugates of nalidixic acid and hydroxy nalidixic acid, and the dicarboxylic acid derivative. The hydroxy metabolite represents 30 percent of the biologically active drug in the blood and 85 percent in the urine. Peak serum levels of active drug average approximately 20 mcg to 40 mcg per mL (90 percent protein bound), one to two hours after administration of a 1 g dose to a fasting normal individual, with a half-life of about 90 minutes. Peak urine levels of active drug average approximately 150 mcg to 200 mcg per mL, three to four hours after administration, with a half-life of about six hours. Approximately four percent of NegGram is excreted in the feces. Traces of nalidixic acid were found in blood and urine of an infant whose mother had received the drug during the last trimester of pregnancy. (See PRECAUTIONS—Drug Interactions.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Microbiology NegGram has marked antibacterial activity against gram-negative bacteria including Enterobacter species, Escherichia coli, Morganella Morganii; Proteus Mirabilis, Proteus vulgaris, and Providencia rettgeri. Pseudomonas species are generally resistant to the drug. NegGram is bactericidal and is effective over the entire urinary pH range. Conventional chromosomal resistance to NegGram taken in full dosage has been reported to emerge in approximately 2 to 14 percent of patients during treatment; however, bacterial resistance to NegGram has not been shown to be transferable via R factor. Susceptibility Test Diffusion Techniques: Quantitative methods that require measurement of zone diameters give the most precise estimates of antibacterial susceptibility. One such procedure recommended for use with a disc containing 30 mcg of nalidixic acid is the National Committee for Clinical Laboratory Standards (NCCLS) approved procedure. Only organisms from urinary tract infections should be tested. Results of laboratory tests using 30 mcg nalidixic acid discs should be interpreted using the following criteria: Zone Diameter (mm) Interpretation ≥19 (S) Susceptible 14-18 (I) Intermediate ≤13 (R) Resistant Dilution Techniques: Broth and agar dilution methods, such as those recommended by the NCCLS, may be used to determine the minimum inhibitory concentration (MIC) of nalidixic acid. MIC test results should be interpreted according to the following criteria: MIC (mcg/mL) Interpretation ≤16 (S) Susceptible ≥32 (R) Resistant For any susceptibility test, a report of "susceptible" indicates that the pathogen is likely to respond to nalidixic acid therapy. A report of "resistant" indicates that the pathogen is not likely to respond. A report of "intermediate" generally indicates that the test result is equivocal. The Quality Control strains should have the following assigned daily ranges for nalidixic acid: QC Strains E. Coli (ATCC 25922) Disc Zone Diameter 22-28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MIC (mcg/mL) 1.0-4.0 INDICATIONS AND USAGE NegGram (nalidixic acid, USP) is indicated for the treatment of urinary tract infections caused by susceptible gram-negative microorganisms, including the majority of E. Coli, Enterobacter species, Klebsiella species, and Proteus species. Disc susceptibility testing with the 30 mcg disc should be performed prior to administration of the drug, and during treatment if clinical response warrants. To reduce the development of drug-resistant bacteria and maintain effectiveness of NegGram and other antibacterial drugs, NegGram 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 when 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 NegGram is contraindicated in patients with known hypersensitivity to nalidixic acid or to related compounds, infants less than three months of age, and in patients with porphyria or a history of convulsive disorders. NegGram is contraindicated in patients undergoing concomitant therapy with melphalan or other related cancer chemotherapeutic alkylating agents because of serious gastrointestinal toxicity such as hemorrhagic ulcerative colitis or intestinal necrosis. WARNINGS Central Nervous System (CNS) effects including convulsions, increased intracranial pressure, and toxic psychosis have been reported with nalidixic acid therapy. Convulsive seizures have been reported with other drugs in this class. Quinolones may also cause CNS stimulation which may lead to tremor, restlessness, lightheadedness, confusion, and hallucinations. Therefore, nalidixic acid should be used with caution in patients with known or suspected CNS disorders, such as, cerebral arteriosclerosis or epilepsy, or other factors which predispose seizures. (See ADVERSE REACTIONS.) If these reactions occur in patients receiving nalidixic acid, the drug should be discontinued and appropriate measures instituted. Serious and occasionally fatal hypersensitivity (anaphylactoid) 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. Serious anaphylactoid reactions required immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nalidixic acid and other members of the quinolone drug class have been shown to cause arthropathy in juvenile animals. (See PRECAUTIONS and ANIMAL PHARMACOLOGY.) Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NegGram, 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 nalidixic acid. Nalidixic acid 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 tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including nalidixic acid. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. Nalidixic acid 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 tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including nalidixic acid. PRECAUTIONS General This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Blood counts and renal and liver function tests should be performed periodically if treatment is continued for more than two weeks. NegGram should be used with caution in patients with liver disease, epilepsy, or severe cerebral arteriosclerosis. (See WARNINGS.) While caution should be used in patients with severe renal failure, therapeutic concentrations of NegGram in the urine, without increased toxicity due to drug accumulation in the blood, have been observed in patients on full dosage with creatinine clearances as low as 2 mL/minute to 8 mL/minute. Moderate to severe phototoxicity reactions have been observed in patients who are exposed to direct sunlight while receiving NegGram or other members of this drug class. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs. If bacterial resistance to NegGram emerges during treatment, it usually does so within 48 hours, permitting rapid change to another antimicrobial. Therefore, if the clinical response is unsatisfactory or if relapse occurs, cultures and sensitivity tests should be repeated. Underdosage with NegGram during initial treatment (with less than 4 g per day for adults) may predispose to emergence of bacterial resistance. (See DOSAGE AND ADMINISTRATION.) Cross-resistance between nalidixic acid and other quinolone derivatives such as oxolinic acid and cinoxacin has been observed. Caution should be observed in patients with glucose-6-phosphate dehydrogenase deficiency. (See ADVERSE REACTIONS). Prescribing NegGram 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 NegGram may be taken with or without meals. Patients should be advised to drink fluids liberally and not take antacids. Patients should be advised that quinolones may be associated with hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash or other allergic reactions. Quinolones may cause dizziness and light-headedness, therefore, patients should know how they react to NegGram before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination. Patients should be advised that quinolones may increase the effects of theophylline and caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones. Patients should be advised to avoid excessive sunlight or artificial ultraviolet light while receiving nalidixic acid and to discontinue therapy if phototoxicity occurs. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should be advised that convulsions have been reported in patients taking quinolones, including nalidixic acid, and to notify their physician before taking this drug if there is a history of this condition. Patients should be advised that mineral supplements, vitamins with iron or minerals, calcium-, aluminum-, magnesium-based antacids, sucralfate or Videx® , (didanosine), chewable/buffered tablets of the pediatric powder for oral solution should not be taken within the two-hour period before or within the two-hour period after taking nalidixic acid (see Drug Interactions). Patients should be advised: - that nalidixic acid may cause changes in the electrocardiogram (QTc interval prolongation) - that nalidixic acid should be avoided in patients receiving class IA (e.g. quinidine, Procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents - that nalidixic acid 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 nalidixic acid use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. - 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 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 NegGram should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NegGram 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 NegGram or other antibacterial drugs in the future. 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 quinolones and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted, as required. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Quinolones have been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and the prolongation of its plasma half-life. Quinolones, including nalidixic acid, may enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation test should be closely monitored. Since active proliferation of organisms is a necessary condition for its antibacterial activity, the action of nalidixic acid may be inhibited by the presence of other antibacterial substances, especially bacteriostatic agents such as tetracycline, chloramphenicol, or nitrofurantoin, which is antagonistic to nalidixic acid in vitro. Probenecid inhibits the tubular secretion of nalidixic acid and may reduce its efficacy in the treatment of urinary tract infections while increasing the risk of systemic side effects. Serious gastrointestinal toxicity has been associated with the concomitant use of nalidixic acid and the anti-cancer drug melphalan. (see CONTRAINDICATIONS) Antacids containing magnesium, aluminum, or calcium; sucralfate or divalent or trivalent cations such as iron; multivitamins containing zinc; and Videx®, (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution may substantially interfere with the absorption of quinolones, resulting in systemic levels considerably lower than desired. These agents should not be taken within the two-hour period before or within the two-hour period after nalidixic acid administration. Elevated serum levels of cyclosporine have been reported with the concomitant use of some quinolones and cyclosporine. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Drug Laboratory Test Interactions When Benedict's or Fehling's solution or Clinitest® Reagent Tablets are used to test the urine of patients taking NegGram, a false-positive reaction for glucose may be obtained, due to the liberation of glucuronic acid from the metabolites excreted. However, a colorimetric test for glucose based on an enzyme reaction (e.g., with Clinistix® Reagent Strips or Tes-Tape®) does not give a false-positive reaction to the liberated glucuronic acid. Incorrect values may be obtained for urinary 17-keto and ketogenic steroids in patients receiving NegGram, because of an interaction between the drug and the m-dinitrobenzene used in the usual assay method. In such cases, the Porter-Silber test for 17-hydroxycorticoids may be used. Carcinogenesis, Mutagenesis, Impairment of Fertility In lifetime studies in the rat given nalidixic acid in the diet, there was an increased incidence of preputial gland neoplasms in the treated males and clitoral gland neoplasms in the treated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda females. Studies in mice in which nalidixic acid was administered in the feed for two years, or was given in the feed for 76 weeks followed by no treatment for 9 weeks, gave equivocal evidence of carcinogenic activity. Nalidixic acid was tested in the Ames bacterial mutagenicity test (maximum dose 33 mcg/plate) and the mouse lymphoma assay (L5178Y/TK; maximum dose 100 mcg/mL) with and without metabolic activation, and results were negative. Pregnancy: Teratogenic Effects. Pregnancy Category C NegGram has been shown to be teratogenic and embryocidal in rats when given in oral doses six times the human dose. NegGram also prolonged the duration of pregnancy especially at four times the clinical dose. There are no adequate and well-controlled studies in pregnant women. Since nalidixic acid, like other drugs in this class, causes arthropathy in immature animals, NegGram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See WARNINGS and ANIMAL PHARMACOLOGY.) Nursing Mothers Since nalidixic acid is excreted in breast milk, it is contraindicated during lactation. Pediatric Use Safety and effectiveness in infants below the age of three months have not been established. Usage in Patients Under 18 Years of Age Toxicological studies have shown that nalidixic acid and related drugs can produce erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of most species tested. No such joint lesions have been reported in humans to date. Nevertheless, until the significance of this finding is clarified, this drug should only be used in patients under 18 years of age when the potential benefit justifies the potential risk. If arthralgia occurs, treatment with nalidixic acid should be stopped. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Clinical studies of NegGram 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. Caution should therefore be observed in using nalidixic acid in elderly patients. 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See PRECAUTIONS, General.) ADVERSE REACTIONS Reactions reported after oral administration of NegGram include the following. CNS effects: drowsiness, weakness, headache, dizziness and vertigo. Reversible subjective visual disturbances without objective findings have occurred infrequently (generally with each dose during the first few days of treatment). These reactions include overbrightness of lights, change in color perception, difficulty in focusing, decrease in visual acuity, and double vision. They usually disappeared promptly when dosage was reduced or therapy was discontinued. Toxic psychosis or brief convulsions have been reported rarely, usually following excessive doses. In general, the convulsions have occurred in patients with predisposing factors such as epilepsy or cerebral arteriosclerosis. In infants and children receiving therapeutic doses of NegGram, increased intracranial pressure with bulging anterior fontanel, papilledema, and headache has occasionally been observed. A few cases of 6th cranial nerve palsy have been reported. Although the mechanisms of these reactions are unknown, the signs and symptoms usually disappeared rapidly with no sequelae when treatment was discontinued. Gastrointestinal: abdominal pain, nausea, vomiting, and diarrhea. Allergic: rash, pruritus, urticaria, angioedema, eosinophilia, arthralgia with joint stiffness and swelling, and anaphylactoid reaction, including anaphylactic shock. Erythema Multiforme and Stevens- Johnson syndrome have been reported with nalidixic acid and other drugs in this class. Rash was the most frequently reported adverse reaction. Photosensitivity reactions consisting of erythema and bullae on exposed skin surfaces usually resolve completely in 2 weeks to 2 months after NegGram is discontinued; however, bullae may continue to appear with successive exposures to sunlight or with mild skin trauma for up to 3 months after discontinuation of drug. (See PRECAUTIONS.) Other: rarely, cholestasis, paresthesia, metabolic acidosis, thrombocytopenia, leukopenia, or hemolytic anemia, sometimes associated with glucose 6-phosphate dehydrogenase deficiency and peripheral neuropathy. OVERDOSAGE Manifestations: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Toxic psychosis, convulsions, increased intracranial pressure, or metabolic acidosis may occur in patients taking more than the recommended dosage. Vomiting, nausea, and lethargy may also occur following overdosage. Treatment: Reactions are short-lived (two to three hours) because the drug is rapidly excreted. If absorption has occurred, increased fluid administration is advisable and supportive measures such as oxygen and means of artificial respiration should be available. Although anticonvulsant therapy has not been used in the few instances of overdosage reported, it may be indicated in a severe case. DOSAGE AND ADMINISTRATION Antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent cations such as iron; multivitamins containing zinc; or Videx® (Didanosine), chewable/buffered tablets of the pediatric powder for oral solution should not be taken within the two-hour period before or within the two-hour period after taking nalidixic acid. Adults. The recommended dosage for initial therapy in adults is 1 g administered four times daily for one or two weeks (total daily dose, 4 g). For prolonged therapy, the total daily dose may be reduced to 2 g after the initial treatment period. Underdosage during initial treatment may predispose to emergence of bacterial resistance. Pediatric Patients. Until further experience is gained, NegGram should not be administered to infants younger than three months. Dosage in pediatric patients 12 years of age and under should be calculated on the basis of body weight. The recommended total daily dosage for initial therapy is 25 mg/lb/day (55 mg/kg/day), administered in four equally divided doses. For prolonged therapy, the total daily dose may be reduced to 15 mg/lb/day (33 mg/kg/day). NegGram Caplets of 250 mg may be used. HOW SUPPLIED NegGram (nalidixic acid, USP) is supplied as: Caplets of 500 mg, light buff-colored capsule-shaped tablets, bottles of 56 (NDC 0024-1322-03) Store at room temperature, up to 30° C (86° F). ANIMAL PHARMACOLOGY This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NegGram (nalidixic acid) and related drugs have been shown to cause arthropathy in juvenile animals of most species tested. (See WARNINGS.) Long-term administration of nalidixic acid to rats resulted in retinal degeneration and cataracts. Hydroxynalidixic acid, the principal metabolite of NegGram, did not produce any oculotoxic effects at any dosage level in seven species of animals including three primate species. However, oral administration of this metabolite in high doses has been shown to have oculotoxic potential, namely in dogs and cats where it produced retinal degeneration upon prolonged administration leading, in some cases, to blindness. In experiments with NegGram itself, little if any such activity could be elicited in either dogs or cats. Sensitivity to CNS side effects in these species limited the doses of NegGram that could be used; this factor, together with a low conversion rate to the hydroxy metabolite in these species, may explain the absence of these effects. Rx Only Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 Revised April 2007 © 2007 sanofi-aventis U.S. LLC This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:51.864152	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/014214s057lbl.pdf', 'application_number': 14214, 'submission_type': 'SUPPL ', 'submission_number': 57}
10,839	company logo CELESTONE SYRUP PAGE 1 NDA 14-215/S-009, 015 CELESTONE® betamethasone syrup, USP DESCRIPTION CELESTONE Syrup, for oral administration, contains 0.6 mg betamethasone in each 5 mL. The inactive ingredients for CELESTONE Syrup include: alcohol (less than 1%), citric acid, FD&C Red No. 40, FD&C Yellow No. 6, flavors, propylene glycol, sodium benzoate, sodium chloride, sorbitol, sugar, and water. The formula for betamethasone is C22H29F05 and it has a molecular weight of 392.47. Chemically, it is 9-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione and has the following structure: (Add structure) Betamethasone is a white to practically white, odorless crystalline powder. It melts at about 240°C with some decomposition. Betamethasone is sparingly soluble in acetone, alcohol, dioxane, and methanol; very slightly soluble in chloroform and ether; and is insoluble in water. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs, such as betamethasone, are primarily used for their anti-inflammatory effects in disorders of many organ systems. A derivative of prednisolone, betamethasone has a 16β methyl group that enhances the anti-inflammatory action of the molecule and reduces the sodium- and water-retaining properties of the fluorine atom bound at carbon 9. INDICATIONS AND USAGE Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness. Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine disorders: Congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 2 NDA 14-215/S-009, 015 Hydrocortisone or cortisone is the drug of choice in primary or secondary adrenocortical insufficiency. Synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. Nervous System: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, craniotomy, or head injury. Ophthalmic diseases: Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. CONTRAINDICATIONS CELESTONE Syrup is contraindicated in patients who are hypersensitive to any components of this product. WARNINGS General: Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). In patients on corticosteroid therapy subjected to any unusual stress hydrocortisone or cortisone areis the drugs of choice as a supplement during and after the event. company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 3 NDA 14-215/S-009, 015 Cardio-renal: Average and large doses of corticosteroids 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. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. 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: Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal infections: Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS, Drug Interactions, Amphotericin B injection and potassium-depleting agents). Special pathogens: Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis 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 company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 4 NDA 14-215/S-009, 015 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 corticosteroids 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. 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. Viral infections: Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. 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. PRECAUTIONS General: The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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. company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 5 NDA 14-215/S-009, 015 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 congestive heart failure, hypertension, 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, naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used asrather than betamethasone, are the appropriate choices as replacement therapy in adrenocortical deficiency states. Gastrointestinal: Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. 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 lead to inhibition of bone growth in pediatric patients 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, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 6 NDA 14-215/S-009, 015 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 corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on 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: Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin-B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases: 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. Anticoagulants, oral: 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. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 7 NDA 14-215/S-009, 015 Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other nonsteroidal 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. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility: No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy: Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have 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. Corticosteroids 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 corticosteroids are administered to a nursing woman. Pediatric Use: The efficacy and safety of corticosteroids 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). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 8 NDA 14-215/S-009, 015 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 corticosteroids 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. Pediatric patients 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 pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use: No overall differences in safety or effectiveness were observed between elderly 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. ADVERSE REACTIONS (listed alphabetically, under each subsection) Allergic reactions: Anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, dry scaly skin, ecchymoses and petechiae, edema, erythema, impaired wound healing, increased sweating, rash, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, 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 pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 9 NDA 14-215/S-009, 015 Gastrointestinal: Abdominal distention, elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), 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. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE 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 the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION The initial dosage of CELESTONE Syrup may vary from 0.6 mg to 7.2 mg per day depending on the specific disease entity being treated. 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. 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 the corticosteroid 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 30 mg of betamethasone for a week followed by 12 mg every other day for one month are recommended (see PRECAUTIONS, Neuro-psychiatric). company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 10 NDA 14-215/S-009, 015 In pediatric patients, the initial dose of betamethasone may vary depending on the specific disease entity being treated. The range of initial doses is 0.02 to 0.3 mg/kg/day in three or four divided doses (0.6 to 9 mg/m2 bsa/day). 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 CELESTONE Syrup, 0.6 mg per 5 mL, orange-red colored liquid, bottle of 4 fluid ounces (118 mL) (NDC 0085-0942-05). Protect from light. Store at controlled room temperature 20°to 25°C (68° to 77°F). Rx only. Schering Corporation Kenilworth, NJ 07033 USA Rev 2/04 Copyright © 1968, 1993, 1994, 1995, Schering Corporation. All rights reserved. CELESTONE® brand of betamethasone syrup, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:52.079576	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/014215s009s015lbl.pdf', 'application_number': 14215, 'submission_type': 'SUPPL ', 'submission_number': 9}
10,840	company logo CELESTONE SYRUP PAGE 1 NDA 14-215/S-009, 015 CELESTONE® betamethasone syrup, USP DESCRIPTION CELESTONE Syrup, for oral administration, contains 0.6 mg betamethasone in each 5 mL. The inactive ingredients for CELESTONE Syrup include: alcohol (less than 1%), citric acid, FD&C Red No. 40, FD&C Yellow No. 6, flavors, propylene glycol, sodium benzoate, sodium chloride, sorbitol, sugar, and water. The formula for betamethasone is C22H29F05 and it has a molecular weight of 392.47. Chemically, it is 9-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione and has the following structure: (Add structure) Betamethasone is a white to practically white, odorless crystalline powder. It melts at about 240°C with some decomposition. Betamethasone is sparingly soluble in acetone, alcohol, dioxane, and methanol; very slightly soluble in chloroform and ether; and is insoluble in water. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs, such as betamethasone, are primarily used for their anti-inflammatory effects in disorders of many organ systems. A derivative of prednisolone, betamethasone has a 16β methyl group that enhances the anti-inflammatory action of the molecule and reduces the sodium- and water-retaining properties of the fluorine atom bound at carbon 9. INDICATIONS AND USAGE Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness. Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine disorders: Congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 2 NDA 14-215/S-009, 015 Hydrocortisone or cortisone is the drug of choice in primary or secondary adrenocortical insufficiency. Synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. Nervous System: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, craniotomy, or head injury. Ophthalmic diseases: Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. CONTRAINDICATIONS CELESTONE Syrup is contraindicated in patients who are hypersensitive to any components of this product. WARNINGS General: Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). In patients on corticosteroid therapy subjected to any unusual stress hydrocortisone or cortisone areis the drugs of choice as a supplement during and after the event. company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 3 NDA 14-215/S-009, 015 Cardio-renal: Average and large doses of corticosteroids 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. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. 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: Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal infections: Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS, Drug Interactions, Amphotericin B injection and potassium-depleting agents). Special pathogens: Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis 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 company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 4 NDA 14-215/S-009, 015 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 corticosteroids 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. 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. Viral infections: Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. 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. PRECAUTIONS General: The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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. company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 5 NDA 14-215/S-009, 015 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 congestive heart failure, hypertension, 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, naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used asrather than betamethasone, are the appropriate choices as replacement therapy in adrenocortical deficiency states. Gastrointestinal: Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. 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 lead to inhibition of bone growth in pediatric patients 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, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 6 NDA 14-215/S-009, 015 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 corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on 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: Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin-B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases: 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. Anticoagulants, oral: 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. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 7 NDA 14-215/S-009, 015 Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other nonsteroidal 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. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility: No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy: Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have 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. Corticosteroids 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 corticosteroids are administered to a nursing woman. Pediatric Use: The efficacy and safety of corticosteroids 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). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 8 NDA 14-215/S-009, 015 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 corticosteroids 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. Pediatric patients 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 pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use: No overall differences in safety or effectiveness were observed between elderly 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. ADVERSE REACTIONS (listed alphabetically, under each subsection) Allergic reactions: Anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, dry scaly skin, ecchymoses and petechiae, edema, erythema, impaired wound healing, increased sweating, rash, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, 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 pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 9 NDA 14-215/S-009, 015 Gastrointestinal: Abdominal distention, elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), 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. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE 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 the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION The initial dosage of CELESTONE Syrup may vary from 0.6 mg to 7.2 mg per day depending on the specific disease entity being treated. 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. 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 the corticosteroid 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 30 mg of betamethasone for a week followed by 12 mg every other day for one month are recommended (see PRECAUTIONS, Neuro-psychiatric). company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CELESTONE SYRUP PAGE 10 NDA 14-215/S-009, 015 In pediatric patients, the initial dose of betamethasone may vary depending on the specific disease entity being treated. The range of initial doses is 0.02 to 0.3 mg/kg/day in three or four divided doses (0.6 to 9 mg/m2 bsa/day). 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 CELESTONE Syrup, 0.6 mg per 5 mL, orange-red colored liquid, bottle of 4 fluid ounces (118 mL) (NDC 0085-0942-05). Protect from light. Store at controlled room temperature 20°to 25°C (68° to 77°F). Rx only. Schering Corporation Kenilworth, NJ 07033 USA Rev 2/04 Copyright © 1968, 1993, 1994, 1995, Schering Corporation. All rights reserved. CELESTONE® brand of betamethasone syrup, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:52.286927	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/014215s009s015lbl.pdf', 'application_number': 14215, 'submission_type': 'SUPPL ', 'submission_number': 15}
10,833	NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/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	2025-02-12T13:43:52.290386	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/013684s092,016677s139,et al_lbl.pdf', 'application_number': 13684, 'submission_type': 'SUPPL ', 'submission_number': 92}
10,841	1 Rev. February 2006 NORPRAMIN® (desipramine hydrochloride tablets USP) Suicidality in Children and Adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short- term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of NORPRAMIN or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. NORPRAMIN is not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS: Pediatric Use.) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. DESCRIPTION NORPRAMIN® (desipramine hydrochloride USP) is an antidepressant drug of the tricyclic type, and is chemically: 5H-Dibenz[bƒ]azepine-5-propanamine,10,11-dihydro-N-methyl-, monohydrochloride. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Inactive Ingredients The following inactive ingredients are contained in all dosage strengths: acacia, calcium carbonate, corn starch, D&C Red No. 30 and D&C Yellow No. 10 (except 10 mg and 150 mg), FD&C Blue No. 1 (except 50 mg, 75 mg, and 100 mg), hydrogenated soy oil, iron oxide, light mineral oil, magnesium stearate, mannitol, polyethylene glycol 8000, pregelatinized corn starch, sodium benzoate (except 150 mg), sucrose, talc, titanium dioxide, and other ingredients. CLINICAL PHARMACOLOGY Mechanism of Action Available evidence suggests that many depressions have a biochemical basis in the form of a relative deficiency of neurotransmitters such as norepinephrine and serotonin. Norepinephrine deficiency may be associated with relatively low urinary 3-methoxy-4-hydroxyphenyl glycol (MHPG) levels, while serotonin deficiencies may be associated with low spinal fluid levels of 5- hydroxyindoleacetic acid. While the precise mechanism of action of the tricyclic antidepressants is unknown, a leading theory suggests that they restore normal levels of neurotransmitters by blocking the re-uptake of these substances from the synapse in the central nervous system. Evidence indicates that the secondary amine tricyclic antidepressants, including NORPRAMIN, may have greater activity in blocking the re-uptake of norepinephrine. Tertiary amine tricyclic antidepressants, such as amitriptyline, may have greater effect on serotonin re-uptake. NORPRAMIN is not a monoamine oxidase (MAO) inhibitor and does not act primarily as a central nervous system stimulant. It has been found in some studies to have a more rapid onset of action than imipramine. Earliest therapeutic effects may occasionally be seen in 2 to 5 days, but full treatment benefit usually requires 2 to 3 weeks to obtain. Metabolism Tricyclic antidepressants, such as desipramine hydrochloride, are rapidly absorbed from the gastrointestinal tract. Tricyclic antidepressants or their metabolites are to some extent excreted through the gastric mucosa and reabsorbed from the gastrointestinal tract. Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. The rate of metabolism of tricyclic antidepressants varies widely from individual to individual, chiefly on a genetically determined basis. Up to a 36-fold difference in plasma level may be noted among individuals taking the same oral dose of desipramine. The ratio of 2- hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. Certain drugs, particularly the psychostimulants and the phenothiazines, increase plasma levels of concomitantly administered tricyclic antidepressants through competition for the same metabolic enzyme systems. Concurrent administration of cimetidine and tricyclic antidepressants This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressants. Conversely, decreases in plasma levels of the tricyclic antidepressants have been reported upon discontinuation of cimetidine, which may result in the loss of the therapeutic efficacy of the tricyclic antidepressant. Other substances, particularly barbiturates and alcohol, induce liver enzyme activity and thereby reduce tricyclic antidepressant plasma levels. Similar effects have been reported with tobacco smoke. Research on the relationship of plasma level to therapeutic response with the tricyclic antidepressants has produced conflicting results. While some studies report no correlation, many studies cite therapeutic levels for most tricyclics in the range of 50 to 300 nanograms per milliliter. The therapeutic range is different for each tricyclic antidepressant. For desipramine, an optimal range of therapeutic plasma levels has not been established. INDICATIONS AND USAGE NORPRAMIN is indicated for the treatment of depression. CONTRAINDICATIONS NORPRAMIN should not be given in conjunction with, or within 2 weeks of, treatment with an MAO inhibitor drug; hyperpyretic crises, severe convulsions, and death have occurred in patients taking MAO inhibitors and tricyclic antidepressants. When NORPRAMIN is substituted for an MAO inhibitor, at least 2 weeks should elapse between treatments. NORPRAMIN should then be started cautiously and should be increased gradually. NORPRAMIN is contraindicated in the acute recovery period following myocardial infarction. It should not be used in those who have shown prior hypersensitivity to the drug. Cross-sensitivity between this and other dibenzazepines is a possibility. WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long- standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. A causal role for antidepressants in inducing suicidality has been established in pediatric patients. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for NORPRAMIN should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that NORPRAMIN is not approved for use in treating bipolar depression. General Extreme caution should be used when this drug is given in the following situations: a. In patients with cardiovascular disease, because of the possibility of conduction defects, arrhythmias, tachycardias, strokes, and acute myocardial infarction. b. In patients with a history of urinary retention or glaucoma, because of the anticholinergic properties of the drug. c. In patients with thyroid disease or those taking thyroid medication, because of the possibility of cardiovascular toxicity, including arrhythmias. d. In patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold. This drug is capable of blocking the antihypertensive effect of guanethidine and similarly acting compounds. The patient should be cautioned that this drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage. Use in Pregnancy Safe use of NORPRAMIN during pregnancy and lactation has not been established; therefore, if it is to be given to pregnant patients, nursing mothers, or women of childbearing potential, the possible benefits must be weighed against the possible hazards to mother and child. Animal reproductive studies have been inconclusive. Geriatric Use Clinical studies of NORPRAMIN 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 patients. Lower doses are recommended for elderly patients. (See DOSAGE AND ADMINISTRATION.) The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. 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. NORPRAMIN use in the elderly has been associated with a proneness to falling as well as confusional states. (See ADVERSE REACTIONS.) PRECAUTIONS Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with NORPRAMIN and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Adolescents is available for NORPRAMIN. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking NORPRAMIN. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Therefore, NORPRAMIN (desipramine hydrochloride) is not recommended for use in children. Anyone considering the use of NORPRAMIN in a child or adolescent must balance the potential risks with the clinical need (see also ADVERSE REACTIONS-Cardiovascular). General It is important that this drug be dispensed in the least possible quantities to depressed outpatients, since suicide has been accomplished with this class of drug (see WARNINGS-Clinical Worsening and Suicide Risk). Ordinary prudence requires that children not have access to this drug or to potent drugs of any kind; if possible, this drug should be dispensed in containers with child-resistant safety closures. Storage of this drug in the home must be supervised responsibly. If serious adverse effects occur, dosage should be reduced or treatment should be altered. NORPRAMIN therapy in patients with manic-depressive illness may induce a hypomanic state after the depressive phase terminates. The drug may cause exacerbation of psychosis in schizophrenic patients. Both elevation and lowering of blood sugar levels have been reported. Leukocyte and differential counts should be performed in any patient who develops fever and sore throat during therapy; the drug should be discontinued if there is evidence of pathologic neutrophil depression. Clinical experience in the concurrent administration of ECT and antidepressant drugs is limited. Thus, if such treatment is essential, the possibility of increased risk relative to benefits should be considered. This drug should be discontinued as soon as possible prior to elective surgery because of possible cardiovascular effects. Hypertensive episodes have been observed during surgery in patients taking desipramine hydrochloride. Drug Interactions Drugs Metabolized by P450 2D6. The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type ΙC antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Close supervision and careful adjustment of dosage are required when this drug is given concomitantly with anticholinergic or sympathomimetic drugs. Patients should be warned that while taking this drug their response to alcoholic beverages may be exaggerated. If NORPRAMIN is to be combined with other psychotropic agents such as tranquilizers or sedative/hypnotics, careful consideration should be given to the pharmacology of the agents employed since the sedative effects of NORPRAMIN and benzodiazepines (e.g., chlordiazepoxide or diazepam) are additive. Both the sedative and anticholinergic effects of the major tranquilizers are also additive to those of NORPRAMIN. ADVERSE REACTIONS Included in the following listing are a few adverse reactions that have not been reported with this specific drug. However, the pharmacologic similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when NORPRAMIN is given. Cardiovascular: Hypotension, hypertension, palpitations, heart block, myocardial infarction, stroke, arrhythmias, premature ventricular contractions, tachycardia, ventricular tachycardia, ventricular fibrillation, sudden death This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 There has been a report of an "acute collapse" and "sudden death" in an 8-year-old (18 kg) male, treated for 2 years for hyperactivity. There have been additional reports of sudden death in children. (See PRECAUTIONS-Pediatric Use) Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis Neurologic: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures; alterations in EEG patterns; tinnitus Symptoms attributed to Neuroleptic Malignant Syndrome have been reported during desipramine use with and without concomitant neuroleptic therapy. Anticholinergic: Dry mouth, and rarely associated sublingual adenitis; blurred vision, disturbance of accommodation, mydriasis, increased intraocular pressure; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of urinary tract Allergic: Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive exposure to sunlight), edema (of face and tongue or general), drug fever, cross-sensitivity with other tricyclic drugs Hematologic: Bone marrow depressions including agranulocytosis, eosinophilia, purpura, thrombocytopenia Gastrointestinal: Anorexia, nausea and vomiting, epigastric distress, peculiar taste, abdominal cramps, diarrhea, stomatitis, black tongue, hepatitis, jaundice (simulating obstructive), altered liver function, elevated liver function tests, increased pancreatic enzymes Endocrine: Gynecomastia in the male, breast enlargement and galactorrhea in the female; increased or decreased libido, impotence, painful ejaculation, testicular swelling; elevation or depression of blood sugar levels; syndrome of inappropriate antidiuretic hormone secretion (SIADH) Other: Weight gain or loss; perspiration, flushing; urinary frequency, nocturia; parotid swelling; drowsiness, dizziness, proneness to falling, weakness and fatigue, headache; fever; alopecia; elevated alkaline phosphatase Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise. OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Higher case fatality rates have been reported with desipramine overdose compared to other tricyclic antidepressants. Multiple drug This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. There is no specific antidote for desipramine overdosage. Oral LD50 The oral LD50 of desipramine is 290 mg/kg in male mice and 320 mg/kg in female rats. Manifestations of Overdosage Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Management Aggressive supportive care and serum alkalinization are the mainstays of therapy. General. Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. Follow ECG, renal function, CPK, and arterial blood gasses as clinically indicated. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death, and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination. All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular. A maximal limb-lead QRS duration of ≥0.10 seconds may be the best indication of the severity of the overdose. Serum alkalinization, to a pH of 7.45 to 7.55, using intravenous sodium bicarbonate and hyperventilation (as needed) should be instituted for patients with dysrhythmias and/or QRS widening. A pH >7.60 or a pCO2 <20mm Hg is undesirable. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type ΙA and ΙC antiarrhythmics are generally contraindicated (eg, quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS. In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines. If these are ineffective or seizures recur, other anticonvulsants (eg, phenobarbital, phenytoin) may be used. Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up. Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management. The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. DOSAGE AND ADMINISTRATION Not recommended for use in children (see WARNINGS). Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients compared to hospitalized patients, who are closely supervised. Dosage should be initiated at a low level and increased according to clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a period of time and should be at the lowest dose that will maintain remission. Usual Adult Dose The usual adult dose is 100 to 200 mg per day. In more severely ill patients, dosage may be further increased gradually to 300 mg/day if necessary. Dosages above 300 mg/day are not recommended. Dosage should be initiated at a lower level and increased according to tolerance and clinical response. Treatment of patients requiring as much as 300 mg should generally be initiated in hospitals, where regular visits by the physician, skilled nursing care, and frequent electrocardiograms (ECGs) are available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 The best available evidence of impending toxicity from very high doses of NORPRAMIN is prolongation of the QRS or QT intervals on the ECG. Prolongation of the PR interval is also significant, but less closely correlated with plasma levels. Clinical symptoms of intolerance, especially drowsiness, dizziness, and postural hypotension, should also alert the physician to the need for reduction in dosage. Plasma desipramine measurement would constitute the optimal guide to dosage monitoring. Initial therapy may be administered in divided doses or a single daily dose. Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. Adolescent and Geriatric Dose The usual adolescent and geriatric dose is 25 to 100 mg daily. Dosage should be initiated at a lower level and increased according to tolerance and clinical response to a usual maximum of 100 mg daily. In more severely ill patients, dosage may be further increased to 150 mg/day. Doses above 150 mg/day are not recommended in these age groups. Initial therapy may be administered in divided doses or a single daily dose. Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. HOW SUPPLIED 10 mg blue coated tablets imprinted 68-7 NDC 0068-0007-01: bottles of 100 25 mg yellow coated tablets imprinted NORPRAMIN 25 NDC 0068-0011-01: bottles of 100 50 mg green coated tablets imprinted NORPRAMIN 50 NDC 0068-0015-01: bottles of 100 75 mg orange coated tablets imprinted NORPRAMIN 75 NDC 0068-0019-01: bottles of 100 100 mg peach coated tablets imprinted NORPRAMIN 100 NDC 0068-0020-01: bottles of 100 150 mg white coated tablets imprinted NORPRAMIN 150 NDC 0068-0021-50: bottles of 50 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NORPRAMIN tablets should be stored at room temperature, preferably below 86°F (30°C). Protect from excessive heat. Dispense in tight container. Rx only Rev. February 2006 Mfd by: Patheon Pharmaceuticals Inc. Cincinnati, OH 45237 USA Mfd for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Medication Guide Norpramin® (desipramine hydrochloride tablets USP) About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions 2. How to try to prevent suicidal thoughts or actions in your child 3. You should watch for certain signs if your child is taking an antidepressant 4. There are benefits and risks when using antidepressants 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child’s life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. Whenever an antidepressant is started or its dose is changed, pay close attention to your child. After starting an antidepressant, your child should generally see his or her healthcare provider: • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your healthcare provider’s advice about how often to come back • More often if problems or questions arise (see other side) You should call your child’s healthcare provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child’s healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child’s teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms. 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Of all the antidepressants, only fluoxetine (Prozac™) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac™), sertraline (Zoloft™), fluvoxamine, and clomipramine (Anafranil™). Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Mfd by: Patheon Pharmaceuticals Inc. Cincinnati, OH 45237 USA Mfd for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:52.582847	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/014399s063lbl.pdf', 'application_number': 14399, 'submission_type': 'SUPPL ', 'submission_number': 63}
10,842	NORPRAMIN® (desipramine hydrochloride tablets USP) Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of NORPRAMIN or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. NORPRAMIN is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.) DESCRIPTION NORPRAMIN® (desipramine hydrochloride USP) is an antidepressant drug of the tricyclic type, and is chemically: 5H-Dibenz[bƒ]azepine-5-propanamine,10,11-dihydro-N-methyl-, monohydrochloride. Structural Formula 1 Inactive Ingredients The following inactive ingredients are contained in all dosage strengths: acacia, calcium carbonate, corn starch, D&C Red No. 30 and D&C Yellow No. 10 (except 10 mg and 150 mg), FD&C Blue No. 1 (except 50 mg, 75 mg, and 100 mg), hydrogenated soy oil, iron oxide, light mineral oil, magnesium stearate, mannitol, polyethylene glycol 8000, pregelatinized corn starch, sodium benzoate (except 150 mg), sucrose, talc, titanium dioxide, and other ingredients. CLINICAL PHARMACOLOGY Mechanism of Action Available evidence suggests that many depressions have a biochemical basis in the form of a relative deficiency of neurotransmitters such as norepinephrine and serotonin. Norepinephrine deficiency may be associated with relatively low urinary 3-methoxy-4-hydroxyphenyl glycol (MHPG) levels, while serotonin deficiencies may be associated with low spinal fluid levels of 5 hydroxyindoleacetic acid. While the precise mechanism of action of the tricyclic antidepressants is unknown, a leading theory suggests that they restore normal levels of neurotransmitters by blocking the re-uptake of these substances from the synapse in the central nervous system. Evidence indicates that the secondary amine tricyclic antidepressants, including NORPRAMIN, may have greater activity in blocking the re-uptake of norepinephrine. Tertiary amine tricyclic antidepressants, such as amitriptyline, may have greater effect on serotonin re-uptake. NORPRAMIN is not a monoamine oxidase (MAO) inhibitor and does not act primarily as a central nervous system stimulant. It has been found in some studies to have a more rapid onset of action than imipramine. Earliest therapeutic effects may occasionally be seen in 2 to 5 days, but full treatment benefit usually requires 2 to 3 weeks to obtain. Metabolism Tricyclic antidepressants, such as desipramine hydrochloride, are rapidly absorbed from the gastrointestinal tract. Tricyclic antidepressants or their metabolites are to some extent excreted through the gastric mucosa and reabsorbed from the gastrointestinal tract. Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. The rate of metabolism of tricyclic antidepressants varies widely from individual to individual, chiefly on a genetically determined basis. Up to a 36-fold difference in plasma level may be noted among individuals taking the same oral dose of desipramine. The ratio of 2 hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. Certain drugs, particularly the psychostimulants and the phenothiazines, increase plasma levels of concomitantly administered tricyclic antidepressants through competition for the same metabolic enzyme systems. Concurrent administration of cimetidine and tricyclic antidepressants 2 can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressants. Conversely, decreases in plasma levels of the tricyclic antidepressants have been reported upon discontinuation of cimetidine, which may result in the loss of the therapeutic efficacy of the tricyclic antidepressant. Other substances, particularly barbiturates and alcohol, induce liver enzyme activity and thereby reduce tricyclic antidepressant plasma levels. Similar effects have been reported with tobacco smoke. Research on the relationship of plasma level to therapeutic response with the tricyclic antidepressants has produced conflicting results. While some studies report no correlation, many studies cite therapeutic levels for most tricyclics in the range of 50 to 300 nanograms per milliliter. The therapeutic range is different for each tricyclic antidepressant. For desipramine, an optimal range of therapeutic plasma levels has not been established. INDICATIONS AND USAGE NORPRAMIN is indicated for the treatment of depression. CONTRAINDICATIONS NORPRAMIN should not be given in conjunction with, or within 2 weeks of, treatment with an MAO inhibitor drug; hyperpyretic crises, severe convulsions, and death have occurred in patients taking MAO inhibitors and tricyclic antidepressants. When NORPRAMIN is substituted for an MAO inhibitor, at least 2 weeks should elapse between treatments. NORPRAMIN should then be started cautiously and should be increased gradually. NORPRAMIN is contraindicated in the acute recovery period following myocardial infarction. It should not be used in those who have shown prior hypersensitivity to the drug. Cross-sensitivity between this and other dibenzazepines is a possibility. WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with 3 antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short- term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo- controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short- term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. 4 Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for NORPRAMIN should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that NORPRAMIN is not approved for use in treating bipolar depression. General Extreme caution should be used when this drug is given in the following situations: a. In patients with cardiovascular disease, because of the possibility of conduction defects, arrhythmias, tachycardias, strokes, and acute myocardial infarction. b. In patients who have a family history of sudden death, cardiac dysrhythmias, or cardiac conduction disturbances. c. In patients with a history of urinary retention or glaucoma, because of the anticholinergic properties of the drug. d. In patients with thyroid disease or those taking thyroid medication, because of the possibility of cardiovascular toxicity, including arrhythmias. e. In patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold. Seizures precede cardiac dysrhythmias and death in some patients. This drug is capable of blocking the antihypertensive effect of guanethidine and similarly acting compounds. The patient should be cautioned that this drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. 5 In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage. Use in Pregnancy Safe use of NORPRAMIN during pregnancy and lactation has not been established; therefore, if it is to be given to pregnant patients, nursing mothers, or women of childbearing potential, the possible benefits must be weighed against the possible hazards to mother and child. Animal reproductive studies have been inconclusive. Geriatric Use Clinical studies of NORPRAMIN 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. Lower doses are recommended for elderly patients. (See DOSAGE AND ADMINISTRATION.) The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. 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. NORPRAMIN use in the elderly has been associated with a proneness to falling as well as confusional states. (See ADVERSE REACTIONS.) PRECAUTIONS Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with NORPRAMIN and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for NORPRAMIN. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking NORPRAMIN. 6 Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Therefore, NORPRAMIN (desipramine hydrochloride) is not recommended for use in children. Anyone considering the use of NORPRAMIN in a child or adolescent must balance the potential risks with the clinical need (see also ADVERSE REACTIONS-Cardiovascular). General It is important that this drug be dispensed in the least possible quantities to depressed outpatients, since suicide has been accomplished with this class of drug (see WARNINGS-Clinical Worsening and Suicide Risk). Ordinary prudence requires that children not have access to this drug or to potent drugs of any kind; if possible, this drug should be dispensed in containers with child-resistant safety closures. Storage of this drug in the home must be supervised responsibly. If serious adverse effects occur, dosage should be reduced or treatment should be altered. NORPRAMIN therapy in patients with manic-depressive illness may induce a hypomanic state after the depressive phase terminates. The drug may cause exacerbation of psychosis in schizophrenic patients. Both elevation and lowering of blood sugar levels have been reported. Leukocyte and differential counts should be performed in any patient who develops fever and sore throat during therapy; the drug should be discontinued if there is evidence of pathologic neutrophil depression. Clinical experience in the concurrent administration of ECT and antidepressant drugs is limited. Thus, if such treatment is essential, the possibility of increased risk relative to benefits should be considered. 7 This drug should be discontinued as soon as possible prior to elective surgery because of possible cardiovascular effects. Hypertensive episodes have been observed during surgery in patients taking desipramine hydrochloride. Drug Interactions Drugs Metabolized by P450 2D6. The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type ΙC antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Close supervision and careful adjustment of dosage are required when this drug is given concomitantly with anticholinergic or sympathomimetic drugs. Patients should be warned that while taking this drug their response to alcoholic beverages may be exaggerated. If NORPRAMIN is to be combined with other psychotropic agents such as tranquilizers or sedative/hypnotics, careful consideration should be given to the pharmacology of the agents 8 employed since the sedative effects of NORPRAMIN and benzodiazepines (e.g., chlordiazepoxide or diazepam) are additive. Both the sedative and anticholinergic effects of the major tranquilizers are also additive to those of NORPRAMIN. ADVERSE REACTIONS Included in the following listing are a few adverse reactions that have not been reported with this specific drug. However, the pharmacologic similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when NORPRAMIN is given. Cardiovascular: Hypotension, hypertension, palpitations, heart block, myocardial infarction, stroke, arrhythmias, premature ventricular contractions, tachycardia, ventricular tachycardia, ventricular fibrillation, sudden death There has been a report of an "acute collapse" and "sudden death" in an 8-year-old (18 kg) male, treated for 2 years for hyperactivity. There have been additional reports of sudden death in children. (See PRECAUTIONS-Pediatric Use) Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis Neurologic: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures; alterations in EEG patterns; tinnitus Symptoms attributed to Neuroleptic Malignant Syndrome have been reported during desipramine use with and without concomitant neuroleptic therapy. Anticholinergic: Dry mouth, and rarely associated sublingual adenitis; blurred vision, disturbance of accommodation, mydriasis, increased intraocular pressure; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of urinary tract Allergic: Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive exposure to sunlight), edema (of face and tongue or general), drug fever, cross-sensitivity with other tricyclic drugs Hematologic: Bone marrow depressions including agranulocytosis, eosinophilia, purpura, thrombocytopenia Gastrointestinal: Anorexia, nausea and vomiting, epigastric distress, peculiar taste, abdominal cramps, diarrhea, stomatitis, black tongue, hepatitis, jaundice (simulating obstructive), altered liver function, elevated liver function tests, increased pancreatic enzymes Endocrine: Gynecomastia in the male, breast enlargement and galactorrhea in the female; increased or decreased libido, impotence, painful ejaculation, testicular swelling; elevation or 9 depression of blood sugar levels; syndrome of inappropriate antidiuretic hormone secretion (SIADH) Other: Weight gain or loss; perspiration, flushing; urinary frequency, nocturia; parotid swelling; drowsiness, dizziness, proneness to falling, weakness and fatigue, headache; fever; alopecia; elevated alkaline phosphatase Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise. OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Overdose of desipramine has resulted in a higher death rate compared to overdoses of other tricyclic antidepressants. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. There is no specific antidote for desipramine overdosage. Oral LD50 The oral LD50 of desipramine is 290 mg/kg in male mice and 320 mg/kg in female rats. Manifestations of Overdosage Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Early changes in the QRS complex include a widening of the terminal 40 msec with a rightward axis in the frontal plane, recognized by the presence of a terminal S wave in Lead 1 and AVL and an R wave in AVR. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Management Aggressive supportive care and serum alkalinization are the mainstays of therapy. General. Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is 10 required. Follow ECG, renal function, CPK, and arterial blood gasses as clinically indicated. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death, and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination. Emesis is contraindicated. Activated charcoal should be administered to patients who present early after an overdose. Cardiovascular. A maximal limb-lead QRS duration widening to greater than 100 msec is a significant indicator of toxicity, specifically for the risk of seizures and, eventually, cardiac dysrhythmias. Serum alkalinization with intravenous sodium bicarbonate and hyperventilation (as needed) should be instituted in patients manifesting significant toxicity such as QRS widening. Dysrhythmias despite adequate alkalemia may respond to overdrive pacing, beta- agonist infusions, and magnesium therapy. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). CNS. In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines. If these are ineffective or seizures recur, other anticonvulsants (eg, phenobarbital, propofol) may be used. Psychiatric Follow-up. Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management. The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. DOSAGE AND ADMINISTRATION Not recommended for use in children (see WARNINGS). Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients compared to hospitalized patients, who are closely supervised. Dosage should be initiated at a low level and increased according to clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a period of time and should be at the lowest dose that will maintain remission. Usual Adult Dose The usual adult dose is 100 to 200 mg per day. In more severely ill patients, dosage may be further increased gradually to 300 mg/day if necessary. Dosages above 300 mg/day are not recommended. Dosage should be initiated at a lower level and increased according to tolerance and clinical response. 11 Treatment of patients requiring as much as 300 mg should generally be initiated in hospitals, where regular visits by the physician, skilled nursing care, and frequent electrocardiograms (ECGs) are available. The best available evidence of impending toxicity from very high doses of NORPRAMIN is prolongation of the QRS or QT intervals on the ECG. Prolongation of the PR interval is also significant, but less closely correlated with plasma levels. Clinical symptoms of intolerance, especially drowsiness, dizziness, and postural hypotension, should also alert the physician to the need for reduction in dosage. Initial therapy may be administered in divided doses or a single daily dose. Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. Adolescent and Geriatric Dose The usual adolescent and geriatric dose is 25 to 100 mg daily. Dosage should be initiated at a lower level and increased according to tolerance and clinical response to a usual maximum of 100 mg daily. In more severely ill patients, dosage may be further increased to 150 mg/day. Doses above 150 mg/day are not recommended in these age groups. Initial therapy may be administered in divided doses or a single daily dose. Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. HOW SUPPLIED 10 mg blue coated tablets imprinted 68-7 NDC 0068-0007-01: bottles of 100 25 mg yellow coated tablets imprinted NORPRAMIN 25 NDC 0068-0011-01: bottles of 100 50 mg green coated tablets imprinted NORPRAMIN 50 NDC 0068-0015-01: bottles of 100 75 mg orange coated tablets imprinted NORPRAMIN 75 NDC 0068-0019-01: bottles of 100 100 mg peach coated tablets imprinted NORPRAMIN 100 NDC 0068-0020-01: bottles of 100 12 150 mg white coated tablets imprinted NORPRAMIN 150 NDC 0068-0021-50: bottles of 50 NORPRAMIN tablets should be stored at room temperature, preferably below 86°F (30°C). Protect from excessive heat. Dispense in tight container. Rx only Rev. October 2009 Mfd for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 © 2009 sanofi-aventis U.S. LLC 13	custom-source	2025-02-12T13:43:52.586033	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/014399s065lbl.pdf', 'application_number': 14399, 'submission_type': 'SUPPL ', 'submission_number': 65}
10,844	CELESTONE® SOLUSPAN® (betamethasone sodium phosphate and betamethasone acetate) Injectable Suspension, USP 30 mg/5 mL (6 mg/mL) DESCRIPTION CELESTONE® SOLUSPAN® Injectable Suspension is a sterile aqueous suspension containing 3 mg per milliliter betamethasone, as betamethasone sodium phosphate, and 3 mg per milliliter betamethasone acetate. Inactive ingredients per mL: 7.1 mg dibasic sodium phosphate; 3.4 mg monobasic sodium phosphate; 0.1 mg edetate disodium; and 0.2 mg benzalkonium chloride as preservative. The pH is adjusted to between 6.8 and 7.2. The formula for betamethasone sodium phosphate is C22H28FNa208P and it has a molecular weight of 516.40. Chemically, it is 9-Fluoro-11β,17,21-trihydroxy-16β methylpregna-1,4-diene-3,20-dione 21-(disodium phosphate). The formula for betamethasone acetate is C24H31FO6 and it has a molecular weight of 434.50. Chemically, it is 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene 3,20-dione 21-acetate. The chemical structures for betamethasone sodium phosphate and betamethasone acetate are as follows: 1 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Betamethasone sodium phosphate is a white to practically white, odorless powder, and is hygroscopic. It is freely soluble in water and in methanol, but is practically insoluble in acetone and in chloroform. Betamethasone acetate is a white to creamy white, odorless powder that sinters and resolidifies at about 165°C, and remelts at about 200°C-220°C with decomposition. It is practically insoluble in water, but freely soluble in acetone, and is soluble in alcohol and in chloroform. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders of many organ systems. A derivative of prednisolone, betamethasone has a 16ß-methyl group that enhances the anti-inflammatory action of the molecule and reduces the sodium- and water-retaining properties of the fluorine atom bound at carbon 9. 2 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Betamethasone sodium phosphate, a soluble ester, provides prompt activity, while betamethasone acetate is only slightly soluble and affords sustained activity. INDICATIONS AND USAGE When oral therapy is not feasible, the intramuscular use of CELESTONE® SOLUSPAN® Injectable Suspension is indicated as follows: Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. Dermatologic Diseases Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine Disorders Congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis. Hydrocortisone or cortisone is the drug of choice in primary or secondary adrenocortical insufficiency. Synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance. Gastrointestinal Diseases To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis. Hematologic Disorders Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, selected cases of secondary thrombocytopenia. 3 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Miscellaneous Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy. Neoplastic Diseases For palliative management of leukemias and lymphomas. Nervous System Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy. Ophthalmic Diseases Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal Diseases To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory Diseases Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. The intra-articular or soft tissue administration of CELESTONE SOLUSPAN Injectable Suspension is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. 4 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The intralesional administration of CELESTONE SOLUSPAN Injectable Suspension is indicated for alopecia areata; discoid lupus erythematosus; keloids; localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; necrobiosis lipoidica diabeticorum. CELESTONE SOLUSPAN Injectable Suspension may also be useful in cystic tumors of an aponeurosis or tendon (ganglia). CONTRAINDICATIONS CELESTONE® SOLUSPAN® Injectable Suspension is contraindicated in patients who are hypersensitive to any components of this product. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. WARNINGS CELESTONE® SOLUSPAN® Injectable Suspension should not be administered intravenously. Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use. General Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). In patients on corticosteroid therapy subjected to any unusual stress, hydrocortisone or cortisone is the drug of choice as a supplement during and after the event. 5 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardio-renal Average and large doses of corticosteroids 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. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. 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 Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of 6 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS, Drug Interactions, Amphotericin B Injection and Potassium-Depleting Agents section). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma. It is recommended that latent amebiasis 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 corticosteroids 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. 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 7 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, eg, for Addison’s disease. Viral Infections Chickenpox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, 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 chickenpox develops, treatment with antiviral agents should be considered. Neurologic Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS, Gastrointestinal and Neurologic/Psychiatric sections). Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early mortality (at 2 weeks) and late mortality (at 6 months) in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of corticosteroids, including CELESTONE SOLUSPAN, should not be used for the treatment of traumatic brain injury. 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 8 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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. 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 congestive heart failure, hypertension, 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, naturally occurring glucocorticoids (hydrocortisone cortisone), which also have salt-retaining properties, rather than betamethasone, are the appropriate choices as replacement therapy in adrenocortical deficiency states. 9 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Intra-Articular and Soft Tissue Administration Intra-articular injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously injected joint is not usually recommended. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS, Musculoskeletal section). Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (ie, decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a 10 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (ie, 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 (eg, myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (eg, 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 corticosteroids abruptly or without medical supervision, to advise any medical 11 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions Aminoglutethimide Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B Injection and Potassium-Depleting Agents When corticosteroids are administered concomitantly with potassium-depleting agents (ie, amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases 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. Anticoagulants, Oral 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. Antidiabetics Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. 12 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antitubercular Drugs Serum concentrations of isoniazid may be decreased. Cholestyramine Cholestyramine may increase the clearance of corticosteroids. Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis Glycosides Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, Including Oral Contraceptives Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (eg, barbiturates, phenytoin, carbamazepine, rifampin) Drugs which induce hepatic microsomal drug-metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal Anti-inflammatory Agents (NSAIDS) Concomitant use of aspirin (or other nonsteroidal 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. Skin Tests Corticosteroids may suppress reactions to skin tests. 13 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Vaccines Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Route administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination section). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have 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. Corticosteroids 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 corticosteroids are administered to a nursing woman. Pediatric Use The efficacy and safety of corticosteroids 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 14 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, eg, 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 corticosteroids 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. Pediatric patients 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 (ie, cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and young patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS (listed alphabetically, under each subsection) Allergic Reactions Anaphylactoid reaction, anaphylaxis, angioedema. 15 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiovascular Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine Decreased carbohydrate and glucose tolerance, development of cushingoid state, glucosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and Electrolyte Disturbances Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic Negative nitrogen balance due to protein catabolism. Musculoskeletal Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare 16 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS, Neurologic section). Ophthalmic Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdose is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION Benzyl alcohol as a preservative has been associated with a fatal “Gasping Syndrome” in premature infants and infants of low birth weight. Solutions used for further dilution of this product should be preservative-free when used in the neonate, especially the premature infant. The initial dosage of parenterally administered CELESTONE® SOLUSPAN® Injectable Suspension may vary from 0.25 to 9.0 mg per day depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administrations in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. 17 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. 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 the corticosteroid 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 30 mg of betamethasone for a week followed by 12 mg every other day for 1 month are recommended (see PRECAUTIONS, Neuro-psychiatric section). In pediatric patients, the initial dose of betamethasone may vary depending on the specific disease entity being treated. The range of initial doses is 0.02 to 0.3 mg/kg/day in three or four divided doses (0.6 to 9 mg/m2bsa/day). 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 18 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. If coadministration of a local anesthetic is desired, CELESTONE SOLUSPAN Injectable Suspension may be mixed with 1% or 2% lidocaine hydrochloride, using the formulations which do not contain parabens. Similar local anesthetics may also be used. Diluents containing methylparaben, propylparaben, phenol, etc., should be avoided, since these compounds may cause flocculation of the steroid. The required dose of CELESTONE SOLUSPAN Injectable Suspension is first withdrawn from the vial into the syringe. The local anesthetic is then drawn in, and the syringe shaken briefly. Do not inject local anesthetics into the vial of CELESTONE SOLUSPAN Injectable Suspension. Bursitis, Tenosynovitis, Peritendinitis In acute subdeltoid, subacromial, olecranon, and prepatellar bursitis, one intrabursal injection of 1.0 mL CELESTONE SOLUSPAN Injectable Suspension can relieve pain and restore full range of movement. Several intrabursal injections of corticosteroids are usually required in recurrent acute bursitis and in acute exacerbations of chronic bursitis. Partial relief of pain and some increase in mobility can be expected in both conditions after one or two injections. Chronic bursitis may be treated with reduced dosage once the acute condition is controlled. In tenosynovitis and tendinitis, three or four local injections at intervals of 1 to 2 weeks between injections are given in most cases. Injections should be made into the affected tendon sheaths rather than into the tendons themselves. In ganglions of joint capsules and tendon sheaths, injection of 0.5 mL directly into the ganglion cysts has produced marked reduction in the size of the lesions. Rheumatoid Arthritis and Osteoarthritis Following intra-articular administration of 0.5 to 2.0 mL of CELESTONE SOLUSPAN Injectable Suspension, relief of pain, soreness, and stiffness may be experienced. Duration of relief varies widely in both diseases. Intra-articular Injection of CELESTONE SOLUSPAN Injectable Suspension is well 19 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda tolerated in joints and periarticular tissues. There is virtually no pain on injection, and the “secondary flare” that sometimes occurs a few hours after intra-articular injection of corticosteroids has not been reported with CELESTONE SOLUSPAN Injectable Suspension. Using sterile technique, a 20- to 24-gauge needle on an empty syringe is inserted into the synovial cavity and a few drops of synovial fluid are withdrawn to confirm that the needle is in the joint. The aspirating syringe is replaced by a syringe containing CELESTONE SOLUSPAN Injectable Suspension and injection is then made into the joint. Recommended Doses for Intra-articular Injection Size of joint Location Dose (mL) Very large Hip 1.0-2.0 Large Knee, ankle, shoulder 1.0 Medium Elbow, wrist 0.5-1.0 Small (metacarpophalangeal, interphalangeal) (sternoclavicular) Hand, chest 0.25-0.5 A portion of the administered dose of CELESTONE SOLUSPAN Injectable Suspension is absorbed systemically following intra-articular injection. In patients being treated concomitantly with oral or parenteral corticosteroids, especially those receiving large doses, the systemic absorption of the drug should be considered in determining intra articular dosage. Dermatologic Conditions In intralesional treatment, 0.2 mL/cm2 of CELESTONE SOLUSPAN Injectable Suspension is injected intradermally (not subcutaneously) using a tuberculin syringe with a 25-gauge, ½-inch needle. Care should be taken to deposit a uniform depot of medication intradermally. A total of no more than 1.0 mL at weekly intervals is recommended. 20 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Disorders of the Foot A tuberculin syringe with a 25-gauge, ¾-inch needle is suitable for most injections into the foot. The following doses are recommended at intervals of 3 days to a week. Diagnosis CELESTONE SOLUSPAN Injectable Suspension Dose (mL) Bursitis under heloma durum or heloma molle 0.25-0.5 under calcaneal spur 0.5 over hallux rigidus or digiti quinti varus 0.5 Tenosynovitis, periostitis of cuboid 0.5 Acute gouty arthritis 0.5-1.0 HOW SUPPLIED CELESTONE® SOLUSPAN® Injectable Suspension, 5-mL multiple- dose vial; box of one (NDC 0085-0566-05). SHAKE WELL BEFORE USING. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from light. Rx only company logo Manufactured by: Patheon UK Limited, Covingham, Swindon, Wiltshire, SN3 5BZ, United Kingdom For patent information: www.merck.com/product/patent/home.html Copyright © 1969, 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: xx/xxxx uspi-mk5166a-soi-xxxxrxxx 21 Reference ID: 3697288 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:52.659814	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/014602s059lbl.pdf', 'application_number': 14602, 'submission_type': 'SUPPL ', 'submission_number': 59}
10,846	NDAs 14-685/S-028 Page 3 NORTRIPTYLINE HYDROCHLORIDE ORAL SOLUTION, USP Rx only DESCRIPTION Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Nortriptyline Hydrochloride Oral Solution or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Nortriptyline hydrochloride is not approved for use in pediatric patients. (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use) Nortriptyline Hydrochloride, USP is 1-propanamine, 3-(10, 11-dihydro-5H-dibenzo [a,d] cyclohepten- 5-ylidene)-N-methyl, hydrochloride. Its molecular weight is 299.8, and its molecular formula is C19H21N•HCl. The oral solution contains nortriptyline hydrochloride equivalent to 10 mg/5 mL (38.0 µmol) of the base and 4% alcohol. It also contains benzoic acid, flavors, sorbitol, and water. The structural formula is as follows: ACTIONS The mood elevating mechanism of tricyclic antidepressants is at present unknown. Nortriptyline hydrochloride is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine. Studies suggest that nortriptyline hydrochloride interferes with the transport, release, and storage of catecholamines. Operant conditioning techniques in rats and pigeons suggest that nortriptyline hydrochloride has a combination of stimulant and depressant properties. INDICATIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 4 Nortriptyline hydrochloride is indicated for the relief of symptoms of depression. Endogenous depressions are more likely to be alleviated than are other depressive states. CONTRAINDICATIONS The concurrent use of nortriptyline hydrochloride or other tricyclic antidepressants with a monoamine oxidase (MAO) inhibitor is contraindicated. Hyperpyretic crises, severe convulsions, and fatalities have occurred when similar tricyclic antidepressants were used in such combinations. It is advisable to discontinue the MAO inhibitor at least 2 weeks before treatment with nortriptyline hydrochloride is to be started. Patients hypersensitive to nortriptyline hydrochloride should not be given the drug. Cross-sensitivity between nortriptyline hydrochloride and other dibenzazepines is a possibility. Nortriptyline hydrochloride is contraindicated during the acute recovery period after myocardial infarction. WARNINGS-Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 5 TABLE 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case >65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for nortriptyline hydrochloride oral solution should be written for the smallest quantity consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 6 are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that nortriptyline hydrochloride is not approved for use in treating bipolar depression. Patients with cardiovascular disease should be given nortriptyline hydrochloride only under close supervision because of the tendency of the drug to produce sinus tachycardia and to prolong the conduction time. Myocardial infarction, arrhythmia, and strokes have occurred. The antihypertensive action of guanethidine and similar agents may be blocked. Because of its anticholinergic activity, nortriptyline hydrochloride should be used with great caution in patients who have glaucoma or a history of urinary retention. Patients with a history of seizures should be followed closely when nortriptyline hydrochloride is administered, because this drug is known to lower the convulsive threshold. Great care is required if nortriptyline hydrochloride is given to hyperthyroid patients or to those receiving thyroid medication, because cardiac arrhythmias may develop. Nortriptyline hydrochloride may impair the mental and/or physical abilities required for the performance of hazardous tasks, such as operating machinery or driving a car; therefore, the patient should be warned accordingly. Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation. Use in Pregnancy--Safe use of nortriptyline hydrochloride during pregnancy and lactation has not been established; therefore, when the drug is administered to pregnant patients, nursing mothers, or women of childbearing potential, the potential benefits must be weighed against the possible hazards. Animal reproduction studies have yielded inconclusive results. PRECAUTIONS-Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with nortriptyline hydrochloride and should counsel them in its appropriate use. A patient Medication Guide About Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions is available for nortriptyline hydrochloride. The prescriber or health professional should instruct patients and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescribers if these occur while taking nortriptyline hydrochloride. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 7 Pediatric Use--Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of nortriptyline hydrochloride in a child or adolescent must balance the potential risks with the clinical need. General: The use of nortriptyline hydrochloride in schizophrenic patients may result in exacerbation of the psychosis or may activate latent schizophrenic symptoms. If the drug is given to overactive or agitated patients, increased anxiety and agitation may occur. In manic-depressive patients, nortriptyline hydrochloride may cause symptoms of the manic phase to emerge. Troublesome patient hostility may be aroused by the use of nortriptyline hydrochloride. As may happen with other drugs of its class, epileptiform seizures may accompany its administration. When it is essential, the drug may be administered concurrently with electroconvulsive therapy, although the hazards may be increased. Discontinue the drug for several days, if possible, prior to elective surgery. The possibility of a suicidal attempt by a depressed patient remains after the initiation of treatment; in this regard, it is important that the least possible quantity of drug be dispensed at any given time. Both elevation and lowering of blood sugar levels have been reported. A case of significant hypoglycemia has been reported after the addition of nortriptyline (125mg/day) in a type II diabetic patient maintained on chlorpropamide (250 mg/day). Drug Interactions: Steady-state serum concentrations of tricyclic antidepressants are reported to fluctuate significantly when cimetidine is either added or deleted from the drug regimen. Serious anticholinergic symptoms (severe dry mouth, urinary retention, blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressants when cimetidine is added to the drug regimen. In addition, higher-than expected steady-state serum concentrations of tricyclic antidepressants have been observed when therapy is initiated in patients already taking cimetidine. In well-controlled patients undergoing concurrent therapy with cimetidine, a decrease in the steady- state serum concentrations of tricyclic antidepressants may occur when cimetidine therapy is discontinued. The therapeutic efficacy of tricyclic antidepressants may be compromised in these patients when cimetidine is discontinued. Several of the tricyclic antidepressants have been cited in these reports. There have been greater than 2-fold increases in previously stable plasma levels of other antidepressants, including nortriptyline, when fluoxetine hydrochloride has been administered in combination with these agents. Fluoxetine and its active metabolite, norfluoxetine, have long half-lives (4 to 16 days for norfluoxetine), that may affect strategies during conversion from one drug to the other. Administration of reserpine during therapy with a tricyclic antidepressant has been shown to produce a “stimulating” effect in some depressed patients. Close supervision and careful adjustment of the dosage are required when nortriptyline hydrochloride is used with other anticholinergic drugs or sympathomimetic drugs. The patient should be informed that the response to alcohol may be exaggerated. Drugs Metabolized by P450IID6--A subset (3% to 10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isoenzyme P450IID6. Such This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 8 individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants. These individuals may have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. In addition, certain drugs that are metabolized by this isoenzyme, including many antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isoenzyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interactions. Concomitant use of tricyclic antidepressants with other drugs metabolized by cytochrome P450IID6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Therefore, co-administration of tricyclic antidepressants with other drugs that are metabolized by this isoenzyme, including other antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (eg, propafenone, flecainide, and encainide), or that inhibit this enzyme (eg, quinidine), should be approached with caution. Geriatric Use--Confusional states following tricyclic antidepressant administration have been reported in the elderly (see Adverse Reactions). Higher plasma concentrations of the active nortriptyline metabolite 10-hydroxynortriptyline have been reported in elderly patients (see Plasma Levels under Dosage and Administration). Lower than usual dosages are recommended for elderly patients (see Elderly Patients under Dosage and Administration). ADVERSE REACTIONS NOTE: Included in the following list are a few adverse reactions that have not been reported with this specific drug. However, the pharmacologic similarities among the tricyclic antidepressant drugs require that each of these reactions be considered when nortriptyline is administered. Cardiovascular--Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke. Psychiatric--Confusional states (especially in the elderly), with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia, panic, nightmares; hypomania; exacerbation of psychosis. Neurologic--Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alteration of EEG patterns; tinnitus. Anticholinergic--Dry mouth and, rarely, associated sublingual adenitis or gingivitis; blurred vision, disturbance of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. Allergic--Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive exposure to sunlight); edema (general or of face and tongue), drug fever, cross-sensitivity with other tricyclic drugs. Hematologic--Bone-marrow depression, including agranulocytosis; aplastic anemia; eosinophilia; purpura; thrombocytopenia. Gastrointestinal--Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue, constipation, paralytic ileus. Endocrine--Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; syndrome of inappropriate ADH (antidiuretic hormone) secretion. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 9 Other--Jaundice (simulating obstructive); altered liver function, hepatitis, and liver necrosis; weight gain or loss; perspiration; flushing; urinary frequency, nocturia; drowsiness, dizziness, weakness, fatigue; headache; parotid swelling; alopecia. Withdrawal Symptoms--Though these are not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise. OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations--Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or many of the symptoms listed under ADVERSE REACTIONS. Management- General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination: All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular: A maximal limb-lead QRS duration of > 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (eg, quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricycic antidepressant poisoning. CNS: In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 10 anticonvulsants (eg, phenobarbital, phenytoin). Physostigmine is not recommended except to treat life- threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management: The principles of management of pediatric and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. DOSAGE AND ADMINISTRATION Nortriptyline hydrochloride is not recommended for pediatric patients. Nortriptyline hydrochloride is administered orally in the form of an oral solution. Lower than usual dosages are recommended for elderly patients. The use of lower dosages for outpatients is more important than for hospitalized patients who will be treated under close supervision. The physician should initiate dosage at a low level and increase it gradually, checking the clinical response carefully and noting any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission. If a patient develops minor side effects, the dosage should be reduced. The drug should be discontinued promptly if adverse effects of a serious nature or allergic manifestations occur. Usual Adult Dose--25 mg 3 or 4 times daily; dosage should begin at a low level and be increased as required. As an alternate regimen, the total daily dose may be given once a day. When doses above 100 mg daily are administered, plasma levels of nortriptyline should be monitored and maintained in the optimum range of 50 to 150 ng/mL. Doses above 150 mg per day are not recommended. Elderly Patients--30 to 50 mg/day in divided doses. Plasma Levels--Optimal responses to nortriptyline have been associated with plasma concentrations of 50 to 150 ng/mL. Higher concentrations may be associated with more adverse experiences. Plasma concentrations are difficult to measure, and physicians should consult with the laboratory professional staff. Larger plasma concentrations of the active nortriptyline metabolite 10-hydroxynortriptyline have been reported in older patients. In one case, such a condition was associated with apparent cardiotoxicity despite the fact that nortriptyline concentrations were within the “therapeutic range.” Clinical findings should predominate over plasma concentrations as primary determinants of dosage changes. HOW SUPPLIED Liquid, Oral Solution: 10 mg/5 mL -- (16 fl oz) NDC 63304-202-01 Equivalent to base. Store at 20 - 25° C (68 - 77° F). (See USP Controlled Room Temperature). Manufactured for: Ranbaxy Pharmaceuticals Inc. Jacksonville, FL 32257 USA by: Ohm Laboratories Inc. Gloversville, NY 12078 USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 11 June 2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 12 Medication Guide NORTRIPTYLINE HYDROCHLORIDE ORAL SOLUTION Rx only Antidepressant Medicines, Depression and other Serious Mental Illness and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 14-685/S-028 Page 13 • other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Manufactured for: Ranbaxy Pharmaceuticals Inc. Jacksonville, FL 32257 USA by: Ohm Laboratories Inc. Gloversville, NY 12078 USA June 2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:52.888672	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/014685s028lbl.pdf', 'application_number': 14685, 'submission_type': 'SUPPL ', 'submission_number': 28}
10,845	Attachment 1 Page 1 Class Suicidality Labeling Language for Antidepressants [This section should be located at the beginning of the package insert with bolded font and enclosed in a black box] [Insert established name] Suicidality in Children and Adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Insert established name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. [Insert established name] is not approved for use in pediatric patients. (See Warnings and Precautions: Pediatric Use) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. [This section should be located under WARNINGS. Please note that the title of this section should be bolded, and it should be the first paragraph in this section.] WARNINGS-Clinical Worsening and Suicide Risk Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. A causal role for antidepressants in inducing suicidality has been established in pediatric patients. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 1 Page 2 There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for [Insert established name] should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 1 Page 3 above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established name] is not approved for use in treating bipolar depression. [This section should be located under PRECAUTIONS, Information for Patients.] Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with [Insert established name] and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Adolescents is available for [Insert established name]. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking [Insert established name]. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. [This section should be located under PRECAUTIONS, Pediatric Use.] Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of [Insert established name] in a child or adolescent must balance the potential risks with the clinical need. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 1 Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions 2. How to try to prevent suicidal thoughts or actions in your child 3. You should watch for certain signs if your child is taking an antidepressant 4. There are benefits and risks when using antidepressants 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. Whenever an antidepressant is started or its dose is changed, pay close attention to your child. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 2 After starting an antidepressant, your child should generally see his or her healthcare provider: • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your healthcare provider's advice about how often to come back • More often if problems or questions arise (see other side) You should call your child's healthcare provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child's healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms. 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) . This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 3 Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:52.981131	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/14685s026lbl.pdf', 'application_number': 14685, 'submission_type': 'SUPPL ', 'submission_number': 26}
10,847	1 PRESCRIBING INFORMATION 1 ALKERAN® 2 (melphalan) 3 Tablets 4 5 WARNING 6 ALKERAN (melphalan) should be administered under the supervision of a qualified 7 physician experienced in the use of cancer chemotherapeutic agents. Severe bone marrow 8 suppression with resulting infection or bleeding may occur. Melphalan is leukemogenic in 9 humans. 10 Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be 11 considered potentially mutagenic in humans. 12 13 DESCRIPTION 14 ALKERAN (melphalan), also known as L-phenylalanine mustard, phenylalanine mustard, 15 L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a 16 bifunctional alkylating agent which is active against selective human neoplastic diseases. It is 17 known chemically as 4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular formula is 18 C13H18Cl2N2O2 and the molecular weight is 305.20. The structural formula is: 19 20 21 22 Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by 23 Bergel and Stock; the D-isomer, known as medphalan, is less active against certain animal 24 tumors, and the dose needed to produce effects on chromosomes is larger than that required with 25 the L-isomer. The racemic (DL–) form is known as merphalan or sarcolysin. 26 Melphalan is practically insoluble in water and has a pKa1 of ∼2.5. 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c:\data\my documents\ndas\14691\slr-024\s024_clean_label.doc DRAFT 13 May 03 2 ALKERAN (melphalan) is available in tablet form for oral administration. Each film-coated 28 tablet contains 2 mg melphalan and the inactive ingredients colloidal silicon dioxide, 29 crospovidone, hypromellose, macrogol/PEG 400, magnesium stearate, microcrystalline cellulose, 30 and titanium dioxide. 31 32 CLINICAL PHARMACOLOGY 33 Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity 34 appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding 35 at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both 36 resting and rapidly dividing tumor cells. 37 Pharmacokinetics: The pharmacokinetics of ALKERAN after oral administration has been 38 extensively studied in adult patients. Plasma melphalan levels are highly variable after oral 39 dosing, both with respect to the time of the first appearance of melphalan in plasma (range 40 approximately 0 to 6 hours) and to the peak plasma concentration (Cmax) (range 70 to 41 4,000 ng/mL, depending upon the dose) achieved. These results may be due to incomplete 42 intestinal absorption, a variable “first pass” hepatic metabolism, or to rapid hydrolysis. Five 43 patients were studied after both oral and intravenous (IV) dosing with 0.6 mg/kg as a single 44 bolus dose by each route. The areas under the plasma concentration-time curves (AUC) after oral 45 administration averaged 61% ± 26% (± standard deviation [SD]; range 25% to 89%) of those 46 following IV administration. In 18 patients given a single oral dose of 0.6 mg/kg of ALKERAN, 47 the terminal elimination plasma half-life (t1/2) of parent drug was 1.5 ± 0.83 hours. The 24-hour 48 urinary excretion of parent drug in these patients was 10% ± 4.5%, suggesting that renal 49 clearance is not a major route of elimination of parent drug. In a separate study in 18 patients 50 given single oral doses of 0.2 to 0.25 mg/kg of ALKERAN, Cmax and AUC, when dose adjusted 51 to a dose of 14 mg, were (mean ± SD) 212 ± 74 ng/mL and 498 ± 137 ng•hr/mL, respectively. 52 Elimination phase t½ in these patients was approximately 1 hour and the median tmax was 1 hour. 53 One study using universally labeled 14C-melphalan, found substantially less radioactivity in 54 the urine of patients given the drug by mouth (30% of administered dose in 9 days) than in the 55 urine of those given it intravenously (35% to 65% in 7 days). Following either oral or IV 56 administration, the pattern of label recovery was similar, with the majority being recovered in the 57 first 24 hours. Following oral administration, peak radioactivity occurred in plasma at 2 hours 58 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c:\data\my documents\ndas\14691\slr-024\s024_clean_label.doc DRAFT 13 May 03 3 and then disappeared with a half-life of approximately 160 hours. In 1 patient where parent drug 59 (rather than just radiolabel) was determined, the melphalan half-disappearance time was 60 67 minutes. 61 The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into 62 cerebrospinal fluid (CSF) is low. The extent of melphalan binding to plasma proteins ranges 63 from 60% to 90%. Serum albumin is the major binding protein, while α1-acid glycoprotein 64 appears to account for about 20% of the plasma protein binding. Approximately 30% of 65 melphalan is (covalently) irreversibly bound to plasma proteins. Interactions with 66 immunoglobulins have been found to be negligible. 67 Melphalan is eliminated from plasma primarily by chemical hydrolysis to 68 monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no 69 other melphalan metabolites have been observed in humans. Although the contribution of renal 70 elimination to melphalan clearance appears to be low, one pharmacokinetic study showed a 71 significant positive correlation between the elimination rate constant for melphalan and renal 72 function and a significant negative correlation between renal function and the area under the 73 plasma melphalan concentration/time curve. 74 75 INDICATIONS AND USAGE 76 ALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the 77 palliation of non-resectable epithelial carcinoma of the ovary. 78 79 CONTRAINDICATIONS 80 ALKERAN should not be used in patients whose disease has demonstrated a prior resistance 81 to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given 82 the drug. 83 84 WARNINGS 85 ALKERAN should be administered in carefully adjusted dosage by or under the 86 supervision of experienced physicians who are familiar with the drug's actions and the 87 possible complications of its use. 88 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c:\data\my documents\ndas\14691\slr-024\s024_clean_label.doc DRAFT 13 May 03 4 As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow 89 suppression. Bone marrow suppression is the most significant toxicity associated with 90 ALKERAN in most patients. Therefore, the following tests should be performed at the start of 91 therapy and prior to each subsequent course of ALKERAN: platelet count, hemoglobin, white 92 blood cell count, and differential. Thrombocytopenia and/or leukopenia are indications to 93 withhold further therapy until the blood counts have sufficiently recovered. Frequent blood 94 counts are essential to determine optimal dosage and to avoid toxicity (see PRECAUTIONS: 95 Laboratory Tests). Dose adjustment on the basis of blood counts at the nadir and day of 96 treatment should be considered. 97 Hypersensitivity reactions, including anaphylaxis, have occurred rarely (see ADVERSE 98 REACTIONS). These reactions have occurred after multiple courses of treatment and have 99 recurred in patients who experienced a hypersensitivity reaction to IV ALKERAN. If a 100 hypersensitivity reaction occurs, oral or IV ALKERAN should not be readministered. 101 Carcinogenesis: Secondary malignancies, including acute nonlymphocytic leukemia, 102 myeloproliferative syndrome, and carcinoma have been reported in patients with cancer treated 103 with alkylating agents (including melphalan). Some patients also received other 104 chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukemia, 105 myeloproliferative syndrome, or carcinoma is not possible. Published reports of leukemia in 106 patients who have received melphalan (and other alkylating agents) suggest that the risk of 107 leukemogenesis increases with chronicity of treatment and with cumulative dose. In one study, 108 the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after 109 melphalan therapy was 19.5% for cumulative doses ranging from 730 mg to 9,652 mg. In this 110 same study, as well as in an additional study, the 10-year cumulative risk of developing acute 111 leukemia or myeloproliferative syndrome after melphalan therapy was less than 2% for 112 cumulative doses under 600 mg. This does not mean that there is a cumulative dose below which 113 there is no risk of the induction of secondary malignancy. The potential benefits from melphalan 114 therapy must be weighed on an individual basis against the possible risk of the induction of a 115 second malignancy. 116 Adequate and well-controlled carcinogenicity studies have not been conducted in animals. 117 However, i.p. administration of melphalan in rats (5.4 to 10.8 mg/m2) and in mice (2.25 to 118 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c:\data\my documents\ndas\14691\slr-024\s024_clean_label.doc DRAFT 13 May 03 5 4.5 mg/m2) 3 times per week for 6 months followed by 12 months post-dose observation 119 produced peritoneal sarcoma and lung tumors, respectively. 120 Mutagenesis: ALKERAN has been shown to cause chromatid or chromosome damage in 121 humans. Intramuscular administration of ALKERAN at 6 and 60 mg/m2 produced structural 122 aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats. 123 Impairment of Fertility: ALKERAN causes suppression of ovarian function in premenopausal 124 women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible 125 testicular suppression have also been reported. 126 Pregnancy: Pregnancy Category D. ALKERAN may cause fetal harm when administered to a 127 pregnant woman. Melphalan was embryolethal and teratogenic in rats following oral (6 to 128 18 mg/m2/day for 10 days) and intraperitoneal (18 mg/m2) administration. Malformations 129 resulting from melphalan included alterations of the brain (underdevelopment, deformation, 130 meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the 131 mandible and tail, as well as hepatocele (exomphaly). 132 There are no adequate and well-controlled studies in pregnant women. If this drug is used 133 during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be 134 apprised of the potential hazard to the fetus. Women of childbearing potential should be advised 135 to avoid becoming pregnant. 136 137 PRECAUTIONS 138 General: In all instances where the use of ALKERAN is considered for chemotherapy, the 139 physician must evaluate the need and usefulness of the drug against the risk of adverse events. 140 ALKERAN should be used with extreme caution in patients whose bone marrow reserve may 141 have been compromised by prior irradiation or chemotherapy, or whose marrow function is 142 recovering from previous cytotoxic therapy. If the leukocyte count falls below 3,000 cells/mcL, 143 or the platelet count below 100,000 cells/mcL, ALKERAN should be discontinued until the 144 peripheral blood cell counts have recovered. 145 A recommendation as to whether or not dosage reduction should be made routinely in patients 146 with renal insufficiency cannot be made because: 147 a) There is considerable inherent patient-to-patient variability in the systemic availability of 148 melphalan in patients with normal renal function. 149 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c:\data\my documents\ndas\14691\slr-024\s024_clean_label.doc DRAFT 13 May 03 6 b) Only a small amount of the administered dose appears as parent drug in the urine of patients 150 with normal renal function. 151 Patients with azotemia should be closely observed, however, in order to make dosage 152 reductions, if required, at the earliest possible time. 153 Information for Patients: Patients should be informed that the major toxicities of ALKERAN 154 are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and 155 pulmonary toxicity. The major long-term toxicities are related to infertility and secondary 156 malignancies. Patients should never be allowed to take the drug without close medical 157 supervision and should be advised to consult their physician if they experience skin rash, 158 vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or 159 unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming 160 pregnant. 161 Laboratory Tests: Periodic complete blood counts with differentials should be performed 162 during the course of treatment with ALKERAN. At least one determination should be obtained 163 prior to each treatment course. Patients should be observed closely for consequences of bone 164 marrow suppression, which include severe infections, bleeding, and symptomatic anemia (see 165 WARNINGS). 166 Drug Interactions: There are no known drug/drug interactions with oral ALKERAN. 167 Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section. 168 Pregnancy: Teratogenic Effects: Pregnancy Category D: See WARNINGS section. 169 Nursing Mothers: It is not known whether this drug is excreted in human milk. ALKERAN 170 should not be given to nursing mothers. 171 Pediatric Use: The safety and effectiveness of ALKERAN in pediatric patients have not been 172 established. 173 Geriatric Use: Clinical studies of ALKERAN Tablets did not include sufficient numbers of 174 subjects aged 65 and over to determine whether they respond differently from younger subjects. 175 Other reported clinical experience has not identified differences in responses between the elderly 176 and younger patients In general, dose selection for an elderly patient should be cautious, usually 177 starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, 178 renal, or cardiac function, and of concomitant disease or other drug therapy. 179 180 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c:\data\my documents\ndas\14691\slr-024\s024_clean_label.doc DRAFT 13 May 03 7 ADVERSE REACTIONS 181 Hematologic: The most common side effect is bone marrow suppression. Although bone 182 marrow suppression frequently occurs, it is usually reversible if melphalan is withdrawn early 183 enough. However, irreversible bone marrow failure has been reported. 184 Gastrointestinal: Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral 185 ulceration occur infrequently. Hepatic disorders ranging from abnormal liver function tests to 186 clinical manifestations such as hepatitis and jaundice have been reported. 187 Miscellaneous: Other reported adverse reactions include: pulmonary fibrosis and interstitial 188 pneumonitis, skin hypersensitivity, vasculitis, alopecia, and hemolytic anemia. Allergic 189 reactions, including rare anaphylaxis, have occurred after multiple courses of treatment. 190 191 OVERDOSAGE 192 Overdoses, including doses up to 50 mg/day for 16 days, have been reported. Immediate 193 effects are likely to be vomiting, ulceration of the mouth, diarrhea, and hemorrhage of the 194 gastrointestinal tract. The principal toxic effect is bone marrow suppression. Hematologic 195 parameters should be closely followed for 3 to 6 weeks. An uncontrolled study suggests that 196 administration of autologous bone marrow or hematopoietic growth factors (i.e., sargramostim, 197 filgrastim) may shorten the period of pancytopenia. General supportive measures, together with 198 appropriate blood transfusions and antibiotics, should be instituted as deemed necessary by the 199 physician. This drug is not removed from plasma to any significant degree by hemodialysis. 200 201 DOSAGE AND ADMINISTRATION 202 Multiple Myeloma: The usual oral dose is 6 mg (3 tablets) daily. The entire daily dose may be 203 given at one time. The dose is adjusted, as required, on the basis of blood counts done at 204 approximately weekly intervals. After 2 to 3 weeks of treatment, the drug should be discontinued 205 for up to 4 weeks, during which time the blood count should be followed carefully. When the 206 white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be 207 instituted. Because of the patient-to-patient variation in melphalan plasma levels following oral 208 administration of the drug, several investigators have recommended that the dosage of 209 ALKERAN be cautiously escalated until some myelosuppression is observed in order to assure 210 that potentially therapeutic levels of the drug have been reached. 211 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c:\data\my documents\ndas\14691\slr-024\s024_clean_label.doc DRAFT 13 May 03 8 Other dosage regimens have been used by various investigators. Osserman and Takatsuki 212 have used an initial course of 10 mg/day for 7 to 10 days. They report that maximal suppression 213 of the leukocyte and platelet counts occurs within 3 to 5 weeks and recovery within 4 to 8 weeks. 214 Continuous maintenance therapy with 2 mg/day is instituted when the white blood cell count is 215 greater than 4,000 cells/mcL and the platelet count is greater than 100,000 cells/mcL. Dosage is 216 adjusted to between 1 and 3 mg/day depending upon the hematological response. It is desirable 217 to try to maintain a significant degree of bone marrow depression so as to keep the leukocyte 218 count in the range of 3,000 to 3,500 cells/mcL. 219 Hoogstraten et al have started treatment with 0.15 mg/kg/day for 7 days. This is followed by a 220 rest period of at least 14 days, but it may be as long as 5 to 6 weeks. Maintenance therapy is 221 started when the white blood cell and platelet counts are rising. The maintenance dose is 222 0.05 mg/kg/day or less and is adjusted according to the blood count. 223 Available evidence suggests that about one third to one half of the patients with multiple 224 myeloma show a favorable response to oral administration of the drug. 225 One study by Alexanian et al has shown that the use of ALKERAN in combination with 226 prednisone significantly improves the percentage of patients with multiple myeloma who achieve 227 palliation. One regimen has been to administer courses of ALKERAN at 0.25 mg/kg/day for 228 4 consecutive days (or, 0.20 mg/kg/day for 5 consecutive days) for a total dose of 229 1 mg/kg/course. These 4- to 5-day courses are then repeated every 4 to 6 weeks if the 230 granulocyte count and the platelet count have returned to normal levels. 231 It is to be emphasized that response may be very gradual over many months; it is important 232 that repeated courses or continuous therapy be given since improvement may continue slowly 233 over many months, and the maximum benefit may be missed if treatment is abandoned too soon. 234 In patients with moderate to severe renal impairment, currently available pharmacokinetic 235 data do not justify an absolute recommendation on dosage reduction to those patients, but it may 236 be prudent to use a reduced dose initially. 237 Epithelial Ovarian Cancer: One commonly employed regimen for the treatment of ovarian 238 carcinoma has been to administer ALKERAN at a dose of 0.2 mg/kg daily for 5 days as a single 239 course. Courses are repeated every 4 to 5 weeks depending upon hematologic tolerance. 240 Administration Precautions: Procedures for proper handling and disposal of anticancer 241 drugs should be considered. Several guidelines on this subject have been published.1-8 242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c:\data\my documents\ndas\14691\slr-024\s024_clean_label.doc DRAFT 13 May 03 9 There is no general agreement that all of the procedures recommended in the guidelines are 243 necessary or appropriate. 244 245 HOW SUPPLIED 246 ALKERAN is supplied as white, film-coated, round, biconvex tablets containing 2 mg 247 melphalan in amber glass bottles with child-resistant closures. One side is engraved with “GX 248 EH3” and the other side is engraved with an “A.” 249 Bottle of 50 (NDC 0173-0045-35). 250 Store in a refrigerator, 2° to 8°C (36° to 46°F). Protect from light. 251 252 REFERENCES 253 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations 254 for Practice. Pittsburgh, PA: Oncology Nursing Society;1999:32-41. 255 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: 256 Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, 257 National Institutes of Health; 1992. US Dept of Health and Human Services. Public Health 258 Service publication NIH 92-2621. 259 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 260 1985;253:1590-1591. 261 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling 262 cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study 263 Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health 264 Sciences, 179 Longwood Avenue, Boston, MA 02115. 265 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling 266 of antineoplastic agents. Med J Australia. 1983;1:426-428. 267 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the 268 Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263. 269 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling 270 cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 271 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) 272 Am J Health-Syst Pharm. 1996;53:1669-1685. 273 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c:\data\my documents\ndas\14691\slr-024\s024_clean_label.doc DRAFT 13 May 03 10 274 275 276 GlaxoSmithKline 277 Research Triangle Park, NC 27709 278 279 , GlaxoSmithKline 280 All rights reserved. 281 282 Date RL-1161 283 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:53.036351	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/14691slr024_alkeran_lbl.pdf', 'application_number': 14691, 'submission_type': 'SUPPL ', 'submission_number': 24}
10,843	NORPRAMIN® (desipramine hydrochloride tablets USP) Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of NORPRAMIN or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. NORPRAMIN is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.) DESCRIPTION NORPRAMIN® (desipramine hydrochloride USP) is an antidepressant drug of the tricyclic type, and is chemically: 5H-Dibenz[bƒ]azepine-5-propanamine,10,11-dihydro-N-methyl-, monohydrochloride. structural formula 1 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inactive Ingredients The following inactive ingredients are contained in all dosage strengths: acacia, calcium carbonate, corn starch, D&C Red No. 30 and D&C Yellow No. 10 (except 10 mg and 150 mg), FD&C Blue No. 1 (except 25 mg, 75 mg, and 100 mg), hydrogenated soy oil, iron oxide, light mineral oil, magnesium stearate, mannitol, polyethylene glycol 8000, pregelatinized corn starch, sodium benzoate (except 150 mg), sucrose, talc, titanium dioxide, and other ingredients. CLINICAL PHARMACOLOGY Mechanism of Action Available evidence suggests that many depressions have a biochemical basis in the form of a relative deficiency of neurotransmitters such as norepinephrine and serotonin. Norepinephrine deficiency may be associated with relatively low urinary 3-methoxy-4-hydroxyphenyl glycol (MHPG) levels, while serotonin deficiencies may be associated with low spinal fluid levels of 5 hydroxyindoleacetic acid. While the precise mechanism of action of the tricyclic antidepressants is unknown, a leading theory suggests that they restore normal levels of neurotransmitters by blocking the re-uptake of these substances from the synapse in the central nervous system. Evidence indicates that the secondary amine tricyclic antidepressants, including NORPRAMIN, may have greater activity in blocking the re-uptake of norepinephrine. Tertiary amine tricyclic antidepressants, such as amitriptyline, may have greater effect on serotonin re-uptake. NORPRAMIN is not a monoamine oxidase inhibitor (MAOI) and does not act primarily as a central nervous system stimulant. It has been found in some studies to have a more rapid onset of action than imipramine. Earliest therapeutic effects may occasionally be seen in 2 to 5 days, but full treatment benefit usually requires 2 to 3 weeks to obtain. Metabolism Tricyclic antidepressants, such as desipramine hydrochloride, are rapidly absorbed from the gastrointestinal tract. Tricyclic antidepressants or their metabolites are to some extent excreted through the gastric mucosa and reabsorbed from the gastrointestinal tract. Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. The rate of metabolism of tricyclic antidepressants varies widely from individual to individual, chiefly on a genetically determined basis. Up to a 36-fold difference in plasma level may be noted among individuals taking the same oral dose of desipramine. The ratio of 2 hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. Certain drugs, particularly the psychostimulants and the phenothiazines, increase plasma levels of concomitantly administered tricyclic antidepressants through competition for the same metabolic enzyme systems. Concurrent administration of cimetidine and tricyclic antidepressants 2 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressants. Conversely, decreases in plasma levels of the tricyclic antidepressants have been reported upon discontinuation of cimetidine, which may result in the loss of the therapeutic efficacy of the tricyclic antidepressant. Other substances, particularly barbiturates and alcohol, induce liver enzyme activity and thereby reduce tricyclic antidepressant plasma levels. Similar effects have been reported with tobacco smoke. Research on the relationship of plasma level to therapeutic response with the tricyclic antidepressants has produced conflicting results. While some studies report no correlation, many studies cite therapeutic levels for most tricyclics in the range of 50 to 300 nanograms per milliliter. The therapeutic range is different for each tricyclic antidepressant. For desipramine, an optimal range of therapeutic plasma levels has not been established. INDICATIONS AND USAGE NORPRAMIN is indicated for the treatment of depression. CONTRAINDICATIONS The use of MAOIs intended to treat psychiatric disorders with NORPRAMIN or within 14 days of stopping treatment with NORPRAMIN is contraindicated because of an increased risk of serotonin syndrome. The use of NORPRAMIN within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). Starting NORPRAMIN in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION). NORPRAMIN is contraindicated in the acute recovery period following myocardial infarction. It should not be used in those who have shown prior hypersensitivity to the drug. Cross-sensitivity between this and other dibenzazepines is a possibility. WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] 3 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short- term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo- controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short- term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. 4 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for NORPRAMIN should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that NORPRAMIN is not approved for use in treating bipolar depression. Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with serotonin norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including NORPRAMIN, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of NORPRAMIN with MAOIs intended to treat psychiatric disorders is contraindicated. NORPRAMIN should also not be started in a patient who is being treated with 5 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking NORPRAMIN. NORPRAMIN should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of NORPRAMIN with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome particularly during treatment initiation and dose increases. Treatment with NORPRAMIN and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including Norpramin may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. General Extreme caution should be used when this drug is given in the following situations: a. In patients with cardiovascular disease, because of the possibility of conduction defects, arrhythmias, tachycardias, strokes, and acute myocardial infarction. b. In patients who have a family history of sudden death, cardiac dysrhythmias, or cardiac conduction disturbances. c. In patients with a history of urinary retention or glaucoma, because of the anticholinergic properties of the drug. d. In patients with thyroid disease or those taking thyroid medication, because of the possibility of cardiovascular toxicity, including arrhythmias. e. In patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold. Seizures precede cardiac dysrhythmias and death in some patients. This drug is capable of blocking the antihypertensive effect of guanethidine and similarly acting compounds. The patient should be cautioned that this drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage. 6 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use in Pregnancy Safe use of NORPRAMIN during pregnancy and lactation has not been established; therefore, if it is to be given to pregnant patients, nursing mothers, or women of childbearing potential, the possible benefits must be weighed against the possible hazards to mother and child. Animal reproductive studies have been inconclusive. Geriatric Use Clinical studies of NORPRAMIN 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. Lower doses are recommended for elderly patients. (See DOSAGE AND ADMINISTRATION.) The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. 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. NORPRAMIN use in the elderly has been associated with a proneness to falling as well as confusional states. (See ADVERSE REACTIONS.) PRECAUTIONS Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with NORPRAMIN and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for NORPRAMIN. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking NORPRAMIN. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, 7 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be advised that taking Norpramin can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Therefore, NORPRAMIN (desipramine hydrochloride) is not recommended for use in children. Anyone considering the use of NORPRAMIN in a child or adolescent must balance the potential risks with the clinical need (see also ADVERSE REACTIONS-Cardiovascular). General It is important that this drug be dispensed in the least possible quantities to depressed outpatients, since suicide has been accomplished with this class of drug (see WARNINGS-Clinical Worsening and Suicide Risk). Ordinary prudence requires that children not have access to this drug or to potent drugs of any kind; if possible, this drug should be dispensed in containers with child-resistant safety closures. Storage of this drug in the home must be supervised responsibly. If serious adverse effects occur, dosage should be reduced or treatment should be altered. NORPRAMIN therapy in patients with manic-depressive illness may induce a hypomanic state after the depressive phase terminates. The drug may cause exacerbation of psychosis in schizophrenic patients. Both elevation and lowering of blood sugar levels have been reported. Leukocyte and differential counts should be performed in any patient who develops fever and sore throat during therapy; the drug should be discontinued if there is evidence of pathologic neutrophil depression. 8 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical experience in the concurrent administration of ECT and antidepressant drugs is limited. Thus, if such treatment is essential, the possibility of increased risk relative to benefits should be considered. This drug should be discontinued as soon as possible prior to elective surgery because of possible cardiovascular effects. Hypertensive episodes have been observed during surgery in patients taking desipramine hydrochloride. Drug Interactions Drugs Metabolized by P450 2D6. The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type C antiarrhythmics propafenone and flecainide). While all the SSRIs, e.g., fluoxetine, sertraline, paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Close supervision and careful adjustment of dosage are required when this drug is given concomitantly with anticholinergic or sympathomimetic drugs. Patients should be warned that while taking this drug their response to alcoholic beverages may be exaggerated. 9 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If NORPRAMIN is to be combined with other psychotropic agents such as tranquilizers or sedative/hypnotics, careful consideration should be given to the pharmacology of the agents employed since the sedative effects of NORPRAMIN and benzodiazepines (e.g., chlordiazepoxide or diazepam) are additive. Both the sedative and anticholinergic effects of the major tranquilizers are also additive to those of NORPRAMIN. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) and serotonergic drugs may potentially cause life threatening adverse events (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Included in the following listing are a few adverse reactions that have not been reported with this specific drug. However, the pharmacologic similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when NORPRAMIN is given. Cardiovascular: Hypotension, hypertension, palpitations, heart block, myocardial infarction, stroke, arrhythmias, premature ventricular contractions, tachycardia, ventricular tachycardia, ventricular fibrillation, sudden death There has been a report of an "acute collapse" and "sudden death" in an 8-year-old (18 kg) male, treated for 2 years for hyperactivity. There have been additional reports of sudden death in children. (See PRECAUTIONS-Pediatric Use) Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis Neurologic: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures; alterations in EEG patterns; tinnitus Symptoms attributed to Neuroleptic Malignant Syndrome have been reported during desipramine use with and without concomitant neuroleptic therapy. Anticholinergic: Dry mouth, and rarely associated sublingual adenitis; blurred vision, disturbance of accommodation, mydriasis, increased intraocular pressure; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of urinary tract Allergic: Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive exposure to sunlight), edema (of face and tongue or general), drug fever, cross-sensitivity with other tricyclic drugs Hematologic: Bone marrow depressions including agranulocytosis, eosinophilia, purpura, thrombocytopenia 10 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal: Anorexia, nausea and vomiting, epigastric distress, peculiar taste, abdominal cramps, diarrhea, stomatitis, black tongue, hepatitis, jaundice (simulating obstructive), altered liver function, elevated liver function tests, increased pancreatic enzymes Endocrine: Gynecomastia in the male, breast enlargement and galactorrhea in the female; increased or decreased libido, impotence, painful ejaculation, testicular swelling; elevation or depression of blood sugar levels; syndrome of inappropriate antidiuretic hormone secretion (SIADH) Other: Weight gain or loss; perspiration, flushing; urinary frequency, nocturia; parotid swelling; drowsiness, dizziness, proneness to falling, weakness and fatigue, headache; fever; alopecia; elevated alkaline phosphatase Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise. OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Overdose of desipramine has resulted in a higher death rate compared to overdoses of other tricyclic antidepressants. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. There is no specific antidote for desipramine overdosage. Oral LD50 The oral LD50 of desipramine is 290 mg/kg in male mice and 320 mg/kg in female rats. Manifestations of Overdosage Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Early changes in the QRS complex include a widening of the terminal 40 msec with a rightward axis in the frontal plane, recognized by the presence of a terminal S wave in Lead 1 and AVL and an R wave in AVR. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Management 11 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Aggressive supportive care and serum alkalinization are the mainstays of therapy. General. Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. Follow ECG, renal function, CPK, and arterial blood gasses as clinically indicated. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death, and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination. Emesis is contraindicated. Activated charcoal should be administered to patients who present early after an overdose. Cardiovascular. A maximal limb-lead QRS duration widening to greater than 100 msec is a significant indicator of toxicity, specifically for the risk of seizures and, eventually, cardiac dysrhythmias. Serum alkalinization with intravenous sodium bicarbonate and hyperventilation (as needed) should be instituted in patients manifesting significant toxicity such as QRS widening. Dysrhythmias despite adequate alkalemia may respond to overdrive pacing, beta- agonist infusions, and magnesium therapy. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). CNS. In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines. If these are ineffective or seizures recur, other anticonvulsants (eg, phenobarbital, propofol) may be used. Psychiatric Follow-up. Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management. The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. DOSAGE AND ADMINISTRATION Not recommended for use in children (see WARNINGS). Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients compared to hospitalized patients, who are closely supervised. Dosage should be initiated at a low level and increased according to clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a period of time and should be at the lowest dose that will maintain remission. 12 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usual Adult Dose The usual adult dose is 100 to 200 mg per day. In more severely ill patients, dosage may be further increased gradually to 300 mg/day if necessary. Dosages above 300 mg/day are not recommended. Dosage should be initiated at a lower level and increased according to tolerance and clinical response. Treatment of patients requiring as much as 300 mg should generally be initiated in hospitals, where regular visits by the physician, skilled nursing care, and frequent electrocardiograms (ECGs) are available. The best available evidence of impending toxicity from very high doses of NORPRAMIN is prolongation of the QRS or QT intervals on the ECG. Prolongation of the PR interval is also significant, but less closely correlated with plasma levels. Clinical symptoms of intolerance, especially drowsiness, dizziness, and postural hypotension, should also alert the physician to the need for reduction in dosage. Initial therapy may be administered in divided doses or a single daily dose. Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. Adolescent and Geriatric Dose The usual adolescent and geriatric dose is 25 to 100 mg daily. Dosage should be initiated at a lower level and increased according to tolerance and clinical response to a usual maximum of 100 mg daily. In more severely ill patients, dosage may be further increased to 150 mg/day. Doses above 150 mg/day are not recommended in these age groups. Initial therapy may be administered in divided doses or a single daily dose. Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with NORPRAMIN. Conversely, at least 14 days should be allowed after stopping NORPRAMIN before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of NORPRAMIN With Other MAOI’s Such as Linezolid or Methylene Blue: 13 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not start NORPRAMIN in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). In some cases, a patient already receiving NORPRAMIN therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, NORPRAMIN should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with NORPRAMIN may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with NORPRAMIN is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). HOW SUPPLIED 10 mg blue coated tablets imprinted 68-7 NDC 0068-0007-01: bottles of 100 25 mg yellow coated tablets imprinted NORPRAMIN 25 NDC 0068-0011-01: bottles of 100 50 mg green coated tablets imprinted NORPRAMIN 50 NDC 0068-0015-01: bottles of 100 75 mg orange coated tablets imprinted NORPRAMIN 75 NDC 0068-0019-01: bottles of 100 100 mg peach coated tablets imprinted NORPRAMIN 100 NDC 0068-0020-01: bottles of 100 150 mg white coated tablets imprinted NORPRAMIN 150 NDC 0068-0021-50: bottles of 50 Store at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) [see USP Controlled Room Temperature]. Protect from excessive heat. Dispense in tight container. Rx only 14 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mfd for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY © 2014 sanofi-aventis U.S. LLC 15 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide Norpramin® (desipramine hydrochloride tablets USP) Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with your, or your family member’s, antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:  all risks and benefits of treatment with antidepressant medicines  all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?  Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.  Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.  Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Who should not take NORPRAMIN?  You should not take NORPRAMIN if you take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.  Do not take an MAOI within 2 weeks of stopping NORPRAMIN unless directed to do so by your physician.  Do not start NORPRAMIN if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. 16 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:  thoughts about suicide or dying  attempts to commit suicide  new or worse depression  new or worse anxiety  feeling very agitated or restless  panic attacks  trouble sleeping (insomnia)  new or worse irritability  acting aggressive, being angry, or violent  acting on dangerous impulses  an extreme increase in activity and talking (mania)  other unusual changes in behavior or mood Visual Problems  eye pain  changes in vision  swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. What else do I need to know about antidepressant medicines?  Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.  Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.  Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.  Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. 17 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 800-FDA-1088. You may also report side effects to sanofi-aventis U.S. at 1-800-633-1610. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Rev. June 2014 Mfd for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY © 2014 sanofi-aventis U.S. LLC 18 Reference ID: 3536021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:53.115670	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/014399s069lbl.pdf', 'application_number': 14399, 'submission_type': 'SUPPL ', 'submission_number': 69}
10,849	DOPRAM Injection (doxapram hydrochloride injection, USP) NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL Rx only DESCRIPTION DOPRAM Injection (doxapram hydrochloride injection, USP) is a clear, colorless, sterile, non-pyrogenic, aqueous solution with pH 3.5 to 5, for intravenous administration. Each 1 mL contains: Doxapram Hydrochloride, USP ................................................................. 20 mg Benzyl Alcohol, NF (as preservative) ......................................................... 0.9% Water for Injection, USP ...........…................................................................. q.s. Doxapram Injection is a respiratory stimulant. Doxapram hydrochloride is a white to off-white, crystalline powder, sparingly soluble in water, alcohol and chloroform. Chemically, doxapram hydrochloride is 1-ethyl-4-[2-(4- morpholinyl)ethyl]-3,3-diphenyl-2-pyrrolidinone monohydrochloride, monohydrate. The chemical structure is: C24H31ClN2O2 • H2O M.W. 432.99 CLINICAL PHARMACOLOGY Doxapram hydrochloride produces respiratory stimulation mediated through the peripheral carotid chemoreceptors. As the dosage level is increased, the central respiratory centers in the medulla are stimulated with progressive stimulation of other parts of the brain and spinal cord. The onset of respiratory stimulation following the recommended single intravenous injection of doxapram hydrochloride usually occurs in 20 to 40 seconds with peak effect at 1 to 2 minutes. The duration of effect may vary from 5 to 12 minutes. The respiratory stimulant action is manifested by an increase in tidal volume associated with a slight increase in respiratory rate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A pressor response may result following doxapram administration. Provided there is no impairment of cardiac function, the pressor effect is more marked in hypovolemic than in normovolemic states. The pressor response is due to the improved cardiac output rather than peripheral vasoconstriction. Following doxapram administration, an increased release of catecholamines has been noted. Although opiate-induced respiratory depression is antagonized by doxapram, the analgesic effect is not affected. INDICATIONS AND USAGE Postanesthesia a. When the possibility of airway obstruction and/or hypoxia have been eliminated, doxapram may be used to stimulate respiration in patients with drug-induced postanesthesia respiratory depression or apnea other than that due to muscle relaxant drugs. b. To pharmacologically stimulate deep breathing in the postoperative patient. (A quantitative method of assessing oxygenation, such as pulse oximetry, is recommended.) Drug-Induced Central Nervous System Depression Exercising care to prevent vomiting and aspiration, doxapram may be used to stimulate respiration, hasten arousal, and to encourage the return of laryngopharyngeal reflexes in patients with mild to moderate respiratory and CNS depression due to drug overdosage. Chronic Pulmonary Disease Associated with Acute Hypercapnia Doxapram is indicated as a temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease. Its use should be for a short period of time (see DOSAGE AND ADMINISTRATION) as an aid in the prevention of elevation of arterial CO2 tension during the administration of oxygen. It should not be used in conjunction with mechanical ventilation. CONTRAINDICATIONS Doxapram is contraindicated in patients with known hypersensitivity to the drug or any of the injection components. Doxapram should not be used in patients with epilepsy or other convulsive disorders. Doxapram is contraindicated in patients with proven or suspected pulmonary embolism. Doxapram is contraindicated in patients with mechanical disorders of ventilation such as mechanical obstruction, muscle paresis (including neuromuscular blockade), flail chest, pneumothorax, acute bronchial asthma, pulmonary fibrosis, or other conditions resulting in restriction of the chest wall, muscles of respiration, or alveolar expansion. Doxapram is contraindicated in patients with evidence of head injury, cerebral vascular accident, or cerebral edema, and in those with significant cardiovascular impairment, uncompensated heart failure, severe coronary artery disease, or severe hypertension, including that associated with hyperthyroidism or pheochromocytoma. (See WARNINGS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Doxapram should not be used in conjunction with mechanical ventilation. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS, Pediatric Use). In Postanesthetic Use a. Doxapram is neither an antagonist to muscle relaxant drugs nor a specific narcotic antagonist. More specific tests (eg, peripheral nerve stimulation, airway pressures, head lift, pulse oximetry, and end-tidal carbon dioxide) to assess adequacy of ventilation are recommended before administering doxapram. b. Doxapram should be administered with great care and only under careful supervision to patients with hypermetabolic states such as hyperthyroidism or pheochromocytoma. c. Since narcosis may recur after stimulation with doxapram, care should be taken to maintain close observation until the patient has been fully alert for ½ to 1 hour. d. In patients who have received general anesthesia utilizing a volatile agent known to sensitize the myocardium to catecholamines, administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation (see PRECAUTIONS, Drug Interactions). In Drug-Induced CNS and Respiratory Depression Doxapram alone may not stimulate adequate spontaneous breathing or provide sufficient arousal in patients who are severely depressed either due to respiratory failure or to CNS depressant drugs, but may be used as an adjunct to established supportive measures and resuscitative techniques. In Chronic Obstructive Pulmonary Disease Because of the associated increased work of breathing, do not increase the rate of infusion of doxapram in severely ill patients in an attempt to lower pCO2. PRECAUTIONS General a. An adequate airway is essential and airway protection should be considered since doxapram may stimulate vomiting. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda b. Recommended dosages of doxapram should be employed and maximum total dosages should not be exceeded. In order to avoid side effects, it is advisable to use the minimum effective dosage. c. Monitoring of the blood pressure, pulse rate, and deep tendon reflexes is recommended to prevent overdosage. d. Vascular extravasation or use of a single injection site over an extended period should be avoided since either may lead to thrombophlebitis or local skin irritation. e. Rapid infusion may result in hemolysis. f. Lowered pCO2 induced by hyperventilation produces cerebral vasoconstriction and slowing of the cerebral circulation. This should be taken into consideration on an individual basis. In certain patients a pressor effect of doxapram on the pulmonary circulation may result in a fall of the arterial pO2 probably due to a worsening of ventilation perfusion-matching in the lungs despite an overall improvement in alveolar ventilation and a fall in pCO2. Patients should be carefully supervised taking into account available blood gas measurements. g. There is a risk that doxapram will produce adverse effects (including seizures) due to general central nervous system stimulation. Muscle involvement may range from fasciculation to spasticity. Anticonvulsants such as intravenous short-acting barbiturates, along with oxygen and resuscitative equipment should be readily available to manage overdosage manifested by excessive central nervous system stimulation. Slow administration of the drug and careful observation of the patient during administration and for some time subsequently are advisable. These precautions are to assure that the protective reflexes have been restored and to prevent possible post-hyperventilation or hypoventilation. h. Doxapram should be administered cautiously to patients receiving sympathomimetic or monoamine oxidase inhibiting drugs, since an additive pressor effect may occur. i. Blood pressure increases are generally modest but significant increases have been noted in some patients. Because of this, doxapram is not recommended for use in patients with severe hypertension (see CONTRAINDICATIONS). j. Cardiovascular effects may include various dysrhythmias. Patients receiving doxaprom should be monitored for disturbance of their cardiac rhythm. k. If sudden hypotension or dyspnea develops, doxapram should be stopped. l. Doxapram should be administered with caution to patients with significantly impaired hepatic or renal function as a reduction in the rate of metabolism or excretion of metabolites may alter the response. In Postanesthetic Use a. The same consideration to pre-existing disease states should be exercised as in non- anesthetized individuals. See CONTRAINDICATIONS and WARNINGS covering use in hypertension, asthma, disturbances of respiratory mechanics including airway obstruction, CNS disorders including increased cerebrospinal fluid pressure, convulsive disorders, acute agitation, and profound metabolic disorders. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda b. See PRECAUTIONS, Drug Interactions. In Chronic Obstructive Pulmonary Disease a. Arrhythmias seen in some patients in acute respiratory failure secondary to chronic obstructive pulmonary disease are probably the result of hypoxia. Doxapram should be used with caution in these patients. b. Arterial blood gases should be drawn prior to the initiation of doxapram infusion and oxygen administration, then at least every ½ hour during the infusion period to prevent development of CO2 retention and acidosis in patients with chronic obstructive pulmonary disease with acute hypercapnia. Doxapram administration does not diminish the need for careful monitoring of the patient or the need for supplemental oxygen in patients with acute respiratory failure. Doxapram should be stopped if the arterial blood gases deteriorate, and mechanical ventilation should be initiated. Drug Interactions Administration of doxapram to patients who are receiving sympathomimetic or monoamine oxidase inhibiting drugs may result in an additive pressor effect (see PRECAUTIONS, General). In patients who have received neuromuscular blocking agents, doxapram may temporarily mask the residual effects of these drugs. In patients who have received general anesthesia utilizing a volatile agent known to sensitize the myocardium to catecholamines, administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation (see WARNINGS). There may be an interaction between doxapram and aminophylline and between theophylline manifested by increased skeletal muscle activity, agitation, and hyperactivity. Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenic or mutagenic studies have been performed using doxapram. Doxapram did not adversely affect the breeding performance of rats. Pregnancy Pregnancy Category B Reproduction studies have been performed in rats at doses up to 1.6 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to doxapram. There are, however, no adequate and well-controlled studies in pregnant women. Because the animals in the reproduction studies were dosed by the IM and oral routes and animal reproduction studies, in general, 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 doxapram hydrochloride 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 Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 years have not been established. This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low- birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. Premature neonates given doxapram have developed hypertension, irritability, jitteriness, hyperglycemia, glucosuria, abdominal distension, increased gastric residuals, vomiting, bloody stools, necrotizing enterocolitis, erratic limb movements, excessive crying, disturbed sleep, premature eruption of teeth, and QT prolongation that has resulted in heart block. In premature neonates with risk factors such as a previous seizure, perinatal asphyxia, or intracerebral hemorrhage, seizures have occurred. In many instances, doxapram was administered following administration of xanthine derivatives such as caffeine, aminophylline or theophylline. ADVERSE REACTIONS Adverse reactions reported coincident with the administration of DOPRAM (doxapram hydrochloride, USP) include: 1. Central and Autonomic Nervous Systems Pyrexia, flushing, sweating; pruritus and paresthesia, such as a feeling of warmth, burning, or hot sensation, especially in the area of genitalia and perineum; apprehension, disorientation, pupillary dilatation, hallucinations, headache, dizziness, hyperactivity, involuntary movements, muscle spasticity, muscle fasciculations, increased deep tendon reflexes, clonus, bilateral Babinski, and convulsions. 2. Respiratory Dyspnea, cough, hyperventilation, tachypnea, laryngospasm, bronchospasm, hiccough, and rebound hypoventilation. 3. Cardiovascular Phlebitis, variations in heart rate, lowered T-waves, arrhythmias (including ventricular tachycardia and ventricular fibrillation), chest pain, tightness in chest. A mild to moderate increase in blood pressure is commonly noted and may be of concern in patients with severe cardiovascular diseases. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4. Gastrointestinal Nausea, vomiting, diarrhea, desire to defecate. 5. Genitourinary Stimulation of urinary bladder with spontaneous voiding; urinary retention. Elevation of BUN and albuminuria. 6. Hemic and Lymphatic Hemolysis with rapid infusion. A decrease in hemoglobin, hematocrit, or red blood cell count has been observed in postoperative patients. In the presence of pre-existing leukopenia, a further decrease in WBC has been observed following anesthesia and treatment with doxapram hydrochloride. OVERDOSAGE Signs and Symptoms Symptoms of overdosage are extensions of the pharmacologic effects of the drug. Excessive pressor effect, such as hypertension, tachycardia, skeletal muscle hyperactivity, and enhanced deep tendon reflexes may be early signs of overdosage. Therefore, the blood pressure, pulse rate, and deep tendon reflexes should be evaluated periodically and the dosage or infusion rate adjusted accordingly. Other effects may include agitation, confusion, sweating, cough, and dyspnea. Convulsive seizures are unlikely at recommended dosages. In unanesthetized animals, the convulsant dose is 70 times greater than the respiratory stimulant dose. Intravenous LD50 values in the mouse and rat were approximately 75 mg/kg and in the cat and dog were 40 to 80 mg/kg. Except for management of chronic obstructive pulmonary disease associated with acute hypercapnia, the maximum recommended dosage is 3 GRAMS/24 HOURS. (See DOSAGE AND ADMINISTRATION.) Management There is no specific antidote for doxapram. Management should be symptomatic. Anticonvulsants, along with oxygen and resuscitative equipment should be readily available to manage overdosage manifested by excessive central nervous system stimulation. Slow administration of the drug and careful observation of the patient during administration and for some time subsequently are advisable. These precautions are to assure that the protective reflexes have been restored and to prevent possible post- hyperventilation or hypoventilation. There is no evidence that doxapram is dialyzable; further, the half-life of doxapram makes it unlikely that dialysis would be appropriate in managing overdose with this drug. DOSAGE AND ADMINISTRATION NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Postanesthetic Use Table I. Dosage for postanesthetic use—I.V. and infusion. Recommended Dosage Maximum dose per single injection Maximum total dose* I.V. Administration mg/kg mg/kg mg/kg Single Injection 0.5-1 1.5 1.5 Repeat Injections (5 min. intervals) 0.5-1 1.5 2 Infusion 0.5-1 – 4 Dose not to exceed 3 grams/24 hours. By I.V. Injection (See Table I. Dosage for postanesthetic use—I.V.) The recommended dose for I.V. administration is 0.5 – 1 mg/kg for a single injection and at 5-minute intervals. Careful observation of the patient during administration and for some time subsequently are advisable. The maximum total dosage by I.V. injection is 2 mg/kg. By Infusion The solution is prepared by adding 250 mg of doxapram (12.5 mL) to 250 mL of dextrose 5% or 10% in water or normal saline solution. The infusion is initiated at a rate of approximately 5 mg/minute until a satisfactory respiratory response is observed, and maintained at a rate of 1 to 3 mg/minute. The rate of infusion should be adjusted to sustain the desired level of respiratory stimulation with a minimum of side effects. The maximum total dosage by infusion is 4 mg/kg, or approximately 300 mg for the average adult. In the Management of Drug-Induced CNS Depression (See Table II. Dosage for drug-induced CNS depression.) Table II. Dosage for drug-induced CNS depression. METHOD ONE Priming dose single/repeat I.V. Injection METHOD TWO Rate of Intermittent I.V. Infusion Level of Depression mg/kg mg/kg/hr Mild 1 1-2 Moderate† 2 2-3 *Mild Depression Class 0: Asleep, but can be aroused and can answer questions. Class 1: Comatose, will withdraw from painful stimuli, reflexes intact. †Moderate Depression Class 2: Comatose, will not withdraw from painful stimuli, reflexes intact. Class 3: Comatose, reflexes absent, no depression of circulation or respiration. Method One Using Single and/or Repeat Single I.V. Injections a. Give priming dose of 2 mg/kg body weight and repeat in 5 minutes. The priming dose for moderate depression is 2 mg/kg and the priming dose for mild depression is 1 mg/kg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda b. Repeat same dose q 1 to 2h until patient wakens. Watch for relapse into unconsciousness or development of respiratory depression, since DOPRAM does not affect the metabolism of CNS-depressant drugs. c. If relapse occurs, resume injections q 1 to 2h until arousal is sustained, or total maximum daily dose (3 grams) is given. After maximum dose has been given (3 grams), allow patient to sleep until 24 hours have elapsed from first injection of DOPRAM, using assisted or automatic respiration if necessary. d. Repeat procedure the following day until patient breathes spontaneously and sustains desired level of consciousness, or until maximum dosage (3 grams) is given. e. Repetitive doses should be administered only to patients who have shown response to the initial dose. f. Failure to respond appropriately indicates the need for neurologic evaluation for a possible central nervous system source of sustained coma. Method Two By Intermittent I.V. Infusion a. Give priming dose as in Method One. b. If patient wakens, watch for relapse; if no response, continue general supportive treatment for 1 to 2 hours and repeat priming dose of DOPRAM. If some respiratory stimulation occurs, prepare I.V. infusion by adding 250 mg of DOPRAM (12.5 mL) to 250 mL of saline or dextrose solution. Deliver at rate of 1 to 3 mg/min (60 to 180 mL/hr) according to size of patient and depth of coma. Discontinue DOPRAM if patient begins to waken or at end of 2 hours. c. Continue supportive treatment for ½ to 2 hours and repeat Step b. d. Do not exceed 3 grams/day. Chronic Obstructive Pulmonary Disease Associated with Acute Hypercapnia a. One vial of doxapram (400 mg) should be mixed with 180 mL of dextrose 5% or 10% or normal saline solution (concentration of 2 mg/mL). The infusion should be started at 1 to 2 mg/minute (½ to 1 mL/minute); if indicated, increase to a maximum of 3 mg/minute. Arterial blood gases should be determined prior to the onset of doxapram’s administration and at least every half hour during the two hours of infusion to insure against the insidious development of CO2-RETENTION AND ACIDOSIS. Alteration of oxygen concentration or flow rate may necessitate adjustment in the rate of doxapram infusion. b. Predictable blood gas patterns are more readily established with a continuous infusion of doxapram. If the blood gases show evidence of deterioration, the infusion of doxapram should be discontinued. c. ADDITIONAL INFUSIONS BEYOND THE SINGLE MAXIMUM TWO HOUR ADMINISTRATION PERIOD ARE NOT RECOMMENDED. 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 Diluent Compatibility Doxapram hydrochloride is compatible with 5% and 10% dextrose in water or normal saline. Incompatibility ADMIXTURE OF DOXAPRAM WITH ALKALINE SOLUTIONS SUCH AS 2.5% THIOPENTAL SODIUM, SODIUM BICARBONATE, FUROSEMIDE, OR AMINOPHYLLINE WILL RESULT IN PRECIPITATION OR GAS FORMATION. Doxapram is also not compatible with ascorbic acid, cefoperazone sodium, cefotaxime sodium, cefotetan sodium, cefuroxime sodium, folic acid, dexamethasone disodium phosphate, diazepam, hydrocortisone sodium phospate, methylprednisolone sodium, or hydrocortisone sodium succinate. Admixture of doxapram and ticarcillin disodium results in an 18% loss of doxapram in 3 hours. When doxapram is mixed with minocycline hydrochloride, there is a loss of 8% of doxapram in 3 hours and a 13% loss of doxapram in 6 hours. HOW SUPPLIED DOPRAM Injection (doxapram hydrochloride injection, USP) containing 20 mg of doxapram hydrochloride per mL with benzyl alcohol 0.9% as the preservative is available in: 20 mL multiple dose vials in packages of 6 (NDC 60977-144-02). CONTAINS BENZYL ALCOHOL. Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. ESI Stylized Logo and Dopram are trademarks of Baxter International Inc., or its subsidiaries. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-31/2.0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:53.243890	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/14879s044lbl.pdf', 'application_number': 14879, 'submission_type': 'SUPPL ', 'submission_number': 44}
10,848	PRESCRIBING INFORMATION ALKERAN® (melphalan) Tablets WARNING ALKERAN (melphalan) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe bone marrow suppression with resulting infection or bleeding may occur. Melphalan is leukemogenic in humans. Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans. DESCRIPTION ALKERAN (melphalan), also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent which is active against selective human neoplastic diseases. It is known chemically as 4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular formula is C13H18Cl2N2O2 and the molecular weight is 305.20. The structural formula is: structural formula Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by Bergel and Stock; the D-isomer, known as medphalan, is less active against certain animal tumors, and the dose needed to produce effects on chromosomes is larger than that required with the L-isomer. The racemic (DL–) form is known as merphalan or sarcolysin. Melphalan is practically insoluble in water and has a pKa1 of ∼2.5. ALKERAN (melphalan) is available in tablet form for oral administration. Each film-coated tablet contains 2 mg melphalan and the inactive ingredients colloidal silicon dioxide, crospovidone, hypromellose, macrogol/PEG 400, magnesium stearate, microcrystalline cellulose, and titanium dioxide. CLINICAL PHARMACOLOGY Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells. Pharmacokinetics: The pharmacokinetics of ALKERAN after oral administration has been 1 Reference ID: 2940447 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda extensively studied in adult patients. Plasma melphalan levels are highly variable after oral dosing, both with respect to the time of the first appearance of melphalan in plasma (range approximately 0 to 6 hours) and to the peak plasma concentration (Cmax) (range 70 to 4,000 ng/mL, depending upon the dose) achieved. These results may be due to incomplete intestinal absorption, a variable “first pass” hepatic metabolism, or to rapid hydrolysis. Five patients were studied after both oral and intravenous (IV) dosing with 0.6 mg/kg as a single bolus dose by each route. The areas under the plasma concentration-time curves (AUC) after oral administration averaged 61% ± 26% (± standard deviation [SD]; range 25% to 89%) of those following IV administration. In 18 patients given a single oral dose of 0.6 mg/kg of ALKERAN, the terminal elimination plasma half-life (t1/2) of parent drug was 1.5 ± 0.83 hours. The 24-hour urinary excretion of parent drug in these patients was 10% ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug. In a separate study in 18 patients given single oral doses of 0.2 to 0.25 mg/kg of ALKERAN, Cmax and AUC, when dose adjusted to a dose of 14 mg, were (mean ± SD) 212 ± 74 ng/mL and 498 ± 137 ng•hr/mL, respectively. Elimination phase t½ in these patients was approximately 1 hour and the median tmax was 1 hour. One study using universally labeled 14C-melphalan, found substantially less radioactivity in the urine of patients given the drug by mouth (30% of administered dose in 9 days) than in the urine of those given it intravenously (35% to 65% in 7 days). Following either oral or IV administration, the pattern of label recovery was similar, with the majority being recovered in the first 24 hours. Following oral administration, peak radioactivity occurred in plasma at 2 hours and then disappeared with a half-life of approximately 160 hours. In 1 patient where parent drug (rather than just radiolabel) was determined, the melphalan half-disappearance time was 67 minutes. The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The extent of melphalan binding to plasma proteins ranges from 60% to 90%. Serum albumin is the major binding protein, while α1-acid glycoprotein appears to account for about 20% of the plasma protein binding. Approximately 30% of melphalan is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible. Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one pharmacokinetic study showed a significant positive correlation between the elimination rate constant for melphalan and renal function and a significant negative correlation between renal function and the area under the plasma melphalan concentration/time curve. INDICATIONS AND USAGE ALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. 2 Reference ID: 2940447 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS ALKERAN should not be used in patients whose disease has demonstrated a prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug. WARNINGS ALKERAN should be administered in carefully adjusted dosage by or under the supervision of experienced physicians who are familiar with the drug's actions and the possible complications of its use. As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow suppression. Bone marrow suppression is the most significant toxicity associated with ALKERAN in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent course of ALKERAN: platelet count, hemoglobin, white blood cell count, and differential. Thrombocytopenia and/or leukopenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity (see PRECAUTIONS: Laboratory Tests). Dose adjustment on the basis of blood counts at the nadir and day of treatment should be considered. Hypersensitivity reactions, including anaphylaxis, have occurred rarely (see ADVERSE REACTIONS). These reactions have occurred after multiple courses of treatment and have recurred in patients who experienced a hypersensitivity reaction to IV ALKERAN. If a hypersensitivity reaction occurs, oral or IV ALKERAN should not be readministered. Carcinogenesis: Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukemia, myeloproliferative syndrome, or carcinoma is not possible. Published reports of leukemia in patients who have received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis increases with chronicity of treatment and with cumulative dose. In one study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was 19.5% for cumulative doses ranging from 730 mg to 9,652 mg. In this same study, as well as in an additional study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was less than 2% for cumulative doses under 600 mg. This does not mean that there is a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy. Adequate and well-controlled carcinogenicity studies have not been conducted in animals. However, i.p. administration of melphalan in rats (5.4 to 10.8 mg/m2) and in mice (2.25 to 4.5 mg/m2) 3 times per week for 6 months followed by 12 months post-dose observation produced peritoneal sarcoma and lung tumors, respectively. 3 Reference ID: 2940447 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mutagenesis: ALKERAN has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of ALKERAN at 6 and 60 mg/m2 produced structural aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats. Impairment of Fertility: ALKERAN causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported. Pregnancy: Pregnancy Category D. ALKERAN may cause fetal harm when administered to a pregnant woman. Melphalan was embryolethal and teratogenic in rats following oral (6 to 18 mg/m2/day for 10 days) and intraperitoneal (18 mg/m2) administration. Malformations resulting from melphalan included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as hepatocele (exomphaly). There are no adequate and well-controlled studies in pregnant women. 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 hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. PRECAUTIONS General: In all instances where the use of ALKERAN is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events. ALKERAN should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from previous cytotoxic therapy. If the leukocyte count falls below 3,000 cells/mcL, or the platelet count below 100,000 cells/mcL, ALKERAN should be discontinued until the peripheral blood cell counts have recovered. A recommendation as to whether or not dosage reduction should be made routinely in patients with renal insufficiency cannot be made because: a) There is considerable inherent patient-to-patient variability in the systemic availability of melphalan in patients with normal renal function. b) Only a small amount of the administered dose appears as parent drug in the urine of patients with normal renal function. Patients with azotemia should be closely observed, however, in order to make dosage reductions, if required, at the earliest possible time. Administration of live vaccines to immunocompromised patients should be avoided. Information for Patients: Patients should be informed that the major toxicities of ALKERAN are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and pulmonary toxicity. The major long-term toxicities are related to infertility and secondary malignancies. Patients should never be allowed to take the drug without close medical supervision and should be advised to consult their physician if they experience skin rash, vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or 4 Reference ID: 2940447 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming pregnant. Laboratory Tests: Periodic complete blood counts with differentials should be performed during the course of treatment with ALKERAN. At least one determination should be obtained prior to each treatment course. Patients should be observed closely for consequences of bone marrow suppression, which include severe infections, bleeding, and symptomatic anemia (see WARNINGS). Drug Interactions: There are no known drug/drug interactions with oral ALKERAN. Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section. Pregnancy: Teratogenic Effects: Pregnancy Category D: See WARNINGS section. Nursing Mothers: It is not known whether this drug is excreted in human milk. ALKERAN should not be given to nursing mothers. Pediatric Use: The safety and effectiveness of ALKERAN in pediatric patients have not been established. Geriatric Use: Clinical studies of ALKERAN 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. ADVERSE REACTIONS Hematologic: The most common side effect is bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. Although bone marrow suppression frequently occurs, it is usually reversible if melphalan is withdrawn early enough. However, irreversible bone marrow failure has been reported. Gastrointestinal: Nausea, vomiting, diarrhea, and oral ulceration occur. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported. Miscellaneous: Other reported adverse reactions include: pulmonary fibrosis (including fatal outcomes) and interstitial pneumonitis, skin hypersensitivity, maculopapular rashes, vasculitis, alopecia, and hemolytic anemia. Allergic reactions, including urticaria, edema, skin rashes, and rare anaphylaxis, have occurred after multiple courses of treatment. Cardiac arrest has also been reported rarely in association with such reports. OVERDOSAGE Overdoses, including doses up to 50 mg/day for 16 days, have been reported. Immediate effects are likely to be vomiting, ulceration of the mouth, diarrhea, and hemorrhage of the gastrointestinal tract. The principal toxic effect is bone marrow suppression. Hematologic parameters should be closely followed for 3 to 6 weeks. An uncontrolled study suggests that administration of autologous bone marrow or hematopoietic growth factors (i.e., sargramostim, 5 Reference ID: 2940447 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda filgrastim) may shorten the period of pancytopenia. General supportive measures, together with appropriate blood transfusions and antibiotics, should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by hemodialysis. DOSAGE AND ADMINISTRATION Multiple Myeloma: The usual oral dose is 6 mg (3 tablets) daily. The entire daily dose may be given at one time. The dose is adjusted, as required, on the basis of blood counts done at approximately weekly intervals. After 2 to 3 weeks of treatment, the drug should be discontinued for up to 4 weeks, during which time the blood count should be followed carefully. When the white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be instituted. Because of the patient-to-patient variation in melphalan plasma levels following oral administration of the drug, several investigators have recommended that the dosage of ALKERAN be cautiously escalated until some myelosuppression is observed in order to assure that potentially therapeutic levels of the drug have been reached. Other dosage regimens have been used by various investigators. Osserman and Takatsuki have used an initial course of 10 mg/day for 7 to 10 days. They report that maximal suppression of the leukocyte and platelet counts occurs within 3 to 5 weeks and recovery within 4 to 8 weeks. Continuous maintenance therapy with 2 mg/day is instituted when the white blood cell count is greater than 4,000 cells/mcL and the platelet count is greater than 100,000 cells/mcL. Dosage is adjusted to between 1 and 3 mg/day depending upon the hematological response. It is desirable to try to maintain a significant degree of bone marrow depression so as to keep the leukocyte count in the range of 3,000 to 3,500 cells/mcL. Hoogstraten et al have started treatment with 0.15 mg/kg/day for 7 days. This is followed by a rest period of at least 14 days, but it may be as long as 5 to 6 weeks. Maintenance therapy is started when the white blood cell and platelet counts are rising. The maintenance dose is 0.05 mg/kg/day or less and is adjusted according to the blood count. Available evidence suggests that about one third to one half of the patients with multiple myeloma show a favorable response to oral administration of the drug. One study by Alexanian et al has shown that the use of ALKERAN in combination with prednisone significantly improves the percentage of patients with multiple myeloma who achieve palliation. One regimen has been to administer courses of ALKERAN at 0.25 mg/kg/day for 4 consecutive days (or, 0.20 mg/kg/day for 5 consecutive days) for a total dose of 1 mg/kg/course. These 4- to 5-day courses are then repeated every 4 to 6 weeks if the granulocyte count and the platelet count have returned to normal levels. It is to be emphasized that response may be very gradual over many months; it is important that repeated courses or continuous therapy be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned too soon. In patients with moderate to severe renal impairment, currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction to those patients, but it may be prudent to use a reduced dose initially. 6 Reference ID: 2940447 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Epithelial Ovarian Cancer: One commonly employed regimen for the treatment of ovarian carcinoma has been to administer ALKERAN at a dose of 0.2 mg/kg daily for 5 days as a single course. Courses are repeated every 4 to 5 weeks depending upon hematologic tolerance. Administration Precautions: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. HOW SUPPLIED ALKERAN is supplied as white, film-coated, round, biconvex tablets containing 2 mg melphalan in amber glass bottles with child-resistant closures. One side is engraved with “GX EH3” and the other side is engraved with an “A.” Bottle of 50 (NDC 59572-302-50). Store in a refrigerator, 2° to 8°C (36° to 46°F). Protect from light. REFERENCES 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society;1999:32-41. 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992. US Dept of Health and Human Services. Public Health Service publication NIH 92-2621. 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591. 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428. 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263. 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685. gsk GlaxoSmithKline 7 Reference ID: 2940447 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Research Triangle Park, NC 27709 Celgene Celgene Corporation Summit, NJ 07901 ©2007, GlaxoSmithKline All rights reserved. June 2007 ALT:1PI 8 Reference ID: 2940447 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:53.366437	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf', 'application_number': 14691, 'submission_type': 'SUPPL ', 'submission_number': 30}
10,850	1 KENALOG®-40 INJECTION triamcinolone acetonide injectable suspension, USP NOT FOR USE IN ---- ------------- NEONATES CONTAINS BENZYL ALCOHOL For Intramuscular or Intra-articular Use NOT FOR INTRAVENOUS,----- INTRADERMAL, OR INTRAOCULAR USE DESCRIPTION Kenalog®-40 Injection (triamcinolone acetonide injectable suspension, USP) is a synthetic glucocorticoid corticosteroid with anti-inflammatory action. THIS FORMULATION IS SUITABLE FOR INTRAMUSCULAR AND INTRA- ARTICULAR USE ONLY. THIS FORMULATION IS NOT FOR INTRA-DERMAL INJECTION. Each mL of the sterile aqueous suspension provides 40 mg triamcinolone acetonide, with sodium chloride for isotonicity, 0.99% (w/v) benzyl alcohol as a preservative, 0.75% carboxymethylcellulose sodium, and 0.04% polysorbate 80. Sodium hydroxide or hydrochloric acid may be present to adjust pH to 5.0-7.5. At the time of manufacture, the air in the container is replaced by nitrogen. The chemical name for triamcinolone acetonide is 9-Fluoro-11β,16α,17,21- tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. Its structural formula is: MW 434.50 (b)(4) (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) (b)(4) (b)(4) 2 Triamcinolone acetonide occurs as a white to cream-colored, crystalline powder having not more than a slight odor and is practically insoluble in water and very soluble in alcohol. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Synthetic analogs such as triamcinolone are primarily used for their anti-inflammatory effects in disorders of many organ systems. Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) has an extended duration of effect which may be sustained over a period of several weeks. Studies indicate that following a single intramuscular dose of 60 to 100 mg of triamcinolone acetonide, adrenal suppression occurs within 24 to 48 hours and then gradually returns to normal, usually in 30 to 40 days. This finding correlates closely with the extended duration of therapeutic action achieved with the drug. INDICATIONS AND USAGE Intramuscular Where oral therapy is not feasible, injectable corticosteroid therapy, including Kenalog- 40 Injection (triamcinolone acetonide injectable suspension, USP) is indicated for intramuscular use as follows: Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of 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. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. Nervous Ssystem: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, craniotomy, or head injury. Ophthalmic diseases: Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Intra-Articular The intra-articular or soft tissue administration of Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. CONTRAINDICATIONS Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is contraindicated in patients who are hypersensitive to any components of this product. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. WARNINGS General -------------------------------------------------------- --------------------------------------------------- -------------- --------- ------------- -------------- ----------------------------------------- .Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS, Pediatric Use). Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). (b)(4) (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) (b)(4) (b)(4) 5 Because Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is a suspension, it should not be administered intravenously. Unless a deep intramuscular injection is given, local atrophy is likely to occur. (For recommendations on injection techniques, see DOSAGE AND ADMINISTRATION.) Due to the significantly higher incidence of local atrophy when the material is injected into the deltoid area, this injection site should be avoided in favor of the gluteal area. Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is a long-acting preparation, and is not suitable for use in acute stress situations. To avoid drug-induced adrenal insufficiency, supportive dosage may be required in times of stress (such as trauma, surgery or severe illness) both during treatment with Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) and for a year afterwards. Cardio-Renal Average and large doses of corticosteroids 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 they are used in large doses. Dietary salt restriction and potassium supplementation may be necessary (see PRECAUTIONS). All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Infections General Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS: Drug Interactions: Amphotericin B injection and potassium- depleting agents). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Tuberculosis The use of corticosteroids in patients with 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 anti-tuberculosis regimen. 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 cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease. Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. 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. Neurologic Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS: Gastrointestinal and Neurologic/ Psychiatric). 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 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. Adequate studies to demonstrate the safety of Kenalog Injection use by intraturbinal, subconjunctival, sub-Tenons, retrobulbar and intraocular (intravitreal) injections have not been performed. Endophthalmitis, eye inflammation, increased intraocular pressure and visual disturbances including vision loss have been reported with intravitreal administration. Several instances of blindness have been reported following injection of corticosteroid suspensions into the nasal turbinates and intralesional injection about the head. Administration of Kenalog Injection (triamcinolone acetonide injectable suspension, USP) by any of these routes is not recommended. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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. 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 congestive heart failure, hypertension, or renal insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 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 active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Intra-Articular and Soft Tissue Administration Intra-articularly injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS: Musculoskeletal). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 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 lead to inhibition of bone growth in pediatric patients 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Information for Patients Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on 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 Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases: 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. Anticoagulants, oral: 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. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Eenzyme Iinducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other nonsteroidal 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. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections: Vaccination). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects: Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have 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. Corticosteroids 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 corticosteroids are administered to a nursing woman. Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids 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). Other indications for pediatric use of corticosteroids, 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 corticosteroids 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. Pediatric patients 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 pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use No overall differences in safety or effectiveness were observed between elderly 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 ADVERSE REACTIONS (listed alphabetically under each subsection) The following adverse reactions may be associated with corticosteroid therapy: Allergic reactions: Anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypo- pigmentation, impaired wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, 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 pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS: Neurologic). Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION General NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS). The initial dose of Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) may vary from 2.5 mg to 100 mg per day depending on the specific disease entity being treated (see Dosage section below). However, in certain overwhelming, acute, life- threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 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. 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 the corticosteroid 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. Dosage SYSTEMIC The suggested initial dose is 60 mg, injected deeply into the gluteal muscle. Atrophy of subcutaneous fat may occur if the injection is not properly given. Dosage is usually adjusted within the range of 40 to 80 mg, depending upon patient response and duration of relief. However, some patients may be well controlled on doses as low as 20 mg or less. Hay fever or pollen asthma: Patients with hay fever or pollen asthma who are not responding to pollen administration and other conventional therapy may obtain a remission of symptoms lasting throughout the pollen season after a single injection of 40 to 100 mg. In the treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of triamcinolone for a week followed by 64 mg every other day for one month are recommended (see PRECAUTIONS: Neuro-Psychiatric). In pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in three or four divided doses (3.2 to 48 mg/m2bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 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. LOCAL Intra-articular administration: A single local injection of triamcinolone acetonide is frequently sufficient, but several injections may be needed for adequate relief of symptoms. Initial dose: 2.5 to 5 mg for smaller joints and from 5 to 15 mg for larger joints, depending on the specific disease entity being treated. For adults, doses up to 10 mg for smaller areas and up to 40 mg for larger areas have usually been sufficient. Single injections into several joints, up to a total of 80 mg, have been given. Administration GENERAL STRICT ASEPTIC TECHNIQUE IS MANDATORY. The vial should be shaken before use to ensure a uniform suspension. Prior to withdrawal, the suspension should be inspected for clumping or granular appearance (agglomeration). An agglomerated product results from exposure to freezing temperatures and should not be used. After withdrawal, Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) should be injected without delay to prevent settling in the syringe. Careful technique should be employed to avoid the possibility of entering a blood vessel or introducing infection. SYSTEMIC For systemic therapy, injection should be made deeply into the gluteal muscle (see WARNINGS). For adults, a minimum needle length of 1½ inches is recommended. In This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 obese patients, a longer needle may be required. Use alternative sites for subsequent injections. LOCAL For treatment of joints, the usual intra-articular injection technique should be followed. If an excessive amount of synovial fluid is present in the joint, some, but not all, should be aspirated to aid in the relief of pain and to prevent undue dilution of the steroid. With intra-articular administration, prior use of a local anesthetic may often be desirable. Care should be taken with this kind of injection, particularly in the deltoid region, to avoid injecting the suspension into the tissues surrounding the site, since this may lead to tissue atrophy. In treating acute nonspecific tenosynovitis, care should be taken to ensure that the injection of the corticosteroid is made into the tendon sheath rather than the tendon substance. Epicondylitis may be treated by infiltrating the preparation into the area of greatest tenderness. HOW SUPPLIED Kenalog®-40 Injection (triamcinolone acetonide injectable suspension, USP) is supplied in vials providing 40 mg triamcinolone acetonide per mL. 40 mg/mL, 1 mL vial NDC 0003-0293-05 40 mg/mL, 5 mL vial NDC 0003-0293-20 40 mg/mL, 10 mL vial NDC 0003-0293-28 Storage Store at controlled room temperature, 20°–25°C (68°–77°F), avoid freezing and protect from light. Bristol-Myers Squibb Company Princeton, NJ 08543 USA Product of Italy 1221153 Revised October 2006 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/ --------------------- Rigoberto Roca 11/20/2006 07:56:16 PM for Bob Rappaport, M.D. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:53.634285	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/014901s034lbl.pdf', 'application_number': 14901, 'submission_type': 'SUPPL ', 'submission_number': 34}
10,851	NDA 12-041/S-036 NDA 14-901/S-037 Page 4 KENALOG®-10 INJECTION triamcinolone acetonide injectable suspension, USP NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL For Intra-articular or Intralesional Use NOT FOR INTRAVENOUS, INTRAMUSCULAR, OR INTRAOCULAR USE DESCRIPTION Kenalog®-10 Injection (triamcinolone acetonide injectable suspension, USP) is triamcinolone acetonide, a synthetic glucocorticoid corticosteroid with marked anti-inflammatory action, in a sterile aqueous suspension suitable for intralesional and intra-articular injection. THIS FORMULATION IS SUITABLE FOR INTRA-ARTICULAR AND INTRALESIONAL USE ONLY. Each mL of the sterile aqueous suspension provides 10 mg triamcinolone acetonide, with sodium chloride for isotonicity, 0.9% (w/v) benzyl alcohol as a preservative, 0.75% carboxymethylcellulose sodium, and 0.04% polysorbate 80; sodium hydroxide or hydrochloric acid may have been added to adjust pH between 5.0 and 7.5. At the time of manufacture, the air in the container is replaced by nitrogen. The chemical name for triamcinolone acetonide is 9-Fluoro-11β,16α,17,21-tetrahydroxy pregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. Its 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 12-041/S-036 NDA 14-901/S-037 Page 5 Structural Formula MW 434.50 CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Synthetic analogs such as triamcinolone are primarily used for their anti-inflammatory effects in disorders of many organ systems. INDICATIONS AND USAGE The intra-articular or soft tissue administration of Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis or osteoarthritis. The intralesional administration of Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) is indicated for alopecia areata; discoid lupus erythematosus; keloids; localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; necrobiosis lipoidica diabeticorum. Kenalog-10 Injection may also be useful in cystic tumors of an aponeurosis or tendon (ganglia). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 6 CONTRAINDICATIONS Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) is contraindicated in patients who are hypersensitive to any components of this product. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. WARNINGS General Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS: Pediatric Use). Because Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) is a suspension, it should not be administered intravenously. Strict aseptic technique is mandatory. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) is a long-acting preparation, and is not suitable for use in acute stress situations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 7 Results from one multicenter, randomized, placebo controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including Kenalog, should not be used for the treatment of traumatic brain injury. Cardio-Renal Average and large doses of corticosteroids 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 they are used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. 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 Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 8 corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS: Drug Interactions: Amphotericin B injection and potassium-depleting agents). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 9 Tuberculosis 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 cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, eg, for Addison’s disease. Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. 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. Neurologic Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS: Gastrointestinal and Neurologic/Psychiatric). 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 10 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. Adequate studies to demonstrate the safety of Kenalog Injection use by intraturbinal, subconjunctival, sub-Tenons, retrobulbar and intraocular (intravitreal) injections have not been performed. Endophthalmitis, eye inflammation, increased intraocular pressure and visual disturbances including vision loss have been reported with intravitreal administration. Administration of Kenalog Injection (triamcinolone acetonide injectable suspension, USP) intraocularly or into the nasal turbinates is not recommended. Intraocular injection of corticosteroid formulations containing benzyl alcohol, such as Kenalog Injection, is not recommended because of potential toxicity from the benzyl alcohol. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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. 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 11 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 congestive heart failure, hypertension, 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 active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Intra-Articular and Soft Tissue Administration Intra-articularly injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 12 Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS: Musculoskeletal). Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (ie, 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 lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (ie, 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 (eg, myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (eg, 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 13 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 corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on 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 Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (ie, amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 14 Anticholinesterases: 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. Anticoagulants, oral: 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. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic enzyme inducers (eg, barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 15 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. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections: Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects: Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have 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. Corticosteroids 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 16 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 corticosteroids are administered to a nursing woman. Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids 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). Other indications for pediatric use of corticosteroids, eg, 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 corticosteroids 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 17 ulcers, cataracts, and osteoporosis. Pediatric patients 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 (ie, cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use No overall differences in safety or effectiveness were observed between elderly 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. ADVERSE REACTIONS (listed alphabetically under each subsection) The following adverse reactions may be associated with corticosteroid therapy: Allergic reactions: Anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 18 wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, 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 pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra- articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS: Neurologic). Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 19 Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION General NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS). 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. 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 the corticosteroid 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 pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in 3 or 4 divided doses (3.2 to 48 mg/m2bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 20 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. Intra-Articular Administration Dosage The initial dose of Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) for intra-articular administration may vary from 2.5 mg to 5 mg for smaller joints and from 5 to 15 mg for larger joints, depending on the specific disease entity being treated. Single injections into several joints, up to a total of 20 mg or more, have been given. Intralesional For intralesional administration, the initial dose per injection site will vary depending on the specific disease entity and lesion being treated. The site of injection and volume of injection should be carefully considered due to the potential for cutaneous atrophy. Multiple sites separated by one centimeter or more may be injected, keeping in mind that the greater the total volume employed the more corticosteroid becomes available for systemic absorption and systemic effects. Such injections may be repeated, if necessary, at weekly or less frequent intervals. Localization of Doses The lower dosages in the initial dosage range of triamcinolone acetonide may produce the desired effect when the corticosteroid is administered to provide a localized concentration. The site and volume of the injection should be carefully considered when triamcinolone acetonide is administered for this purpose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 21 Administration STRICT ASEPTIC TECHNIQUE IS MANDATORY. The vial should be shaken before use to ensure a uniform suspension. Prior to withdrawal, the suspension should be inspected for clumping or granular appearance (agglomeration). An agglomerated product results from exposure to freezing temperatures and should not be used. After withdrawal, inject without delay to prevent settling in the syringe. Injection Technique For treatment of joints, the usual intra-articular injection technique should be followed. If an excessive amount of synovial fluid is present in the joint, some, but not all, should be aspirated to aid in the relief of pain and to prevent undue dilution of the steroid. With intra-articular administration, prior use of a local anesthetic may often be desirable. Care should be taken with this kind of injection, particularly in the deltoid region, to avoid injecting the suspension into the tissues surrounding the site, since this may lead to tissue atrophy. In treating acute nonspecific tenosynovitis, care should be taken to ensure that the injection of Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) is made into the tendon sheath rather than the tendon substance. Epicondylitis may be treated by infiltrating the preparation into the area of greatest tenderness. Intralesional For treatment of dermal lesions, Kenalog-10 Injection (triamcinolone acetonide injectable suspension, USP) should be injected directly into the lesion, ie, intradermally or subcutaneously. For accuracy of dosage measurement and ease of administration, it is preferable to employ a tuberculin syringe and a small-bore needle (23 to 25 gauge). Ethyl chloride spray may be used to alleviate the discomfort 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 12-041/S-036 NDA 14-901/S-037 Page 22 HOW SUPPLIED Kenalog®-10 Injection (triamcinolone acetonide injectable suspension, USP) is supplied in 5 mL multiple dose vials (NDC 0003-0494-20) providing 10 mg triamcinolone acetonide per mL. Storage Store at controlled room temperature, 20°–25°C (68°–77°F), avoid freezing and protect from light. Bristol-Myers Squibb Company Princeton, NJ 08543 USA Product of Italy TBD Rev TBD This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 23 KENALOG®-40 INJECTION triamcinolone acetonide injectable suspension, USP NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL For Intramuscular or Intra-articular Use NOT FOR INTRAVENOUS, INTRADERMAL, OR INTRAOCULAR USE DESCRIPTION Kenalog®-40 Injection (triamcinolone acetonide injectable suspension, USP) is a synthetic glucocorticoid corticosteroid with anti-inflammatory action. THIS FORMULATION IS SUITABLE FOR INTRAMUSCULAR AND INTRA-ARTICULAR USE ONLY. THIS FORMULATION IS NOT FOR INTRADERMAL INJECTION. Each mL of the sterile aqueous suspension provides 40 mg triamcinolone acetonide, with sodium chloride for isotonicity, 0.99% (w/v) benzyl alcohol as a preservative, 0.75% carboxymethylcellulose sodium, and 0.04% polysorbate 80. Sodium hydroxide or hydrochloric acid may be present to adjust pH to 5.0-7.5. At the time of manufacture, the air in the container is replaced by nitrogen. The chemical name for triamcinolone acetonide is 9-Fluoro-11β,16α,17,21 tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. Its 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 12-041/S-036 NDA 14-901/S-037 Page 24 Structural Formula MW 434.50 Triamcinolone acetonide occurs as a white to cream-colored, crystalline powder having not more than a slight odor and is practically insoluble in water and very soluble in alcohol. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Synthetic analogs such as triamcinolone are primarily used for their anti-inflammatory effects in disorders of many organ systems. Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) has an extended duration of effect which may be sustained over a period of several weeks. Studies indicate that following a single intramuscular dose of 60 mg to 100 mg of triamcinolone acetonide, adrenal suppression occurs within 24 to 48 hours and then gradually returns to normal, usually in 30 to 40 days. This finding correlates closely with the extended duration of therapeutic action achieved with the drug. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 25 INDICATIONS AND USAGE Intramuscular Where oral therapy is not feasible, injectable corticosteroid therapy, including Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is indicated for intramuscular use as follows: Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of 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. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 26 Nervous system: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, craniotomy, or head injury. Ophthalmic diseases: Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. Intra-Articular The intra-articular or soft tissue administration of Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis or osteoarthritis. CONTRAINDICATIONS Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is contraindicated in patients who are hypersensitive to any components of this product. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 27 WARNINGS General Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS: Pediatric Use). Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Because Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is a suspension, it should not be administered intravenously. Unless a deep intramuscular injection is given, local atrophy is likely to occur. (For recommendations on injection techniques, see DOSAGE AND ADMINISTRATION.) Due to the significantly higher incidence of local atrophy when the material is injected into the deltoid area, this injection site should be avoided in favor of the gluteal area. Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is a long-acting preparation, and is not suitable for use in acute stress situations. To avoid drug-induced adrenal insufficiency, supportive dosage may be required in times of stress (such as trauma, surgery or severe illness) both during treatment with Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) and for a year afterwards. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 28 Results from one multicenter, randomized, placebo controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including Kenalog, should not be used for the treatment of traumatic brain injury. Cardio-Renal Average and large doses of corticosteroids 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 they are used in large doses. Dietary salt restriction and potassium supplementation may be necessary (see PRECAUTIONS). All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 29 Infections General Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS: Drug Interactions: Amphotericin B injection and potassium-depleting agents). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 30 Corticosteroids should not be used in cerebral malaria. Tuberculosis The use of corticosteroids in patients with 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 anti-tuberculosis regimen. 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 cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, eg, for Addison’s disease. Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. 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. Neurologic Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS: Gastrointestinal and Neurologic/Psychiatric). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 31 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. Adequate studies to demonstrate the safety of Kenalog Injection use by intraturbinal, subconjunctival, sub-Tenons, retrobulbar and intraocular (intravitreal) injections have not been performed. Endophthalmitis, eye inflammation, increased intraocular pressure and visual disturbances including vision loss have been reported with intravitreal administration. Administration of Kenalog Injection (triamcinolone acetonide injectable suspension, USP) intraocularly or into the nasal turbinates is not recommended. Intraocular injection of corticosteroid formulations containing benzyl alcohol, such as Kenalog Injection, is not recommended because of potential toxicity from the benzyl alcohol. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 32 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 congestive heart failure, hypertension, 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 active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Intra-Articular and Soft Tissue Administration Intra-articularly injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 33 A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS: Musculoskeletal). Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (ie, 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 lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (ie, 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 (eg, myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (eg, pancuronium). This acute myopathy is generalized, may involve ocular and respiratory This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 34 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 corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on 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 Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (ie, amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 35 Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases: 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. Anticoagulants, oral: 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. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic enzyme inducers (eg, barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 36 Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other nonsteroidal 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. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections: Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects: Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have 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. Corticosteroids 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 37 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 corticosteroids are administered to a nursing woman. Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids 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). Other indications for pediatric use of corticosteroids, eg, 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 corticosteroids 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 38 ulcers, cataracts, and osteoporosis. Pediatric patients 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 (ie, cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use No overall differences in safety or effectiveness were observed between elderly 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. ADVERSE REACTIONS (listed alphabetically under each subsection) The following adverse reactions may be associated with corticosteroid therapy: Allergic reactions: Anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 39 impaired wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, 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 pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra- articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS: Neurologic). Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 40 Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION General NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS). The initial dose of Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) may vary from 2.5 mg to 100 mg per day depending on the specific disease entity being treated (see Dosage section below). However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. 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. 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 the corticosteroid 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 41 Dosage SYSTEMIC The suggested initial dose is 60 mg, injected deeply into the gluteal muscle. Atrophy of subcutaneous fat may occur if the injection is not properly given. Dosage is usually adjusted within the range of 40 mg to 80 mg, depending upon patient response and duration of relief. However, some patients may be well controlled on doses as low as 20 mg or less. Hay fever or pollen asthma: Patients with hay fever or pollen asthma who are not responding to pollen administration and other conventional therapy may obtain a remission of symptoms lasting throughout the pollen season after a single injection of 40 mg to 100 mg. In the treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of triamcinolone for a week followed by 64 mg every other day for one month are recommended (see PRECAUTIONS: Neuro-Psychiatric). In pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in 3 or 4 divided doses (3.2 to 48 mg/m2bsa/day). 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 42 LOCAL Intra-articular administration: A single local injection of triamcinolone acetonide is frequently sufficient, but several injections may be needed for adequate relief of symptoms. Initial dose: 2.5 mg to 5 mg for smaller joints and from 5 mg to 15 mg for larger joints, depending on the specific disease entity being treated. For adults, doses up to 10 mg for smaller areas and up to 40 mg for larger areas have usually been sufficient. Single injections into several joints, up to a total of 80 mg, have been given. Administration GENERAL STRICT ASEPTIC TECHNIQUE IS MANDATORY. The vial should be shaken before use to ensure a uniform suspension. Prior to withdrawal, the suspension should be inspected for clumping or granular appearance (agglomeration). An agglomerated product results from exposure to freezing temperatures and should not be used. After withdrawal, Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) should be injected without delay to prevent settling in the syringe. Careful technique should be employed to avoid the possibility of entering a blood vessel or introducing infection. SYSTEMIC For systemic therapy, injection should be made deeply into the gluteal muscle (see WARNINGS). For adults, a minimum needle length of 1½ inches is recommended. In obese patients, a longer needle may be required. Use alternative sites for subsequent injections. LOCAL For treatment of joints, the usual intra-articular injection technique should be followed. If an excessive amount of synovial fluid is present in the joint, some, but not all, should be aspirated to aid in the relief of pain and to prevent undue dilution of the steroid. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 12-041/S-036 NDA 14-901/S-037 Page 43 With intra-articular administration, prior use of a local anesthetic may often be desirable. Care should be taken with this kind of injection, particularly in the deltoid region, to avoid injecting the suspension into the tissues surrounding the site, since this may lead to tissue atrophy. In treating acute nonspecific tenosynovitis, care should be taken to ensure that the injection of the corticosteroid is made into the tendon sheath rather than the tendon substance. Epicondylitis may be treated by infiltrating the preparation into the area of greatest tenderness. HOW SUPPLIED Kenalog®-40 Injection (triamcinolone acetonide injectable suspension, USP) is supplied in vials providing 40 mg triamcinolone acetonide per mL. 40 mg/mL, 1 mL vial NDC 0003-0293-05 40 mg/mL, 5 mL vial NDC 0003-0293-20 40 mg/mL, 10 mL vial NDC 0003-0293-28 Storage Store at controlled room temperature, 20°–25°C (68°–77°F), avoid freezing and protect from light. Bristol-Myers Squibb Company Princeton, NJ 08543 USA Product of Italy TBD Rev TBD This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:53.819132	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012041s036,014901s037lbl.pdf', 'application_number': 14901, 'submission_type': 'SUPPL ', 'submission_number': 37}
10,852	1 KENALOG-40 INJECTION (triamcinolone acetonide injectable suspension, USP) NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL For Intramuscular or Intra-articular Use Only NOT FOR INTRAVENOUS, INTRADERMAL, INTRAOCULAR, EPIDURAL, OR INTRATHECAL USE DESCRIPTION Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is a synthetic glucocorticoid corticosteroid with anti-inflammatory action. THIS FORMULATION IS SUITABLE FOR INTRAMUSCULAR AND INTRA- ARTICULAR USE ONLY. THIS FORMULATION IS NOT FOR INTRADERMAL INJECTION. Each mL of the sterile aqueous suspension provides 40 mg triamcinolone acetonide, with 0.65% sodium chloride for isotonicity, 0.99% (w/v) benzyl alcohol as a preservative, 0.75% carboxymethylcellulose sodium, and 0.04% polysorbate 80. Sodium hydroxide or hydrochloric acid may be present to adjust pH to 5.0 to 7.5. At the time of manufacture, the air in the container is replaced by nitrogen. The chemical name for triamcinolone acetonide is 9-Fluoro-11,16,17,21- tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. Its structural formula is: MW 434.50 Approved v4.0 Reference ID: 3537181 2 Triamcinolone acetonide occurs as a white to cream-colored, crystalline powder having not more than a slight odor and is practically insoluble in water and very soluble in alcohol. CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Synthetic analogs such as triamcinolone are primarily used for their anti-inflammatory effects in disorders of many organ systems. Kenalog-40 Injection has an extended duration of effect which may be sustained over a period of several weeks. Studies indicate that following a single intramuscular dose of 60 mg to 100 mg of triamcinolone acetonide, adrenal suppression occurs within 24 to 48 hours and then gradually returns to normal, usually in 30 to 40 days. This finding correlates closely with the extended duration of therapeutic action achieved with the drug. INDICATIONS AND USAGE Intramuscular Where oral therapy is not feasible, injectable corticosteroid therapy, including Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is indicated for intramuscular use as follows: Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Approved v4.0 Reference ID: 3537181 3 Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of 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. Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy. Neoplastic diseases: For the palliative management of leukemias and lymphomas. Nervous system: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy. Ophthalmic diseases: Sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. Approved v4.0 Reference ID: 3537181 4 Intra-Articular The intra-articular or soft tissue administration of Kenalog-40 Injection is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis, or osteoarthritis. CONTRAINDICATIONS Kenalog-40 Injection is contraindicated in patients who are hypersensitive to any components of this product (see WARNINGS: General). Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. WARNINGS Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids (see WARNINGS: Neurologic). Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use. General Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or Approved v4.0 Reference ID: 3537181 5 other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS: Pediatric Use). Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Cases of serious anaphylaxis, including death, have been reported in individuals receiving triamcinolone acetonide injection, regardless of the route of administration. Because Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is a suspension, it should not be administered intravenously. Unless a deep intramuscular injection is given, local atrophy is likely to occur. (For recommendations on injection techniques, see DOSAGE AND ADMINISTRATION.) Due to the significantly higher incidence of local atrophy when the material is injected into the deltoid area, this injection site should be avoided in favor of the gluteal area. Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Kenalog-40 Injection is a long-acting preparation, and is not suitable for use in acute stress situations. To avoid drug-induced adrenal insufficiency, supportive dosage may be required in times of stress (such as trauma, surgery, or severe illness) both during treatment with Kenalog-40 Injection and for a year afterwards. Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an intravenous corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including Kenalog-40 Injection, should not be used for the treatment of traumatic brain injury. Cardio-Renal Average and large doses of corticosteroids 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 they are used in large doses. Dietary salt restriction and potassium supplementation may be necessary (see PRECAUTIONS). All corticosteroids increase calcium excretion. Approved v4.0 Reference ID: 3537181 6 Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. 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 Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS: Drug Interactions: Amphotericin B injection and potassium- depleting agents). Approved v4.0 Reference ID: 3537181 7 Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, or Toxoplasma. It is recommended that latent amebiasis 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 corticosteroids in patients with 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 anti-tuberculosis regimen. 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 cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, eg, for Addison’s disease. Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the Approved v4.0 Reference ID: 3537181 8 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. Neurologic Epidural and intrathecal administration of this product is not recommended. Reports of serious medical events, including death, have been associated with epidural and intrathecal routes of corticosteroid administration (see ADVERSE REACTIONS: Gastrointestinal and Neurologic/Psychiatric). 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. Adequate studies to demonstrate the safety of Kenalog Injection use by intraturbinal, subconjunctival, sub-Tenons, retrobulbar, and intraocular (intravitreal) injections have not been performed. Endophthalmitis, eye inflammation, increased intraocular pressure, and visual disturbances including vision loss have been reported with intravitreal administration. Administration of Kenalog Injection intraocularly or into the nasal turbinates is not recommended. Intraocular injection of corticosteroid formulations containing benzyl alcohol, such as Kenalog Injection, is not recommended because of potential toxicity from the benzyl alcohol. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. Approved v4.0 Reference ID: 3537181 9 The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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. 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 congestive heart failure, hypertension, 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 active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Intra-Articular and Soft Tissue Administration Intra-articularly injected corticosteroids may be systemically absorbed. Approved v4.0 Reference ID: 3537181 10 Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS: Musculoskeletal). Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (ie, 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 lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (ie, 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 (eg, myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (eg, pancuronium). This acute myopathy is generalized, may involve ocular and Approved v4.0 Reference ID: 3537181 11 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. Psychiatric 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 corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids, and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on 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 Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (ie, amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Approved v4.0 Reference ID: 3537181 12 Anticholinesterases: 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. Anticoagulants, oral: 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. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic enzyme inducers (eg, barbiturates, phenytoin, carbamazepine, rifampin): Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory drugs) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with Approved v4.0 Reference ID: 3537181 13 corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections: Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects: Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have 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. Corticosteroids 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 corticosteroids are administered to a nursing woman. Approved v4.0 Reference ID: 3537181 14 Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids 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). Other indications for pediatric use of corticosteroids, eg, 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 corticosteroids 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. Pediatric patients 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 (ie, cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of Approved v4.0 Reference ID: 3537181 15 systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use No overall differences in safety or effectiveness were observed between elderly 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. ADVERSE REACTIONS (listed alphabetically under each subsection) The following adverse reactions may be associated with corticosteroid therapy: Allergic reactions: Anaphylaxis including death, angioedema. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypo- pigmentation, impaired wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in Approved v4.0 Reference ID: 3537181 16 times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration [see WARNINGS: Neurologic]), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration. Spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke (including brainstem) have been reported after epidural administration of corticosteroids (see WARNINGS: Serious Neurologic Adverse Reactions with Epidural Administration and WARNINGS: Neurologic). Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. Approved v4.0 Reference ID: 3537181 17 OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION General NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS). The initial dose of Kenalog-40 Injection may vary from 2.5 mg to 100 mg per day depending on the specific disease entity being treated (see Dosage section below). However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. 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. 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 the corticosteroid 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. Approved v4.0 Reference ID: 3537181 18 Dosage SYSTEMIC The suggested initial dose is 60 mg, injected deeply into the gluteal muscle. Atrophy of subcutaneous fat may occur if the injection is not properly given. Dosage is usually adjusted within the range of 40 mg to 80 mg, depending upon patient response and duration of relief. However, some patients may be well controlled on doses as low as 20 mg or less. Hay fever or pollen asthma: Patients with hay fever or pollen asthma who are not responding to pollen administration and other conventional therapy may obtain a remission of symptoms lasting throughout the pollen season after a single injection of 40 mg to 100 mg. In the treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of triamcinolone for a week followed by 64 mg every other day for one month are recommended (see PRECAUTIONS: Neuro-Psychiatric). In pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in 3 or 4 divided doses (3.2 to 48 mg/m2bsa/day). 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. Approved v4.0 Reference ID: 3537181 19 LOCAL Intra-articular administration: A single local injection of triamcinolone acetonide is frequently sufficient, but several injections may be needed for adequate relief of symptoms. Initial dose: 2.5 mg to 5 mg for smaller joints and from 5 mg to 15 mg for larger joints, depending on the specific disease entity being treated. For adults, doses up to 10 mg for smaller areas and up to 40 mg for larger areas have usually been sufficient. Single injections into several joints, up to a total of 80 mg, have been given. Administration GENERAL STRICT ASEPTIC TECHNIQUE IS MANDATORY. The vial should be shaken before use to ensure a uniform suspension. Prior to withdrawal, the suspension should be inspected for clumping or granular appearance (agglomeration). An agglomerated product results from exposure to freezing temperatures and should not be used. After withdrawal, Kenalog-40 Injection should be injected without delay to prevent settling in the syringe. Careful technique should be employed to avoid the possibility of entering a blood vessel or introducing infection. SYSTEMIC For systemic therapy, injection should be made deeply into the gluteal muscle (see WARNINGS). For adults, a minimum needle length of 1½ inches is recommended. In obese patients, a longer needle may be required. Use alternative sites for subsequent injections. LOCAL For treatment of joints, the usual intra-articular injection technique should be followed. If an excessive amount of synovial fluid is present in the joint, some, but not all, should be aspirated to aid in the relief of pain and to prevent undue dilution of the steroid. With intra-articular administration, prior use of a local anesthetic may often be desirable. Care should be taken with this kind of injection, particularly in the deltoid region, to avoid injecting the suspension into the tissues surrounding the site, since this may lead to tissue atrophy. Approved v4.0 Reference ID: 3537181 20 In treating acute nonspecific tenosynovitis, care should be taken to ensure that the injection of the corticosteroid is made into the tendon sheath rather than the tendon substance. Epicondylitis may be treated by infiltrating the preparation into the area of greatest tenderness. HOW SUPPLIED Kenalog-40 Injection (triamcinolone acetonide injectable suspension, USP) is supplied in vials providing 40 mg triamcinolone acetonide per mL. 40 mg/mL, 1 mL vial NDC 0003-0293-05 40 mg/mL, 5 mL vial NDC 0003-0293-20 40 mg/mL, 10 mL vial NDC 0003-0293-28 Storage Store at controlled room temperature, 20–25C (68°–77°F), avoid freezing and protect from light. Do not refrigerate. Bristol-Myers Squibb Company Princeton, NJ 08543 USA Product of Italy Rev July 2014 Approved v4.0 Reference ID: 3537181	custom-source	2025-02-12T13:43:53.826896	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/014901s042lbledt.pdf', 'application_number': 14901, 'submission_type': 'SUPPL ', 'submission_number': 42}
10,853	Mefenamic Acid Capsules, USP 250 mg Rx only WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS).  Mefenamic acid is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS, WARNINGS). Gastrointestinal Bleeding, Ulceration, and Perforation  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (see WARNINGS). DESCRIPTION Mefenamic Acid Capsules are a member of the fenamate group of nonsteroidal anti- inflammatory drugs (NSAIDs). Each blue-banded, ivory capsule contains 250 mg of mefenamic acid for oral administration. Mefenamic acid is a white to greyish-white, odorless, microcrystalline powder with a melting point of 230°-231°C and water solubility of 0.004% at pH 7.1. The chemical name is N-2,3-xylylanthranilic acid. The molecular weight is 241.29. Its molecular formula is C15H15N02 and the structural formula of mefenamic acid is: structural formula Each capsule also contains lactose, NF. The capsule shell and/or band contains citric acid, USP; D&C yellow No. 10; FD&C blue No. 1; FD&C red No. 3; FD&C yellow No. 6; gelatin, NF; glycerol monooleate; silicon dioxide, NF; sodium benzoate, NF; sodium lauryl sulfate, NF; titanium dioxide, USP. CLINICAL PHARMACOLOGY Mechanism of Action Mefenamic acid has analgesic, anti-inflammatory, and antipyretic properties. Reference ID: 3928117 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The mechanism of action of mefenamic acid, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Mefenamic acid is a potent inhibitor of prostaglandin synthesis in vitro. Mefenamic acid concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because mefenamic acid is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Pharmacokinetics Absorption Mefenamic acid is rapidly absorbed after oral administration. In two 500-mg single oral dose studies, the mean extent of absorption was 30.5 mcg/hr/mL (17%CV). The bioavailability of the capsule relative to an IV dose or an oral solution has not been studied. Following a single 1-gram oral dose, mean peak plasma levels ranging from 10-20 mcg/mL have been reported. Peak plasma levels are attained in 2 to 4 hours and the elimination half-life approximates 2 hours. Following multiple doses, plasma levels are proportional to dose with no evidence of drug accumulation. In a multiple dose trial of normal adult subjects (n= 6) receiving 1-gram doses of mefenamic acid four times daily, steady-state concentrations of 20 mcg/mL were reached on the second day of administration, consistent with the short half-life. The effect of food on the rate and extent of absorption of mefenamic acid has not been studied. Concomitant ingestion of antacids containing magnesium hydroxide has been shown to significantly increase the rate and extent of mefenamic acid absorption (see PRECAUTIONS; Drug Interactions). Distribution Mefenamic acid has been reported as being greater than 90% bound to albumin. The relationship of unbound fraction to drug concentration has not been studied. The apparent volume of distribution (Vzss/F) estimated following a 500-mg oral dose of mefenamic acid was 1.06 L/kg. Based on its physical and chemical properties, mefenamic acid is expected to be excreted in human breast milk (see PRECAUTIONS; Nursing Mothers). Elimination Metabolism Mefenamic acid is metabolized by cytochrome P450 enzyme CYP2C9 to 3-hydroxymethyl mefenamic acid (Metabolite I). Further oxidation to a 3-carboxymefenamic acid (Metabolite II) may occur. The activity of these metabolites has not been studied. The metabolites may undergo glucuronidation and mefenamic acid is also glucuronidated directly. A peak plasma level approximating 20 mcg/mL was observed at 3 hours for the hydroxy metabolite and its glucuronide (n= 6) after a single 1-gram dose. Similarly, a peak plasma level of 8 mcg/mL was observed at 6-8 hours for the carboxy metabolite and its glucuronide. Reference ID: 3928117 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Excretion Approximately fifty-two percent of a mefenamic acid dose is excreted into the urine primarily as glucuronides of mefenamic acid (6%), 3-hydroxymefenamic acid (25%) and 3 carboxymefenamic acid (21%). The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxymefenamic acid. The elimination half-life of mefenamic acid is approximately two hours. Half-lives of metabolites I and II have not been precisely reported, but appear to be longer than the parent compound. The metabolites may accumulate in patients with renal or hepatic failure. The mefenamic acid glucuronide may bind irreversibly to plasma proteins. Because both renal and hepatic excretions are significant pathways of elimination, dosage adjustments in patients with renal or hepatic dysfunction may be necessary. Mefenamic acid should not be administered to patients with pre-existing renal disease or in patients with significantly impaired renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). TABLE 1. Pharmacokinetic Parameter Estimates for Mefenamic Acid PK Parameters Normal Healthy Adults (18-45 yr) Tmax (hr) Oral clearance (L/hr) Apparent volume of distribution; Vz/F (L/kg) Half-life; t ½ (hrs) Value 2 21.13 1.06 2 to 4 CV 66 38 60 N/A Special Populations Pediatric: Mefenamic acid has not been adequately investigated in pediatric patients less than 14 years of age. A study in 17 preterm infants administered 2 mg/kg indicated that the half-life was about five times as long as adults, consistent with the low activity of metabolic enzymes in newborn infants. The mean Cmax in this study was 4 mcg/mL (range 2.9-6.1). The mean time to maximum concentration (Tmax) was 8 hours (range 2-18 hours). Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: Mefenamic acid pharmacokinetics have not been studied in patients with hepatic dysfunction. As hepatic metabolism is a significant pathway of mefenamic acid elimination, patients with acute and chronic hepatic disease may require reduced doses of mefenamic acid compared to patients with normal hepatic function (see WARNINGS; Hepatotoxicity). Renal Impairment: Mefenamic acid pharmacokinetics have not been investigated in subjects with renal insufficiency. Given that mefenamic acid, its metabolites and conjugates are primarily excreted by the kidneys, the potential exists for mefenamic acid metabolites to accumulate. Mefenamic acid should not be administered to patients with pre-existing renal disease or in patients with significantly impaired renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). Reference ID: 3928117 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin (see PRECAUTIONS; Drug Interactions). Clinical Studies In controlled, double-blind, clinical trials, mefenamic acid was evaluated for the treatment of primary spasmodic dysmenorrhea. The parameters used in determining efficacy included pain assessment by both patient and investigator; the need for concurrent analgesic medication; and evaluation of change in frequency and severity of symptoms characteristic of spasmodic dysmenorrhea. Patients received either mefenamic acid, 500 mg (2 capsules) as an initial dose of 250 mg every 6 hours, or placebo at onset of bleeding or of pain, whichever began first. After three menstrual cycles, patients were crossed over to the alternate treatment for an additional three cycles. Mefenamic acid was significantly superior to placebo in all parameters, and both treatments (drug and placebo) were equally tolerated. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of mefenamic acid and other treatment options before deciding to use mefenamic acid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). Mefenamic acid is indicated:  For relief of mild to moderate pain in patients ≥ 14 years of age, when therapy will not exceed one week (7 days).  For treatment of primary dysmenorrhea. CONTRAINDICATIONS Mefenamic acid is contraindicated in the following patients:  Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to mefenamic acid or any components of the drug product (see WARNINGS; Anaphylactic Reactions, Serious Skin Reactions).  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS; Anaphylactic Reaction, Exacerbation of Asthma Related to Aspirin Sensitivity).  In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS; Cardiovascular Thrombotic Events). Reference ID: 3928117 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS 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, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as mefenamic acid, increases the risk of serious gastrointestinal (GI) events (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). Status Post Coronary Artery Bypass Graft (CABG) Surgery 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. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of mefenamic acid in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If mefenamic acid is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including mefenamic acid, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or Reference ID: 3928117 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients:  Use the lowest effective dosage for the shortest possible duration.  Avoid administration of more than one NSAID at a time.  Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.  Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.  If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue mefenamic acid until a serious GI adverse event is ruled out.  In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding (see PRECAUTIONS; Drug Interactions). Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including mefenamic acid. 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). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue mefenamic acid immediately, and perform a clinical evaluation of the patient. Reference ID: 3928117 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypertension NSAIDs, including mefenamic acid, can lead to new onset of hypertension or worsening of pre existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see PRECAUTIONS; Drug Interactions). Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of mefenamic acid may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) (see PRECAUTIONS; Drug Interactions). Avoid the use of mefenamic acid in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If mefenamic acid is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Renal Toxicity and Hyperkalemia Renal Toxicity 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 an NSAID 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of mefenamic acid in patients with advanced renal disease. The renal effects of mefenamic acid may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating mefenamic acid. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of mefenamic acid (see PRECAUTIONS; Drug Interactions). Avoid the use of mefenamic acid in patients with advanced renal disease unless the benefits are expected to Reference ID: 3928117 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda outweigh the risk of worsening renal function. If mefenamic acid is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions Mefenamic acid has been associated with anaphylactic reactions in patients with and without known hypersensitivity to mefenamic acid and in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS, WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity). Seek emergency help if anaphylactic reaction occurs. Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, mefenamic acid is contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS). When mefenamic acid is used in patients with pre-existing asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Serious Skin Reactions NSAIDs, including mefenamic acid, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of mefenamic acid at the first appearance of skin rash or any other sign of hypersensitivity. Mefenamic acid is contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS). Premature Closure of Fetal Ducts Arteriosus Mefenamic acid may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including mefenamic acid, in pregnant women starting at 30 weeks of gestation (third trimester) (see PRECAUTIONS; Pregnancy). Hematological Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with mefenamic acid has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including mefenamic acid, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin Reference ID: 3928117 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding (see PRECAUTIONS; Drug Interactions). PRECAUTIONS General Mefenamic acid 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. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families and their caregivers of the following information before initiating therapy with mefenamic acid and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS; Cardiovascular Thrombotic Events). Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop mefenamic acid and seek immediate medical therapy (see WARNINGS; Hepatotoxicity). Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS; Heart Failure and Edema). Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (see CONTRAINDICATIONS, WARNINGS; Anaphylactic Reactions). Reference ID: 3928117 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serious Skin Reactions Advise patients to stop mefenamic acid immediately if they develop any type of rash and contact their healthcare provider as soon as possible (see WARNINGS; Serious Skin Reactions). Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including mefenamic acid, may be associated with a reversible delay in ovulation. (see PRECAUTIONS; Carcinogenesis, Mutagenesis, Impairment of Fertility). Fetal Toxicity Inform pregnant women to avoid use of mefenamic acid and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closure of the fetal ductus arteriosus (see WARNINGS; Premature Closure of Fetal Ductus Arteriosus). Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, PRECAUTIONS; Drug Interactions). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with mefenamic acid until they talk to their healthcare provider (see PRECAUTIONS; Drug Interactions). Masking of Inflammation and Fever The pharmacological activity of mefenamic acid in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile checked periodically (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, and Hepatotoxicity). Drug Interactions See Table 2 for clinically significant drug interactions with mefenamic acid. Table 2: Clinically Significant Drug Interactions with Mefenamic Acid Drugs That Interfere with Hemostasis Clinical Impact: • Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin Reference ID: 3928117 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity). Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation). Intervention: Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia).  When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia). Digoxin Clinical Impact: The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of mefenamic acid and methotrexate, monitor patients for Reference ID: 3928117 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation). Intervention: The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of mfenamic acid and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacid Clinical Impact: In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively. Intervention: Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events. Drug/Laboratory Test Interactions Mefenamic acid may prolong prothrombin time. Therefore, when the drug is administered to patients receiving oral anticoagulant drugs, frequent monitoring of prothrombin time is necessary. A false-positive reaction for urinary bile, using the diazo tablet test, may result after mefenamic acid administration. If biliuria is suspected, other diagnostic procedures, such as the Harrison spot test, should be performed. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of mefenamic acid have not been conducted. Mutagenesis Studies to evaluate the mutagenic potential of mefenamic acid have not been completed. Reference ID: 3928117 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Impairment of Fertility Dietary administration of mefenamic acid to male rats 61 days- and to female rats 15 days- prior to mating through to Gestation Day (GD) 21 at a dose of 155 mg/kg/day (equivalent to the Maximum Recommended Human Dose [MRHD] of 1500 mg/day on a mg/m2 basis) resulted in decreased corpora lutea. In another study, rats administered up to 10-times a human dose of 250 mg showed decreased fertility. Pregnancy Risk Summary Use of NSAIDs, including mefenamic acid, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including mefenamic acid, in pregnant women starting at 30 weeks of gestation (third trimester) (see WARNINGS; Premature Closure of Fetal Ductus Arterious). There are no adequate and well-controlled studies of mefenamic acid in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats and rabbits when dosed throughout gestation, there were no evidence of developmental effects at a dose of mefenamic acid 1.6-times and 0.6-times the maximum recommended human dose (MRHD), respectively. Dietary administration of mefenamic acid at a dose 1.2-times the MRHD from gestation day (GD) 15 to weaning or at a dose equivalent to the MRHD from 15 days prior to mating through to weaning resulted in greater incidences of perinatal death [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as mefenamic acid, resulted in increased pre- and post-implantation loss. Data Animal data Pregnant rats administered 249 mg/kg of mefenamic acid (1.6-times the MRHD of 1500 mg/day on a mg/m2 basis) from GD 6 to GD 15 did not result in any clear adverse developmental effects. Pregnant rabbits given 50 mg/kg of mefenamic acid (0.6-times the MRHD on a mg/m2 basis) from GD 6 to GD 18 did not result in any clear treatment-related adverse developmental effects. However, incidences of resorption were greater in treated compared to control animals. This dose was associated with some evidence of maternal toxicity with 4 of 18 rabbits exhibiting diarrhea and weight loss. Dietary administration of mefenamic acid at a dose of 181 mg/kg (1.2-times the MRHD on a mg/m2 basis) to pregnant rats from GD 15 to weaning resulted in an increased incidence of perinatal death. Treated dams were associated with decreased weight gain and delayed Reference ID: 3928117 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda parturition. In another study, dietary administration of mefenamic acid at a dose of 155 mg/kg (equivalent to the MRHD of 1500 mg/day on a mg/m2 basis) to females 15 days prior to mating through to weaning resulted in smaller average litter sizes and higher incidence of perinatal death. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, decreased pup survival occurred and increased the incidence of stillbirth. The effects of mefenamic acid on labor and delivery in pregnant women are unknown. Nursing Mothers Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant. Because of the potential for serious adverse reactions in nursing infants from mefenamic acid, 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. Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including mefenamic acid may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin in mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including mefenamic acid, in women who have difficulties conceiving or who are undergoing investigation of infertility. Pediatric Use Safety and effectiveness in pediatric patients below the age of 14 have not been established. Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hepatotoxicity, Renal Toxicity and Hyperkalemia, PRECAUTIONS; Laboratory Monitoring). Clinical studies of mefenamic acid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As with any NSAID, caution should be exercised in treating the elderly (65 years and older). 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 Reference ID: 3928117 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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). ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events (see WARNINGS) • GI Bleeding, Ulceration and Perforation (see WARNINGS) • Hepatotoxicity (see WARNINGS) • Hypertension (see WARNINGS) • Heart Failure and Edema (see WARNINGS)) • Renal Toxicity and Hyperkalemia (see WARNINGS) • Anaphylactic Reactions (see WARNINGS) • Serious Skin Reactions (see WARNINGS) • Hematologic Toxicity (see WARNINGS) 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 practice. In patients taking mefenamic acid 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), vomiting, abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, tinnitus Additional adverse experiences reported occasionally and listed here by body system 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 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, pruritus, sweat Special senses - blurred vision Reference ID: 3928117 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Urogenital system - cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions, which occur rarely are: Body as a whole - anaphylactoid reactions, appetite changes, death Cardiovascular system - arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive system - eructation, liver failure, pancreatitis Hemic and lymphatic system - agranulocytosis, hemolytic anemia, aplastic anemia, lymph adenopathy, pancytopenia Metabolic and nutritional - hyperglycemia Nervous system - convulsions, coma, hallucinations, meningitis Respiratory - respiratory depression, pneumonia Skin and appendages - angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria Special senses - conjunctivitis, hearing impairment OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hypertension, Renal Toxicity and Hyperkalemia). Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdose (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment, contact a poison control center (1-800-222-1222). DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of mefenamic acid and other treatment options before deciding to use mefenamic acid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). After observing the response to initial therapy with mefenamic acid, the dose and frequency should be adjusted to suit an individual patient's needs. Reference ID: 3928117 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For the relief of acute pain in adults and adolescents ≥14 years of age, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours as needed, usually not to exceed one week. For the treatment of primary dysmenorrhea, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours, given orally, starting with the onset of bleeding and associated symptoms. Clinical studies indicate that effective treatment can be initiated with the start of menses and should not be necessary for more than 2 to 3 days. HOW SUPPLIED Mefenamic acid is available as 250 mg blue-banded, ivory capsules, imprinted with “ FHPC 400" and "PONSTEL®". Bottles of 30 NDC 66993-070-30 Dispense in a tight container as defined in the USP. Storage Store at room temperature 20° to 25°C (68°to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Distributed by: Prasco Laboratories Mason, OH 45050 USA Rev. XX/2016 For inquiries call 1-800-849-9707 Reference ID: 3928117 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDS) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAID can cause serious side effects, including:  Increase risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)". Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.  Increase risk of bleeding, ulcers and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAID should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o or the shortest time needed What are NSAIDs? NSAIDs 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 NSAIDs? Do not take NSAIDs:  if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.  right before or after heart bypass surgery. Before taking NSAIDs, tell our healthcare provider about all of your medical conditions, including if you:  have liver or kidney problems  have high blood pressure Reference ID: 3928117 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  have asthma  are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy  are breastfeeding or plan to breastfeed Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?  new or worse high blood pressure  heart failure  liver problems including liver failure  kidney problem including kidney failure  low red blood cells (anemia)  life-threatening skin reactions  life-threatening allergic reactions  Other side effects if NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get 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 taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:  nausea  vomit blood  more tired or weaker than usual  there is blood in the bowel movement or it is black and sticky like tar  diarrhea  unusual weight gain  itching  skin rash or blisters with fever  your skin or eyes look yellow  swelling of the arms, legs, hands, and feet  indigestion or stomach pain  flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all of the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at Reference ID: 3928117 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1-800-FDA-1088. Other information about 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 NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAID for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: Prasco Laboratories Mason, OH 45050 USA For more information, call 1-800-849-9707 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 5/16 Reference ID: 3928117 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:53.870770	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/015034s044lbl.pdf', 'application_number': 15034, 'submission_type': 'SUPPL ', 'submission_number': 44}
10,854	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	2025-02-12T13:43:53.964347	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/15193s18lbl.pdf', 'application_number': 15193, 'submission_type': 'SUPPL ', 'submission_number': 18}
10,855	NDA 15-197/S-036, 037, 038, 039 Page 3 AMICAR Injection AMICAR Syrup AMICAR Tablets (aminocaproic acid) Rx only DESCRIPTION AMICAR (aminocaproic acid) is 6-aminohexanoic acid, which acts as an inhibitor of fibrinolysis. Its chemical structure is: H2C(CH2)3CH2COOH │ NH2 C6H13NO2 MW 131.17 AMICAR is soluble in water, acid and alkaline solutions; it is sparingly soluble in methanol and practically insoluble in chloroform. AMICAR (aminocaproic acid) Injection, for intravenous administration, is a sterile pyrogen-free solution containing 250 mg/mL of aminocaproic acid with benzyl alcohol 0.9% as preservative and Water for Injection. Hydrochloric acid may be added to adjust pH to approximately 6.8 during manufacture. AMICAR (aminocaproic acid) Syrup, 25%, for oral administration, contains 250 mg/mL of aminocaproic acid with methylparaben 0.20%, propylparaben 0.05%, edetate disodium 0.30% as preservatives and the following inactive ingredients: sodium saccharin, sorbitol solution, citric acid anhydrous, natural and artificial raspberry flavor and an artificial bitterness modifier. Each AMICAR (aminocaproic acid) Tablet, for oral administration, contains 500 mg or 1000 mg of aminocaproic acid and the following inactive ingredients: povidone, crospovidone, stearic acid and magnesium stearate. CLINICAL PHARMACOLOGY The fibrinolysis-inhibitory effects of AMICAR appear to be exerted principally via inhibition of plasminogen activators and to a lesser degree through antiplasmin activity. In adults, oral absorption appears to be a zero-order process with an absorption rate of 5.2 g/hr. The mean lag time in absorption is 10 minutes. After a single oral dose of 5 g, absorption was complete (F=1). Mean ± SD peak plasma concentrations (164 ± 28 mcg/mL) were reached within 1.2 ± 0.45 hours. After oral administration, the apparent volume of distribution was estimated to be 23.1 ± 6.6 L (mean ± SD). Correspondingly, the volume of distribution after intravenous administration has been reported to be 30.0 ± 8.2 L. After prolonged administration, AMICAR has been found to distribute throughout This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-197/S-036, 037, 038, 039 Page 4 extravascular and intravascular compartments of the body, penetrating human red blood cells as well as other tissue cells. Renal excretion is the primary route of elimination, whether AMICAR is administered orally or intravenously. Sixty-five percent of the dose is recovered in the urine as unchanged drug and 11% of the dose appears as the metabolite adipic acid. Renal clearance (116 mL/min) approximates endogenous creatinine clearance. The total body clearance is 169 mL/min. The terminal elimination half-life for AMICAR is approximately 2 hours. INDICATIONS AND USAGE AMICAR is useful in enhancing hemostasis when fibrinolysis contributes to bleeding. In life- threatening situations, fresh whole blood transfusions, fibrinogen infusions, and other emergency measures may be required. Fibrinolytic bleeding may frequently be associated with surgical complications following heart surgery (with or without cardiac bypass procedures) and portacaval shunt; hematological disorders such as aplastic anemia; abruptio placentae; hepatic cirrhosis; neoplastic disease such as carcinoma of the prostate, lung, stomach, and cervix. Urinary fibrinolysis, usually a normal physiological phenomenon, may frequently be associated with life-threatening complications following severe trauma, anoxia, and shock. Symptomatic of such complications is surgical hematuria (following prostatectomy and nephrectomy) or nonsurgical hematuria (accompanying polycystic or neoplastic diseases of the genitourinary system). (See WARNINGS.) CONTRAINDICATIONS AMICAR should not be used when there is evidence of an active intravascular clotting process. When there is uncertainty as to whether the cause of bleeding is primary fibrinolysis or disseminated intravascular coagulation (DIC), this distinction must be made before administering AMICAR. The following tests can be applied to differentiate the two conditions: • Platelet count is usually decreased in DIC but normal in primary fibrinolysis. • Protamine paracoagulation test is positive in DIC; a precipitate forms when protamine sulfate is dropped into citrated plasma. The test is negative in the presence of primary fibrinolysis. • The euglobulin clot lysis test is abnormal in primary fibrinolysis but normal in DIC. AMICAR must not be used in the presence of DIC without concomitant heparin. WARNINGS In patients with upper urinary tract bleeding, AMICAR administration has been known to cause intrarenal obstruction in the form of glomerular capillary thrombosis or clots in the renal pelvis and ureters. For this reason, AMICAR should not be used in hematuria of upper urinary tract origin, unless the possible benefits outweigh the risk. Subendocardial hemorrhages have been observed in dogs given intravenous infusions of 0.2 times the maximum human therapeutic dose of AMICAR and in monkeys given 8 times the maximum human therapeutic dose of AMICAR. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-197/S-036, 037, 038, 039 Page 5 Fatty degeneration of the myocardium has been reported in dogs given intravenous doses of AMICAR at 0.8 to 3.3 times the maximum human therapeutic dose and in monkeys given intravenous doses of AMICAR at 6 times the maximum human therapeutic dose. Rarely, skeletal muscle weakness with necrosis of muscle fibers has been reported following prolonged administration. Clinical presentation may range from mild myalgias with weakness and fatigue to a severe proximal myopathy with rhabdomyolysis, myoglobinuria, and acute renal failure. Muscle enzymes, especially creatine phosphokinase (CPK) are elevated. CPK levels should be monitored in patients on long-term therapy. AMICAR administration should be stopped if a rise in CPK is noted. Resolution follows discontinuation of AMICAR; however, the syndrome may recur if AMICAR is restarted. The possibility of cardiac muscle damage should also be considered when skeletal myopathy occurs. One case of cardiac and hepatic lesions observed in man has been reported. The patient received 2 g of aminocaproic acid every 6 hours for a total dose of 26 g. Death was due to continued cerebrovascular hemorrhage. Necrotic changes in the heart and liver were noted at autopsy. PRECAUTIONS General AMICAR Injection contains benzyl alcohol as a preservative and is not recommended for use in newborns. AMICAR inhibits both the action of plasminogen activators and to a lesser degree, plasmin activity. The drug should NOT be administered without a definite diagnosis and/or laboratory finding indicative of hyperfibrinolysis (hyperplasminemia).1 Rapid intravenous administration of the drug should be avoided since this may induce hypotension, bradycardia, and/or arrhythmia. Inhibition of fibrinolysis by aminocaproic acid may theoretically result in clotting or thrombosis. However, there is no definite evidence that administration of aminocaproic acid has been responsible for the few reported cases of intravascular clotting which followed this treatment. Rather, it appears that such intravascular clotting was most likely due to the patient’s preexisting clinical condition, e.g., the presence of DIC. It has been postulated that extravascular clots formed in vivo may not undergo spontaneous lysis as do normal clots. Reports have appeared in the literature of an increased incidence of certain neurological deficits such as hydrocephalus, cerebral ischemia, or cerebral vasospasm associated with the use of antifibrinolytic agents in the treatment of subarachnoid hemorrhage (SAH). All of these events have also been described as part of the natural course of SAH, or as a consequence of diagnostic procedures such as angiography. Drug relatedness remains unclear. Thrombophlebitis, a possibility with all intravenous therapy, should be guarded against by strict attention to the proper insertion of the needle and the fixing of its position. Epsilon-aminocaproic acid should not be administered with Factor IX Complex concentrates or Anti- Inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-197/S-036, 037, 038, 039 Page 6 Laboratory Tests The use of AMICAR should be accompanied by tests designed to determine the amount of fibrinolysis present. There are presently available: (a) general tests such as those for the determination of the lysis of a clot of blood or plasma; and (b) more specific tests for the study of various phases of fibrinolytic mechanisms. These latter tests include both semiquantitative and quantitative techniques for the determination of profibrinolysin, fibrinolysin, and antifibrinolysin. Drug Laboratory Test Interactions Prolongation of the template bleeding time has been reported during continuous intravenous infusion of AMICAR at dosages exceeding 24 g/day. Platelet function studies in these patients have not demonstrated any significant platelet dysfunction. However, in vitro studies have shown that at high concentrations (7.4 mMol/L or 0.97 mg/mL and greater) EACA inhibits ADP and collagen-induced platelet aggregation, the release of ATP and serotonin, and the binding of fibrinogen to the platelets in a concentration-response manner. Following a 10 g bolus of AMICAR, transient peak plasma concentrations of 4.6 mMol/L or 0.60 mg/mL have been obtained. The concentration of AMICAR necessary to maintain inhibition of fibrinolysis is 0.99 mMol/L or 0.13 mg/mL. Administration of a 5 g bolus followed by 1 to 1.25 g/hr should achieve and sustain plasma levels of 0.13 mg/mL. Thus, concentrations which have been obtained in vivo clinically in patients with normal renal function are considerably lower than the in vitro concentrations found to induce abnormalities in platelet function tests. However, higher plasma concentrations of AMICAR may occur in patients with severe renal failure. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential of AMICAR and studies to evaluate its mutagenic potential have not been conducted. Dietary administration of an equivalent of the maximum human therapeutic dose of AMICAR to rats of both sexes impaired fertility as evidenced by decreased implantations, litter sizes and number of pups born. Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with AMICAR. It is also not known whether AMICAR can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. AMICAR 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 AMICAR is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS AMICAR is generally well tolerated. The following adverse experiences have been reported: General: Edema, headache, malaise. Hypersensitivity Reactions: Allergic and anaphylactoid reactions, anaphylaxis. Local Reactions: Injection site reactions, pain and necrosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-197/S-036, 037, 038, 039 Page 7 Cardiovascular: Bradycardia, hypotension, peripheral ischemia, thrombosis. Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting. Hematologic: Agranulocytosis, coagulation disorder, leukopenia, thrombocytopenia. Musculoskeletal: CPK increased, muscle weakness, myalgia, myopathy (see WARNINGS), myositis, rhabdomyolysis. Neurologic: Confusion, convulsions, delirium, dizziness, hallucinations, intracranial hypertension, stroke, syncope. Respiratory: Dyspnea, nasal congestion, pulmonary embolism. Skin: Pruritus, rash. Special Senses: Tinnitus, vision decreased, watery eyes. Urogenital: BUN increased, renal failure. There have been some reports of dry ejaculation during the period of AMICAR treatment. These have been reported to date only in hemophilia patients who received the drug after undergoing dental surgical procedures. However, this symptom resolved in all patients within 24 to 48 hours of completion of therapy. OVERDOSAGE A few cases of acute overdosage with AMICAR administered intravenously have been reported. The effects have ranged from no reaction to transient hypotension to severe acute renal failure leading to death. One patient with a history of brain tumor and seizures experienced seizures after receiving an 8 gram bolus injection of AMICAR. The single dose of AMICAR causing symptoms of overdosage or considered to be life-threatening is unknown. Patients have tolerated doses as high as 100 grams while acute renal failure has been reported following a dose of 12 grams. The intravenous and oral LD50 of AMICAR were 3.0 and 12.0 g/kg, respectively, in the mouse and 3.2 and 16.4 g/kg, respectively, in the rat. An intravenous infusion dose of 2.3 g/kg was lethal in the dog. On intravenous administration, tonic-clonic convulsions were observed in dogs and mice. No treatment for overdosage is known, although evidence exists that AMICAR is removed by hemodialysis and may be removed by peritoneal dialysis. Pharmacokinetic studies have shown that toal body clearance of AMICAR is markedly decreased in patients with severe renal failure. DOSAGE AND ADMINISTRATION Intravenous AMICAR (aminocaproic acid) Injection is administered by infusion, utilizing the usual compatible intravenous vehicles (e.g., Sterile Water for Injection, Sodium Chloride for Injection, 5% Dextrose or Ringer’s Injection). Although Sterile Water for Injection is compatible for intravenous injection the resultant solution is hypo-osmolar. RAPID INJECTION OF AMICAR INJECTION UNDILUTED INTO A VEIN 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 15-197/S-036, 037, 038, 039 Page 8 For the treatment of acute bleeding syndromes due to elevated fibrinolytic activity, it is suggested that 16 to 20 mL (4 to 5 g) of AMICAR Injection in 250 mL of diluent be administered by infusion during the first hour of treatment, followed by a continuing infusion at the rate of 4 mL (1 g) per hour in 50 mL of diluent. This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Oral Therapy If the patient is able to take medication by mouth, an identical dosage regimen may be followed by administering AMICAR Tablets or AMICAR Syrup, 25% as follows: For the treatment of acute bleeding syndromes due to elevated fibrinolytic activity, it is suggested that 5 AMICAR 1000 mg Tablets or 10 AMICAR 500 mg Tablets (5 g) or 4 teaspoonfuls of AMICAR Syrup (5 g) be administered during the first hour of treatment, followed by a continuing rate of 1 AMICAR 1000 mg Tablet or 2 AMICAR 500 mg Tablets (1 g) or 1 teaspoonful of AMICAR Syrup (1.25 g) per hour. This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled. HOW SUPPLIED AMICAR (aminocaproic acid) AMICAR Injection Each 20 mL vial contains 5 g of aminocaproic acid (250 mg/mL) as an aqueous solution with benzyl alcohol 0.9% as preservative. 20 mL vial – NDC 66479-025-39 Store Between 15°- 30°C (59°- 86°F); Do Not Freeze. AMICAR Syrup, 25% Each mL of raspberry-flavored syrup contains 250 mg of aminocaproic acid. 16 Fl. Oz. (473 mL) Bottle – NDC 66479-023-56 Store Between 15°- 30°C (59°- 86°F); Dispense in Tight Containers; Do Not Freeze. AMICAR 500 mg Tablets Each round, white tablet, engraved with XP on one side and scored on the other with A to the left of the score and 10 on the right, contains 500 mg of aminocaproic acid. Bottle of 100 – NDC 66479-021-82 Store Between 15°- 30°C (59°- 86°F); Dispense in Tight Containers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-197/S-036, 037, 038, 039 Page 9 AMICAR 1000 mg Tablets Each oblong, white tablet, engraved with XP on one side and scored on the other with A to the left of the score and 20 on the right, contains 1000 mg of aminocaproic acid. Bottle of 100 – NDC 66479-022-82 Store Between 15°- 30°C (59°- 86°F); Dispense in Tight Containers. Marketed by XANODYNE PHARMACEUTICALS, INC., Florence, KY 41042. REFERENCES 1. Stefanini M, Dameshek W: The Hemorrhagic Disorders, Ed. 2, New York, Grune and Stratton. 1962; pp. 510–514. X A N O D Y N E Revised XX/XXXX CI XXXX-X This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:54.205481	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/15197scm036,scf037,scp038,scm039_amicar_lbl.pdf', 'application_number': 15197, 'submission_type': 'SUPPL ', 'submission_number': 38}
10,856	NDA 15-230/S-035, NDA 15-197/S-043 Page 3 AMICAR® (aminocaproic acid) Oral Solution and Tablets Rx only DESCRIPTION AMICAR (aminocaproic acid) is 6-aminohexanoic acid, which acts as an inhibitor of fibrinolysis. Its chemical structure is: Chemical Structure AMICAR is soluble in water, acid, and alkaline solutions; it is sparingly soluble in methanol and practically insoluble in chloroform. AMICAR (aminocaproic acid) Oral Solution, 25%, for oral administration, contains 250 mg/mL of aminocaproic acid with methylparaben 0.20%, propylparaben 0.05%, edetate disodium 0.30% as preservatives and the following inactive ingredients: sodium saccharin, sorbitol solution, citric acid anhydrous, natural and artificial raspberry flavor and an artificial bitterness modifier. Each AMICAR (aminocaproic acid) Tablet, for oral administration contains 500 mg or 1000 mg of aminocaproic acid and the following inactive ingredients: povidone, crospovidone, stearic acid, and magnesium stearate. CLINICAL PHARMACOLOGY The fibrinolysis-inhibitory effects of AMICAR appear to be exerted principally via inhibition of plasminogen activators and to a lesser degree through antiplasmin activity. In adults, oral absorption appears to be a zero-order process with an absorption rate of 5.2 g/hr. The mean lag time in absorption is 10 minutes. After a single oral dose of 5 g, absorption was complete (F=1). Mean ± SD peak plasma concentrations (164 ± 28 mcg/mL) were reached within 1.2 ± 0.45 hours. After oral administration, the apparent volume of distribution was estimated to be 23.1 ± 6.6 L (mean± SD). Correspondingly, the volume of distribution after intravenous administration has been reported to be 30.0 ± 8.2 L. After prolonged administration, AMICAR has been found to distribute throughout This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 4 extravascular and intravascular compartments of the body, penetrating human red blood cells as well as other tissue cells. Renal excretion is the primary route of elimination. Sixty-five percent of the dose is recovered in the urine as unchanged drug and 11% of the dose appears as the metabolite adipic acid. Renal clearance (116 mL/min) approximates endogenous creatinine clearance. The total body clearance is 169 mL/min. The terminal elimination half-life for AMICAR is approximately 2 hours. INDICATIONS AND USAGE AMICAR is useful in enhancing hemostasis when fibrinolysis contributes to bleeding. In life- threatening situations, transfusion of appropriate blood products and other emergency measures may be required. Fibrinolytic bleeding may frequently be associated with surgical complications following heart surgery (with or without cardiac bypass procedures) and portacaval shunt; hematological disorders such as amegakaryocytic thrombocytopenia (accompanying aplastic anemia); acute and life-threatening abruptio placentae; hepatic cirrhosis; and neoplastic disease such as carcinoma of the prostate, lung, stomach, and cervix. Urinary fibrinolysis, usualIy a normal physiological phenomenon, may contribute to excessive urinary tract fibrinolytic bleeding associated with surgical hematuria (following prostatectomy and nephrectomy) or nonsurgical hematuria (accompanying polycystic or neoplastic diseases of the genitourinary system). (See WARNINGS.) CONTRAINDICATIONS AMICAR should not be used when there is evidence of an active intravascular clotting process. When there is uncertainty as to whether the cause of bleeding is primary fibrinolysis or disseminated intravascular coagulation (DIC), this distinction must be made before administering AMICAR. The following tests can be applied to differentiate the two conditions: • Platelet count is usually decreased in DIC but normal in primary fibrinolysis. • Protamine paracoagulation test is positive in DIC; a precipitate forms when protamine sulfate is dropped into citrated plasma. The test is negative in the presence of primary fibrinolysis. • The euglobulin clot lysis test is abnormal in primary fibrinolysis but normal in DIC. AMICAR must not be used in the presence of DIC without concomitant heparin. WARNINGS In patients with upper urinary tract bleeding, AMICAR administration has been known to cause intrarenal obstruction in the form of glomerular capillary thrombosis or clots in the renal pelvis and ureters. For this reason, AMICAR should not be used in hematuria of upper urinary tract origin, unless the possible benefits outweigh the risk. Subendocardial hemorrhages have been observed in dogs given intravenous infusions of 0.2 times the maximum human therapeutic dose of AMICAR and in monkeys given 8 times the maximum human therapeutic dose of AMICAR. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 5 Fatty degeneration of the myocardium has been reported in dogs given intravenous doses of AMICAR at 0.8 to 3.3 times the maximum human therapeutic dose and in monkeys given intravenous doses of AMICAR at 6 times the maximum human therapeutic dose. Rarely, skeletal muscle weakness with necrosis of muscle fibers has been reported following prolonged administration. Clinical presentation may range from mild myalgias with weakness and fatigue to a severe proximal myopathy with rhabdomyolysis, myoglobinuria, and acute renal failure. Muscle enzymes, especially creatine phosphokinase (CPK) are elevated. CPK levels should be monitored in patients on long-term therapy. AMICAR administration should be stopped if a rise in CPK is noted. Resolution follows discontinuation of AMICAR; however, the syndrome may recur if AMICAR is restarted. The possibility of cardiac muscle damage should also be considered when skeletal myopathy occurs. One case of cardiac and hepatic lesions observed in man has been reported. The patient received 2 g of aminocaproic acid every 6 hours for a total dose of 26 g. Death was due to continued cerebrovascular hemorrhage. Necrotic changes in the heart and liver were noted at autopsy. PRECAUTIONS General AMICAR inhibits both the action of plasminogen activators and to a lesser degree, plasmin activity. The drug should NOT be administered without a definite diagnosis and/or laboratory finding indicative of hyperfibrinolysis (hyperplasminemia).1 Inhibition of fibrinolysis by aminocaproic acid may theoretically result in clotting or thrombosis. However, there is no definite evidence that administration of aminocaproic acid has been responsible for the few reported cases of intravascular clotting which followed this treatment. Rather, it appears that such intravascular clotting was most likely due to the patient's preexisting clinical condition, e.g., the presence of DIC. It has been postulated that extravascular clots formed in vivo may not undergo spontaneous lysis as do normal clots. Reports have appeared in the literature of an increased incidence of certain neurological deficits such as hydrocephalus, cerebral ischemia, or cerebral vasospasm associated with the use of antifibrinolytic agents in the treatment of subarachnoid hemorrhage (SAH). All of these events have also been described as part of the natural course of SAH, or as a consequence of diagnostic procedures such as angiography. Drug relatedness remains unclear. Aminocaproic acid should not be administered with Factor IX Complex concentrates or Anti-Inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Laboratory Tests The use of AMICAR should be accompanied by tests designed to determine the amount of fibrinolysis present. There are presently available: (a) general tests such as those for the determination of the lysis of a clot of blood or plasma; and (b) more specific tests for the study of various phases of the fibrinolytic mechanisms. These latter tests include both semiquantitative and quantitative techniques for the determination of profibrinolysin, fibrinolysin, and antifibrinolysin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 6 Drug Laboratory Test Interactions Prolongation of the template bleeding time has been reported during continuous intravenous infusion of AMICAR at dosages exceeding 24 g/day. Platelet function studies in these patients have not demonstrated any significant platelet dysfunction. However, in vitro studies have shown that at high concentrations (7.4 mMol/L or 0.97 mg/mL and greater) aminocaproic acid inhibits ADP and collagen- induced platelet aggregation, the release of ATP and serotonin, and the binding of fibrinogen to the platelets in a concentration-response manner. Following a 10 g bolus of AMICAR, transient peak plasma concentrations of 4.6 mMol/L or 0.60 mg/mL have been obtained. The concentration of AMICAR necessary to maintain inhibition of fibrinolysis is 0.99 mMol/L or 0.13 mg/mL. Administration of a 5 g bolus followed by 1 to 1.25 g/hr should achieve and sustain plasma levels of 0.13 mg/mL. Thus, concentrations which have been obtained in vivo clinically in patients with normal renal function are considerably lower than the in vitro concentrations found to induce abnormalities in platelet function tests. However, higher plasma concentrations of AMICAR may occur in patients with severe renal failure. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential of AMICAR and studies to evaluate its mutagenic potential have not been conducted. Dietary administration of an equivalent of the maximum human therapeutic dose of AMICAR to rats of both sexes impaired fertility as evidenced by decreased implantations, litter sizes and number of pups born. Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with AMICAR. It is also not known whether AMICAR can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. AMICAR 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 AMICAR is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS AMICAR is generally well tolerated. The following adverse experiences have been reported: General: Edema, headache, malaise. Hypersensitivity Reactions: Allergic and anaphylactoid reactions, anaphylaxis. Cardiovascular: Bradycardia, hypotension, peripheral ischemia, thrombosis. Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting. Hematologic: Agranulocytosis, coagulation disorder, leukopenia, thrombocytopenia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 7 Musculoskeletal: CPK increased, muscle weakness, myalgia, myopathy (see WARNINGS), myositis, rhabdomyolysis. Neurologic: Confusion, convulsions, delirium, dizziness, hallucinations, intracranial hypertension, stroke, syncope. Respiratory: Dyspnea, nasal congestion, pulmonary embolism. Skin: Pruritis, rash. Special Senses: Tinnitus, vision decreased, watery eyes. Urogenital: BUN increased, renal failure. There have been some reports of dry ejaculation during the period of AMICAR treatment. These have been reported to date only in hemophilia patients who received the drug after undergoing dental surgical procedures. However, this symptom resolved in all patients within 24 to 48 hours of completion of therapy. OVERDOSAGE A few cases of acute overdosage with AMICAR administered intravenously have been reported. The effects have ranged from no reaction to transient hypotension to severe acute renal failure leading to death. One patient with a history of brain tumor and seizures experienced seizures after receiving an 8 gram bolus injection of AMICAR. The single dose of AMICAR causing symptoms of overdosage or considered to be life-threatening is unknown. Patients have tolerated doses as high as 100 grams while acute renal failure has been reported following a dose of 12 grams. The intravenous and oral LD50 of AMICAR were 3.0 and 12.0 g/kg, respectively, in the mouse and 3.2 and 16.4 g/kg, respectively, in the rat. An intravenous infusion dose of 2.3 g/kg was lethal in the dog. On intravenous administration, tonic-clonic convulsions were observed in dogs and mice. No treatment for overdosage is known, although evidence exists that AMICAR is removed by hemodialysis and may be removed by peritoneal dialysis. Pharmacokinetic studies have shown that total body clearance of AMICAR is markedly decreased in patients with severe renal failure. DOSAGE AND ADMINISTRATION An identical dosage regimen may be followed by administering AMICAR Tablets or AMICAR Oral Solution, 25% as follows: For the treatment of acute bleeding syndromes due to elevated fibrinolytic activity, it is suggested that 5 AMICAR 1000 mg Tablets or 10 AMICAR 500 mg Tablets (5 g) or 4 teaspoonfuls of AMICAR Oral Solution (5 g) be administered during the first hour of treatment, followed by a continuing rate of 1 AMICAR 1000 mg Tablet or 2 AMICAR 500 mg Tablets (1 g) or 1 teaspoonful of AMICAR Oral Solution (1.25 g) per hour. This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled. HOW SUPPLIED: AMICAR® (aminocaproic acid) AMICAR Oral Solution, 25% Each mL of raspberry-flavored oral solution contains 250 mg of aminocaproic acid. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 8 16 Fl. Oz. (473 mL) Bottle – NDC 66479-023-56 Store Between 15°-30°C (59°-86°F); Dispense in Tight Containers; Do Not Freeze. AMICAR 500 mg Tablets Each round, white tablet, engraved with XP on one side and scored on the other with A to the left of the score and 10 on the right, contains 500 mg of aminocaproic acid. Bottle of 100 – NDC 66479-021-82 Store Between 15°-30°C (59°-86°F); Dispense in Tight Containers. AMICAR 1000 mg Tablets Each oblong, white tablet, engraved with XP on one side and scored on the other with A to the left of the score and 20 on the right, contains 1000 mg of aminocaproic acid. Bottle of 100 – NDC 66479-022-82 Store Between 15°-30°C (59°-86°F); Dispense in Tight Containers. REFERENCE 1 Stefanini M, Dameshek W: The Hemorrhagic Disorders, Ed. 2, New York, Grune and Stratton; 1962:510-514. logo Rev. 04/08 Code 909A00 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:54.469056	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/015197s043,015230s035lbl.pdf', 'application_number': 15197, 'submission_type': 'SUPPL ', 'submission_number': 43}
10,857	NDA 15-230/S-035, NDA 15-197/S-043 Page 3 AMICAR® (aminocaproic acid) Oral Solution and Tablets Rx only DESCRIPTION AMICAR (aminocaproic acid) is 6-aminohexanoic acid, which acts as an inhibitor of fibrinolysis. Its chemical structure is: Chemical Structure AMICAR is soluble in water, acid, and alkaline solutions; it is sparingly soluble in methanol and practically insoluble in chloroform. AMICAR (aminocaproic acid) Oral Solution, 25%, for oral administration, contains 250 mg/mL of aminocaproic acid with methylparaben 0.20%, propylparaben 0.05%, edetate disodium 0.30% as preservatives and the following inactive ingredients: sodium saccharin, sorbitol solution, citric acid anhydrous, natural and artificial raspberry flavor and an artificial bitterness modifier. Each AMICAR (aminocaproic acid) Tablet, for oral administration contains 500 mg or 1000 mg of aminocaproic acid and the following inactive ingredients: povidone, crospovidone, stearic acid, and magnesium stearate. CLINICAL PHARMACOLOGY The fibrinolysis-inhibitory effects of AMICAR appear to be exerted principally via inhibition of plasminogen activators and to a lesser degree through antiplasmin activity. In adults, oral absorption appears to be a zero-order process with an absorption rate of 5.2 g/hr. The mean lag time in absorption is 10 minutes. After a single oral dose of 5 g, absorption was complete (F=1). Mean ± SD peak plasma concentrations (164 ± 28 mcg/mL) were reached within 1.2 ± 0.45 hours. After oral administration, the apparent volume of distribution was estimated to be 23.1 ± 6.6 L (mean± SD). Correspondingly, the volume of distribution after intravenous administration has been reported to be 30.0 ± 8.2 L. After prolonged administration, AMICAR has been found to distribute throughout This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 4 extravascular and intravascular compartments of the body, penetrating human red blood cells as well as other tissue cells. Renal excretion is the primary route of elimination. Sixty-five percent of the dose is recovered in the urine as unchanged drug and 11% of the dose appears as the metabolite adipic acid. Renal clearance (116 mL/min) approximates endogenous creatinine clearance. The total body clearance is 169 mL/min. The terminal elimination half-life for AMICAR is approximately 2 hours. INDICATIONS AND USAGE AMICAR is useful in enhancing hemostasis when fibrinolysis contributes to bleeding. In life- threatening situations, transfusion of appropriate blood products and other emergency measures may be required. Fibrinolytic bleeding may frequently be associated with surgical complications following heart surgery (with or without cardiac bypass procedures) and portacaval shunt; hematological disorders such as amegakaryocytic thrombocytopenia (accompanying aplastic anemia); acute and life-threatening abruptio placentae; hepatic cirrhosis; and neoplastic disease such as carcinoma of the prostate, lung, stomach, and cervix. Urinary fibrinolysis, usualIy a normal physiological phenomenon, may contribute to excessive urinary tract fibrinolytic bleeding associated with surgical hematuria (following prostatectomy and nephrectomy) or nonsurgical hematuria (accompanying polycystic or neoplastic diseases of the genitourinary system). (See WARNINGS.) CONTRAINDICATIONS AMICAR should not be used when there is evidence of an active intravascular clotting process. When there is uncertainty as to whether the cause of bleeding is primary fibrinolysis or disseminated intravascular coagulation (DIC), this distinction must be made before administering AMICAR. The following tests can be applied to differentiate the two conditions: • Platelet count is usually decreased in DIC but normal in primary fibrinolysis. • Protamine paracoagulation test is positive in DIC; a precipitate forms when protamine sulfate is dropped into citrated plasma. The test is negative in the presence of primary fibrinolysis. • The euglobulin clot lysis test is abnormal in primary fibrinolysis but normal in DIC. AMICAR must not be used in the presence of DIC without concomitant heparin. WARNINGS In patients with upper urinary tract bleeding, AMICAR administration has been known to cause intrarenal obstruction in the form of glomerular capillary thrombosis or clots in the renal pelvis and ureters. For this reason, AMICAR should not be used in hematuria of upper urinary tract origin, unless the possible benefits outweigh the risk. Subendocardial hemorrhages have been observed in dogs given intravenous infusions of 0.2 times the maximum human therapeutic dose of AMICAR and in monkeys given 8 times the maximum human therapeutic dose of AMICAR. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 5 Fatty degeneration of the myocardium has been reported in dogs given intravenous doses of AMICAR at 0.8 to 3.3 times the maximum human therapeutic dose and in monkeys given intravenous doses of AMICAR at 6 times the maximum human therapeutic dose. Rarely, skeletal muscle weakness with necrosis of muscle fibers has been reported following prolonged administration. Clinical presentation may range from mild myalgias with weakness and fatigue to a severe proximal myopathy with rhabdomyolysis, myoglobinuria, and acute renal failure. Muscle enzymes, especially creatine phosphokinase (CPK) are elevated. CPK levels should be monitored in patients on long-term therapy. AMICAR administration should be stopped if a rise in CPK is noted. Resolution follows discontinuation of AMICAR; however, the syndrome may recur if AMICAR is restarted. The possibility of cardiac muscle damage should also be considered when skeletal myopathy occurs. One case of cardiac and hepatic lesions observed in man has been reported. The patient received 2 g of aminocaproic acid every 6 hours for a total dose of 26 g. Death was due to continued cerebrovascular hemorrhage. Necrotic changes in the heart and liver were noted at autopsy. PRECAUTIONS General AMICAR inhibits both the action of plasminogen activators and to a lesser degree, plasmin activity. The drug should NOT be administered without a definite diagnosis and/or laboratory finding indicative of hyperfibrinolysis (hyperplasminemia).1 Inhibition of fibrinolysis by aminocaproic acid may theoretically result in clotting or thrombosis. However, there is no definite evidence that administration of aminocaproic acid has been responsible for the few reported cases of intravascular clotting which followed this treatment. Rather, it appears that such intravascular clotting was most likely due to the patient's preexisting clinical condition, e.g., the presence of DIC. It has been postulated that extravascular clots formed in vivo may not undergo spontaneous lysis as do normal clots. Reports have appeared in the literature of an increased incidence of certain neurological deficits such as hydrocephalus, cerebral ischemia, or cerebral vasospasm associated with the use of antifibrinolytic agents in the treatment of subarachnoid hemorrhage (SAH). All of these events have also been described as part of the natural course of SAH, or as a consequence of diagnostic procedures such as angiography. Drug relatedness remains unclear. Aminocaproic acid should not be administered with Factor IX Complex concentrates or Anti-Inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Laboratory Tests The use of AMICAR should be accompanied by tests designed to determine the amount of fibrinolysis present. There are presently available: (a) general tests such as those for the determination of the lysis of a clot of blood or plasma; and (b) more specific tests for the study of various phases of the fibrinolytic mechanisms. These latter tests include both semiquantitative and quantitative techniques for the determination of profibrinolysin, fibrinolysin, and antifibrinolysin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 6 Drug Laboratory Test Interactions Prolongation of the template bleeding time has been reported during continuous intravenous infusion of AMICAR at dosages exceeding 24 g/day. Platelet function studies in these patients have not demonstrated any significant platelet dysfunction. However, in vitro studies have shown that at high concentrations (7.4 mMol/L or 0.97 mg/mL and greater) aminocaproic acid inhibits ADP and collagen- induced platelet aggregation, the release of ATP and serotonin, and the binding of fibrinogen to the platelets in a concentration-response manner. Following a 10 g bolus of AMICAR, transient peak plasma concentrations of 4.6 mMol/L or 0.60 mg/mL have been obtained. The concentration of AMICAR necessary to maintain inhibition of fibrinolysis is 0.99 mMol/L or 0.13 mg/mL. Administration of a 5 g bolus followed by 1 to 1.25 g/hr should achieve and sustain plasma levels of 0.13 mg/mL. Thus, concentrations which have been obtained in vivo clinically in patients with normal renal function are considerably lower than the in vitro concentrations found to induce abnormalities in platelet function tests. However, higher plasma concentrations of AMICAR may occur in patients with severe renal failure. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential of AMICAR and studies to evaluate its mutagenic potential have not been conducted. Dietary administration of an equivalent of the maximum human therapeutic dose of AMICAR to rats of both sexes impaired fertility as evidenced by decreased implantations, litter sizes and number of pups born. Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with AMICAR. It is also not known whether AMICAR can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. AMICAR 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 AMICAR is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS AMICAR is generally well tolerated. The following adverse experiences have been reported: General: Edema, headache, malaise. Hypersensitivity Reactions: Allergic and anaphylactoid reactions, anaphylaxis. Cardiovascular: Bradycardia, hypotension, peripheral ischemia, thrombosis. Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting. Hematologic: Agranulocytosis, coagulation disorder, leukopenia, thrombocytopenia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 7 Musculoskeletal: CPK increased, muscle weakness, myalgia, myopathy (see WARNINGS), myositis, rhabdomyolysis. Neurologic: Confusion, convulsions, delirium, dizziness, hallucinations, intracranial hypertension, stroke, syncope. Respiratory: Dyspnea, nasal congestion, pulmonary embolism. Skin: Pruritis, rash. Special Senses: Tinnitus, vision decreased, watery eyes. Urogenital: BUN increased, renal failure. There have been some reports of dry ejaculation during the period of AMICAR treatment. These have been reported to date only in hemophilia patients who received the drug after undergoing dental surgical procedures. However, this symptom resolved in all patients within 24 to 48 hours of completion of therapy. OVERDOSAGE A few cases of acute overdosage with AMICAR administered intravenously have been reported. The effects have ranged from no reaction to transient hypotension to severe acute renal failure leading to death. One patient with a history of brain tumor and seizures experienced seizures after receiving an 8 gram bolus injection of AMICAR. The single dose of AMICAR causing symptoms of overdosage or considered to be life-threatening is unknown. Patients have tolerated doses as high as 100 grams while acute renal failure has been reported following a dose of 12 grams. The intravenous and oral LD50 of AMICAR were 3.0 and 12.0 g/kg, respectively, in the mouse and 3.2 and 16.4 g/kg, respectively, in the rat. An intravenous infusion dose of 2.3 g/kg was lethal in the dog. On intravenous administration, tonic-clonic convulsions were observed in dogs and mice. No treatment for overdosage is known, although evidence exists that AMICAR is removed by hemodialysis and may be removed by peritoneal dialysis. Pharmacokinetic studies have shown that total body clearance of AMICAR is markedly decreased in patients with severe renal failure. DOSAGE AND ADMINISTRATION An identical dosage regimen may be followed by administering AMICAR Tablets or AMICAR Oral Solution, 25% as follows: For the treatment of acute bleeding syndromes due to elevated fibrinolytic activity, it is suggested that 5 AMICAR 1000 mg Tablets or 10 AMICAR 500 mg Tablets (5 g) or 4 teaspoonfuls of AMICAR Oral Solution (5 g) be administered during the first hour of treatment, followed by a continuing rate of 1 AMICAR 1000 mg Tablet or 2 AMICAR 500 mg Tablets (1 g) or 1 teaspoonful of AMICAR Oral Solution (1.25 g) per hour. This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled. HOW SUPPLIED: AMICAR® (aminocaproic acid) AMICAR Oral Solution, 25% Each mL of raspberry-flavored oral solution contains 250 mg of aminocaproic acid. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-035, NDA 15-197/S-043 Page 8 16 Fl. Oz. (473 mL) Bottle – NDC 66479-023-56 Store Between 15°-30°C (59°-86°F); Dispense in Tight Containers; Do Not Freeze. AMICAR 500 mg Tablets Each round, white tablet, engraved with XP on one side and scored on the other with A to the left of the score and 10 on the right, contains 500 mg of aminocaproic acid. Bottle of 100 – NDC 66479-021-82 Store Between 15°-30°C (59°-86°F); Dispense in Tight Containers. AMICAR 1000 mg Tablets Each oblong, white tablet, engraved with XP on one side and scored on the other with A to the left of the score and 20 on the right, contains 1000 mg of aminocaproic acid. Bottle of 100 – NDC 66479-022-82 Store Between 15°-30°C (59°-86°F); Dispense in Tight Containers. REFERENCE 1 Stefanini M, Dameshek W: The Hemorrhagic Disorders, Ed. 2, New York, Grune and Stratton; 1962:510-514. logo Rev. 04/08 Code 909A00 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:54.478301	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/015197s043,015230s035lbl.pdf', 'application_number': 15230, 'submission_type': 'SUPPL ', 'submission_number': 35}
10,859	struct ural for mu la SYNALAR® (fluocinolone acetonide) Topical Solution, 0.01% Rx Only DESCRIPTION SYNALAR® (fluocinolone acetonide) Topical Solution, 0.01% is intended for topical administration. The active component is the corticosteroid fluocinolone acetonide, which has the chemical name pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21 dihydroxy-16,17-[(1-methylethylidene)bis (oxy)]-,(6α,11β,16α)-. It has the following chemical structure: SYNALAR® Solution contains fluocinolone acetonide 0.1 mg/mL in a water-washable base of citric acid and propylene glycol. 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 vasocon strictor 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. 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. Corticosteroids Reference ID: 3219028 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 SYNALAR® Solution is indicated for the relief of the inflammatory and pruritic manifestations of corticosteriod-responsive dermatoses. CONTRAINDICATIONS Topical corticosteroids 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 hypotha lamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syn drome, 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 addi tion 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 periodi cally for evidence of HPA axis suppression 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 substi tute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinu ation of the drug. Infrequently, signs and symptoms of steroid 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. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues.When used on intertriginous or flexor areas, or on the face, this may occur even with short-term use. 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 ad equately 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 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. 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 adminis tered 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 terato genic effects from topically applied corticosteroids. Therefore, topical corticoste roids 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 administered corticosteroids are secreted into breast milk in quanti ties 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 Pediatric patients may demonstrate greater susceptibility to topical corticosteroid induced hypothalmic-pituitary-adrenal (HPA) axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. Hypothalmic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in children receiving topical cortico steroids. 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. 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. Reference ID: 3219028 ADVERSE REACTIONS The following local adverse reactions are reported infrequently with topical cortico steroids, but may occur more frequently with the use of occlusive dressings.These reactions are listed in an approximate decreasing order of occurrence: Burning Perioral dermatitis Itching Allergic contact dermatitis Irritation Maceration of the skin Dryness Secondary infection Folliculitis Skin atrophy Hypertrichosis Striae Acneiform eruptions Miliaria Hypopigmentation OVERDOSAGE Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS). DOSAGE AND ADMINISTRATION SYNALAR® Solution is generally applied to the affected area as a thin film from two to four times daily depending on the severity of the condition. In hairy sites, the hair should be parted to allow direct contact with the lesion. Occlusive dressing 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 instituted. HOW SUPPLIED SYNALAR® (fluocinolone acetonide) Topical Solution, 0.01% 60 mL Bottle with applicator tip – NDC 43538-920-60 90 mL Bottle with applicator tip – NDC 43538-920-90 STORAGE Store at room temperature 15-25°C (59-77°F); avoid freezing and excessive heat above 40°C (104°F). To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda/gov/medwatch. company logo IP030-R2 Rev. 11/12	custom-source	2025-02-12T13:43:54.535585	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/015296s064lbl.pdf', 'application_number': 15296, 'submission_type': 'SUPPL ', 'submission_number': 64}
10,858	NDA 15-230/S-037 Page 3 AMICAR® (aminocaproic acid) Oral Solution and Tablets Rx only DESCRIPTION AMICAR (aminocaproic acid) is 6-aminohexanoic acid, which acts as an inhibitor of fibrinolysis. Its chemical structure is: C hemical Sructure AMICAR is soluble in water, acid, and alkaline solutions; it is sparingly soluble in methanol and practically insoluble in chloroform. AMICAR (aminocaproic acid) Oral Solution for oral administration, contains 0.25 g/mL of aminocaproic acid with methylparaben 0.20%, propylparaben 0.05%, edetate disodium 0.30% as preservatives and the following inactive ingredients: sodium saccharin, sorbitol solution, citric acid anhydrous, natural and artificial raspberry flavor and an artificial bitterness modifier. Each AMICAR (aminocaproic acid) Tablet, for oral administration contains 500 mg or 1000 mg of aminocaproic acid and the following inactive ingredients: povidone, crospovidone, stearic acid, and magnesium stearate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-037 Page 4 CLINICAL PHARMACOLOGY The fibrinolysis-inhibitory effects of AMICAR appear to be exerted principally via inhibition of plasminogen activators and to a lesser degree through antiplasmin activity. In adults, oral absorption appears to be a zero-order process with an absorption rate of 5.2 g/hr. The mean lag time in absorption is 10 minutes. After a single oral dose of 5 g, absorption was complete (F=1). Mean ± SD peak plasma concentrations (164 ± 28 mcg/mL) were reached within 1.2 ± 0.45 hours. After oral administration, the apparent volume of distribution was estimated to be 23.1 ± 6.6 L (mean ± SD). Correspondingly, the volume of distribution after intravenous administration has been reported to be 30.0 ± 8.2 L. After prolonged administration, AMICAR has been found to distribute throughout extravascular and intravascular compartments of the body, penetrating human red blood cells as well as other tissue cells. Renal excretion is the primary route of elimination. Sixty-five percent of the dose is recovered in the urine as unchanged drug and 11% of the dose appears as the metabolite adipic acid. Renal clearance (116 mL/min) approximates endogenous creatinine clearance. The total body clearance is 169 mL/min. The terminal elimination half-life for AMICAR is approximately 2 hours. INDICATIONS AND USAGE AMICAR is useful in enhancing hemostasis when fibrinolysis contributes to bleeding. In life- threatening situations, transfusion of appropriate blood products and other emergency measures may be required. Fibrinolytic bleeding may frequently be associated with surgical complications following heart surgery (with or without cardiac bypass procedures) and portacaval shunt; hematological disorders such as amegakaryocytic thrombocytopenia (accompanying aplastic anemia); acute and life-threatening abruptio placentae; hepatic cirrhosis; and neoplastic disease such as carcinoma of the prostate, lung, stomach, and cervix. Urinary fibrinolysis, usualIy a normal physiological phenomenon, may contribute to excessive urinary tract fibrinolytic bleeding associated with surgical hematuria (following prostatectomy This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-037 Page 5 and nephrectomy) or nonsurgical hematuria (accompanying polycystic or neoplastic diseases of the genitourinary system). (See WARNINGS.) CONTRAINDICATIONS AMICAR should not be used when there is evidence of an active intravascular clotting process. When there is uncertainty as to whether the cause of bleeding is primary fibrinolysis or disseminated intravascular coagulation (DIC), this distinction must be made before administering AMICAR. The following tests can be applied to differentiate the two conditions: • Platelet count is usually decreased in DIC but normal in primary fibrinolysis. • Protamine paracoagulation test is positive in DIC; a precipitate forms when protamine sulfate is dropped into citrated plasma. The test is negative in the presence of primary fibrinolysis. • The euglobulin clot Iysis test is abnormal in primary fibrinolysis but normal in DIC. AMICAR must not be used in the presence of DIC without concomitant heparin. WARNINGS In patients with upper urinary tract bleeding, AMICAR administration has been known to cause intrarenal obstruction in the form of glomerular capillary thrombosis or clots in the renal pelvis and ureters. For this reason, AMICAR should not be used in hematuria of upper urinary tract origin, unless the possible benefits outweigh the risk. Subendocardial hemorrhages have been observed in dogs given intravenous infusions of 0.2 times the maximum human therapeutic dose of AMICAR and in monkeys given 8 times the maximum human therapeutic dose of AMICAR. Fatty degeneration of the myocardium has been reported in dogs given intravenous doses of AMICAR at 0.8 to 3.3 times the maximum human therapeutic dose and in monkeys given intravenous doses of AMICAR at 6 times the maximum human therapeutic dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-037 Page 6 Rarely, skeletal muscle weakness with necrosis of muscle fibers has been reported following prolonged administration. Clinical presentation may range from mild myalgias with weakness and fatigue to a severe proximal myopathy with rhabdomyolysis, myoglobinuria, and acute renal failure. Muscle enzymes, especially creatine phosphokinase (CPK) are elevated. CPK levels should be monitored in patients on long-term therapy. AMICAR administration should be stopped if a rise in CPK is noted. Resolution follows discontinuation of AMICAR; however, the syndrome may recur if AMICAR is restarted. The possibility of cardiac muscle damage should also be considered when skeletal myopathy occurs. One case of cardiac and hepatic lesions observed in man has been reported. The patient received 2 g of aminocaproic acid every 6 hours for a total dose of 26 g. Death was due to continued cerebrovascular hemorrhage. Necrotic changes in the heart and liver were noted at autopsy. PRECAUTIONS General AMICAR inhibits both the action of plasminogen activators and to a lesser degree, plasmin activity. The drug should NOT be administered without a definite diagnosis and/or laboratory finding indicative of hyperfibrinolysis (hyperplasminemia).1 Inhibition of fibrinolysis by aminocaproic acid may theoretically result in clotting or thrombosis. However, there is no definite evidence that administration of aminocaproic acid has been responsible for the few reported cases of intravascular clotting which followed this treatment. Rather, it appears that such intravascular clotting was most likely due to the patient's preexisting clinical condition, e.g., the presence of DIC. It has been postulated that extravascular clots formed in vivo may not undergo spontaneous Iysis as do normal clots. Reports have appeared in the literature of an increased incidence of certain neurological deficits such as hydrocephalus, cerebral ischemia, or cerebral vasospasm associated with the use of antifibrinolytic agents in the treatment of subarachnoid hemorrhage (SAH). All of these events have also been described as part of the natural course of SAH, or as a consequence of diagnostic procedures such as angiography. Drug relatedness remains unclear. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-037 Page 7 Aminocaproic acid should not be administered with Factor IX Complex concentrates or Anti- Inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Laboratory Tests The use of AMICAR should be accompanied by tests designed to determine the amount of fibrinolysis present. There are presently available: (a) general tests such as those for the determination of the Iysis of a clot of blood or plasma; and (b) more specific tests for the study of various phases of the fibrinolytic mechanisms. These latter tests include both semiquantitative and quantitative techniques for the determination of profibrinolysin, fibrinolysin, and antifibrinolysin. Drug Laboratory Test Interactions Prolongation of the template bleeding time has been reported during continuous intravenous infusion of AMICAR at dosages exceeding 24 g/day. Platelet function studies in these patients have not demonstrated any significant platelet dysfunction. However, in vitro studies have shown that at high concentrations (7.4 mMol/L or 0.97 mg/mL and greater) aminocaproic acid inhibits ADP and collagen-induced platelet aggregation, the release of ATP and serotonin, and the binding of fibrinogen to the platelets in a concentration-response manner. Following a 10 g bolus of AMICAR, transient peak plasma concentrations of 4.6 mMol/L or 0.60 mg/mL have been obtained. The concentration of AMICAR necessary to maintain inhibition of fibrinolysis is 0.99 mMol/L or 0.13 mg/mL. Administration of a 5 g bolus followed by 1 to 1.25 g/hr should achieve and sustain plasma levels of 0.13 mg/mL. Thus, concentrations which have been obtained in vivo clinically in patients with normal renal function are considerably lower than the in vitro concentrations found to induce abnormalities in platelet function tests. However, higher plasma concentrations of AMICAR may occur in patients with severe renal failure. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential of AMICAR and studies to evaluate its mutagenic potential have not been conducted. Dietary administration of an equivalent of the maximum human therapeutic dose of AMICAR to rats of both sexes This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-037 Page 8 impaired fertility as evidenced by decreased implantations, litter sizes and number of pups born. Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with AMICAR. It is also not known whether AMICAR can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. AMICAR 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 AMICAR is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS AMICAR is generally well tolerated. The following adverse experiences have been reported: General: Edema, headache, malaise. Hypersensitivity Reactions: Allergic and anaphylactoid reactions, anaphylaxis. Cardiovascular: Bradycardia, hypotension, peripheral ischemia, thrombosis. Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting. Hematologic: Agranulocytosis, coagulation disorder, leukopenia, thrombocytopenia. Musculoskeletal: CPK increased, muscle weakness, myalgia, myopathy (see WARNINGS), myositis, rhabdomyolysis. Neurologic: Confusion, convulsions, delirium, dizziness, hallucinations, intracranial hypertension, stroke, syncope. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-037 Page 9 Respiratory: Dyspnea, nasal congestion, pulmonary embolism. Skin: Pruritis, rash. Special Senses: Tinnitus, vision decreased, watery eyes. Urogenital: BUN increased, renal failure. There have been some reports of dry ejaculation during the period of AMICAR treatment. These have been reported to date only in hemophilia patients who received the drug after undergoing dental surgical procedures. However, this symptom resolved in all patients within 24 to 48 hours of completion of therapy. OVERDOSAGE A few cases of acute overdosage with AMICAR administered intravenously have been reported. The effects have ranged from no reaction to transient hypotension to severe acute renal failure leading to death. One patient with a history of brain tumor and seizures experienced seizures after receiving an 8 gram bolus injection of AMICAR. The single dose of AMICAR causing symptoms of overdosage or considered to be life-threatening is unknown. Patients have tolerated doses as high as 100 grams while acute renal failure has been reported following a dose of 12 grams. The intravenous and oral LD50 of AMICAR were 3.0 and 12.0 g/kg, respectively, in the mouse and 3.2 and 16.4 g/kg, respectively, in the rat. An intravenous infusion dose of 2.3 g/kg was lethal in the dog. On intravenous administration, tonic-clonic convulsions were observed in dogs and mice. No treatment for overdosage is known, although evidence exists that AMICAR is removed by hemodialysis and may be removed by peritoneal dialysis. Pharmacokinetic studies have shown that total body clearance of AMICAR is markedly decreased in patients with severe renal failure. DOSAGE AND ADMINISTRATION An identical dosage regimen may be followed by administering AMICAR Tablets or AMICAR Oral Solution as follows: For the treatment of acute bleeding syndromes due to elevated fibrinolytic activity, it is suggested that 5 AMICAR 1000 mg Tablets or 10 AMICAR 500 mg Tablets (5 g) or 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 15-230/S-037 Page 10 milliliter of AMICAR Oral Solution (5 g) be administered during the first hour of treatment, followed by a continuing rate of 1 AMICAR 1000 mg Tablet or 2 AMICAR 500 mg Tablets (1 g) or 5 milliliter of AMICAR Oral Solution (1.25 g) per hour. This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled. HOW SUPPLIED: AMICAR® (aminocaproic acid) AMICAR Oral Solution, 0.25 g/mL Each mL of raspberry-flavored oral solution contains 0.25 g/mL of aminocaproic acid. 16 Fl. Oz. (473 mL) Bottle – NDC 66479-023-56 Store Between 15°-30°C (59°-86°F); Dispense in Tight Containers; Do Not Freeze. AMICAR 500 mg Tablets Each round, white tablet, engraved with XP on one side and scored on the other with A to the left of the score and 10 on the right, contains 500 mg of aminocaproic acid. Bottle of 100 – NDC 66479-021-82 Store Between 15°-30°C (59°-86°F); Dispense in Tight Containers. AMICAR 1000 mg Tablets Each oblong, white tablet, engraved with XP on one side and scored on the other with A to the left of the score and 20 on the right, contains 1000 mg of aminocaproic acid. Bottle of 100 – NDC 66479-022-82 Store Between 15°-30°C (59°-86°F); Dispense in Tight Containers. REFERENCE 1 Stefanini M, Dameshek W: The Hemorrhagic Disorders, Ed. 2, New York, Grune and Stratton; 1962:510-514. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda l o g o NDA 15-230/S-037 Page 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:54.610176	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/015230s037lbl.pdf', 'application_number': 15230, 'submission_type': 'SUPPL ', 'submission_number': 37}
10,861	1 HALDOL® BRAND OF HALOPERIDOL INJECTION (FOR IMMEDIATE RELEASE) Rx only DESCRIPTION Haloperidol is the first of the butyrophenone series of major antipsychotics. The chemical designation is 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]- 4’-fluorobutyrophenone and it has the following structural formula: HALDOL (haloperidol) is available as a sterile parenteral form for intramuscular injection. The injection provides 5 mg haloperidol (as the lactate) and lactic acid for pH adjustment between 3.0 – 3.6. ACTIONS The precise mechanism of action has not been clearly established. INDICATIONS HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia. HALDOL is indicated for the control of tics and vocal utterances of Tourette’s Disorder. CONTRAINDICATIONS HALDOL (haloperidol) is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Cardiovascular Effects Cases of sudden death have been reported in psychiatric patients receiving antipsychotic drugs, including HALDOL. Since QT-prolongation has been observed during HALDOL treatment, it is advised to be cautious in patients with QT-prolonging conditions (long QT-syndromes, hypokalaemia, electrolyte imbalance, drugs known to prolong QT, cardiovascular This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 diseases, family history of QT prolongation). HALDOL INJECTION IS NOT APPROVED FOR INTRAVENOUS ADMINISTRATION. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. Usage in Pregnancy Rodents given 2 to 20 times the usual maximum human dose of haloperidol by oral or parenteral routes showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality. No teratogenic effect has been reported in rats, rabbits or dogs at dosages within this range, but cleft palate has been observed in mice given 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Combined Use of HALDOL and Lithium An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL. It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. HALDOL may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. PRECAUTIONS HALDOL (haloperidol) should be administered cautiously to patients: − with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL may block its vasopressor activity and paradoxical further lowering of the blood This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. − receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. − with known allergies, or with a history of allergic reactions to drugs. − receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). If concomitant antiparkinson medication is required, it may have to be continued after HALDOL is discontinued because of the difference in excretion rates. If both are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with HALDOL. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol. In a study of 12 schizophrenic patients coadministered haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Thus, careful monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol-treated patients. When HALDOL is used to control mania in cyclic disorders, there may be a rapid mood swing to depression. Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL. No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high-dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Pediatric Use Safety and effectiveness in pediatric patients 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 7 Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS: Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment, EPS can be categorized generally as Parkinson-like symptoms, akathisia or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs but until further evidence becomes available, it seems reasonable to gradually withdraw use of HALDOL. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Body as a Whole Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia, and hypoanatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reaction would be manifest by muscular weakness or rigidity and a generalized or localized tremor as demonstrated by the akinetic or agitans types respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsades de pointes should be considered. (For further information regarding torsades pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION There is considerable variation from patient to patient in the amount of medication required for treatment. As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient. Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control. To determine the initial dosage, consideration should be given to the patient’s age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state. Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less HALDOL (haloperidol). The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels. Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Switchover Procedure An oral form should supplant the injectable as soon as practicable. In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover. In this way, dosage adjustments, either upward or downward, can be quickly accomplished. Depending on the patient’s clinical status, the first oral dose should be given within 12-24 hours following the last parenteral dose. HOW SUPPLIED HALDOL® brand of haloperidol Injection (For Immediate Release) 5 mg per mL (as the lactate) – NDC 0045-0255-01, units of 10 x 1 mL ampuls. Store HALDOL® haloperidol Injection at controlled room temperature (15°-30°C, 59°-86°F). Protect from light. Do not freeze. Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium Distributed by: ORTHO-McNEIL PHARMACEUTICAL, INC. Raritan, New Jersey 08869 Revised May 2007 ©OMP 2005 US -XXXXXX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 HALDOL® Decanoate 50 (haloperidol) HALDOL® Decanoate 100 (haloperidol) For IM Injection Only Rx only DESCRIPTION Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL (haloperidol). It has a markedly extended duration of effect. It is available in sesame oil in sterile form for intramuscular (IM) injection. The structural formula of haloperidol decanoate, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate, is: Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in most organic solvents. Each mL of HALDOL Decanoate 50 for IM injection contains 50 mg haloperidol (present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. Each mL of HALDOL Decanoate 100 for IM injection contains 100 mg haloperidol (present as haloperidol decanoate 141.04 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. CLINICAL PHARMACOLOGY HALDOL Decanoate 50 and HALDOL Decanoate 100 are the long-acting forms of HALDOL (haloperidol). The basic effects of haloperidol decanoate are no different from those of HALDOL with the exception of duration of action. Haloperidol blocks the effects of dopamine and increases its turnover rate; however, the precise mechanism of action is unknown. Administration of haloperidol decanoate in sesame oil results in slow and sustained release of haloperidol. The plasma concentrations of haloperidol gradually rise, reaching a peak at about 6 days after the injection, and falling thereafter, with an apparent half-life of about 3 weeks. Steady state plasma concentrations are achieved after the third or fourth dose. The relationship between dose of haloperidol decanoate This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 and plasma haloperidol concentration is roughly linear for doses below 450 mg. It should be noted, however, that the pharmacokinetics of haloperidol decanoate following intramuscular injections can be quite variable between subjects. INDICATIONS AND USAGE HALDOL Decanoate 50 and HALDOL Decanoate 100 are indicated for the treatment of schizophrenic patients who require prolonged parenteral antipsychotic therapy. CONTRAINDICATIONS Since the pharmacologic and clinical actions of HALDOL Decanoate 50 and HALDOL Decanoate 100 are attributed to HALDOL (haloperidol) as the active medication, Contraindications, Warnings, and additional information are those of HALDOL, modified only to reflect the prolonged action. HALDOL is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Cardiovascular Effects Cases of sudden death have been reported in psychiatric patients receiving antipsychotic drugs, including HALDOL Decanoate. Since QT-prolongation has been observed during HALDOL Decanoate treatment, it is advised to be cautious in patients with QT-prolonging conditions (long QT- syndromes, hypokalaemia, electrolyte imbalance, drugs known to prolong QT, cardiovascular diseases, family history of QT prolongation). HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL (haloperidol). It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. PRECAUTIONS HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered cautiously to patients: − with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL (haloperidol) may block its vasopressor activity, and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. − receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. − with known allergies, or with a history of allergic reactions to drugs. − receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 If concomitant antiparkinson medication is required, it may have to be continued after HALDOL Decanoate 50 or HALDOL Decanoate 100 is discontinued because of the prolonged action of haloperidol decanoate. If both drugs are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with haloperidol decanoate. In patients with thyrotoxicosis who are also receiving antipsychotic medication, including haloperidol decanoate, severe neurotoxicity (rigidity, inability to walk or talk) may occur. When HALDOL is used to control mania in bipolar disorders, there may be a rapid mood swing to depression. Information for Patients Haloperidol decanoate may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. Drug Interactions An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol. In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with oral haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Thus, careful This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol-treated patients. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of short-acting haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high- dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Usage in Pregnancy Pregnancy Category C. Rodents given up to 3 times the usual maximum human dose of haloperidol decanoate showed an increase in incidence of resorption, fetal mortality, and pup mortality. No fetal abnormalities were observed. Cleft palate has been observed in mice given oral haloperidol at 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no adequate and well-controlled studies in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established with these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, haloperidol decanoate should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Nursing Mothers Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol decanoate. Pediatric Use Safety and effectiveness of haloperidol decanoate in children have not been established. Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS: Tardive dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Adverse reactions following the administration of HALDOL Decanoate 50 or HALDOL Decanoate 100 are those of HALDOL (haloperidol). Since vast experience This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 has accumulated with HALDOL, the adverse reactions are reported for that compound as well as for haloperidol decanoate. As with all injectable medications, local tissue reactions have been reported with haloperidol decanoate. Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. Although the long- acting properties of haloperidol decanoate provide gradual withdrawal, it is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy with haloperidol decanoate or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Body as a Whole Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5 1 /2 year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE While overdosage is less likely to occur with a parenteral than with an oral medication, information pertaining to HALDOL (haloperidol) is presented, modified only to reflect the extended duration of action of haloperidol decanoate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor, as demonstrated by the akinetic or agitans types, respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks, and then withdrawn gradually as extrapyramidal symptoms may emerge. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HALDOL Decanoate 50 and HALDOL Decanoate 100 are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate. Furthermore, it is recommended that patients being considered for haloperidol decanoate therapy have been treated with, and tolerate well, short-acting HALDOL (haloperidol) in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting forms of haloperidol. The dose of HALDOL Decanoate 50 or HALDOL Decanoate 100 should be expressed in terms of its haloperidol content. The starting dose of haloperidol decanoate should be based on the patient’s age, clinical history, physical condition, and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed. For patients previously maintained on low doses of antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate be 10-15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate. Initial Therapy Conversion from oral haloperidol to haloperidol decanoate can be achieved by using an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose in oral haloperidol equivalents. In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion. In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections. The initial dose of haloperidol decanoate should not exceed 100 mg regardless of previous antipsychotic dose requirements. If, therefore, conversion requires more than This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 100 mg of haloperidol decanoate as an initial dose, that dose should be administered in two injections, i.e. a maximum of 100 mg initially followed by the balance in 3 to 7 days. Maintenance Therapy The maintenance dosage of haloperidol decanoate must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient. Haldol Decanoate Dosing Recommendations Patients Monthly 1st Month Maintenance Stabilized on low daily oral doses (up to 10 mg/day) Elderly or Debilitated 10-15 x Daily Oral Dose 10-15 x Previous Daily Oral Dose High Dose Risk of relapse 20 x Daily Oral Dose 10-15 x Previous Daily Oral Dose Tolerant to oral haloperidol Close clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy. Haloperidol decanoate is usually administered monthly or every 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY). Clinical experience with haloperidol decanoate at doses greater than 450 mg per month has been limited. HOW SUPPLIED HALDOL® (haloperidol) Decanoate 50 for IM injection, 50 mg haloperidol as 70.5 mg per mL haloperidol decanoate—NDC 0045-0253, 10 x 1 mL ampuls and 3 x 1 mL ampuls. HALDOL® (haloperidol) Decanoate 100 for IM injection, 100 mg haloperidol as 141.04 mg per mL haloperidol decanoate—NDC 0045-0254, 5 x 1 mL ampuls. Store at controlled room temperature (15°-30° C, 59°-86° F). Do not refrigerate or freeze. Protect from light. Manufactured by: Janssen Pharmaceutica N.V. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Beerse, Belgium Distributed by: Ortho-McNeil Pharmaceutical, Inc. Raritan, NJ 08869 (ORTHO-McNEIL LOGO) Revised May 2007 ©OMP 2005 XXXXXX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:54.882721	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/015923s078,018701s053lbl.pdf', 'application_number': 15923, 'submission_type': 'SUPPL ', 'submission_number': 78}
10,860	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	2025-02-12T13:43:54.888085	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/15539s52lbl.pdf', 'application_number': 15539, 'submission_type': 'SUPPL ', 'submission_number': 52}
10,862	structural formula HALDOL® brand of haloperidol injection (For Immediate Release) WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol is the first of the butyrophenone series of major antipsychotics. The chemical designation is 4-[4-(p-chlorophenyl)-4-hydroxypiperidino] 4’-fluorobutyrophenone and it has the following structural formula: HALDOL (haloperidol) is available as a sterile parenteral form for intramuscular injection. The injection provides 5 mg haloperidol (as the lactate) and lactic acid for pH adjustment between 3.0 – 3.6. ACTIONS The precise mechanism of action has not been clearly established. INDICATIONS HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia. Reference ID: 2999248 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL is indicated for the control of tics and vocal utterances of Tourette’s Disorder. CONTRAINDICATIONS HALDOL (haloperidol) is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving HALDOL. Higher than recommended doses of any formulation and intravenous administration of HALDOL appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL INJECTION IS NOT APPROVED FOR INTRAVENOUS ADMINISTRATION. If HALDOL is administered intravenously, the ECG should be monitored for QT prolongation and arrhythmias. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. Reference ID: 2999248 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. Reference ID: 2999248 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. Usage in Pregnancy Rodents given 2 to 20 times the usual maximum human dose of haloperidol by oral or parenteral routes showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality. No teratogenic effect has been reported in rats, rabbits or dogs at dosages within this range, but cleft palate has been observed in mice given 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Non-teratogenic Effects Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have Reference ID: 2999248 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. HALDOL Decanoate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Combined Use of HALDOL and Lithium An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and fasting blood sugar) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL. It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. PRECAUTIONS Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including HALDOL. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of HALDOL should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Reference ID: 2999248 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue HALDOL and have their WBC followed until recovery. Other HALDOL (haloperidol) should be administered cautiously to patients: • with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL may block its vasopressor activity and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. • receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. • with known allergies, or with a history of allergic reactions to drugs. • receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). When HALDOL is used to control mania in cyclic disorders, there may be a rapid mood swing to depression. Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL. Drug Interactions Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using haloperidol in combination with other drugs have been evaluated as described below. Pharmacodynamic Interactions Since QT-prolongation has been observed during Haldol treatment, caution is advised when prescribing to patient with QT-prolongation conditions (long QT-syndrome, hypokalemia, electrolyte imbalance) or to patients receiving medications known to prolong the QT-interval or known to cause electrolyte imbalance. If concomitant antiparkinson medication is required, it may have to be continued after HALDOL is discontinued because of the difference in excretion rates. If both are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when Reference ID: 2999248 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda anticholinergic drugs, including antiparkinson agents, are administered concomitantly with HALDOL. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates and alcohol. Ketoconazole is a potent inhibitor of CYP3A4. Increases in QTc have been observed when haloperidol was given in combination with the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to reduce the haloperidol dosage. Pharmacokinetic Interactions The Effect of Other Drugs on Haldol® Haloperidol is metabolized by several routes, including the glucuronidation and the cytochrome P450 enzyme system. Inhibition of these routes of metabolism by another drug may result in increased haloperidol concentrations and potentially increase the risk of certain adverse events, including QT-prolongation. Drugs Characterized as Substrates, Inhibitors or Inducers of CYP3A4, CYP2D6 or Glucuronidation In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterized as substrates or inhibitors of CYP3A4 or CYP2D6 isoenzymes, such as, itraconazole, nefazodone, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine. When prolonged treatment (1-2 weeks) with enzyme-inducing drugs such as rifampin or carbamazepine is added to Haldol therapy, this results in a significant reduction of haloperidol plasma levels. Reference ID: 2999248 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rifampin In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Carbamazepine In a study in 11 schizophrenic patients co-administered haloperidol and increasing doses of carbamazepine, haloperidol plasma concentrations decreased linearly with increasing carbamazepine concentrations. Thus, careful monitoring of clinical status is warranted when enzyme inducing drugs such as rifampin or carbamazepine are administered or discontinued in haloperidol- treated patients. During combination treatment, the Haldol dose should be adjusted, when necessary. After discontinuation of such drugs, it may be necessary to reduce the dosage of Haldol. Valproate Sodium valproate, a drug know to inhibit glucuronidation, does not affect haloperidol plasma concentrations. Information for Patients HALDOL may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high- Reference ID: 2999248 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Nursing Mothers Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Reference ID: 2999248 9 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 haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Reference ID: 2999248 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs but until further evidence becomes available, it seems reasonable to gradually withdraw use of HALDOL. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Reference ID: 2999248 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Body as a Whole Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. (See PRECAUTIONS: Leukopenia, Neutropenia, and Agranulocytosis.) Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Reference ID: 2999248 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor as demonstrated by the akinetic or agitans types respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION There is considerable variation from patient to patient in the amount of medication required for treatment. As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient. Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control. Reference ID: 2999248 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To determine the initial dosage, consideration should be given to the patient’s age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state. Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less HALDOL (haloperidol). The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels. Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Switchover Procedure An oral form should supplant the injectable as soon as practicable. In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover. In this way, dosage adjustments, either upward or downward, can be quickly accomplished. Depending on the patient’s clinical status, the first oral dose should be given within 12-24 hours following the last parenteral dose. Reference ID: 2999248 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INSTRUCTIONS FOR OPENING AMPULE Step usage illustration1 1. Medication often rests in the top part of the ampule. Before breaking the ampule, lightly tap the top of the ampule with your finger until all fluid moves to the bottom portion of the ampule. The ampule has a colored ring(s) and colored point which aids in the placement of fingers while breaking the ampule. Step 2 2. Hold the ampule between thumb and index finger with the colored point facing you. usage illustration Step 3 3. Position the index finger of the other hand to support the neck of the ampule. Position the thumb so that it covers the colored point and is parallel to the colored ring(s). usage illustration Reference ID: 2999248 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Step 4 4. Keeping the thumb on the colored point and with the index fingers close together, apply firm pressure on the colored point in the direction of the arrow to snap the ampule open. usage illustration HOW SUPPLIED HALDOL® brand of haloperidol Injection (For Immediate Release) 5 mg per mL (as the lactate) – NDC 50458-255-01, units of 10 x 1 mL ampules. Store HALDOL® haloperidol Injection at controlled room temperature (15°-30°C, 59°-86°F). Protect from light. Do not freeze. Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium Manufactured for: Ortho-McNeil Neurologics, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Revised June 2011 ©Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2005 Reference ID: 2999248 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:54.952434	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/015923s079lbl.pdf', 'application_number': 15923, 'submission_type': 'SUPPL ', 'submission_number': 79}
10,866	HALDOL brand of haloperidol injection (For Immediate Release) WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol is the first of the butyrophenone series of major antipsychotics. The chemical designation is 4-[4-(p-chlorophenyl)-4-hydroxypiperidino] 4’-fluorobutyrophenone and it has the following structural formula: structural formula HALDOL (haloperidol) is available as a sterile parenteral form for intramuscular injection. The injection provides 5 mg haloperidol (as the lactate) and lactic acid for pH adjustment between 3.0 – 3.6. ACTIONS The precise mechanism of action has not been clearly established. INDICATIONS HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia. Reference ID: 3763663 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL is indicated for the control of tics and vocal utterances of Tourette’s Disorder. CONTRAINDICATIONS HALDOL (haloperidol) is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving HALDOL. Higher than recommended doses of any formulation and intravenous administration of HALDOL appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL INJECTION IS NOT APPROVED FOR INTRAVENOUS ADMINISTRATION. If HALDOL is administered intravenously, the ECG should be monitored for QT prolongation and arrhythmias. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. Reference ID: 3763663 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. Reference ID: 3763663 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. Usage in Pregnancy Rodents given 2 to 20 times the usual maximum human dose of haloperidol by oral or parenteral routes showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality. No teratogenic effect has been reported in rats, rabbits or dogs at dosages within this range, but cleft palate has been observed in mice given 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Non-teratogenic Effects Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have Reference ID: 3763663 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. HALDOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Combined Use of HALDOL and Lithium An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and fasting blood sugar) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL. It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. PRECAUTIONS Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including HALDOL. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of HALDOL should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Reference ID: 3763663 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue HALDOL and have their WBC followed until recovery. Other HALDOL (haloperidol) should be administered cautiously to patients: • with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL may block its vasopressor activity and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. • receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. • with known allergies, or with a history of allergic reactions to drugs. • receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). When HALDOL is used to control mania in cyclic disorders, there may be a rapid mood swing to depression. Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL. Drug Interactions Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using haloperidol in combination with other drugs have been evaluated as described below. Pharmacodynamic Interactions Since QT-prolongation has been observed during Haldol treatment, caution is advised when prescribing to a patient with QT-prolongation conditions (long QT-syndrome, hypokalemia, electrolyte imbalance) or to patients receiving medications known to prolong the QT-interval or known to cause electrolyte imbalance. If concomitant antiparkinson medication is required, it may have to be continued after HALDOL is discontinued because of the difference in excretion rates. If both are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when Reference ID: 3763663 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda anticholinergic drugs, including antiparkinson agents, are administered concomitantly with HALDOL. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates and alcohol. Ketoconazole is a potent inhibitor of CYP3A4. Increases in QTc have been observed when haloperidol was given in combination with the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to reduce the haloperidol dosage. Pharmacokinetic Interactions The Effect of Other Drugs on Haldol® Haloperidol is metabolized by several routes, including the glucuronidation and the cytochrome P450 enzyme system. Inhibition of these routes of metabolism by another drug may result in increased haloperidol concentrations and potentially increase the risk of certain adverse events, including QT-prolongation. Drugs Characterized as Substrates, Inhibitors or Inducers of CYP3A4, CYP2D6 or Glucuronidation In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterized as substrates or inhibitors of CYP3A4 or CYP2D6 isoenzymes, such as itraconazole, nefazodone, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine. When prolonged treatment (1-2 weeks) with enzyme-inducing drugs such as rifampin or carbamazepine is added to Haldol therapy, this results in a significant reduction of haloperidol plasma levels. Rifampin In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Carbamazepine In a study in 11 schizophrenic patients co-administered haloperidol and increasing doses of carbamazepine, haloperidol plasma concentrations decreased linearly with increasing carbamazepine concentrations. Reference ID: 3763663 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thus, careful monitoring of clinical status is warranted when enzyme inducing drugs such as rifampin or carbamazepine are administered or discontinued in haloperidol treated patients. During combination treatment, the Haldol dose should be adjusted, when necessary. After discontinuation of such drugs, it may be necessary to reduce the dosage of Haldol. Valproate Sodium valproate, a drug know to inhibit glucuronidation, does not affect haloperidol plasma concentrations. Information for Patients HALDOL may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high- dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically Reference ID: 3763663 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Nursing Mothers Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). Reference ID: 3763663 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance Reference ID: 3763663 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs but until further evidence becomes available, it seems reasonable to gradually withdraw use of HALDOL. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Reference ID: 3763663 11 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 Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. (See PRECAUTIONS: Leukopenia, Neutropenia, and Agranulocytosis.) Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would Reference ID: 3763663 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor as demonstrated by the akinetic or agitans types respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION There is considerable variation from patient to patient in the amount of medication required for treatment. As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient. Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control. To determine the initial dosage, consideration should be given to the patient’s age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state. Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less HALDOL (haloperidol). The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels. Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, Reference ID: 3763663 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. The maximum dose is 20 mg/day. Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Switchover Procedure An oral form should supplant the injectable as soon as practicable. In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover. In this way, dosage adjustments, either upward or downward, can be quickly accomplished. Depending on the patient’s clinical status, the first oral dose should be given within 12-24 hours following the last parenteral dose. Reference ID: 3763663 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INSTRUCTIONS FOR OPENING AMPULE Step 1 1. Medication often rests in the top part of the ampule. Before breaking the ampule, lightly tap the top of the ampule with your finger until all fluid moves to the bottom portion of the ampule. The ampule has a colored ring(s) and colored point which aids in the placement of fingers while breaking the ampule. usage illustration Step 2 2. Hold the ampule between thumb and index finger with the colored point facing you. usage illustration Step 3 3. Position the index finger of the other hand to support the neck of the ampule. Position the thumb so that it covers the colored point and is parallel to the colored ring(s). usage illustration Reference ID: 3763663 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Step 4 4. Keeping the thumb on the colored point and with the index fingers close together, apply firm pressure on the colored point in the direction of the arrow to snap the ampule open. usage illustration HOW SUPPLIED HALDOL brand of haloperidol Injection (For Immediate Release) 5 mg per mL (as the lactate) – NDC 50458-255-01, units of 10 x 1 mL ampules. Store HALDOL haloperidol Injection at controlled room temperature (15°-30°C, 59°-86°F). Protect from light. Do not freeze. Product of Belgium Manufactured by: GlaxoSmithKline Manufacturing S.p.A. Parma, Italy Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Revised xxx xxxx Janssen Pharmaceuticals, Inc. 2005 Reference ID: 3763663 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:55.957400	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/015923s091lbl.pdf', 'application_number': 15923, 'submission_type': 'SUPPL ', 'submission_number': 91}
10,863	HALDOL® brand of haloperidol injection (For Immediate Release) WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol is the first of the butyrophenone series of major antipsychotics. The chemical designation is 4-[4-(p-chlorophenyl)-4-hydroxypiperidino] 4’-fluorobutyrophenone and it has the following structural formula: Chemical Structure HALDOL (haloperidol) is available as a sterile parenteral form for intramuscular injection. The injection provides 5 mg haloperidol (as the lactate) and lactic acid for pH adjustment between 3.0 – 3.6. ACTIONS The precise mechanism of action has not been clearly established. INDICATIONS HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL is indicated for the control of tics and vocal utterances of Tourette’s Disorder. CONTRAINDICATIONS HALDOL (haloperidol) is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving HALDOL. Higher than recommended doses of any formulation and intravenous administration of HALDOL appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL INJECTION IS NOT APPROVED FOR INTRAVENOUS ADMINISTRATION. If HALDOL is administered intravenously, the ECG should be monitored for QT prolongation and arrhythmias. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. Usage in Pregnancy Rodents given 2 to 20 times the usual maximum human dose of haloperidol by oral or parenteral routes showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality. No teratogenic effect has been reported in rats, rabbits or dogs at dosages within this range, but cleft palate has been observed in mice given 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Combined Use of HALDOL and Lithium An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL. It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. HALDOL may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. PRECAUTIONS HALDOL (haloperidol) should be administered cautiously to patients: − with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL may block its vasopressor activity and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. − receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. − with known allergies, or with a history of allergic reactions to drugs. − receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). If concomitant antiparkinson medication is required, it may have to be continued after HALDOL is discontinued because of the difference in excretion rates. If both are discontinued simultaneously, extrapyramidal symptoms may occur. The physician 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with HALDOL. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol. In a study of 12 schizophrenic patients coadministered haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Thus, careful monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol-treated patients. When HALDOL is used to control mania in cyclic disorders, there may be a rapid mood swing to depression. Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL. No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high- dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs but until further evidence becomes available, it seems reasonable to gradually withdraw use of HALDOL. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. 9 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 Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reaction would be manifest by muscular weakness or rigidity and a generalized or localized tremor as demonstrated by the akinetic or agitans types respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION There is considerable variation from patient to patient in the amount of medication required for treatment. As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient. Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control. To determine the initial dosage, consideration should be given to the patient’s age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state. Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less HALDOL (haloperidol). The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels. Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Switchover Procedure An oral form should supplant the injectable as soon as practicable. In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover. In this way, dosage adjustments, either upward or downward, can be quickly accomplished. Depending on the patient’s clinical status, the first oral dose should be given within 12-24 hours following the last parenteral dose. HOW SUPPLIED HALDOL® brand of haloperidol Injection (For Immediate Release) 5 mg per mL (as the lactate) – NDC 0045-0255-01, units of 10 x 1 mL ampuls. Store HALDOL® haloperidol Injection at controlled room temperature (15°-30°C, 59°-86°F). Protect from light. Do not freeze. Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium Distributed by: Ortho McNeil Pharmaceutical, Inc. Raritan, NJ 08869 Revised Month/Year ©OMP 2005 US-XXXXXX 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL® Decanoate 50 (haloperidol) HALDOL® Decanoate 100 (haloperidol) For IM Injection Only WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Decanoate is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL (haloperidol). It has a markedly extended duration of effect. It is available in sesame oil in sterile form for intramuscular (IM) injection. The structural formula of haloperidol decanoate, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate, is: Chemical Structure Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in most organic solvents. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Each mL of HALDOL Decanoate 50 for IM injection contains 50 mg haloperidol (present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. Each mL of HALDOL Decanoate 100 for IM injection contains 100 mg haloperidol (present as haloperidol decanoate 141.04 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. CLINICAL PHARMACOLOGY HALDOL Decanoate 50 and HALDOL Decanoate 100 are the long-acting forms of HALDOL (haloperidol). The basic effects of haloperidol decanoate are no different from those of HALDOL with the exception of duration of action. Haloperidol blocks the effects of dopamine and increases its turnover rate; however, the precise mechanism of action is unknown. Administration of haloperidol decanoate in sesame oil results in slow and sustained release of haloperidol. The plasma concentrations of haloperidol gradually rise, reaching a peak at about 6 days after the injection, and falling thereafter, with an apparent half-life of about 3 weeks. Steady state plasma concentrations are achieved after the third or fourth dose. The relationship between dose of haloperidol decanoate and plasma haloperidol concentration is roughly linear for doses below 450 mg. It should be noted, however, that the pharmacokinetics of haloperidol decanoate following intramuscular injections can be quite variable between subjects. INDICATIONS AND USAGE HALDOL Decanoate 50 and HALDOL Decanoate 100 are indicated for the treatment of schizophrenic patients who require prolonged parenteral antipsychotic therapy. CONTRAINDICATIONS Since the pharmacologic and clinical actions of HALDOL Decanoate 50 and HALDOL Decanoate 100 are attributed to HALDOL (haloperidol) as the active medication, Contraindications, Warnings, and additional information are those of HALDOL, modified only to reflect the prolonged action. HALDOL is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Decanoate is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL (haloperidol). It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. PRECAUTIONS HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered cautiously to patients: − with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL (haloperidol) may block its vasopressor activity, and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. − receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. − with known allergies, or with a history of allergic reactions to drugs. − receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). If concomitant antiparkinson medication is required, it may have to be continued after HALDOL Decanoate 50 or HALDOL Decanoate 100 is discontinued because of the prolonged action of haloperidol decanoate. If both drugs are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with haloperidol decanoate. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with thyrotoxicosis who are also receiving antipsychotic medication, including haloperidol decanoate, severe neurotoxicity (rigidity, inability to walk or talk) may occur. When HALDOL is used to control mania in bipolar disorders, there may be a rapid mood swing to depression. Information for Patients Haloperidol decanoate may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. Drug Interactions An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol. In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with oral haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Thus, careful monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol-treated patients. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of short-acting haloperidol on 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high-dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. Usage in Pregnancy Pregnancy Category C. Rodents given up to 3 times the usual maximum human dose of haloperidol decanoate showed an increase in incidence of resorption, fetal mortality, and pup mortality. No fetal abnormalities were observed. Cleft palate has been observed in mice given oral haloperidol at 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no adequate and well-controlled studies in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established with these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, haloperidol decanoate should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Nursing Mothers Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol decanoate. Pediatric Use Safety and effectiveness of haloperidol decanoate in children have not been established. Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Adverse reactions following the administration of HALDOL Decanoate 50 or HALDOL Decanoate 100 are those of HALDOL (haloperidol). Since vast experience has accumulated with HALDOL, the adverse reactions are reported for that compound as well as for haloperidol decanoate. As with all injectable medications, local tissue reactions have been reported with haloperidol decanoate. Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. Although the long 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda acting properties of haloperidol decanoate provide gradual withdrawal, it is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy with haloperidol decanoate or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Body as a Whole Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5 1 /2 year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE While overdosage is less likely to occur with a parenteral than with an oral medication, information pertaining to HALDOL (haloperidol) is presented, modified only to reflect the extended duration of action of haloperidol decanoate. Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor, as demonstrated by the akinetic or agitans types, respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks, and then withdrawn gradually as extrapyramidal symptoms may emerge. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HALDOL Decanoate 50 and HALDOL Decanoate 100 are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate. Furthermore, it is recommended that patients being considered for haloperidol decanoate therapy have been treated 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with, and tolerate well, short-acting HALDOL (haloperidol) in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting forms of haloperidol. The dose of HALDOL Decanoate 50 or HALDOL Decanoate 100 should be expressed in terms of its haloperidol content. The starting dose of haloperidol decanoate should be based on the patient’s age, clinical history, physical condition, and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed. For patients previously maintained on low doses of antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate be 10-15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate. Initial Therapy Conversion from oral haloperidol to haloperidol decanoate can be achieved by using an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose in oral haloperidol equivalents. In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion. In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections. The initial dose of haloperidol decanoate should not exceed 100 mg regardless of previous antipsychotic dose requirements. If, therefore, conversion requires more than 100 mg of haloperidol decanoate as an initial dose, that dose should be administered in two injections, i.e. a maximum of 100 mg initially followed by the balance in 3 to 7 days. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Maintenance Therapy The maintenance dosage of haloperidol decanoate must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient. HALDOL DECANOATE DOSING RECOMMENDATIONS Monthly Patients 1st Month Maintenance Stabilized on low daily oral doses 10-15 x Daily Oral Dose 10-15 x Previous Daily Oral Dose (up to 10 mg/day) Elderly or Debilitated High Dose 20 x Daily Oral Dose 10-15 x Previous Daily Oral Dose Risk of relapse Tolerant to oral haloperidol Close clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy. Haloperidol decanoate is usually administered monthly or every 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY). Clinical experience with haloperidol decanoate at doses greater than 450 mg per month has been limited. HOW SUPPLIED HALDOL® (haloperidol) Decanoate 50 for IM injection, 50 mg haloperidol as 70.52 mg per mL haloperidol decanoate—NDC 0045-0253, 10 x 1 mL ampuls and 3 x 1 mL ampuls. HALDOL® (haloperidol) Decanoate 100 for IM injection, 100 mg haloperidol as 141.04 mg per mL haloperidol decanoate—NDC 0045-0254, 5 x 1 mL ampuls. Store at controlled room temperature (15°-30° C, 59°-86° F). Do not refrigerate or freeze. Protect from light. Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distributed by: Ortho-McNeil Pharmaceutical, Inc. Raritan, NJ 08869 (ORTHO-McNEIL LOGO) Revised Month/Year ©OMP 2005 US-XXXXXX 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:55.959857	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/015923s082,018701s057lbl.pdf', 'application_number': 15923, 'submission_type': 'SUPPL ', 'submission_number': 82}
10,864	HALDOL® brand of haloperidol injection (For Immediate Release) WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol is the first of the butyrophenone series of major antipsychotics. The chemical designation is 4-[4-(p-chlorophenyl)-4-hydroxypiperidino] 4’-fluorobutyrophenone and it has the following structural formula: Structural Formula HALDOL (haloperidol) is available as a sterile parenteral form for intramuscular injection. The injection provides 5 mg haloperidol (as the lactate) and lactic acid for pH adjustment between 3.0 – 3.6. ACTIONS The precise mechanism of action has not been clearly established. INDICATIONS HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL is indicated for the control of tics and vocal utterances of Tourette’s Disorder. CONTRAINDICATIONS HALDOL (haloperidol) is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving HALDOL. Higher than recommended doses of any formulation and intravenous administration of HALDOL appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL INJECTION IS NOT APPROVED FOR INTRAVENOUS ADMINISTRATION. If HALDOL is administered intravenously, the ECG should be monitored for QT prolongation and arrhythmias. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. Usage in Pregnancy Rodents given 2 to 20 times the usual maximum human dose of haloperidol by oral or parenteral routes showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality. No teratogenic effect has been reported in rats, rabbits or dogs at dosages within this range, but cleft palate has been observed in mice given 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Combined Use of HALDOL and Lithium An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL. It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. HALDOL may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. PRECAUTIONS Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including HALDOL. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of HALDOL should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue HALDOL and have their WBC followed until recovery. Other HALDOL (haloperidol) should be administered cautiously to patients: 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda − with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL may block its vasopressor activity and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. − receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. − with known allergies, or with a history of allergic reactions to drugs. − receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). If concomitant antiparkinson medication is required, it may have to be continued after HALDOL is discontinued because of the difference in excretion rates. If both are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with HALDOL. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol. In a study of 12 schizophrenic patients coadministered haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Thus, careful monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol-treated patients. When HALDOL is used to control mania in cyclic disorders, there may be a rapid mood swing to depression. Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL. No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of haloperidol on chromosome structure and 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high- dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. 7 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 in pediatric patients have not been established. Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs but until further evidence becomes available, it seems reasonable to gradually withdraw use of HALDOL. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Body as a Whole Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reaction would be manifest by muscular weakness or rigidity and a generalized or localized tremor as demonstrated by the akinetic or agitans types respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION There is considerable variation from patient to patient in the amount of medication required for treatment. As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient. Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To determine the initial dosage, consideration should be given to the patient’s age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state. Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less HALDOL (haloperidol). The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels. Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Switchover Procedure An oral form should supplant the injectable as soon as practicable. In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover. In this way, dosage adjustments, either upward or downward, can be quickly accomplished. Depending on the patient’s clinical status, the first oral dose should be given within 12-24 hours following the last parenteral dose. HOW SUPPLIED HALDOL® brand of haloperidol Injection (For Immediate Release) 5 mg per mL (as the lactate) – NDC 0045-0255-01, units of 10 x 1 mL ampuls. Store HALDOL® haloperidol Injection at controlled room temperature (15°-30°C, 59°-86°F). Protect from light. Do not freeze. Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distributed by: Ortho-McNeil Pharmaceutical, Inc. Raritan, NJ 08869 Revised June 2009 ©OMP 2005 US-XXXXXX 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL® Decanoate 50 (haloperidol) HALDOL® Decanoate 100 (haloperidol) For IM Injection Only WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Decanoate is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL (haloperidol). It has a markedly extended duration of effect. It is available in sesame oil in sterile form for intramuscular (IM) injection. The structural formula of haloperidol decanoate, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate, is: Structural formula Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in most organic solvents. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Each mL of HALDOL Decanoate 50 for IM injection contains 50 mg haloperidol (present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. Each mL of HALDOL Decanoate 100 for IM injection contains 100 mg haloperidol (present as haloperidol decanoate 141.04 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. CLINICAL PHARMACOLOGY HALDOL Decanoate 50 and HALDOL Decanoate 100 are the long-acting forms of HALDOL (haloperidol). The basic effects of haloperidol decanoate are no different from those of HALDOL with the exception of duration of action. Haloperidol blocks the effects of dopamine and increases its turnover rate; however, the precise mechanism of action is unknown. Administration of haloperidol decanoate in sesame oil results in slow and sustained release of haloperidol. The plasma concentrations of haloperidol gradually rise, reaching a peak at about 6 days after the injection, and falling thereafter, with an apparent half-life of about 3 weeks. Steady state plasma concentrations are achieved after the third or fourth dose. The relationship between dose of haloperidol decanoate and plasma haloperidol concentration is roughly linear for doses below 450 mg. It should be noted, however, that the pharmacokinetics of haloperidol decanoate following intramuscular injections can be quite variable between subjects. INDICATIONS AND USAGE HALDOL Decanoate 50 and HALDOL Decanoate 100 are indicated for the treatment of schizophrenic patients who require prolonged parenteral antipsychotic therapy. CONTRAINDICATIONS Since the pharmacologic and clinical actions of HALDOL Decanoate 50 and HALDOL Decanoate 100 are attributed to HALDOL (haloperidol) as the active medication, Contraindications, Warnings, and additional information are those of HALDOL, modified only to reflect the prolonged action. HALDOL is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Decanoate is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL (haloperidol). It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. PRECAUTIONS Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including HALDOL Decanoate. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of HALDOL Decanoate should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue HALDOL Decanoate and have their WBC followed until recovery. Other HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered cautiously to patients: 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda − with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL (haloperidol) may block its vasopressor activity, and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. − receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. − with known allergies, or with a history of allergic reactions to drugs. − receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). If concomitant antiparkinson medication is required, it may have to be continued after HALDOL Decanoate 50 or HALDOL Decanoate 100 is discontinued because of the prolonged action of haloperidol decanoate. If both drugs are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with haloperidol decanoate. In patients with thyrotoxicosis who are also receiving antipsychotic medication, including haloperidol decanoate, severe neurotoxicity (rigidity, inability to walk or talk) may occur. When HALDOL is used to control mania in bipolar disorders, there may be a rapid mood swing to depression. Information for Patients Haloperidol decanoate may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. Drug Interactions An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol. In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with oral haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Thus, careful monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol-treated patients. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of short-acting haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high-dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. Usage in Pregnancy Pregnancy Category C. Rodents given up to 3 times the usual maximum human dose of haloperidol decanoate showed an increase in incidence of resorption, fetal mortality, and pup mortality. No fetal abnormalities were observed. Cleft palate has been observed in mice given oral haloperidol at 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no adequate and well-controlled studies in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established with these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, haloperidol decanoate should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Nursing Mothers Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol decanoate. Pediatric Use Safety and effectiveness of haloperidol decanoate in children have not been established. 8 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 haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Adverse reactions following the administration of HALDOL Decanoate 50 or HALDOL Decanoate 100 are those of HALDOL (haloperidol). Since vast experience has accumulated with HALDOL, the adverse reactions are reported for that compound as well as for haloperidol decanoate. As with all injectable medications, local tissue reactions have been reported with haloperidol decanoate. Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. Although the long- acting properties of haloperidol decanoate provide gradual withdrawal, it is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy with haloperidol decanoate or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Body as a Whole Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5 1 /2 year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE While overdosage is less likely to occur with a parenteral than with an oral medication, information pertaining to HALDOL (haloperidol) is presented, modified only to reflect the extended duration of action of haloperidol decanoate. Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor, as demonstrated by the akinetic or agitans types, respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks, and then withdrawn gradually as extrapyramidal symptoms may emerge. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HALDOL Decanoate 50 and HALDOL Decanoate 100 are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate. Furthermore, it is recommended that patients being considered for haloperidol decanoate therapy have been treated with, and tolerate well, short-acting HALDOL (haloperidol) in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting forms of haloperidol. The dose of HALDOL Decanoate 50 or HALDOL Decanoate 100 should be expressed in terms of its haloperidol content. The starting dose of haloperidol decanoate should be based on the patient’s age, clinical history, physical condition, and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed. For patients previously maintained on low doses of antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate be 10-15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Initial Therapy Conversion from oral haloperidol to haloperidol decanoate can be achieved by using an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose in oral haloperidol equivalents. In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion. In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections. The initial dose of haloperidol decanoate should not exceed 100 mg regardless of previous antipsychotic dose requirements. If, therefore, conversion requires more than 100 mg of haloperidol decanoate as an initial dose, that dose should be administered in two injections, i.e. a maximum of 100 mg initially followed by the balance in 3 to 7 days. Maintenance Therapy The maintenance dosage of haloperidol decanoate must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient. HALDOL DECANOATE DOSING RECOMMENDATIONS Monthly Patients 1st Month Maintenance Stabilized on low daily oral doses 10-15 x Daily Oral Dose 10-15 x Previous Daily Oral Dose (up to 10 mg/day) Elderly or Debilitated High dose 20 x Daily Oral Dose 10-15 x Previous Daily Oral Dose Risk of relapse Tolerant to oral haloperidol Close clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy. Haloperidol decanoate is usually administered monthly or every 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY). 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical experience with haloperidol decanoate at doses greater than 450 mg per month has been limited. HOW SUPPLIED HALDOL® (haloperidol) Decanoate 50 for IM injection, 50 mg haloperidol as 70.52 mg per mL haloperidol decanoate—NDC 0045-0253, 10 x 1 mL ampuls and 3 x 1 mL ampuls. HALDOL® (haloperidol) Decanoate 100 for IM injection, 100 mg haloperidol as 141.04 mg per mL haloperidol decanoate—NDC 0045-0254, 5 x 1 mL ampuls. Store at controlled room temperature (15°-30° C, 59°-86° F). Do not refrigerate or freeze. Protect from light. Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium Distributed by: Ortho-McNeil Pharmaceutical, Inc. Raritan, NJ 08869 (ORTHO-McNEIL LOGO) Revised June 2009 ©OMP 2005 US-XXXXXX 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:55.992630	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/015923s084lbl.pdf', 'application_number': 15923, 'submission_type': 'SUPPL ', 'submission_number': 84}
10,865	structural formula HALDOL® BRAND OF HALOPERIDOL INJECTION (FOR IMMEDIATE RELEASE) WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol is the first of the butyrophenone series of major antipsychotics. The chemical designation is 4-[4-(p-chlorophenyl)-4-hydroxypiperidino] 4’-fluorobutyrophenone and it has the following structural formula: HALDOL (haloperidol) is available as a sterile parenteral form for intramuscular injection. The injection provides 5 mg haloperidol (as the lactate) and lactic acid for pH adjustment between 3.0 – 3.6. ACTIONS The precise mechanism of action has not been clearly established. INDICATIONS HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia. Reference ID: 2911916 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL is indicated for the control of tics and vocal utterances of Tourette’s Disorder. CONTRAINDICATIONS HALDOL (haloperidol) is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving HALDOL. Higher than recommended doses of any formulation and intravenous administration of HALDOL appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL INJECTION IS NOT APPROVED FOR INTRAVENOUS ADMINISTRATION. If HALDOL is administered intravenously, the ECG should be monitored for QT prolongation and arrhythmias. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, Reference ID: 2911916 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. Reference ID: 2911916 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. Usage in Pregnancy Rodents given 2 to 20 times the usual maximum human dose of haloperidol by oral or parenteral routes showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality. No teratogenic effect has been reported in rats, rabbits or dogs at dosages within this range, but cleft palate has been observed in mice given 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Non-teratogenic Effects Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support Reference ID: 2911916 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and prolonged hospitalization. HALDOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Combined Use of HALDOL and Lithium An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL. It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. HALDOL may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. PRECAUTIONS Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including HALDOL. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced Reference ID: 2911916 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of HALDOL should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue HALDOL and have their WBC followed until recovery. Other HALDOL (haloperidol) should be administered cautiously to patients: − with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL may block its vasopressor activity and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. − receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. − with known allergies, or with a history of allergic reactions to drugs. − receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). If concomitant antiparkinson medication is required, it may have to be continued after HALDOL is discontinued because of the difference in excretion rates. If both are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with HALDOL. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol. In a study of 12 schizophrenic patients coadministered haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic Reference ID: 2911916 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients treated with haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Thus, careful monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol-treated patients. When HALDOL is used to control mania in cyclic disorders, there may be a rapid mood swing to depression. Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL. No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high- dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An Reference ID: 2911916 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in Reference ID: 2911916 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs but until further evidence becomes available, it seems reasonable to gradually withdraw use of HALDOL. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms Reference ID: 2911916 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Body as a Whole Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. Liver Effects Impaired liver function and/or jaundice have been reported. Reference ID: 2911916 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reaction would be manifest by muscular weakness or rigidity and a generalized or localized tremor as demonstrated by the akinetic or agitans types respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and Reference ID: 2911916 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION There is considerable variation from patient to patient in the amount of medication required for treatment. As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient. Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control. To determine the initial dosage, consideration should be given to the patient’s age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state. Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less HALDOL (haloperidol). The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels. Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Switchover Procedure An oral form should supplant the injectable as soon as practicable. In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the Reference ID: 2911916 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda initiation of switchover. In this way, dosage adjustments, either upward or downward, can be quickly accomplished. Depending on the patient’s clinical status, the first oral dose should be given within 12-24 hours following the last parenteral dose. Instructions for Opening Ampule Step 1 1. Medication often rests in the top part of the ampule. Before breaking the ampule, lightly tap the top of the ampule with your finger until all fluid moves to the bottom portion of the ampule. The ampule has a colored ring(s) and colored point which aids in the placement of fingers while breaking the ampule. Step 2 2. Hold the ampule between thumb and index finger with the colored point facing you. usage illustrationusage illustration Step 3 3. Position the index finger of the other hand to support the neck of the ampule. Position the thumb so that it covers the colored point and is parallel to the colored ring(s). Reference ID: 2911916 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration Step 4 4. Keeping the thumb on the colored point and with the index fingers close together, apply firm pressure on the colored point in the direction of the arrow to snap the ampule open. usage illustration HOW SUPPLIED HALDOL® brand of haloperidol Injection (For Immediate Release) 5 mg per mL (as the lactate) – NDC50458-255-01, units of 10 x 1 mL ampuls. Store HALDOL® haloperidol Injection at controlled room temperature (15°-30°C, 59°-86°F). Protect from light. Do not freeze. Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium Manufactured for: Ortho-McNeil Neurologics, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Revised February 2011 ©Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2005 980395 Reference ID: 2911916 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula HALDOL® DECANOATE 50 (haloperidol) HALDOL® DECANOATE 100 (haloperidol) for IM Injection only WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Decanoate is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL (haloperidol). It has a markedly extended duration of effect. It is available in sesame oil in sterile form for intramuscular (IM) injection. The structural formula of haloperidol decanoate, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate, is: Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in most organic solvents. Each mL of HALDOL Decanoate 50 for IM injection contains 50 mg haloperidol (present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. Reference ID: 2911916 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Each mL of HALDOL Decanoate 100 for IM injection contains 100 mg haloperidol (present as haloperidol decanoate 141.04 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. CLINICAL PHARMACOLOGY HALDOL Decanoate 50 and HALDOL Decanoate 100 are the long-acting forms of HALDOL (haloperidol). The basic effects of haloperidol decanoate are no different from those of HALDOL with the exception of duration of action. Haloperidol blocks the effects of dopamine and increases its turnover rate; however, the precise mechanism of action is unknown. Administration of haloperidol decanoate in sesame oil results in slow and sustained release of haloperidol. The plasma concentrations of haloperidol gradually rise, reaching a peak at about 6 days after the injection, and falling thereafter, with an apparent half-life of about 3 weeks. Steady state plasma concentrations are achieved after the third or fourth dose. The relationship between dose of haloperidol decanoate and plasma haloperidol concentration is roughly linear for doses below 450 mg. It should be noted, however, that the pharmacokinetics of haloperidol decanoate following intramuscular injections can be quite variable between subjects. INDICATIONS AND USAGE HALDOL Decanoate 50 and HALDOL Decanoate 100 are indicated for the treatment of schizophrenic patients who require prolonged parenteral antipsychotic therapy. CONTRAINDICATIONS Since the pharmacologic and clinical actions of HALDOL Decanoate 50 and HALDOL Decanoate 100 are attributed to HALDOL (haloperidol) as the active medication, Contraindications, Warnings, and additional information are those of HALDOL, modified only to reflect the prolonged action. HALDOL is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Decanoate is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Reference ID: 2911916 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the Reference ID: 2911916 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. Reference ID: 2911916 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL (haloperidol). It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. PRECAUTIONS Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including HALDOL Decanoate. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of HALDOL Decanoate should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue HALDOL Decanoate and have their WBC followed until recovery. Other HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered cautiously to patients: − with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL (haloperidol) may block its vasopressor activity, and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. Reference ID: 2911916 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda − receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. − with known allergies, or with a history of allergic reactions to drugs. − receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). If concomitant antiparkinson medication is required, it may have to be continued after HALDOL Decanoate 50 or HALDOL Decanoate 100 is discontinued because of the prolonged action of haloperidol decanoate. If both drugs are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with haloperidol decanoate. In patients with thyrotoxicosis who are also receiving antipsychotic medication, including haloperidol decanoate, severe neurotoxicity (rigidity, inability to walk or talk) may occur. When HALDOL is used to control mania in bipolar disorders, there may be a rapid mood swing to depression. Information for Patients Haloperidol decanoate may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. Drug Interactions An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol. Reference ID: 2911916 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with oral haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Thus, careful monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol-treated patients. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of short-acting haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high-dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. Reference ID: 2911916 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. Usage in Pregnancy Pregnancy Category C. Rodents given up to 3 times the usual maximum human dose of haloperidol decanoate showed an increase in incidence of resorption, fetal mortality, and pup mortality. No fetal abnormalities were observed. Cleft palate has been observed in mice given oral haloperidol at 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no adequate and well-controlled studies in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established with these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, haloperidol decanoate should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Non-teratogenic Effects Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. HALDOL Decanoate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reference ID: 2911916 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol decanoate. Pediatric Use Safety and effectiveness of haloperidol decanoate in children have not been established. Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Adverse reactions following the administration of HALDOL Decanoate 50 or HALDOL Decanoate 100 are those of HALDOL (haloperidol). Since vast experience has accumulated with HALDOL, the adverse reactions are reported for that compound as well as for haloperidol decanoate. As with all injectable medications, local tissue reactions have been reported with haloperidol decanoate. Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. Reference ID: 2911916 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. Although the long- acting properties of haloperidol decanoate provide gradual withdrawal, it is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy with haloperidol decanoate or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear Reference ID: 2911916 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Body as a Whole Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. Liver Effects Impaired liver function and/or jaundice have been reported. Reference ID: 2911916 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5 1 /2 year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. OVERDOSAGE While overdosage is less likely to occur with a parenteral than with an oral medication, information pertaining to HALDOL (haloperidol) is presented, modified only to reflect the extended duration of action of haloperidol decanoate. Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor, as demonstrated by the akinetic or agitans types, respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Reference ID: 2911916 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks, and then withdrawn gradually as extrapyramidal symptoms may emerge. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HALDOL Decanoate 50 and HALDOL Decanoate 100 are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate. Furthermore, it is recommended that patients being considered for haloperidol decanoate therapy have been treated with, and tolerate well, short-acting HALDOL (haloperidol) in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting forms of haloperidol. The dose of HALDOL Decanoate 50 or HALDOL Decanoate 100 should be expressed in terms of its haloperidol content. The starting dose of haloperidol decanoate should be based on the patient’s age, clinical history, physical condition, Reference ID: 2911916 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed. For patients previously maintained on low doses of antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate be 10-15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate. Initial Therapy Conversion from oral haloperidol to haloperidol decanoate can be achieved by using an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose in oral haloperidol equivalents. In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion. In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections. The initial dose of haloperidol decanoate should not exceed 100 mg regardless of previous antipsychotic dose requirements. If, therefore, conversion requires more than 100 mg of haloperidol decanoate as an initial dose, that dose should be administered in two injections, i.e. a maximum of 100 mg initially followed by the balance in 3 to 7 days. Maintenance Therapy The maintenance dosage of haloperidol decanoate must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient. Reference ID: 2911916 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL DECANOATE DOSING RECOMMENDATIONS Monthly Patients 1st Month Maintenance Stabilized on low daily oral doses 10-15 x Daily Oral Dose 10-15 x Previous Daily Oral Dose (up to 10 mg/day) Elderly or Debilitated High dose 20 x Daily Oral Dose 10-15 x Previous Daily Oral Dose Risk of relapse Tolerant to oral haloperidol Close clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy. Haloperidol decanoate is usually administered monthly or every 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY). Clinical experience with haloperidol decanoate at doses greater than 450 mg per month has been limited. Instructions for Opening Ampule Step 1 1. Medication often rests in the top part of the ampule. Before breaking the ampule, lightly tap the top of the ampule with your finger until all fluid moves to the bottom portion of the ampule. The ampule has a colored ring(s) and usage illustration colored point which aids in the placement of fingers while breaking the ampule. Step 2 Reference ID: 2911916 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration 2. Hold the ampule between thumb and index finger with the colored point facing you. usage illustration Step 3 3. Position the index finger of the other hand to support the neck of the ampule. Position the thumb so that it covers the colored point and is parallel to the colored ring(s). usage illustration Step 4 4. Keeping the thumb on the colored point and with the index fingers close together, apply firm pressure on the colored point in the direction of the arrow to snap the ampule open. HOW SUPPLIED HALDOL® (haloperidol) Decanoate 50 for IM injection, 50 mg haloperidol as 70.52 mg per mL haloperidol decanoate: Reference ID: 2911916 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 50458-253-01 - 10 x 1 mL ampuls NDC 50458-253-03 - 3 x 1 mL ampuls HALDOL® (haloperidol) Decanoate 100 for IM injection, 100 mg haloperidol as 141.04 mg per mL haloperidol decanoate: NDC 50458-254-14 - 5 x 1 mL ampuls Store at controlled room temperature (15°-30° C, 59°-86° F). Do not refrigerate or freeze. Protect from light. Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium Manufactured for: Ortho-McNeil Neurologics, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Revised February 2011 ©Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2005 US-980445 Reference ID: 2911916 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:56.138414	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/015923s086,018701s063lbl.pdf', 'application_number': 15923, 'submission_type': 'SUPPL ', 'submission_number': 86}
10,868	NDA 16-023/S-039 NDA 18-101/S-014 Page 3 SYMMETREL® (Amantadine Hydrochloride, USP) Tablets and Syrup Rx only DESCRIPTION SYMMETREL (Amantadine Hydrochloride, USP) is designated generically as amantadine hydrochloride and chemically as 1-adamantanamine hydrochloride. Amantadine hydrochloride is a stable white or nearly white crystalline powder, freely soluble in water and soluble in alcohol and in chloroform. Amantadine hydrochloride has pharmacological actions as both an anti-Parkinson and an antiviral drug. SYMMETREL is available in tablets and syrup. Each tablet intended for oral administration contains 100 mg amantadine hydrochloride and has the following inactive ingredients: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, FD&C Yellow No. 6. SYMMETREL syrup contains 50 mg of amantadine hydrochloride per 5 mL and has the following inactive ingredients: artificial raspberry flavor, citric acid, methylparaben, propylparaben, and sorbitol solution. CLINICAL PHARMACOLOGY Pharmacodynamics Mechanism of Action: Antiviral The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine. • HCl NH2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 4 Antiviral Activity Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e., H1N1, H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A quantitative relationship between the in vitro susceptibility of influenza A virus to amantadine and the clinical response to therapy has not been established in man. Sensitivity test results, expressed as the concentration of amantadine required to inhibit by 50% the growth of virus (ED50) in tissue culture vary greatly (from 0.1 µg/mL to 25.0 µg/mL) depending upon the assay protocol used, size of virus inoculum, isolates of influenza A virus strains tested, and the cell type used. Host cells in tissue culture readily tolerated amantadine up to a concentration of 100 µg/mL. Drug Resistance Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from epidemic strains in areas where adamantane derivatives are being used. Influenza viruses with reduced in vitro sensitivity have been shown to be transmissible and to cause typical influenza illness. The quantitative relationship between the in vitro sensitivity of influenza A variants to amantadine and the clinical response to therapy has not been established. Mechanism of Action: Parkinson’s Disease The mechanism of action of amantadine in the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that SYMMETREL may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (Ki = 10µM). Although amantadine has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation. Pharmacokinetics SYMMETREL is well absorbed orally. Maximum plasma concentrations are directly related to dose for doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase in maximum plasma concentrations. It is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion. Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5-15% of the administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent amantadine plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg dose of amantadine. Acetylamantadine was not detected in the plasma of the remaining seven volunteers. The contribution of this metabolite to efficacy or toxicity is not known. There appears to be a relationship between plasma amantadine concentrations and toxicity. As concentration increases, toxicity seems to be more prevalent, however, absolute values of amantadine concentrations associated with adverse effects have not been fully defined. Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean ± SD maximum plasma concentration was 0.22 ± 0.03 µg/mL (range: 0.18 to 0.32 µg/mL). The time to peak This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 5 concentration was 3.3 ± 1.5 hours (range: 1.5 to 8.0 hours). The apparent oral clearance was 0.28 ± 0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17 ± 4 hours (range: 10 to 25 hours). Across other studies, amantadine plasma half-life has averaged 16 ± 6 hours (range: 9 to 31 hours) in 19 healthy volunteers. After oral administration of a single dose of 100 mg amantadine syrup to five healthy volunteers, the mean ± SD maximum plasma concentration Cmax was 0.24 ± 0.04 µg/mL and ranged from 0.18 to 0.28 µg/mL. After 15 days of amantadine 100 mg b.i.d., the Cmax was 0.47 ± 0.11 µg/mL in four of the five volunteers. The administration of amantadine tablets as a 200 mg single dose to 6 healthy subjects resulted in a Cmax of 0.51 ± 0.14 µg/mL. Across studies, the time to Cmax (Tmax) averaged about 2 to 4 hours. Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg intravenous doses of amantadine to 15 healthy volunteers. In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma clearance was 0.79 ± 0.17 (mean ± SD). The volume of distribution determined after the intravenous administration of amantadine to 15 healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg doses to 6 healthy young subjects and to 6 healthy elderly subjects has been found in nasal mucus at mean ± SD concentrations of 0.15 ± 0.16, 0.28 ± 0.26, and 0.39 ± 0.34 µg/g at 1, 4, and 8 hours after dosing, respectively. These concentrations represented 31 ± 33%, 59 ± 61%, and 95 ± 86% of the corresponding plasma amantadine concentrations. Amantadine is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL. Following the administration of amantadine 100 mg as a single dose, the mean ± SD red blood cell to plasma ratio ranged from 2.7 ± 0.5 in 6 healthy subjects to 1.4 ± 0.2 in 8 patients with renal insufficiency. The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma concentrations are increased in healthy elderly individuals age 60 and older. After single dose administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma clearance of amantadine was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the half-life was 29 ± 7 hours (range 20 to 41 hours). Whether these changes are due to decline in renal function or other age related factors is not known. In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for body mass index, was 1.5 fold higher in males compared to females (p<0.032). Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly reduced in adult patients with renal insufficiency. The elimination half-life increases two to three fold or greater when creatinine clearance is less than 40 mL/min/1.73 m2 and averages eight days in patients on chronic maintenance hemodialysis. Amantadine is removed in negligible amounts by hemodialysis. The pH of the urine has been reported to influence the excretion rate of SYMMETREL. Since the excretion rate of SYMMETREL increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 6 INDICATIONS AND USAGE SYMMETREL is indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus. SYMMETREL is also indicated in the treatment of parkinsonism and drug-induced extrapyramidal reactions. Influenza A Prophylaxis SYMMETREL (Amantadine Hydrochloride, USP) is indicated for chemoprophylaxis against signs and symptoms of influenza A virus infection when early vaccination is not feasible or when the vaccine is contraindicated or not available. In the prophylaxis of influenza, early vaccination on an annual basis as recommended by the Centers for Disease Control’s Immunization Practices Advisory Committee is the method of choice. Because SYMMETREL does not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically related viruses. Following vaccination during an influenza A outbreak, SYMMETREL prophylaxis should be considered for the 2- to 4-week time period required to develop an antibody response. Influenza A Treatment SYMMETREL is also indicated in the treatment of uncomplicated respiratory tract illness caused by influenza A virus strains especially when administered early in the course of illness. There are no well- controlled clinical studies demonstrating that treatment with SYMMETREL will avoid the development of influenza A virus pneumonitis or other complications in high risk patients. There is no clinical evidence indicating that SYMMETREL is effective in the prophylaxis or treatment of viral respiratory tract illnesses other than those caused by influenza A virus strains. Parkinson’s Disease/Syndrome SYMMETREL is indicated in the treatment of idiopathic Parkinson’s disease (Paralysis Agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication. It is indicated in those elderly patients believed to develop parkinsonism in association with cerebral arteriosclerosis. In the treatment of Parkinson’s disease, SYMMETREL is less effective than levodopa, (-)-3-(3,4-dihydroxyphenyl)-L-alanine, and its efficacy in comparison with the anticholinergic antiparkinson drugs has not yet been established. Drug-Induced Extrapyramidal Reactions SYMMETREL is indicated in the treatment of drug-induced extrapyramidal reactions. Although anticholinergic-type side effects have been noted with SYMMETREL when used in patients with drug- induced extrapyramidal reactions, there is a lower incidence of these side effects than that observed with the anticholinergic antiparkinson drugs. CONTRAINDICATIONS SYMMETREL is contraindicated in patients with known hypersensitivity to amantadine hydrochloride or to any of the other ingredients in SYMMETREL. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 7 WARNINGS Deaths Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension (see OVERDOSAGE). Suicide Attempts Suicide attempts, some of which have been fatal, have been reported in patients treated with SYMMETREL, many of whom received short courses for influenza treatment or prophylaxis. The incidence of suicide attempts is not known and the pathophysiologic mechanism is not understood. Suicide attempts and suicidal ideation have been reported in patients with and without prior history of psychiatric illness. SYMMETREL can exacerbate mental problems in patients with a history of psychiatric disorders or substance abuse. Patients who attempt suicide may exhibit abnormal mental states which include disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions, and somnolence or insomnia. Because of the possibility of serious adverse effects, caution should be observed when prescribing SYMMETREL to patients being treated with drugs having CNS effects, or for whom the potential risks outweigh the benefit of treatment. CNS Effects Patients with a history of epilepsy or other “seizures” should be observed closely for possible increased seizure activity. Patients receiving SYMMETREL who note central nervous system effects or blurring of vision should be cautioned against driving or working in situations where alertness and adequate motor coordination are important. Other Patients with a history of congestive heart failure or peripheral edema should be followed closely as there are patients who developed congestive heart failure while receiving SYMMETREL. Patients with Parkinson’s disease improving on SYMMETREL should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis. Because SYMMETREL has anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma. PRECAUTIONS SYMMETREL should not be discontinued abruptly in patients with Parkinson’s disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of SYMMETREL should be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 8 reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech. Neuroleptic Malignant Syndrome (NMS) Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of SYMMETREL therapy. Therefore, patients should be observed carefully when the dosage of SYMMETREL is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin. The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies. Renal disease Because SYMMETREL is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of SYMMETREL should be reduced in patients with renal impairment and in individuals who are 65 years of age or older (see DOSAGE AND ADMINISTRATION; Dosage for Impaired Renal Function). Liver disease Care should be exercised when administering SYMMETREL to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving SYMMETREL, though a specific relationship between the drug and such changes has 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 16-023/S-039 NDA 18-101/S-014 Page 9 Other The dose of SYMMETREL may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering SYMMETREL to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. SYMMETREL has not been shown to prevent such complications. Information for Patients Patients should be advised of the following information: Blurry vision and/or impaired mental acuity may occur. Gradually increase physical activity as the symptoms of Parkinson’s disease improve. Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness and orthostatic hypotension. Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs, notify physician. Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness of breath occur. Do not take more medication than prescribed because of the risk of overdose. If there is no improvement in a few days, or if medication appears less effective after a few weeks, discuss with a physician. Consult physician before discontinuing medication. Seek medical attention immediately if it is suspected that an overdose of medication has been taken. Drug Interactions Careful observation is required when SYMMETREL is administered concurrently with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson’s disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine concentration in a 61-year-old man receiving SYMMETREL (Amantadine Hydrochloride, USP) 100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 10 mg TID for Parkinson’s disease.1 It is not known which of the components of Dyazide contributed to the observation or if related drugs produce a similar response. Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of amantadine by about 30%. The concurrent use of SYMMETREL with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of SYMMETREL, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of SYMMETREL. Carcinogenesis and Mutagenesis Long-term in vivo animal studies designed to evaluate the carcinogenic potential of SYMMETREL have not been performed. In several in vitro assays for gene mutation, SYMMETREL did not increase the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed either with or without a liver metabolic activation extract. Further, there was no evidence of chromosome damage observed in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test (140-550 mg/kg; estimated human equivalent doses of 11.7-45.8 mg/kg based on body surface area conversion). Impairment of Fertility The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. In a three litter, non-GLP, reproduction study in rats, Symmetrel at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m2 basis) administered to both males and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m2 basis); intermediate doses were not tested. Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to, and during the IVF cycle. Pregnancy Category C The effect of amantadine on embryofetal and peri-postnatal development has not been adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. However, in two non-GLP studies in rats in which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7-14 of gestation, Symmetrel produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m2 basis). In the non-GLP rat study in which females were dosed on Days 7-14 of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 11 mg/m2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m2 basis). The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate and well-controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy. SYMMETREL should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus. Nursing Mothers SYMMETREL is excreted in human milk. Use is not recommended in nursing mothers. Pediatric Use The safety and efficacy of SYMMETREL in newborn infants and infants below the age of 1 year have not been established. Usage in the Elderly Because SYMMETREL is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of SYMMETREL should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of SYMMETREL may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS The adverse reactions reported most frequently at the recommended dose of SYMMETREL (5-10%) are: nausea, dizziness (lightheadedness), and insomnia. Less frequently (1-5%) reported adverse reactions are: depression, anxiety and irritability, hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral edema, orthostatic hypotension, headache, somnolence, nervousness, dream abnormality, agitation, dry nose, diarrhea and fatigue. Infrequently (0.1-1%) occurring adverse reactions are: congestive heart failure, psychosis, urinary retention, dyspnea, skin rash, vomiting, weakness, slurred speech, euphoria, thinking abnormality, amnesia, hyperkinesia, hypertension, decreased libido, and visual disturbance, including punctate subepithelial or other corneal opacity, corneal edema, decreased visual acuity, sensitivity to light, and optic nerve palsy. Rare (less than 0.1%) occurring adverse reactions are: instances of convulsion, leukopenia, neutropenia, eczematoid dermatitis, oculogyric episodes, suicidal attempt, suicide, and suicidal ideation (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 12 Other adverse reactions reported during postmarketing experience with SYMMETREL usage include: Nervous System/Psychiatric coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, and tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech; Cardiovascular cardiac arrest, arrhythmias including malignant arrhythmias, hypotension, and tachycardia; Respiratory acute respiratory failure, pulmonary edema, and tachypnea; Gastrointestinal dysphagia; Hematologic leukocytosis; agranulocytosis Special Senses keratitis and mydriasis; Skin and Appendages pruritus and diaphoresis; Miscellaneous neuroleptic malignant syndrome (see WARNINGS), allergic reactions including anaphylactic reactions, edema, and fever; Laboratory Test elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and SGPT. OVERDOSAGE Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal dose was 1 gram. Because some patients have attempted suicide by overdosing with amantadine, prescriptions should be written for the smallest quantity consistent with good patient management. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome - ARDS) have been reported; renal dysfunction including increased This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 13 BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, gait abnormality, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred. There is no specific antidote for an overdose of SYMMETREL. However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult2 at 1- to 2-hour intervals and 0.5 mg doses in a child3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported to be effective in the control of central nervous system toxicity caused by amantadine hydrochloride. For acute overdosing, general supportive measures should be employed along with immediate gastric lavage or induction of emesis. Fluids should be forced, and if necessary, given intravenously. The pH of the urine has been reported to influence the excretion rate of SYMMETREL. Since the excretion rate of SYMMETREL increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. The blood pressure, pulse, respiration and temperature should be monitored. The patient should be observed for hyperactivity and convulsions; if required, sedation, and anticonvulsant therapy should be administered. The patient should be observed for the possible development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and antihypotensive therapy should be given. Electrocardiographic monitoring may be required after ingestion, since malignant tachyarrhythmias can appear after overdose. Care should be exercised when administering adrenergic agents, such as isoproterenol, to patients with a SYMMETREL overdose, since the dopaminergic activity of SYMMETREL has been reported to induce malignant arrhythmias. The blood electrolytes, urine pH and urinary output should be monitored. If there is no record of recent voiding, catheterization should be done. DOSAGE AND ADMINISTRATION The dose of SYMMETREL (Amantadine Hydrochloride, USP) may need reduction in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function (see Dosage for Impaired Renal Function). Dosage for Prophylaxis and Treatment of Uncomplicated Influenza A Virus Illness Adult The adult daily dosage of SYMMETREL is 200 mg; two 100 mg tablets (or four teaspoonfuls of syrup) as a single daily dose. The daily dosage may be split into one tablet of 100 mg (or two teaspoonfuls of syrup) twice a day. If central nervous system effects develop in once-a-day dosage, a split dosage schedule may reduce such complaints. In persons 65 years of age or older, the daily dosage of SYMMETREL is 100 mg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 14 A 100 mg daily dose has also been shown in experimental challenge studies to be effective as prophylaxis in healthy adults who are not at high risk for influenza-related complications. However, it has not been demonstrated that a 100 mg daily dose is as effective as a 200 mg daily dose for prophylaxis, nor has the 100 mg daily dose been studied in the treatment of acute influenza illness. In recent clinical trials, the incidence of central nervous system (CNS) side effects associated with the 100 mg daily dose was at or near the level of placebo. The 100 mg dose is recommended for persons who have demonstrated intolerance to 200 mg of SYMMETREL daily because of CNS or other toxicities. Pediatric Patients: 1 yr.-9 yrs. of age The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day), but not to exceed 150 mg per day. 9 yrs.-12 yrs. of age The total daily dose is 200 mg given as one tablet of 100 mg (or two teaspoonfuls of syrup) twice a day. The 100 mg daily dose has not been studied in this pediatric population. Therefore, there are no data which demonstrate that this dose is as effective as or is safer than the 200 mg daily dose in this patient population. Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or after contact with individuals with influenza A virus respiratory tract illness. SYMMETREL should be continued daily for at least 10 days following a known exposure. If SYMMETREL is used chemoprophylactically in conjunction with inactivated influenza A virus vaccine until protective antibody responses develop, then it should be administered for 2 to 4 weeks after the vaccine has been given. When inactivated influenza A virus vaccine is unavailable or contraindicated, SYMMETREL should be administered for the duration of known influenza A in the community because of repeated and unknown exposure. Treatment of influenza A virus illness should be started as soon as possible, preferably within 24 to 48 hours after onset of signs and symptoms, and should be continued for 24 to 48 hours after the disappearance of signs and symptoms. Dosage for Parkinsonism Adult The usual dose of SYMMETREL is 100 mg twice a day when used alone. SYMMETREL has an onset of action usually within 48 hours. The initial dose of SYMMETREL is 100 mg daily for patients with serious associated medical illnesses or who are receiving high doses of other antiparkinson drugs. After one to several weeks at 100 mg once daily, the dose may be increased to 100 mg twice daily, if necessary. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 15 Occasionally, patients whose responses are not optimal with SYMMETREL at 200 mg daily may benefit from an increase up to 400 mg daily in divided doses. However, such patients should be supervised closely by their physicians. Patients initially deriving benefit from SYMMETREL not uncommonly experience a fall-off of effectiveness after a few months. Benefit may be regained by increasing the dose to 300 mg daily. Alternatively, temporary discontinuation of SYMMETREL for several weeks, followed by reinitiation of the drug, may result in regaining benefit in some patients. A decision to use other antiparkinson drugs may be necessary. Dosage for Concomitant Therapy Some patients who do not respond to anticholinergic antiparkinson drugs may respond to SYMMETREL. When SYMMETREL or anticholinergic antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional benefit. When SYMMETREL and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic benefits. SYMMETREL should be held constant at 100 mg daily or twice daily while the daily dose of levodopa is gradually increased to optimal benefit. When SYMMETREL is added to optimal well-tolerated doses of levodopa, additional benefit may result, including smoothing out the fluctuations in improvement which sometimes occur in patients on levodopa alone. Patients who require a reduction in their usual dose of levodopa because of development of side effects may possibly regain lost benefit with the addition of SYMMETREL. Dosage for Drug-Induced Extrapyramidal Reactions Adult The usual dose of SYMMETREL is 100 mg twice a day. Occasionally, patients whose responses are not optimal with SYMMETREL at 200 mg daily may benefit from an increase up to 300 mg daily in divided doses. Dosage for Impaired Renal Function Depending upon creatinine clearance, the following dosage adjustments are recommended: CREATININE CLEARANCE (mL/min/1.73m2) SYMMETREL DOSAGE 30-50 200 mg 1st day and 100 mg each day thereafter 15-29 200 mg 1st day followed by 100 mg on alternate days <15 200 mg every 7 days The recommended dosage for patients on hemodialysis is 200 mg every 7 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-023/S-039 NDA 18-101/S-014 Page 16 HOW SUPPLIED SYMMETREL (Amantadine Hydrochloride, USP) is available in light orange, convex curved, triangular shaped 100 mg tablets with “SYMMETREL” debossed on one side and plain on the other side as follows: Bottles of 100 NDC 63481-108-70 As a clear, colorless syrup [each 5 mL (1 teaspoonful) contains 50 mg amantadine hydrochloride] in: 16 oz. (480 mL) bottles NDC 63481-205-16 Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP, with a child-resistant closure (as required). REFERENCES 1W.W. Wilson and A.H. Rajput, Amantadine-Dyazide Interaction, Can. Med. Assoc. J. 129:974-975, 1983. 2D.F. Casey, N. Engl. J. Med. 298:516, 1978. 3C.D. Berkowitz, J. Pediatr. 95:144, 1979. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, PA 19317 SYMMETREL® is a Registered Trademark of Endo Pharmaceuticals Inc. Copyright © Endo Pharmaceuticals Inc. 2007 Printed in U.S.A. 2007129/February, 2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:57.069866	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016023s039,018101s014lbl.pdf', 'application_number': 16023, 'submission_type': 'SUPPL ', 'submission_number': 39}
10,870	NDA 16-092/S-042 NDA 16-093/S-044 Page 3 TABLETS EDECRIN® (ETHACRYNIC ACID) and INTRAVENOUS SODIUM EDECRIN® (ETHACRYNATE SODIUM) EDECRIN* (Ethacrynic Acid) is a potent diuretic which, if given in excessive amounts, may lead to profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required, and dose and dose schedule must be adjusted to the individual patient's needs (see DOSAGE AND ADMINISTRATION). DESCRIPTION Ethacrynic acid is an unsaturated ketone derivative of an aryloxyacetic acid. It is designated chemically as [2,3-dichloro-4-(2-methylene-1-oxobutyl)phenoxy] acetic acid, and has a molecular weight of 303.14. Ethacrynic acid is a white, or practically white, crystalline powder, very slightly soluble in water, but soluble in most organic solvents such as alcohols, chloroform, and benzene. Its empirical formula is C13H12Cl2O4 and its structural formula is: Ethacrynate sodium, the sodium salt of ethacrynic acid, is soluble in water at 25°C to the extent of about 7 percent. Solutions of the sodium salt are relatively stable at about pH 7 at room temperature for short periods, but as the pH or temperature increases the solutions are less stable. The molecular weight of ethacrynate sodium is 325.12. Its empirical formula is C13H11Cl2NaO4 and its structural formula is: EDECRIN is supplied as 25 mg tablets for oral use. The tablets contain the following inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, starch and talc. Intravenous SODIUM EDECRIN* (Ethacrynate Sodium) is a sterile freeze-dried powder and is supplied in a vial containing: Ethacrynate sodium equivalent * Registered trademark of MERCK & CO., Inc. COPYRIGHT © MERCK & CO., Inc., 1984 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 16-092/S-042 NDA 16-093/S-044 Page 4 to ethacrynic acid....................................................................................... 50.0 mg Inactive ingredient: Mannitol.......................................................................................................... 62.5 mg CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism EDECRIN acts on the ascending limb of the loop of Henle and on the proximal and distal tubules. Urinary output is usually dose dependent and related to the magnitude of fluid accumulation. Water and electrolyte excretion may be increased several times over that observed with thiazide diuretics, since EDECRIN inhibits reabsorption of a much greater proportion of filtered sodium than most other diuretic agents. Therefore, EDECRIN is effective in many patients who have significant degrees of renal insufficiency (see WARNINGS concerning deafness). EDECRIN has little or no effect on glomerular filtration or on renal blood flow, except following pronounced reductions in plasma volume when associated with rapid diuresis. The electrolyte excretion pattern of ethacrynic acid varies from that of the thiazides and mercurial diuretics. Initial sodium and chloride excretion is usually substantial and chloride loss exceeds that of sodium. With prolonged administration, chloride excretion declines, and potassium and hydrogen ion excretion may increase. EDECRIN is effective whether or not there is clinical acidosis or alkalosis. Although EDECRIN, in carefully controlled studies in animals and experimental subjects, produces a more favorable sodium/potassium excretion ratio than the thiazides, in patients with increased diuresis excessive amounts of potassium may be excreted. Onset of action is rapid, usually within 30 minutes after an oral dose of EDECRIN or within 5 minutes after an intravenous injection of SODIUM EDECRIN. After oral use, diuresis peaks in about 2 hours and lasts about 6 to 8 hours. The sulfhydryl binding propensity of ethacrynic acid differs somewhat from that of the organomercurials. Its mode of action is not by carbonic anhydrase inhibition. Ethacrynic acid does not cross the blood-brain barrier. INDICATIONS AND USAGE EDECRIN is indicated for treatment of edema when an agent with greater diuretic potential than those commonly employed is required. 1. Treatment of the edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. 2. Short-term management of ascites due to malignancy, idiopathic edema, and lymphedema. 3. Short-term management of hospitalized pediatric patients, other than infants, with congenital heart disease or the nephrotic syndrome. 4. Intravenous SODIUM EDECRIN is indicated when a rapid onset of diuresis is desired, e.g., in acute pulmonary edema, or when gastrointestinal absorption is impaired or oral medication is not practicable. CONTRAINDICATIONS All diuretics, including ethacrynic acid, are contraindicated in anuria. If increasing electrolyte imbalance, azotemia, and/or oliguria occur during treatment of severe, progressive renal disease, the diuretic should be discontinued. In a few patients this diuretic has produced severe, watery diarrhea. If this occurs, it should be discontinued and not used again. Until further experience in infants is accumulated, therapy with oral and parenteral EDECRIN is contraindicated. Hypersensitivity to any component of this product. WARNINGS The effects of EDECRIN on electrolytes are related to its renal pharmacologic activity and are dose dependent. The possibility of profound electrolyte and water loss may be avoided by weighing the patient throughout the treatment period, by careful adjustment of dosage, by initiating treatment with small doses, and by using the drug on an intermittent schedule when possible. When excessive diuresis occurs, the drug should be withdrawn until homeostasis is restored. When excessive electrolyte loss occurs, the dosage should be reduced or the drug temporarily withdrawn. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-092/S-042 NDA 16-093/S-044 Page 5 Initiation of diuretic therapy with EDECRIN in the cirrhotic patient with ascites is best carried out in the hospital. When maintenance therapy has been established, the individual can be satisfactorily followed as an outpatient. EDECRIN should be given with caution to patients with advanced cirrhosis of the liver, particularly those with a history of previous episodes of electrolyte imbalance or hepatic encephalopathy. Like other diuretics it may precipitate hepatic coma and death. Too vigorous a diuresis, as evidenced by rapid and excessive weight loss, may induce an acute hypotensive episode. In elderly cardiac patients, rapid contraction of plasma volume and the resultant hemoconcentration should be avoided to prevent the development of thromboembolic episodes, such as cerebral vascular thromboses and pulmonary emboli which may be fatal. Excessive loss of potassium in patients receiving digitalis glycosides may precipitate digitalis toxicity. Care should also be exercised in patients receiving potassium-depleting steroids. A number of possibly drug-related deaths have occurred in critically ill patients refractory to other diuretics. These generally have fallen into two categories: (1) patients with severe myocardial disease who have been receiving digitalis and presumably developed acute hypokalemia with fatal arrhythmia; (2) patients with severely decompensated hepatic cirrhosis with ascites, with or without accompanying encephalopathy, who were in electrolyte imbalance and died because of intensification of the electrolyte defect. Deafness, tinnitus, and vertigo with a sense of fullness in the ears have occurred, most frequently in patients with severe impairment of renal function. These symptoms have been associated most often with intravenous administration and with doses in excess of those recommended. The deafness has usually been reversible and of short duration (one to 24 hours). However, in some patients the hearing loss has been permanent. A number of these patients were also receiving drugs known to be ototoxic. EDECRIN may increase the ototoxic potential of other drugs (see PRECAUTIONS, Drug Interactions). Lithium generally should not be given with diuretics (see PRECAUTIONS, Drug Interactions). PRECAUTIONS General Weakness, muscle cramps, paresthesias, thirst, anorexia, and signs of hyponatremia, hypokalemia, and/or hypochloremic alkalosis may occur following vigorous or excessive diuresis and these may be accentuated by rigid salt restriction. Rarely, tetany has been reported following vigorous diuresis. During therapy with ethacrynic acid, liberalization of salt intake and supplementary potassium chloride are often necessary. When a metabolic alkalosis may be anticipated, e.g., in cirrhosis with ascites, the use of potassium chloride or a potassium-sparing agent before and during therapy with EDECRIN may mitigate or prevent the hypokalemia. Loop diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. The safety and efficacy of ethacrynic acid in hypertension have not been established. However, the dosage of coadministered antihypertensive agents may require adjustment. Orthostatic hypotension may occur in patients receiving other antihypertensive agents when given ethacrynic acid. EDECRIN has little or no effect on glomerular filtration or on renal blood flow, except following pronounced reductions in plasma volume when associated with rapid diuresis. A transient increase in serum urea nitrogen may occur. Usually, this is readily reversible when the drug is discontinued. As with other diuretics used in the treatment of renal edema, hypoproteinemia may reduce responsiveness to ethacrynic acid and the use of salt-poor albumin should be considered. A number of drugs, including ethacrynic acid, have been shown to displace warfarin from plasma protein; a reduction in the usual anticoagulant dosage may be required in patients receiving both drugs. EDECRIN may increase the risk of gastric hemorrhage associated with corticosteroid treatment. Laboratory Tests Frequent serum electrolyte, CO2 and BUN determinations should be performed early in therapy and periodically thereafter during active diuresis. Any electrolyte abnormalities should be corrected or the drug temporarily withdrawn. Increases in blood glucose and alterations in glucose tolerance tests have been observed in patients receiving EDECRIN. Drug Interactions Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read circulars for lithium preparations before use of such concomitant therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-092/S-042 NDA 16-093/S-044 Page 6 EDECRIN may increase the ototoxic potential of other drugs such as aminoglycoside and some cephalosporin antibiotics. Their concurrent use should be avoided. A number of drugs, including ethacrynic acid, have been shown to displace warfarin from plasma protein; a reduction in the usual anticoagulant dosage may be required in patients receiving both 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 EDECRIN 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 There was no evidence of a tumorigenic effect in a 79-week oral chronic toxicity study in rats at doses up to 45 times the human dose. Ethacrynic acid had no effect on fertility in a two-litter study in rats or a two-generation study in mice at 10 times the human dose. Pregnancy Pregnancy Category B: Reproduction studies in the mouse and rabbit at doses up to 50 times the human dose showed no evidence of external abnormalities of the fetus due to EDECRIN. In a two-litter study in the dog and rat, oral doses of 5 or 20 mg/kg/day (2½ or 10 times the human dose), respectively, did not interfere with pregnancy or with growth and development of the pups. Although there was reduction in the mean body weights of the fetuses in a teratogenic study in the rat at a dose level of 100 mg/kg (50 times the human dose), there was no effect on mortality or postnatal development. Functional and morphologic abnormalities were not observed. There are, however, no adequate and well-controlled studies in pregnant women. Since animal reproduction studies are not always predictive of human response, EDECRIN 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 and because of the potential for serious adverse reactions in nursing infants from EDECRIN, 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 There are no well-controlled clinical trials in pediatric patients. The information on oral dosing in pediatric patients, other than infants, is supported by evidence from empiric use in this age group. For information on oral use in pediatric patients, other than infants, see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION. Safety and effectiveness of oral and parenteral use in infants have not been established (see CONTRAINDICATIONS). Safety and effectiveness of intravenous use in pediatric patients have not been established (see DOSAGE AND ADMINISTRATION, Intravenous Use). Geriatric Use Of the total number of subjects in clinical studies of EDECRIN/SODIUM EDECRIN, approximately 224 patients (21%) were 65 to 74 years of age, while approximately 100 patients (9%) were 75 years of age and over. 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. (See WARNINGS.) 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 CONTRAINDICATIONS.) ADVERSE REACTIONS Gastrointestinal Anorexia, malaise, abdominal discomfort or pain, dysphagia, nausea, vomiting, and diarrhea have occurred. These are more frequent with large doses or after one to three months of continuous therapy. A few patients have had sudden onset of profuse, watery diarrhea. Discontinue EDECRIN if diarrhea is severe and do not give it again. Gastrointestinal bleeding has occurred in some patients. Rarely, acute pancreatitis has been reported. Metabolic Reversible hyperuricemia and acute gout have been reported. Acute symptomatic hypoglycemia with convulsions occurred in two uremic patients who received doses above those recommended. Hyperglycemia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-092/S-042 NDA 16-093/S-044 Page 7 has been reported. Rarely, jaundice and abnormal liver function tests have been reported in seriously ill patients receiving multiple drug therapy, including EDECRIN. Hematologic Agranulocytosis or severe neutropenia has been reported in a few critically ill patients also receiving agents known to produce this effect. Thrombocytopenia has been reported rarely. Henoch-Schönlein purpura has been reported rarely in patients with rheumatic heart disease receiving multiple drug therapy, including EDECRIN. Special Senses (see WARNINGS) Deafness, tinnitus and vertigo with a sense of fullness in the ears, and blurred vision have occurred. Central Nervous System Headache, fatigue, apprehension, confusion. Miscellaneous Skin rash, fever, chills, hematuria. SODIUM EDECRIN occasionally has caused local irritation and pain after intravenous use. OVERDOSAGE Overdosage may lead to excessive diuresis with electrolyte depletion and dehydration. In the event of overdosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma, and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment. In the mouse, the oral LD50 of ethacrynic acid is 627 mg/kg and the intravenous LD50 of ethacrynate sodium is 175 mg/kg. DOSAGE AND ADMINISTRATION Dosage must be regulated carefully to prevent a more rapid or substantial loss of fluid or electrolyte than is indicated or necessary. The magnitude of diuresis and natriuresis is largely dependent on the degree of fluid accumulation present in the patient. Similarly, the extent of potassium excretion is determined in large measure by the presence and magnitude of aldosteronism. Oral Use EDECRIN is available for oral use as 25 mg tablets. Dosage: To Initiate Diuresis In Adults: The smallest dose required to produce gradual weight loss (about 1 to 2 pounds per day) is recommended. Onset of diuresis usually occurs at 50 to 100 mg for adults. After diuresis has been achieved, the minimally effective dose (usually from 50 to 200 mg daily) may be given on a continuous or intermittent dosage schedule. Dosage adjustments are usually in 25 to 50 mg increments to avoid derangement of water and electrolyte excretion. The patient should be weighed under standard conditions before and during the institution of diuretic therapy with this compound. Small alterations in dose should effectively prevent a massive diuretic response. The following schedule may be helpful in determining the smallest effective dose. Day 1 — 50 mg once daily after a meal Day 2 — 50 mg twice daily after meals, if necessary Day 3 — 100 mg in the morning and 50 to 100 mg following the afternoon or evening meal, depending upon response to the morning dose. A few patients may require initial and maintenance doses as high as 200 mg twice daily. These higher doses, which should be achieved gradually, are most often required in patients with severe, refractory edema. In Pediatric Patients (excluding infants, see CONTRAINDICATIONS): The initial dose should be 25 mg. Careful stepwise increments in dosage of 25 mg should be made to achieve effective maintenance. Maintenance Therapy It is usually possible to reduce the dosage and frequency of administration once dry weight has been achieved. EDECRIN (Ethacrynic Acid) may be given intermittently after an effective diuresis is obtained with the regimen outlined above. Dosage may be on an alternate daily schedule or more prolonged periods of diuretic therapy may be interspersed with rest periods. Such an intermittent dosage schedule allows time for correction of any electrolyte imbalance and may provide a more efficient diuretic response. The chloruretic effect of this agent may give rise to retention of bicarbonate and a metabolic alkalosis. This may be corrected by giving chloride (ammonium chloride or arginine chloride). Ammonium chloride should not be given to cirrhotic patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-092/S-042 NDA 16-093/S-044 Page 8 EDECRIN has additive effects when used with other diuretics. For example, a patient who is on maintenance dosage of an oral diuretic may require additional intermittent diuretic therapy, such as an organomercurial, for the maintenance of basal weight. The intermittent use of EDECRIN orally may eliminate the need for injections of organomercurials. Small doses of EDECRIN may be added to existing diuretic regimens to maintain basal weight. This drug may potentiate the action of carbonic anhydrase inhibitors, with augmentation of natriuresis and kaliuresis. Therefore, when adding EDECRIN the initial dose and changes of dose should be in 25 mg increments, to avoid electrolyte depletion. Rarely, patients who failed to respond to ethacrynic acid have responded to older established agents. While many patients do not require supplemental potassium, the use of potassium chloride or potassium- sparing agents, or both, during treatment with EDECRIN is advisable, especially in cirrhotic or nephrotic patients and in patients receiving digitalis. Salt liberalization usually prevents the development of hyponatremia and hypochloremia. During treatment with EDECRIN, salt may be liberalized to a greater extent than with other diuretics. Cirrhotic patients, however, usually require at least moderate salt restriction concomitant with diuretic therapy. Intravenous Use Intravenous SODIUM EDECRIN is for intravenous use when oral intake is impractical or in urgent conditions, such as acute pulmonary edema. The usual intravenous dose for the average sized adult is 50 mg, or 0.5 to 1.0 mg per kg of body weight. Usually only one dose has been necessary; occasionally a second dose at a new injection site, to avoid possible thrombophlebitis, may be required. A single intravenous dose not exceeding 100 mg has been used in critical situations. Insufficient pediatric experience precludes recommendation for this age group. To reconstitute the dry material, add 50 mL of 5 percent Dextrose Injection, or Sodium Chloride Injection to the vial. Occasionally, some 5 percent Dextrose Injection solutions may have a low pH (below 5). The resulting solution with such a diluent may be hazy or opalescent. Intravenous use of such a solution is not recommended. Inspect the vial containing Intravenous SODIUM EDECRIN for particulate matter and discoloration before use. The solution may be given slowly through the tubing of a running infusion or by direct intravenous injection over a period of several minutes. Do not mix this solution with whole blood or its derivatives. Discard unused reconstituted solution after 24 hours. SODIUM EDECRIN should not be given subcutaneously or intramuscularly because of local pain and irritation. HOW SUPPLIED No. 3321 — Tablets EDECRIN, 25 mg, are white, capsule shaped, scored tablets, coded MSD 65 on one side and EDECRIN on the other. They are supplied as follows: NDC 0006-0065-68 in bottles of 100. No. 3620 — Intravenous SODIUM EDECRIN is a dry white material either in a plug form or as a powder. It is supplied in vials containing ethacrynate sodium equivalent to 50 mg of ethacrynic acid, NDC 0006-3620-50. Storage Store in a tightly closed container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. 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	2025-02-12T13:43:57.070204	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/16092s042,16093s044lbl.pdf', 'application_number': 16092, 'submission_type': 'SUPPL ', 'submission_number': 42}
10,869	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INDOCIN® CAPSULES safely and effectively. See full prescribing information for INDOCIN. INDOCIN (indomethacin) Capsules, for oral use Initial U.S. Approval: 1965 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning.  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1)  INDOCIN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1)  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) RECENT MAJOR CHANGES Boxed Warning 5/2016 Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 5/2016 Warnings and Precautions, Heart Failure and Edema (5.5) 5/2016 INDICATIONS AND USAGE INDOCIN is a nonsteroidal anti-inflammatory drug indicated for:  Moderate to severe rheumatoid arthritis including acute flares of chronic disease  Moderate to severe ankylosing spondylitis  Moderate to severe osteoarthritis  Acute painful shoulder (bursitis and/or tendinitis)  Acute gouty arthritis (1) DOSAGE AND ADMINISTRATION  Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1)  The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis is INDOCIN 25 mg two or three times a day (2.2)  The dosage for acute painful shoulder (bursitis and/or tendinitis) is 75-150 mg daily in 3 or 4 divided doses (2.3)  The dosage for acute gouty arthritis is INDOCIN 50 mg three times a day (2.4) DOSAGE FORMS AND STRENGTHS INDOCIN (indomethacin) Capsules: 25 mg (3) CONTRAINDICATIONS  Known hypersensitivity to indomethacin or any components of the drug product (4)  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4)  In the setting of CABG surgery (4) WARNINGS AND PRECAUTIONS  Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3)  Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7)  Heart Failure and Edema: Avoid use of INDOCIN in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5)  Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of INDOCIN in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6)  Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7)  Exacerbation of Asthma Related to Aspirin Sensitivity: INDOCIN is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8)  Serious Skin Reactions: Discontinue INDOCIN at first appearance of skin rash or other signs of hypersensitivity (5.9)  Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30 weeks gestation (5.10, 8.1)  Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.11, 7) ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 3%) are headache, dizziness, dyspepsia and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Iroko Pharmaceuticals, LLC at 1-877-757-0676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS  Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking INDOCIN with drugs that interfere with hemostasis. Concomitant use of INDOCIN and analgesic doses of aspirin is not generally recommended (7)  ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with INDOCIN may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7)  ACE Inhibitors and ARBs: Concomitant use with INDOCIN in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7)  Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7)  Digoxin: Concomitant use with INDOCIN can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8) Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of INDOCIN in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 5/2016 Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis 2.3 Acute painful shoulder (bursitis and/or tendinitis) 2.4 Acute Gouty Arthritis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Premature Closure of Fetal Ductus Arteriosus 5.11 Hematologic Toxicity 5.12 Masking of Inflammation and Fever 5.13 Laboratory Monitoring 5.14 Central Nervous System Effects 5.15 Ocular Effects 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3928088 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: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • INDOCIN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE INDOCIN is indicated for:  Moderate to severe rheumatoid arthritis including acute flares of chronic disease  Moderate to severe ankylosing spondylitis  Moderate to severe osteoarthritis  Acute painful shoulder (bursitis and/or tendinitis)  Acute gouty arthritis 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of INDOCIN and other treatment options before deciding to use INDOCIN. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage recommendations for active stages of the following: 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis INDOCIN 25 mg twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 - 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, INDOCIN should be used with greater care in the elderly [see Use in Specific Populations (8.5)]. 2.3 Acute painful shoulder (bursitis and/or tendinitis) INDOCIN 75-150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7-14 days. 2.4 Acute Gouty Arthritis INDOCIN 50 mg three times a day until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. 3 DOSAGE FORMS AND STRENGTHS INDOCIN (indomethacin) Capsules: 25 mg - opaque, blue and white hard shell gelatin capsules, printed INDOCIN and MSD 25. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 CONTRAINDICATIONS INDOCIN is contraindicated in the following patients:  Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]  In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 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, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery 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. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of INDOCIN in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If INDOCIN is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients:  Use the lowest effective dosage for the shortest possible duration.  Avoid administration of more than one NSAID at a time.  Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.  Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.  If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue INDOCIN until a serious GI adverse event is ruled out.  In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. 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). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue INDOCIN immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including INDOCIN, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of INDOCIN in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If INDOCIN is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity 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 an NSAID 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda No information is available from controlled clinical studies regarding the use of INDOCIN in patients with advanced renal disease. The renal effects of INDOCIN may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating INDOCIN. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of INDOCIN [see Drug Interactions (7)]. Avoid the use of INDOCIN in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If INDOCIN is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Both Indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 5.7 Anaphylactic Reactions Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, INDOCIN is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When INDOCIN is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of INDOCIN at the first appearance of skin rash or any other sign of hypersensitivity. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDOCIN is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Premature Closure of Fetal Ductus Arteriosus Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including INDOCIN, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations (8.1)]. 5.11 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with INDOCIN has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including INDOCIN, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.12 Masking of Inflammation and Fever The pharmacological activity of INDOCIN in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.13 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.14 Central Nervous System Effects INDOCIN may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue INDOCIN if severe CNS adverse reactions develop. INDOCIN may cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with INDOCIN. 5.15 Ocular Effects Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with INDOCIN. Be alert to the possible association between the changes noted and INDOCIN. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. INDOCIN is not indicated for long-term treatment. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:  Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]  GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]  Hepatotoxicity [see Warnings and Precautions (5.3)]  Hypertension [see Warnings and Precautions (5.4)]  Heart Failure and Edema [see Warnings and Precautions (5.5)]  Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]  Anaphylactic Reactions [see Warnings and Precautions (5.7)]  Serious Skin Reactions [see Warnings and Precautions (5.9)]  Hematologic Toxicity [see Warnings and Precautions (5.11)] 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. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving INDOCIN Capsules than in the group taking INDOCIN Suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with INDOCIN Capsules or Suppositories was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for INDOCIN Capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between INDOCIN and these adverse reactions, some of which have been reported only rarely. The adverse reactions reported with INDOCIN Capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the capsules. Table 1 Summary of Adverse Reactions for INDOCIN Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea * with or without vomiting dyspepsia * (including indigestion, heartburn and epigastric pain) anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and Reference ID: 3928088 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% Incidence less than 1% diarrhea abdominal distress or pain constipation proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness * vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with INDOCIN blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC None edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia INTEGUMENTARY none pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation Reference ID: 3928088 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% Incidence less than 1% HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia * Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak Genitourinary: Urinary frequency A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome. 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with indomethacin. Table 2 Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact:  Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.  Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of INDOCIN with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda [see Warnings and Precautions (5.11)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of INDOCIN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. INDOCIN is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact:  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention:  During concomitant use of INDOCIN and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  During concomitant use of INDOCIN and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].  When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN resulted in reversible acute renal failure in two of four healthy volunteers. INDOCIN and triamterene should not be administered together. Both INDOCIN and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of INDOCIN and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of INDOCIN with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of INDOCIN and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of INDOCIN and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of INDOCIN and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of INDOCIN and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of INDOCIN and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of INDOCIN and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of INDOCIN and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of INDOCIN and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests INDOCIN reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including INDOCIN, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including INDOCIN, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of INDOCIN in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of INDOCIN during labor or delivery. In animal studies, NSAIDs, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Animal data Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 Lactation Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INDOCIN and any potential adverse effects on the breastfed infant from the INDOCIN or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight- adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/ kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including INDOCIN, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including INDOCIN, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. INDOCIN should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with INDOCIN Capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of INDOCIN Capsules. If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1 800-222-1222). 11 DESCRIPTION INDOCIN (indomethacin) Capsules are nonsteroidal anti-inflammatory drugs, available as capsules containing 25 mg of indomethacin, administered for oral use. The chemical name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4 , and it has the following chemical structure. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The inactive ingredients in INDOCIN Capsules 25 mg include: colloidal silicon dioxide, FD&C Blue 1, FD&C Red 3, gelatin, lactose, lecithin, magnesium stearate, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of INDOCIN, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption Following single oral doses of INDOCIN Capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered INDOCIN Capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of INDOCIN Oral Suspension was found to be bioequivalent to a 50 mg INDOCIN Capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elimination Metabolism Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of INDOCIN has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of INDOCIN has not been investigated in patients with hepatic impairment. Renal Impairment: The pharmacokinetics of INDOCIN has not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)]. When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis, respectively). Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). 14 CLINICAL STUDIES INDOCIN has been shown to be an effective anti-inflammatory agent, appropriate for long- term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. INDOCIN affords relief of symptoms; it does not alter the progressive course of the underlying disease. INDOCIN suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with INDOCIN for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. INDOCIN may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. 16 HOW SUPPLIED/STORAGE AND HANDLING INDOCIN (indomethacin) Capsules, 25 mg each, are opaque, blue and white capsules. NDC 0006-0025-68: bottles of 100 NDC 0006-0025-82: bottles of 1000 Storage Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with INDOCIN and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop INDOCIN and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions Advise patients to stop INDOCIN immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including INDOCIN, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of INDOCIN and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of INDOCIN with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with INDOCIN until they talk to their healthcare provider [see Drug Interactions (7)]. Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Manufactured for and Distributed by: Iroko Pharmaceuticals, LLC Philadelphia, PA 19112 Issued: May/2016 Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including:  Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.  Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o longer use of NSAIDs o smoking o drinking alcohol o older age o poor health o advanced liver disease o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs 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 NSAIDs? Do not take NSAIDs:  if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.  right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:  have liver or kidney problems  have high blood pressure  have asthma  are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.  are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?”  new or worse high blood pressure  heart failure  liver problems including liver failure  kidney problems including kidney failure  low red blood cells (anemia) Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  life-threatening skin reactions  life-threatening allergic reactions  Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get 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 taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:  nausea  more tired or weaker than usual  diarrhea  itching  your skin or eyes look yellow  indigestion or stomach pain  flu-like symptoms  vomit blood  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, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs  Aspirin is an NSAID 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 NSAIDs 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. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for and Distributed by: Iroko Pharmaceuticals, LLC One Kew Place 150 Rouse Boulevard Philadelphia, PA 19112 For more information, go to www.iroko.com or call 1-877-757-0676 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued or Revised: May 2016 Reference ID: 3928088 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:57.301399	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016059s098s099lbl.pdf', 'application_number': 16059, 'submission_type': 'SUPPL ', 'submission_number': 98}
10,867	HALDOL brand of haloperidol injection (For Immediate Release) WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol is the first of the butyrophenone series of major antipsychotics. The chemical designation is 4-[4-(p-chlorophenyl)-4-hydroxypiperidino] 4’-fluorobutyrophenone and it has the following structural formula: structural formula HALDOL (haloperidol) is available as a sterile parenteral form for intramuscular injection. The injection provides 5 mg haloperidol (as the lactate) and lactic acid for pH adjustment between 3.0 – 3.6. ACTIONS The precise mechanism of action has not been clearly established. INDICATIONS HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia. Reference ID: 3933083 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL is indicated for the control of tics and vocal utterances of Tourette’s Disorder. CONTRAINDICATIONS HALDOL (haloperidol) is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Injection is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving HALDOL. Higher than recommended doses of any formulation and intravenous administration of HALDOL appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL INJECTION IS NOT APPROVED FOR INTRAVENOUS ADMINISTRATION. If HALDOL is administered intravenously, the ECG should be monitored for QT prolongation and arrhythmias. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. Reference ID: 3933083 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. Reference ID: 3933083 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. Usage in Pregnancy Rodents given 2 to 20 times the usual maximum human dose of haloperidol by oral or parenteral routes showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality. No teratogenic effect has been reported in rats, rabbits or dogs at dosages within this range, but cleft palate has been observed in mice given 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Infants should not be nursed during drug treatment. Non-teratogenic Effects Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have Reference ID: 3933083 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. HALDOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Combined Use of HALDOL and Lithium An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and fasting blood sugar) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL. It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. PRECAUTIONS Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including HALDOL. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of HALDOL should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Reference ID: 3933083 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue HALDOL and have their WBC followed until recovery. Other HALDOL (haloperidol) should be administered cautiously to patients: • with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL may block its vasopressor activity and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. • receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. • with known allergies, or with a history of allergic reactions to drugs. • receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). When HALDOL is used to control mania in cyclic disorders, there may be a rapid mood swing to depression. Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL. Drug Interactions Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using haloperidol in combination with other drugs have been evaluated as described below. Pharmacodynamic Interactions Since QT-prolongation has been observed during Haldol treatment, caution is advised when prescribing to a patient with QT-prolongation conditions (long QT-syndrome, hypokalemia, electrolyte imbalance) or to patients receiving medications known to prolong the QT-interval or known to cause electrolyte imbalance. If concomitant antiparkinson medication is required, it may have to be continued after HALDOL is discontinued because of the difference in excretion rates. If both are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when Reference ID: 3933083 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda anticholinergic drugs, including antiparkinson agents, are administered concomitantly with HALDOL. As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates and alcohol. Ketoconazole is a potent inhibitor of CYP3A4. Increases in QTc have been observed when haloperidol was given in combination with the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to reduce the haloperidol dosage. Pharmacokinetic Interactions The Effect of Other Drugs on Haldol® Haloperidol is metabolized by several routes, including the glucuronidation and the cytochrome P450 enzyme system. Inhibition of these routes of metabolism by another drug may result in increased haloperidol concentrations and potentially increase the risk of certain adverse events, including QT-prolongation. Drugs Characterized as Substrates, Inhibitors or Inducers of CYP3A4, CYP2D6 or Glucuronidation In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterized as substrates or inhibitors of CYP3A4 or CYP2D6 isoenzymes, such as itraconazole, nefazodone, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine. When prolonged treatment (1-2 weeks) with enzyme-inducing drugs such as rifampin or carbamazepine is added to Haldol therapy, this results in a significant reduction of haloperidol plasma levels. Rifampin In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Carbamazepine In a study in 11 schizophrenic patients co-administered haloperidol and increasing doses of carbamazepine, haloperidol plasma concentrations decreased linearly with increasing carbamazepine concentrations. Reference ID: 3933083 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thus, careful monitoring of clinical status is warranted when enzyme inducing drugs such as rifampin or carbamazepine are administered or discontinued in haloperidol treated patients. During combination treatment, the Haldol dose should be adjusted, when necessary. After discontinuation of such drugs, it may be necessary to reduce the dosage of Haldol. Valproate Sodium valproate, a drug know to inhibit glucuronidation, does not affect haloperidol plasma concentrations. Information for Patients HALDOL may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high- dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically Reference ID: 3933083 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. There are no well controlled studies with HALDOL (haloperidol) in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Nursing Mothers Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). Reference ID: 3933083 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance Reference ID: 3933083 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs but until further evidence becomes available, it seems reasonable to gradually withdraw use of HALDOL. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Reference ID: 3933083 11 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 Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. (See PRECAUTIONS: Leukopenia, Neutropenia, and Agranulocytosis.) Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. Rhabdomyolysis has been reported. Reference ID: 3933083 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor as demonstrated by the akinetic or agitans types respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION There is considerable variation from patient to patient in the amount of medication required for treatment. As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient. Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control. To determine the initial dosage, consideration should be given to the patient’s age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state. Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less HALDOL (haloperidol). The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels. Reference ID: 3933083 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. The maximum dose is 20 mg/day. Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Switchover Procedure An oral form should supplant the injectable as soon as practicable. In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover. In this way, dosage adjustments, either upward or downward, can be quickly accomplished. Depending on the patient’s clinical status, the first oral dose should be given within 12-24 hours following the last parenteral dose. Reference ID: 3933083 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INSTRUCTIONS FOR OPENING AMPULE Step 1 1. Medication often rests in the top part of the ampule. Before breaking the ampule, lightly tap the top of the ampule with your finger until all fluid moves to the bottom portion of the ampule. The ampule has a colored ring(s) and colored point which aids in the placement of fingers while breaking the ampule. usage illustration Step 2 2. Hold the ampule between thumb and index finger with the colored point facing you. usage illustration Step 3 3. Position the index finger of the other hand to support the neck of the ampule. Position the thumb so that it covers the colored point and is parallel to the colored ring(s). usage illustration Reference ID: 3933083 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Step 4 4. Keeping the thumb on the colored point and with the index fingers close together, apply firm pressure on the colored point in the direction of the arrow to snap the ampule open. usage illustration HOW SUPPLIED HALDOL brand of haloperidol Injection (For Immediate Release) 5 mg per mL (as the lactate) – NDC 50458-255-01, units of 10 x 1 mL ampules. Store HALDOL haloperidol Injection at controlled room temperature (15°-30°C, 59°-86°F). Protect from light. Do not freeze. Product of Belgium Manufactured by: GlaxoSmithKline Manufacturing S.p.A. Parma, Italy Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Revised January 2016 Janssen Pharmaceuticals, Inc. 2005 Reference ID: 3933083 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL® Decanoate 50 (haloperidol) HALDOL® Decanoate 100 (haloperidol) For IM Injection Only WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. HALDOL Decanoate is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL (haloperidol). It has a markedly extended duration of effect. It is available in sesame oil in sterile form for intramuscular (IM) injection. The structural formula of haloperidol decanoate, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate, is: structural formula Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in most organic solvents. Each mL of HALDOL Decanoate 50 for IM injection contains 50 mg haloperidol (present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. Reference ID: 3933083 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Each mL of HALDOL Decanoate 100 for IM injection contains 100 mg haloperidol (present as haloperidol decanoate 141.04 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. CLINICAL PHARMACOLOGY HALDOL Decanoate 50 and HALDOL Decanoate 100 are the long-acting forms of HALDOL (haloperidol). The basic effects of haloperidol decanoate are no different from those of HALDOL with the exception of duration of action. Haloperidol blocks the effects of dopamine and increases its turnover rate; however, the precise mechanism of action is unknown. Administration of haloperidol decanoate in sesame oil results in slow and sustained release of haloperidol. The plasma concentrations of haloperidol gradually rise, reaching a peak at about 6 days after the injection, and falling thereafter, with an apparent half-life of about 3 weeks. Steady state plasma concentrations are achieved after the third or fourth dose. The relationship between dose of haloperidol decanoate and plasma haloperidol concentration is roughly linear for doses below 450 mg. It should be noted, however, that the pharmacokinetics of haloperidol decanoate following intramuscular injections can be quite variable between subjects. INDICATIONS AND USAGE HALDOL Decanoate 50 and HALDOL Decanoate 100 are indicated for the treatment of schizophrenic patients who require prolonged parenteral antipsychotic therapy. CONTRAINDICATIONS Since the pharmacologic and clinical actions of HALDOL Decanoate 50 and HALDOL Decanoate 100 are attributed to HALDOL (haloperidol) as the active medication, Contraindications, Warnings, and additional information are those of HALDOL, modified only to reflect the prolonged action. HALDOL is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. HALDOL Decanoate is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Reference ID: 3933083 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiovascular Effects Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY. Tardive Dyskinesia A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. Reference ID: 3933083 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with HALDOL. Combined Use of HALDOL and Lithium An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and fasting blood sugar) followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL. A causal relationship between these events and the concomitant administration of lithium and Reference ID: 3933083 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HALDOL has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. General A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL (haloperidol). It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. PRECAUTIONS Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including HALDOL Decanoate. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of HALDOL Decanoate should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue HALDOL Decanoate and have their WBC followed until recovery. Other HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered cautiously to patients: • with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since HALDOL Reference ID: 3933083 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (haloperidol) may block its vasopressor activity, and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. • receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. • with known allergies, or with a history of allergic reactions to drugs. • receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione). If concomitant antiparkinson medication is required, it may have to be continued after HALDOL Decanoate 50 or HALDOL Decanoate 100 is discontinued because of the prolonged action of haloperidol decanoate. If both drugs are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with haloperidol decanoate. When HALDOL Decanoate is used to control mania in cyclic disorders, there may be a rapid mood swing to depression. Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL. Information for Patients Haloperidol decanoate may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient should be warned accordingly. The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. Drug Interactions Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using haloperidol in combination with other drugs have been evaluated as described below. Pharmacodynamic Interactions Since QT-prolongation has been observed during Haldol treatment, caution is advised when prescribing to a patient with QT-prolongation conditions (long QT-syndrome, hypokalemia, electrolyte imbalance) or to patients receiving medications known to prolong the QT-interval or known to cause electrolyte imbalance. Reference ID: 3933083 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda As with other antipsychotic agents, it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol. Ketoconazole is a potent inhibitor of CYP3A4. Increases in QTc have been observed when haloperidol was given in combination with the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to reduce the haloperidol dosage. Pharmacokinetic Interactions The Effect of Other Drugs on Haldol® Decanoate Haloperidol is metabolized by several routes, including the glucuronidation and the cytochrome P450 enzyme system. Inhibition of these routes of metabolism by another drug may result in increased haloperidol concentrations and potentially increase the risk of certain adverse events, including QT-prolongation. Drugs Characterized as Substrates, Inhibitors or Inducers of CYP3A4, CYP2D6 or Glucuronidation In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterized as substrates or inhibitors of CYP3A4 or CYP2D6 isoenzymes, such as itraconazole, nefazodone, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine. When prolonged treatment (1-2 weeks) with enzyme-inducing drugs such as rifampin or carbamazepine is added to Haldol therapy, this results in a significant reduction of haloperidol plasma levels. Rifampin In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with oral haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Carbamazepine In a study in 11 schizophrenic patients co-administered haloperidol and increasing doses of carbamazepine, haloperidol plasma concentrations decreased linearly with increasing carbamazepine concentrations. Thus, careful monitoring of clinical status is warranted when enzyme inducing drugs such as rifampin or carbamazepine are administered or discontinued in haloperidol-treated patients. During combination treatment, the Haldol dose should be Reference ID: 3933083 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda adjusted, when necessary. After discontinuation of such drugs, it may be necessary to reduce the dosage of Haldol. Valproate Sodium valproate, a drug know to inhibit glucuronidation, does not affect haloperidol plasma concentrations. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects of short-acting haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high-dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a haloperidol related increase in the incidence of neoplasia in rats at doses up to 20 times the usual daily human dose for chronic or resistant patients. In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic Reference ID: 3933083 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. Usage in Pregnancy Pregnancy Category C. Rodents given up to 3 times the usual maximum human dose of haloperidol decanoate showed an increase in incidence of resorption, fetal mortality, and pup mortality. No fetal abnormalities were observed. Cleft palate has been observed in mice given oral haloperidol at 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents. There are no adequate and well-controlled studies in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established with these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, haloperidol decanoate should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Non-teratogenic Effects Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. HALDOL Decanoate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol decanoate. Reference ID: 3933083 9 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 haloperidol decanoate in children have not been established. Geriatric Use Clinical studies of haloperidol 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 consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive dyskinesia). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Adverse reactions following the administration of HALDOL Decanoate 50 or HALDOL Decanoate 100 are those of HALDOL (haloperidol). Since vast experience has accumulated with HALDOL, the adverse reactions are reported for that compound as well as for haloperidol decanoate. As with all injectable medications, local tissue reactions have been reported with haloperidol decanoate. Cardiovascular Effects Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS). Cases of sudden and unexpected death have been reported in association with the administration of HALDOL. The nature of the evidence makes it impossible to determine definitively what role, if any, HALDOL played in the outcome of the reported cases. The possibility that HALDOL caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs. CNS Effects Extrapyramidal Symptoms (EPS) EPS during the administration of HALDOL (haloperidol) have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos Reference ID: 3933083 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Withdrawal Emergent Neurological Signs Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. Although the long-acting properties of haloperidol decanoate provide gradual withdrawal, it is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs. Tardive Dyskinesia As with all antipsychotic agents HALDOL has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy with haloperidol decanoate or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk. There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all Reference ID: 3933083 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop. Tardive Dystonia Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible. Other CNS Effects Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs. Body as a Whole Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with HALDOL. (See WARNINGS for further information concerning NMS.) Hematologic Effects Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of HALDOL, and then only in association with other medication. (See PRECAUTIONS: Leukopenia, Neutropenia, and Agranulocytosis.) Liver Effects Impaired liver function and/or jaundice have been reported. Dermatologic Reactions Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair. Endocrine Disorders Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia. Reference ID: 3933083 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal Effects Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting. Autonomic Reactions Dry mouth, blurred vision, urinary retention, diaphoresis and priapism. Respiratory Effects Laryngospasm, bronchospasm and increased depth of respiration. Special Senses Cataracts, retinopathy and visual disturbances. Postmarketing Events Hyperammonemia has been reported in a 5 1 /2 year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with HALDOL. Rhabdomyolysis has been reported. OVERDOSAGE While overdosage is less likely to occur with a parenteral than with an oral medication, information pertaining to HALDOL (haloperidol) is presented, modified only to reflect the extended duration of action of haloperidol decanoate. Manifestations In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor, as demonstrated by the akinetic or agitans types, respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS.) Treatment Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or Reference ID: 3933083 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks, and then withdrawn gradually as extrapyramidal symptoms may emerge. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. DOSAGE AND ADMINISTRATION HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HALDOL Decanoate 50 and HALDOL Decanoate 100 are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate. Furthermore, it is recommended that patients being considered for haloperidol decanoate therapy have been treated with, and tolerate well, short-acting HALDOL (haloperidol) in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting forms of haloperidol. The dose of HALDOL Decanoate 50 or HALDOL Decanoate 100 should be expressed in terms of its haloperidol content. The starting dose of haloperidol decanoate should be based on the patient’s age, clinical history, physical condition, and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed. For patients previously maintained on low doses of antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate be 10-15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate. Reference ID: 3933083 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Initial Therapy Conversion from oral haloperidol to haloperidol decanoate can be achieved by using an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose in oral haloperidol equivalents. In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion. In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections. The initial dose of haloperidol decanoate should not exceed 100 mg regardless of previous antipsychotic dose requirements. If, therefore, conversion requires more than 100 mg of haloperidol decanoate as an initial dose, that dose should be administered in two injections, i.e. a maximum of 100 mg initially followed by the balance in 3 to 7 days. Maintenance Therapy The maintenance dosage of haloperidol decanoate must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient. HALDOL DECANOATE DOSING RECOMMENDATIONS Monthly Patients 1st Month Maintenance Stabilized on low daily oral doses 10-15 x Daily Oral Dose 10-15 x Previous Daily Oral Dose (up to 10 mg/day) Elderly or Debilitated High dose 20 x Daily Oral Dose 10-15 x Previous Daily Oral Dose Risk of relapse Tolerant to oral haloperidol Close clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy. Haloperidol decanoate is usually administered monthly or every 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY). Reference ID: 3933083 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical experience with haloperidol decanoate at doses greater than 450 mg per month has been limited. INSTRUCTIONS FOR OPENING AMPULE Step 1 1. Medication often rests in the top part of the ampule. Before breaking the ampule, lightly tap the top of the ampule with your finger until all fluid moves to the bottom portion of the ampule. The ampule has a colored ring(s) and colored point which aids in the placement of fingers while breaking the ampule. usage illustration Step 2 2. Hold the ampule between thumb and index finger with the colored point facing you. usage illustration Step 3 3. Position the index finger of the other hand to support the neck of the ampule. Position the thumb so that it covers the colored point and is parallel to the colored ring(s). usage illustration Step 4 Reference ID: 3933083 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4. Keeping the thumb on the colored point, and with the index fingers close together, apply firm pressure on the colored point in the direction of the arrow to snap the ampule open. usage illustration HOW SUPPLIED HALDOL® (haloperidol) Decanoate 50 for IM injection, 50 mg haloperidol as 70.52 mg per mL haloperidol decanoate: NDC 50458-253-03 3 x 1 mL ampules. HALDOL® (haloperidol) Decanoate 100 for IM injection, 100 mg haloperidol as 141.04 mg per mL haloperidol decanoate: NDC 50458-254-14, 5 x 1 mL ampules. Store at controlled room temperature (15°-30° C, 59°-86° F). Do not refrigerate or freeze. Protect from light. Product of Belgium Manufactured by: GlaxoSmithKline Manufacturing S.p.A. Parma, Italy Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Revised January 2016  Janssen Pharmaceuticals, Inc. 2005 Reference ID: 3933083 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:57.389277	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/015923s094,018701s072lbl.pdf', 'application_number': 15923, 'submission_type': 'SUPPL ', 'submission_number': 94}
10,872	NDA 16-096/S-033 NDA 16-097/S-026 Page 3 CHEWABLE TABLETS AND SUSPENSION MINTEZOL® (Thiabendazole) DESCRIPTION MINTEZOL* (Thiabendazole) is an anthelmintic provided as 500 mg chewable tablets, and as a suspension, containing 500 mg thiabendazole per 5 mL. The suspension also contains sorbic acid 0.1% added as a preservative. Inactive ingredients in the tablets are acacia, calcium phosphate, flavors, lactose, magnesium stearate, mannitol, methylcellulose, and sodium saccharin. Inactive ingredients in the suspension are an antifoam agent, flavors, polysorbate, purified water, sorbitol solution, and tragacanth. Thiabendazole is a white to off-white odorless powder with a molecular weight of 201.26, which is practically insoluble in water but readily soluble in dilute acid and alkali. Its chemical name is 2-(4-thiazolyl)-1H- benzimidazole. The empirical formula is C10H7N3S and the structural formula is: CLINICAL PHARMACOLOGY In man, thiabendazole is rapidly absorbed and peak plasma concentration is reached within 1 to 2 hours after the oral administration of a suspension. It is metabolized almost completely to the 5-hydroxy form which appears in the urine as glucuronide or sulfate conjugates. In 48 hours, about 5% of the administered dose is recovered from the feces and about 90% from the urine. Most is excreted in the first 24 hours. Mechanism of Action The precise mode of action of thiabendazole on the parasite is unknown, but it may inhibit the helminth- specific enzyme fumarate reductase. Thiabendazole is vermicidal and/or vermifugal against Ascaris lumbricoides (“common roundworm”), Strongyloides stercoralis (threadworm), Necator americanus, and Ancylostoma duodenale (hookworm), Trichuris trichiura (whipworm), Ancylostoma braziliense (dog and cat hookworm), Toxocara canis and Toxocara cati (ascarids), and Enterobius vermicularis (pinworm). Its effect on larvae of Trichinella spiralis that have migrated to muscle is questionable. Thiabendazole also suppresses egg and/or larval production and may inhibit the subsequent development of those eggs or larvae which are passed in the feces. INDICATIONS AND USAGE MINTEZOL is indicated for the treatment of: Strongyloidiasis (threadworm) Cutaneous larva migrans (creeping eruption) Visceral larva migrans Trichinosis: Relief of symptoms and fever and a reduction of eosinophilia have followed the use of MINTEZOL during the invasion stage of the disease. * Registered trademark of MERCK & CO., Inc. COPYRIGHT © MERCK & CO., Inc., 1983 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 16-096/S-033 NDA 16-097/S-026 Page 4 Thiabendazole is usually inappropriate as first line therapy for enterobiasis (pinworm). However, when enterobiasis occurs with any of the conditions listed above, additional therapy is not required for most patients. MINTEZOL should be used only in the following infestations when more specific therapy is not available or cannot be used or when further therapy with a second agent is desirable: Uncinariasis (hookworm: Necator americanus and Ancylostoma duodenale); Trichuriasis (whipworm); Ascariasis (large roundworm). CONTRAINDICATIONS Hypersensitivity to this product. Thiabendazole is contraindicated as prophylactic treatment for pinworm infestation. WARNINGS If hypersensitivity reactions occur, the drug should be discontinued immediately and not be resumed. Erythema multiforme has been associated with thiabendazole therapy; in severe cases (Stevens-Johnson syndrome), fatalities have occurred. Because CNS side effects may occur quite frequently, activities requiring mental alertness should be avoided. Jaundice, cholestasis, and parenchymal liver damage have been reported in patients treated with MINTEZOL. In rare cases, liver damage has been severe and has led to irreversible hepatic failure. (See ADVERSE REACTIONS.) Abnormal sensation in eyes, xanthopsia, blurred vision, drying of mucous membranes, and Sicca syndrome have been reported in patients treated with MINTEZOL. These adverse effects of the eye were in some cases persistent for prolonged intervals which have exceeded one year. (See ADVERSE REACTIONS.) Thiabendazole should not usually be used as first line therapy for the treatment of enterobiasis. It should be reserved for use in patients who have experienced allergic reactions, or resistance to other treatments. PRECAUTIONS General MINTEZOL is not suitable for the treatment of mixed infections with ascaris because it may cause these worms to migrate. Ideally, supportive therapy is indicated for anemic, dehydrated or malnourished patients prior to initiation of the anthelmintic therapy. In the presence of hepatic or renal dysfunction, patients should be carefully monitored. MINTEZOL should be used only in patients in whom susceptible worm infestation has been diagnosed and should not be used prophylactically. Information for Patients Because CNS side effects may occur quite frequently, activities requiring mental alertness should be avoided. Laboratory Tests Rarely, a transient rise in liver function tests has occurred in patients receiving MINTEZOL. Drug Interactions Thiabendazole may compete with other drugs, such as theophylline, for sites of metabolism in the liver, thus elevating the serum levels of such compounds to potentially toxic levels. Therefore, when concomitant use of thiabendazole and xanthine derivatives is anticipated, it may be necessary to monitor blood levels and/or reduce the dosage of such compounds. Such concomitant use should be administered under careful medical supervision. Carcinogenesis, Mutagenesis, Impairment of Fertility Thiabendazole has been used in numerous short- and long-term studies in animals at doses up to 15 times the usual human dose and was without carcinogenic effects. It did not adversely affect fertility in the mouse at 2½ times the usual human dose or in the rat at a dose equivalent to the usual human dose. Thiabendazole had no mutagenic activity in in vitro microbial mutagen test, the micronucleus test and the host mediated assay in vivo. Pregnancy Pregnancy Category C: Reproduction and teratogenic studies done in the rabbit at a dose up to 15 times the usual human dose, in the rat at a dose equivalent to the human dose, and in the mouse at a dose up to 2½ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-096/S-033 NDA 16-097/S-026 Page 5 times the usual human dose, revealed no evidence of harm to the fetus. In an additional study in the mouse, no defects were observed when thiabendazole was given in aqueous suspension, at a dose 10 times the usual human dose; however, cleft palate and axial skeletal defects were observed when thiabendazole was suspended in olive oil and given at the same dose. There are no adequate and well controlled studies in pregnant women. MINTEZOL 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 of the potential for serious adverse reactions in nursing infants from MINTEZOL, 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 safety and effectiveness of thiabendazole for the treatment of Strongyloidiasis, Ascariasis, Uncinariasis, Trichuriasis and Trichinosis in pediatric patients weighing less than 30 lbs has been limited. Geriatric Use Clinical studies of MINTEZOL 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 metabolized almost completely by the liver, and the metabolites are known to be substantially excreted by the kidney, therefore the risk of toxicity 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: anorexia, nausea, vomiting, diarrhea, epigastric distress, abdominal pain, jaundice, cholestasis, parenchymal liver damage and hepatic failure. (See WARNINGS.) Central Nervous System: dizziness, weariness, drowsiness, giddiness, headache, numbness, hyperirritability, convulsions, collapse, confusion, depression, floating sensation, weakness and lack of coordination. Special Senses: tinnitus, abnormal sensation in eyes, xanthopsia, blurred vision, reduced vision, drying of mucous membranes (mouth, eyes, etc.), Sicca syndrome. (See WARNINGS.) Cardiovascular: hypotension. Metabolic: hyperglycemia. Hematologic: transient leukopenia. Genitourinary: hematuria, enuresis, malodor of the urine, crystalluria. Hypersensitivity: pruritus, fever, facial flush, chills, conjunctival injection, angioedema, anaphylaxis, skin rashes (including perianal), erythema multiforme (including Stevens-Johnson syndrome), and lymphadenopathy. Miscellaneous: appearance of live Ascaris in the mouth and nose. OVERDOSAGE Overdosage may be associated with transient disturbances of vision and psychic alterations. There is no specific antidote in the event of overdosage. Therefore, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed carefully. The oral LD50 of MINTEZOL is 3.6 g/kg, 3.1 g/kg and 3.8 g/kg in the mouse, rat, and rabbit, respectively. DOSAGE AND ADMINISTRATION The recommended maximum daily dose of MINTEZOL is 3 grams. MINTEZOL should be given after meals if possible. Tablets MINTEZOL should be chewed before swallowing. Dietary restriction, complementary medications and cleansing enemas are not needed. The usual dosage schedule for all conditions is two doses per day. The dosage is determined by the patient's weight. A weight-dose chart follows: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-096/S-033 NDA 16-097/S-026 Page 6 Weight Each Dose g mL 30 lb 0.25 (½ tablet) 2.5 (½ teaspoon) 50 lb 0.5 (1 tablet) 5.0 (1 teaspoon) 75 lb 0.75 (1½ tablets) 7.5 (1½ teaspoons) 100 lb 1.0 (2 tablets) 10.0 (2 teaspoons) 125 lb 1.25 (2½ tablets) 12.5 (2½ teaspoons) 150 lb & over 1.5 (3 tablets) 15.0 (3 teaspoons) The regimen for each indication follows: Therapeutic Regimens Indication Regimen Comments STRONGYLOIDIASIS 2 doses per day for 2 successive days. A single dose of 20 mg/lb or 50 mg/kg may be employed as an alternative schedule, but a higher incidence of side effects should be expected. CUTANEOUS LARVA MIGRANS (Creeping Eruption) 2 doses per day for 2 successive days. If active lesions are still present 2 days after completion of therapy, a second course is recommended. VISCERAL LARVA MIGRANS 2 doses per day for 7 successive days. Safety and efficacy data on the seven-day treatment course are limited. TRICHINOSIS 2 doses per day for 2-4 successive days according to the response of the patient. The optimal dosage for the treatment of trichinosis has not been established. Other Indications Intestinal roundworms (including Ascariasis, Uncinariasis and Trichuriasis) 2 doses per day for 2 successive days. A single dose of 20 mg/lb or 50 mg/kg may be employed as an alternative schedule, but a higher incidence of side effects should be expected. Clinical experience with thiabendazole for treatment of each of these conditions in pediatric patients weighing less than 30 lbs has been limited. HOW SUPPLIED No. 3331 — MINTEZOL Suspension, 500 mg per 5 mL, is white to off-white and is supplied as follows: NDC 0006-3331-60 in bottles of 120 mL (6505-00-935-5835, 0.5 g/5 mL, 120 mL). Storage Store in a well-closed container at controlled room temperature [15-30°C (59-86°F)]. Protect from freezing. No. 3332 — MINTEZOL Chewable Tablets, 500 mg, are white to off-white, orange-flavored, round, scored, compressed tablets, coded MSD 907 on one side and MINTEZOL on the other. They are supplied as follows: NDC 0006-0907-36 unit dose packages of 36 (6505-01-226-9909, 500 mg chewable, individually sealed 36's). Storage Store in a well-closed container at controlled room temperature [15-30°C (59-86°F)]. Issued Month Year 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	2025-02-12T13:43:57.630708	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/16096slr033,16097slr026_mintezol_lbl.pdf', 'application_number': 16097, 'submission_type': 'SUPPL ', 'submission_number': 26}
10,871	NDA 16-096/S-033 NDA 16-097/S-026 Page 3 CHEWABLE TABLETS AND SUSPENSION MINTEZOL® (Thiabendazole) DESCRIPTION MINTEZOL* (Thiabendazole) is an anthelmintic provided as 500 mg chewable tablets, and as a suspension, containing 500 mg thiabendazole per 5 mL. The suspension also contains sorbic acid 0.1% added as a preservative. Inactive ingredients in the tablets are acacia, calcium phosphate, flavors, lactose, magnesium stearate, mannitol, methylcellulose, and sodium saccharin. Inactive ingredients in the suspension are an antifoam agent, flavors, polysorbate, purified water, sorbitol solution, and tragacanth. Thiabendazole is a white to off-white odorless powder with a molecular weight of 201.26, which is practically insoluble in water but readily soluble in dilute acid and alkali. Its chemical name is 2-(4-thiazolyl)-1H- benzimidazole. The empirical formula is C10H7N3S and the structural formula is: CLINICAL PHARMACOLOGY In man, thiabendazole is rapidly absorbed and peak plasma concentration is reached within 1 to 2 hours after the oral administration of a suspension. It is metabolized almost completely to the 5-hydroxy form which appears in the urine as glucuronide or sulfate conjugates. In 48 hours, about 5% of the administered dose is recovered from the feces and about 90% from the urine. Most is excreted in the first 24 hours. Mechanism of Action The precise mode of action of thiabendazole on the parasite is unknown, but it may inhibit the helminth- specific enzyme fumarate reductase. Thiabendazole is vermicidal and/or vermifugal against Ascaris lumbricoides (“common roundworm”), Strongyloides stercoralis (threadworm), Necator americanus, and Ancylostoma duodenale (hookworm), Trichuris trichiura (whipworm), Ancylostoma braziliense (dog and cat hookworm), Toxocara canis and Toxocara cati (ascarids), and Enterobius vermicularis (pinworm). Its effect on larvae of Trichinella spiralis that have migrated to muscle is questionable. Thiabendazole also suppresses egg and/or larval production and may inhibit the subsequent development of those eggs or larvae which are passed in the feces. INDICATIONS AND USAGE MINTEZOL is indicated for the treatment of: Strongyloidiasis (threadworm) Cutaneous larva migrans (creeping eruption) Visceral larva migrans Trichinosis: Relief of symptoms and fever and a reduction of eosinophilia have followed the use of MINTEZOL during the invasion stage of the disease. * Registered trademark of MERCK & CO., Inc. COPYRIGHT © MERCK & CO., Inc., 1983 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 16-096/S-033 NDA 16-097/S-026 Page 4 Thiabendazole is usually inappropriate as first line therapy for enterobiasis (pinworm). However, when enterobiasis occurs with any of the conditions listed above, additional therapy is not required for most patients. MINTEZOL should be used only in the following infestations when more specific therapy is not available or cannot be used or when further therapy with a second agent is desirable: Uncinariasis (hookworm: Necator americanus and Ancylostoma duodenale); Trichuriasis (whipworm); Ascariasis (large roundworm). CONTRAINDICATIONS Hypersensitivity to this product. Thiabendazole is contraindicated as prophylactic treatment for pinworm infestation. WARNINGS If hypersensitivity reactions occur, the drug should be discontinued immediately and not be resumed. Erythema multiforme has been associated with thiabendazole therapy; in severe cases (Stevens-Johnson syndrome), fatalities have occurred. Because CNS side effects may occur quite frequently, activities requiring mental alertness should be avoided. Jaundice, cholestasis, and parenchymal liver damage have been reported in patients treated with MINTEZOL. In rare cases, liver damage has been severe and has led to irreversible hepatic failure. (See ADVERSE REACTIONS.) Abnormal sensation in eyes, xanthopsia, blurred vision, drying of mucous membranes, and Sicca syndrome have been reported in patients treated with MINTEZOL. These adverse effects of the eye were in some cases persistent for prolonged intervals which have exceeded one year. (See ADVERSE REACTIONS.) Thiabendazole should not usually be used as first line therapy for the treatment of enterobiasis. It should be reserved for use in patients who have experienced allergic reactions, or resistance to other treatments. PRECAUTIONS General MINTEZOL is not suitable for the treatment of mixed infections with ascaris because it may cause these worms to migrate. Ideally, supportive therapy is indicated for anemic, dehydrated or malnourished patients prior to initiation of the anthelmintic therapy. In the presence of hepatic or renal dysfunction, patients should be carefully monitored. MINTEZOL should be used only in patients in whom susceptible worm infestation has been diagnosed and should not be used prophylactically. Information for Patients Because CNS side effects may occur quite frequently, activities requiring mental alertness should be avoided. Laboratory Tests Rarely, a transient rise in liver function tests has occurred in patients receiving MINTEZOL. Drug Interactions Thiabendazole may compete with other drugs, such as theophylline, for sites of metabolism in the liver, thus elevating the serum levels of such compounds to potentially toxic levels. Therefore, when concomitant use of thiabendazole and xanthine derivatives is anticipated, it may be necessary to monitor blood levels and/or reduce the dosage of such compounds. Such concomitant use should be administered under careful medical supervision. Carcinogenesis, Mutagenesis, Impairment of Fertility Thiabendazole has been used in numerous short- and long-term studies in animals at doses up to 15 times the usual human dose and was without carcinogenic effects. It did not adversely affect fertility in the mouse at 2½ times the usual human dose or in the rat at a dose equivalent to the usual human dose. Thiabendazole had no mutagenic activity in in vitro microbial mutagen test, the micronucleus test and the host mediated assay in vivo. Pregnancy Pregnancy Category C: Reproduction and teratogenic studies done in the rabbit at a dose up to 15 times the usual human dose, in the rat at a dose equivalent to the human dose, and in the mouse at a dose up to 2½ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-096/S-033 NDA 16-097/S-026 Page 5 times the usual human dose, revealed no evidence of harm to the fetus. In an additional study in the mouse, no defects were observed when thiabendazole was given in aqueous suspension, at a dose 10 times the usual human dose; however, cleft palate and axial skeletal defects were observed when thiabendazole was suspended in olive oil and given at the same dose. There are no adequate and well controlled studies in pregnant women. MINTEZOL 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 of the potential for serious adverse reactions in nursing infants from MINTEZOL, 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 safety and effectiveness of thiabendazole for the treatment of Strongyloidiasis, Ascariasis, Uncinariasis, Trichuriasis and Trichinosis in pediatric patients weighing less than 30 lbs has been limited. Geriatric Use Clinical studies of MINTEZOL 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 metabolized almost completely by the liver, and the metabolites are known to be substantially excreted by the kidney, therefore the risk of toxicity 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: anorexia, nausea, vomiting, diarrhea, epigastric distress, abdominal pain, jaundice, cholestasis, parenchymal liver damage and hepatic failure. (See WARNINGS.) Central Nervous System: dizziness, weariness, drowsiness, giddiness, headache, numbness, hyperirritability, convulsions, collapse, confusion, depression, floating sensation, weakness and lack of coordination. Special Senses: tinnitus, abnormal sensation in eyes, xanthopsia, blurred vision, reduced vision, drying of mucous membranes (mouth, eyes, etc.), Sicca syndrome. (See WARNINGS.) Cardiovascular: hypotension. Metabolic: hyperglycemia. Hematologic: transient leukopenia. Genitourinary: hematuria, enuresis, malodor of the urine, crystalluria. Hypersensitivity: pruritus, fever, facial flush, chills, conjunctival injection, angioedema, anaphylaxis, skin rashes (including perianal), erythema multiforme (including Stevens-Johnson syndrome), and lymphadenopathy. Miscellaneous: appearance of live Ascaris in the mouth and nose. OVERDOSAGE Overdosage may be associated with transient disturbances of vision and psychic alterations. There is no specific antidote in the event of overdosage. Therefore, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed carefully. The oral LD50 of MINTEZOL is 3.6 g/kg, 3.1 g/kg and 3.8 g/kg in the mouse, rat, and rabbit, respectively. DOSAGE AND ADMINISTRATION The recommended maximum daily dose of MINTEZOL is 3 grams. MINTEZOL should be given after meals if possible. Tablets MINTEZOL should be chewed before swallowing. Dietary restriction, complementary medications and cleansing enemas are not needed. The usual dosage schedule for all conditions is two doses per day. The dosage is determined by the patient's weight. A weight-dose chart follows: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-096/S-033 NDA 16-097/S-026 Page 6 Weight Each Dose g mL 30 lb 0.25 (½ tablet) 2.5 (½ teaspoon) 50 lb 0.5 (1 tablet) 5.0 (1 teaspoon) 75 lb 0.75 (1½ tablets) 7.5 (1½ teaspoons) 100 lb 1.0 (2 tablets) 10.0 (2 teaspoons) 125 lb 1.25 (2½ tablets) 12.5 (2½ teaspoons) 150 lb & over 1.5 (3 tablets) 15.0 (3 teaspoons) The regimen for each indication follows: Therapeutic Regimens Indication Regimen Comments STRONGYLOIDIASIS 2 doses per day for 2 successive days. A single dose of 20 mg/lb or 50 mg/kg may be employed as an alternative schedule, but a higher incidence of side effects should be expected. CUTANEOUS LARVA MIGRANS (Creeping Eruption) 2 doses per day for 2 successive days. If active lesions are still present 2 days after completion of therapy, a second course is recommended. VISCERAL LARVA MIGRANS 2 doses per day for 7 successive days. Safety and efficacy data on the seven-day treatment course are limited. TRICHINOSIS 2 doses per day for 2-4 successive days according to the response of the patient. The optimal dosage for the treatment of trichinosis has not been established. Other Indications Intestinal roundworms (including Ascariasis, Uncinariasis and Trichuriasis) 2 doses per day for 2 successive days. A single dose of 20 mg/lb or 50 mg/kg may be employed as an alternative schedule, but a higher incidence of side effects should be expected. Clinical experience with thiabendazole for treatment of each of these conditions in pediatric patients weighing less than 30 lbs has been limited. HOW SUPPLIED No. 3331 — MINTEZOL Suspension, 500 mg per 5 mL, is white to off-white and is supplied as follows: NDC 0006-3331-60 in bottles of 120 mL (6505-00-935-5835, 0.5 g/5 mL, 120 mL). Storage Store in a well-closed container at controlled room temperature [15-30°C (59-86°F)]. Protect from freezing. No. 3332 — MINTEZOL Chewable Tablets, 500 mg, are white to off-white, orange-flavored, round, scored, compressed tablets, coded MSD 907 on one side and MINTEZOL on the other. They are supplied as follows: NDC 0006-0907-36 unit dose packages of 36 (6505-01-226-9909, 500 mg chewable, individually sealed 36's). Storage Store in a well-closed container at controlled room temperature [15-30°C (59-86°F)]. Issued Month Year 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	2025-02-12T13:43:57.665371	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/16096slr033,16097slr026_mintezol_lbl.pdf', 'application_number': 16096, 'submission_type': 'SUPPL ', 'submission_number': 33}
10,874	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/ --------------------- Charles Ganley 8/30/01 12:14:57 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:57.771921	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/16126s25lbl.pdf', 'application_number': 16126, 'submission_type': 'SUPPL ', 'submission_number': 25}
10,873	1 TESLAC® (testolactone tablets, USP) DESCRIPTION TESLAC (testolactone tablets, USP) is available for oral administration as tablets providing 50 mg testolactone per tablet. Testolactone is a synthetic antineoplastic agent that is structurally distinct from the androgen steroid nucleus in possessing a six-membered lactone ring in place of the usual five-membered carbocyclic D-ring. Testolactone is chemically designated as 13- hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid δ-lactone. Graphic formula: C19H24O3 MW300.40 CAS-968-93-4 Inactive ingredients: calcium stearate, cornstarch, gelatin, and lactose. Testolactone is a white, odorless, crystalline solid, soluble in ethanol and slightly soluble in water. CLINICAL PHARMACOLOGY Although the precise mechanism by which testolactone produces its clinical antineoplastic effects has not been established, its principal action is reported to be inhibition of steroid aromatase activity and consequent reduction in estrone synthesis from adrenal androstenedione, the major source of estrogen in postmenopausal women. Based on in vitro studies, the aromatase inhibition may be noncompetitive and irreversible. This phenomenon may account for the persistence of testolactone’s effect on estrogen synthesis after drug withdrawal. Rx only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Despite some similarity to testosterone, testolactone has no in vivo androgenic effect. No other hormonal effects have been reported in clinical studies in patients receiving testolactone. In one study, testolactone administered orally (1000 mg/day) was reported to increase renal tubular reabsorption of calcium but to have no effect on serum calcium concentration. The mechanism of the hypocalciuric effect is unknown. No clinical effects in humans of testolactone on adrenal function have been reported; however, one study noted an increase in urinary excretion of 17-ketosteroids in most of the patients treated with 150 mg/day orally. Testolactone is well absorbed from the gastrointestinal tract. It is metabolized to several derivatives in the liver, all of which preserve the lactone D-ring. These metabolites, as well as some unmetabolized drug, are excreted in the urine. Additional pharmacokinetic data in humans are unavailable. For information concerning carcinogenesis, mutagenesis, pregnancy, and lactation, see the corresponding PRECAUTIONS sections. In animals, parenteral but not oral testolactone reduced cortisone acetate induced hepatic glycogen deposits. In animal tests conducted to detect any hormonal activity for testolactone, some evidence of antiandrogenic and antiglucocorticoid activity was seen; increased growth rate in the newborn was suggested. However there was no clear manifestation of androgenic, estrogenic or antiestrogenic, progestational or antiprogestational, gonadotropin-like or antigonadotropic effects. Testolactone did not demonstrate anti-inflammatory, mineralocorticoid- like, or glucocorticoid-like properties. INDICATIONS AND USAGE TESLAC (testolactone tablets, USP) is recommended as adjunctive therapy in the palliative treatment of advanced or disseminated breast cancer in postmenopausal women when hormonal therapy is indicated. It may also be used in women who were diagnosed as having had disseminated breast carcinoma when premenopausal, in whom ovarian function has been subsequently terminated. TESLAC (testolactone tablets, USP) was found to be effective in approximately 15 percent of patients with advanced or disseminated mammary cancer evaluated according to the following criteria: 1) those with a measurable decrease in size of all demonstrable tumor masses; 2) those in whom more than 50 percent of non-osseous lesions decreased in size although all bone lesions remained static; and 3) those in whom more than 50 percent of total lesions improved while the remainder were static. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 CONTRAINDICATIONS Testolactone is contraindicated in the treatment of breast cancer in men and in patients with a history of hypersensitivity to the drug. PRECAUTIONS Information for Patients The physician should be consulted regarding missed doses. Notify the physician if adverse reactions occur or become more pronounced. Laboratory Tests Plasma calcium levels should be routinely determined in any patient receiving therapy for mammary cancer, particularly during periods of active remission of bony metastases. If hypercalcemia occurs, appropriate measures should be instituted. Drug Interactions When administered concurrently, testolactone may increase the effects of oral anticoagulants; monitor and adjust anticoagulant dosage accordingly. Drug/Laboratory Test Interactions Physiologic effects of testolactone may result in decreased estradiol concentrations with radioimmunoassays for estradiol, increased plasma calcium concentrations (see PRECAUTIONS, Laboratory Tests), and increased 24-hour urinary excretion of creatine and 17-ketosteroids. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to evaluate carcinogenic potential or mutagenesis. Testolactone did not affect fertility in male or female rats. Pregnancy: Teratogenic Effects, Category C In rats, testolactone has been shown to produce increased fetal mortality, increased abnormal fetal development, and increased mortality in growing pups when given at doses 5 to 15 times This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 the recommended human dose. In rabbits, no teratologic effects were observed at doses 2.5 to 7.5 times the recommended human dose. There are no adequate and well-controlled studies in pregnant women. Testolactone is intended for use only in postmenopausal women and should not be used during pregnancy. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether or not to discontinue nursing. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Insufficient data from clinical studies of TESLAC are available for patients 65 years of age and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, caution should be exercised when prescribing to elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Testolactone and its metabolites appear 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 Certain signs and symptoms have been reported in association with the use of this drug but, in these instances, it is often impossible to determine the relationship of the underlying disease and drug administration to the reported reaction. Such reactions include maculopapular erythema, increase in blood pressure, paresthesia, malaise, aches and edema of the extremities, glossitis, anorexia and nausea and vomiting. Alopecia alone and with associated nail growth disturbance have been reported rarely; these side effects subsided without interruption of treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 DRUG ABUSE AND DEPENDENCE TESLAC is classified as a controlled substance under the Anabolic Steroids Control Act of 1990 and has been assigned to Schedule III. OVERDOSAGE There have been no reports of acute overdosage with testolactone tablets. DOSAGE AND ADMINISTRATION The recommended oral dose is 250 mg qid. In order to evaluate the response, therapy with testolactone should be continued for a minimum of three months unless there is active progression of the disease. HOW SUPPLIED TESLAC (testolactone tablets, USP), 50 mg/tablet: bottles of 100 (NDC 0003-0690-50). Each round, white, biconvex tablet is imprinted with the identification number 690. Storage Store at controlled room temperature 25º C (77º F) Made in Australia xxxxxx Revised _______________ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:57.784968	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/16118slr023_teslac_lbl.pdf', 'application_number': 16118, 'submission_type': 'SUPPL ', 'submission_number': 23}
10,876	company logo Desferal® deferoxamine mesylate for injection USP Vials Rx only Prescribing Information DESCRIPTION Desferal, deferoxamine mesylate USP, is an iron-chelating agent, available in vials for intramuscular, subcutaneous, and intravenous administration. Desferal is supplied as vials containing 500 mg and 2 g of deferoxamine mesylate USP in sterile, lyophilized form. Deferoxamine mesylate is N-[5-[3-[(5 aminopentyl)hydroxycarbamoyl]propionamido]pentyl]-3-[[5-(N hydroxyacetamido)pentyl]carbamoyl]propionohydroxamic acid monomethanesul-fonate (salt), and its structural formula is structural formula Deferoxamine mesylate USP is a white to off-white powder. It is freely soluble in water and slightly soluble in methanol. Its molecular weight is 656.79. CLINICAL PHARMACOLOGY Desferal chelates iron by forming a stable complex that prevents the iron from entering into further chemical reactions. It readily chelates iron from ferritin and hemosiderin but not readily from transferrin; it does not combine with the iron from cytochromes and hemoglobin. Desferal does not cause any demonstrable increase in the excretion of electrolytes or trace metals. Theoretically, 100 parts by weight of Desferal is capable of binding approximately 8.5 parts by weight of ferric iron. Desferal is metabolized principally by plasma enzymes, but the pathways have not yet been defined. The chelate is readily soluble in water and passes easily through the kidney, giving the urine a characteristic reddish color. Some is also excreted in the feces via the bile. INDICATIONS AND USAGE Desferal is indicated for the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias. Acute Iron Intoxication Desferal is an adjunct to, and not a substitute for, standard measures used in treating acute iron intoxication, which may include the following: induction of emesis with syrup of ipecac; gastric lavage; suction and maintenance of a clear airway; control of shock with intravenous fluids, blood, oxygen, and vasopressors; and correction of acidosis. Reference ID: 3059820 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chronic Iron Overload Desferal can promote iron excretion in patients with secondary iron overload from multiple transfusions (as may occur in the treatment of some chronic anemias, including thalassemia). Long- term therapy with Desferal slows accumulation of hepatic iron and retards or eliminates progression of hepatic fibrosis. Iron mobilization with Desferal is relatively poor in patients under the age of 3 years with relatively little iron overload. The drug should ordinarily not be given to such patients unless significant iron mobilization (e.g., 1 mg or more of iron per day) can be demonstrated. Desferal is not indicated for the treatment of primary hemochromatosis, since phlebotomy is the method of choice for removing excess iron in this disorder. CONTRAINDICATIONS Known hypersensitivity to the active substance. Desferal is contraindicated in patients with severe renal disease or anuria, since the drug and the iron chelate are excreted primarily by the kidney. (See WARNINGS). WARNINGS Ocular and auditory disturbances have been reported when Desferal was administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. The ocular disturbances observed have been blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory abnormalities reported have been tinnitus and hearing loss including high frequency sensorineural hearing loss. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment (see PRECAUTIONS/Information for Patients and ADVERSE REACTIONS/Special Senses). Visual acuity tests, slit-lamp examinations, funduscopy and audiometry are recommended periodically in patients treated for prolonged periods of time. Toxicity is more likely to be reversed if symptoms or test abnormalities are detected early. Increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders, associated with the administration of deferoxamine, have been reported in postmarketing experience (see ADVERSE REACTIONS). Monitor patients for changes in renal function. High doses of Desferal and concomitant low ferritin levels have also been associated with growth retardation. After reduction of Desferal dose, growth velocity may partially resume to pretreatment rates (see PRECAUTIONS/Pediatric Use). Adult respiratory distress syndrome, also reported in children, has been described following treatment with excessively high intravenous doses of Desferal in patients with acute iron intoxication or thalassemia. Reference ID: 3059820 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Flushing of the skin, urticaria, hypotension, and shock have occurred in a few patients when Desferal was administered by rapid intravenous injection. THEREFORE, DESFERAL SHOULD BE GIVEN INTRAMUSCULARLY OR BY SLOW SUBCUTANEOUS OR INTRAVENOUS INFUSION. Iron overload increases susceptibility of patients to Yersinia enterocolitica and Yersinia pseudotuberculosis infections. In some rare cases, treatment with Desferal has enhanced this susceptibility, resulting in generalized infections by providing these bacteria with a siderophore otherwise missing. In such cases, Desferal treatment should be discontinued until the infection is resolved. In patients receiving Desferal, rare cases of mucormycosis, some with a fatal outcome, have been reported. If any of the suspected signs or symptoms occur, Desferal should be discontinued, mycological tests carried out and appropriate treatment instituted immediately. In patients with severe chronic iron overload, impairment of cardiac function has been reported following concomitant treatment with Desferal and high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and Desferal are to be used concomitantly: • Vitamin C supplements should not be given to patients with cardiac failure. • Start supplemental vitamin C only after an initial month of regular treatment with Desferal. • Give vitamin C only if the patient is receiving Desferal regularly, ideally soon after setting up the infusion pump. • Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses. • Clinical monitoring of cardiac function is advisable during such combined therapy. In patients with aluminum-related encephalopathy and receiving dialysis, Desferal may cause neurological dysfunction (seizures), possibly due to an acute increase in circulating aluminum (see ADVERSE REACTIONS). Desferal may precipitate the onset of dialysis dementia. Treatment with Desferal in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism. Drug Interactions Vitamin C: Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. As an adjuvant to iron chelation therapy, vitamin C in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with Desferal (see PRECAUTIONS). Vitamin C increases availability of iron for chelation. In general, 50 mg daily suffices for children under 10 years old and 100 mg daily for older children. Larger doses of vitamin C fail to produce any additional increase in excretion of iron complex. Prochlorperazine: Concurrent treatment with Desferal and prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of consciousness. Gallium-67: Imaging results may be distorted because of the rapid urinary excretion of Desferal-bound gallium-67. Discontinuation of Desferal 48 hours prior to scintigraphy is advisable. Reference ID: 3059820 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 experiencing dizziness or other nervous system disturbances, or impairment of vision or hearing, should refrain from driving or operating potentially hazardous machines (see ADVERSE REACTIONS). Patients should be informed that occasionally their urine may show a reddish discoloration. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in animals have not been performed with Desferal. Cytotoxicity may occur, since Desferal has been shown to inhibit DNA synthesis in vitro. Pregnancy Category C Delayed ossification in mice and skeletal anomalies in rabbits were observed after Desferal was administered in daily doses up to 4.5 times the maximum daily human dose. No adverse effects were observed in similar studies in rats. There are no adequate and well-controlled studies in pregnant women. Desferal 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 Desferal is administered to a nursing woman. Pediatric Use Pediatric patients receiving Desferal should be monitored for body weight and growth every 3 months. Safety and effectiveness in pediatric patients under the age of 3 years have not been established (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS/Drug Interactions/Vitamin C, and ADVERSE REACTIONS). Geriatric Use Clinical Studies of Desferal did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from the younger subjects. Postmarketing reports suggest a possible trend for an increased risk of eye disorders in the geriatric population, specifically the occurrence of color blindness, maculopathy, and scotoma. However, it is unclear if these eye disorders were dose related. Although the number of reports was very small, certain elderly patients may be predisposed to eye disorders when taking Desferal. Postmarketing reports also suggest that there may be an increased risk of deafness and hearing loss in the geriatric population. (see ADVERSE REACTIONS). 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. Hepatic Impairment No studies have been performed in patients with hepatic impairment. Reference ID: 3059820 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency. At the Injection Site: Localized irritation, pain, burning, swelling, induration, infiltration, pruritus, erythema, wheal formation, eschar, crust, vesicles, local edema. Injection site reactions may be associated with systemic allergic reactions (see Body as a Whole, below). Hypersensitivity Reactions and Systemic Allergic Reactions: Generalized rash, urticaria, anaphylactic reaction with or without shock, angioedema. Body as a Whole: Local injection site reactions may be accompanied by systemic reactions like arthralgia, fever, headache, myalgia, nausea, vomiting, abdominal pain, or asthma. Infections with Yersinia and Mucormycosis have been reported in association with Desferal use (see PRECAUTIONS). Cardiovascular: Tachycardia, hypotension, shock. Digestive: Abdominal discomfort, diarrhea, nausea, vomiting. Hematologic: Blood dyscrasia (thrombocytopenia, leucopenia). Hepatic: Increased transaminases, hepatic dysfunction. Musculoskeletal: Muscle spasms. Growth retardation and bone changes (e.g., metaphyseal dysplasia) are common in chelated patients given doses above 60 mg/kg, especially those who begin iron chelation in the first three years of life. If doses are kept to 40 mg/kg or below, the risk may be reduced (see WARNINGS, PRECAUTIONS/Pediatric Use). Nervous System: Neurological disturbances including dizziness, peripheral sensory, motor, or mixed neuropathy, paresthesias, seizures; exacerbation or precipitation of aluminum-related dialysis encephalopathy (see PRECAUTIONS/Information for Patients). Special Senses: High-frequency sensorineural hearing loss and/or tinnitus are uncommon if dosage guidelines are not exceeded and if dose is reduced when ferritin levels decline. Visual disturbances are rare if dosage guidelines are not exceeded. These may include decreased acuity, blurred vision, loss of vision, dyschromatopsia, night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration), optic neuritis, and cataracts (see WARNINGS). Respiratory: Acute respiratory distress syndrome (with dyspnea, cyanosis, and/or interstitial infiltrates) (see WARNINGS). Skin: Very rare generalized rash. Urogenital: Dysuria, acute renal failure, increased serum creatinine and renal tubular disorders (see CONTRAINDICATIONS and WARNINGS). Postmarketing Reports There are postmarketing reports of deferoxamine-associated renal dysfunction, including renal failure. Monitor patients for changes in renal function (e.g., increased serum creatinine). Reference ID: 3059820 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE Acute Toxicity Intravenous LD50s (mg/kg): mice, 287; rats, 329. Signs and Symptoms Inadvertent administration of an overdose or inadvertent intravenous bolus administration/rapid intravenous infusion may be associated with hypotension, tachycardia and gastrointestinal disturbances; acute but transient loss of vision, aphasia, agitation, headache, nausea, pallor, CNS depression including coma, bradycardia and acute renal failure have been reported. Acute respiratory distress syndrome has been reported following treatment with excessively high intravenous doses of Desferal in patients with acute iron intoxication and in patients with thalassemia. Treatment There is no specific antidote. Desferal should be discontinued and appropriate symptomatic measures undertaken. Desferal is readily dialyzable. DOSAGE AND ADMINISTRATION Acute Iron Intoxication Intramuscular Administration This route is preferred and should be used for ALL PATIENTS NOT IN SHOCK. A dose of 1000 mg should be administered initially. This may be followed by 500 mg every 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered every 4-12 hours. The total amount administered should not exceed 6000 mg in 24 hours. For reconstitution instructions for intramuscular administration see Table 1. Intravenous Administration THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN A STATE OF CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW INFUSION. THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR FOR THE FIRST 1000 MG ADMINISTERED. SUBSEQUENT IV DOSING, IF NEEDED, MUST BE AT A SLOWER RATE, NOT TO EXCEED 125 MG/HR. For reconstitution instructions for intravenous administration see Table 2. The reconstituted solution is added to physiologic saline, (e.g., 0.9% sodium chloride, 0.45% sodium chloride), glucose in water, or Ringer’s lactate solution. An initial dose of 1000 mg should be administered at a rate NOT TO EXCEED 15 mg/kg/hr. This may be followed by 500 mg over 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered over 4-12 hours. The total amount administered should not exceed 6000 mg in 24 hours. Reference ID: 3059820 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda As soon as the clinical condition of the patient permits, intravenous administration should be discontinued and the drug should be administered intramuscularly. CHRONIC IRON OVERLOAD SUBCUTANEOUS ADMINISTRATION A daily dose of 1000-2000 mg (20-40 mg/kg/day) should be administered over 8-24 hours, utilizing a small portable pump capable of providing continuous mini-infusion. The duration of infusion must be individualized. In some patients, as much iron will be excreted after a short infusion of 8-12 hours as with the same dose given over 24 hours. For reconstitution instructions for subcutaneous administration see Table 3. Intravenous Administration The standard recommended method of Desferal administration is via slow subcutaneous infusion over 8 – 12 hours. In patients with intravenous access, the daily dose of Desferal can be administered intravenously. The standard dose is 20 – 40 mg/kg/day for children and 40–50 mg/kg/day over 8 – 12 hours in adults for 5 – 7 days per week. In children, average doses should not exceed 40 mg/kg/day until growth has ceased. In adults, average doses should not exceed 60 mg/kg/day. The intravenous infusion rate should not exceed 15 mg/kg/hour. For reconstitution instructions for intravenous administration see Table 2. In patients who are poorly compliant, Desferal may be administered prior to or following same day blood transfusion (for example 1 gram over 4 hours on the day of transfusion); however, the contribution of this mode of administration to iron balance is limited. Desferal should not be administered concurrently with the blood transfusion as this can lead to errors in interpreting side effects such as rash, anaphylaxis and hypotension. Intramuscular Administration A daily dose of 500-1000 mg may be administered intramuscularly. The total daily dose should not exceed 1000 mg. For reconstitution instructions for intramuscular administration see Table 1. Reconstitution and Preparation Table 1: Preparation for Intramuscular Administration RECONSTITUTE DESFERAL WITH STERILE WATER FOR INJECTION Vial Size Amount of Sterile Water for Injection Required for Reconstitution Total Drug Content after Reconstitution Final Concentration per mL after Reconstitution 500 mg 2 mL 500 mg/2.35 mL 213 mg/mL 2 grams 8 mL 2 grams/9.4 mL 213 mg/mL Reference ID: 3059820 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2: Preparation for Intravenous Administrations RECONSTITUTE DESFERAL WITH STERILE WATER FOR INJECTION Vial Size Amount of Sterile Water for Injection Required for Reconstitution Total Drug Content after Reconstitution Final Concentration per mL after Reconstitution 500 mg 5 mL 500 mg/5.3 mL 95 mg/mL 2 grams 20 mL 2 grams/21.1 mL 95 mg/mL Table 3: Preparation for Subcutaneous Administration RECONSTITUTE DESFERAL WITH STERILE WATER FOR INJECTION Vial Size Amount of Sterile Water for Injection Required for Reconstitution Total Drug Content after Reconstitution Final Concentration per mL after Reconstitution 500 mg 5 mL 500 mg/5.3 mL 95 mg/mL 2 grams 20 mL 2 grams/21.1 mL 95 mg/mL The reconstituted Desferal solution is an isotonic, clear and colorless to slightly- yellowish solution. The drug should be completely dissolved before the solution is withdrawn. Desferal reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion. The product should be used immediately after reconstitution (commencement of treatment within 3 hours) for microbiological safety. When reconstitution is carried out under validated aseptic conditions (in a sterile laminar flow hood using aseptic technique), the product may be stored at room temperature for a maximum period of 24 hours before use. Do not refrigerate reconstituted solution. Reconstituting Desferal in solvents or under conditions other than indicated may result in precipitation. Turbid solutions should not be used. HOW SUPPLIED Vials - each containing 500 mg of sterile, lyophilized deferoxamine mesylate Cartons of 4 vials……………………………………………NDC 0078-0467-91 Vials - each containing 2 g of sterile, lyophilized deferoxamine mesylate Cartons of 4 vials……………………………………………NDC 0078-0347-51 Do not store above 25°C (77°F). REV: December 2011 T2010-101 company logo Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation Reference ID: 3059820 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda East Hanover, New Jersey 07936 ©Novartis Reference ID: 3059820 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:57.888065	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016267s050lbl.pdf', 'application_number': 16267, 'submission_type': 'SUPPL ', 'submission_number': 50}
10,875	NDA 16-267/S-045 Page 3 Desferal® deferoxamine mesylate for injection USP Vials Rx only Prescribing Information DESCRIPTION Desferal, deferoxamine mesylate USP, is an iron-chelating agent, available in vials for intramuscular, subcutaneous, and intravenous administration. Desferal is supplied as vials containing 500 mg and 2 g of deferoxamine mesylate USP in sterile, lyophilized form. Deferoxamine mesylate is N-[5-[3-[(5 aminopentyl)hydroxycarbamoyl]propionamido]pentyl]-3-[[5-(N hydroxyacetamido)pentyl]carbamoyl]propionohydroxamic acid monomethanesul-fonate (salt), and its structural formula is Deferoxamine mesylate USP is a white to off-white powder. It is freely soluble in water and slightly soluble in methanol. Its molecular weight is 656.79. CLINICAL PHARMACOLOGY Desferal chelates iron by forming a stable complex that prevents the iron from entering into further chemical reactions. It readily chelates iron from ferritin and hemosiderin but not readily from transferrin; it does not combine with the iron from cytochromes and hemoglobin. Desferal does not cause any demonstrable increase in the excretion of electrolytes or trace metals. Theoretically, 100 parts by weight of Desferal is capable of binding approximately 8.5 parts by weight of ferric iron. Desferal is metabolized principally by plasma enzymes, but the pathways have not yet been defined. The chelate is readily soluble in water and passes easily through the kidney, giving the urine a characteristic reddish color. Some is also excreted in the feces via the bile. INDICATIONS AND USAGE Desferal is indicated for the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias. Acute Iron Intoxication Desferal is an adjunct to, and not a substitute for, standard measures used in treating acute iron intoxication, which may include the following: induction of emesis with syrup of ipecac; gastric lavage; suction and maintenance of a clear airway; control of shock with intravenous fluids, blood, oxygen, and vasopressors; and correction of acidosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-267/S-045 Page 4 Chronic Iron Overload Desferal can promote iron excretion in patients with secondary iron overload from multiple transfusions (as may occur in the treatment of some chronic anemias, including thalassemia). Long- term therapy with Desferal slows accumulation of hepatic iron and retards or eliminates progression of hepatic fibrosis. Iron mobilization with Desferal is relatively poor in patients under the age of 3 years with relatively little iron overload. The drug should ordinarily not be given to such patients unless significant iron mobilization (e.g., 1 mg or more of iron per day) can be demonstrated. Desferal is not indicated for the treatment of primary hemochromatosis, since phlebotomy is the method of choice for removing excess iron in this disorder. CONTRAINDICATIONS Desferal is contraindicated in patients with severe renal disease or anuria, since the drug and the iron chelate are excreted primarily by the kidney. (See WARNINGS). WARNINGS Ocular and auditory disturbances have been reported when Desferal was administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. The ocular disturbances observed have been blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory abnormalities reported have been tinnitus and hearing loss including high frequency sensorineural hearing loss. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment (see PRECAUTIONS/Information for Patients and ADVERSE REACTIONS/Special Senses). Visual acuity tests, slit-lamp examinations, funduscopy and audiometry are recommended periodically in patients treated for prolonged periods of time. Toxicity is more likely to be reversed if symptoms or test abnormalities are detected early. High doses of Desferal and concomitant low ferritin levels have also been associated with growth retardation. After reduction of Desferal dose, growth velocity may partially resume to pretreatment rates (see PRECAUTIONS/Pediatric Use). Adult respiratory distress syndrome, also reported in children, has been described following treatment with excessively high intravenous doses of Desferal in patients with acute iron intoxication or thalassemia. PRECAUTIONS General Flushing of the skin, urticaria, hypotension, and shock have occurred in a few patients when Desferal was administered by rapid intravenous injection. THEREFORE, DESFERAL SHOULD BE GIVEN INTRAMUSCULARLY OR BY SLOW SUBCUTANEOUS OR INTRAVENOUS INFUSION. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-267/S-045 Page 5 Iron overload increases susceptibility of patients to Yersinia enterocolitica and Yersinia pseudotuberculosis infections. In some rare cases, treatment with Desferal has enhanced this susceptibility, resulting in generalized infections by providing this bacteria with a siderophore otherwise missing. In such cases, Desferal treatment should be discontinued until the infection is resolved. In patients receiving Desferal, rare cases of mucormycosis, some with a fatal outcome, have been reported. If any of the suspected signs or symptoms occur, Desferal should be discontinued, mycological tests carried out and appropriate treatment instituted immediately. In patients with severe chronic iron overload, impairment of cardiac function has been reported following concomitant treatment with Desferal and high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and Desferal are to be used concomitantly: • Vitamin C supplements should not be given to patients with cardiac failure. • Start supplemental vitamin C only after an initial month of regular treatment with Desferal. • Give vitamin C only if the patient is receiving Desferal regularly, ideally soon after setting up the infusion pump. • Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses. • Clinical monitoring of cardiac function is advisable during such combined therapy. In patients with aluminum-related encephalopathy, high doses of Desferal may exacerbate neurological dysfunction (seizures), probably owing to an acute increase in circulating aluminum. Desferal may precipitate the onset of dialysis dementia. Treatment with Desferal in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism. Drug Interactions Vitamin C: Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. As an adjuvant to iron chelation therapy, vitamin C in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with Desferal (see PRECAUTIONS). Vitamin C increases availability of iron for chelation. In general, 50 mg daily suffices for children under 10 years old and 100 mg daily for older children. Larger doses of vitamin C fail to produce any additional increase in excretion of iron complex. Prochlorperazine: Concurrent treatment with Desferal and prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of consciousness. Gallium-67: Imaging results may be distorted because of the rapid urinary excretion of Desferal-bound gallium-67. Discontinuation of Desferal 48 hours prior to scintigraphy is advisable. Information for Patients Patients experiencing dizziness or other nervous system disturbances, or impairment of vision or hearing, should refrain from driving or operating potentially hazardous machines (see ADVERSE REACTIONS). Patients should be informed that occasionally their urine may show a reddish discoloration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-267/S-045 Page 6 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in animals have not been performed with Desferal. Cytotoxicity may occur, since Desferal has been shown to inhibit DNA synthesis in vitro. Pregnancy Category C Delayed ossification in mice and skeletal anomalies in rabbits were observed after Desferal was administered in daily doses up to 4.5 times the maximum daily human dose. No adverse effects were observed in similar studies in rats. There are no adequate and well-controlled studies in pregnant women. Desferal 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 Desferal is administered to a nursing woman. Pediatric Use Pediatric patients receiving Desferal should be monitored for body weight and growth every 3 months. Safety and effectiveness in pediatric patients under the age of 3 years have not been established (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS/Drug Interactions/Vitamin C, and ADVERSE REACTIONS). Geriatric Use Clinical Studies of Desferal did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from the younger subjects. Postmarketing reports suggest a possible trend for an increased risk of eye disorders in the geriatric population, specifically the occurrence of color blindness, maculopathy, and scotoma. However, it is unclear if these eye disorders were dose related. Although the number of reports was very small, certain elderly patients may be predisposed to eye disorders when taking Desferal. Postmarketing reports also suggest that there may be an increased risk of deafness and hearing loss in the geriatric population. (see ADVERSE REACTIONS). 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 The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency. At the Injection Site: Localized irritation, pain, burning, swelling, induration, infiltration, pruritus, erythema, wheal formation, eschar, crust, vesicles, local edema. Injection site reactions may be associated with systemic allergic reactions (see Body as a Whole, below). Hypersensitivity Reactions and Systemic Allergic Reactions: Generalized rash, urticaria, anaphylactic reaction with or without shock, angioedema. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-267/S-045 Page 7 Body as a Whole: Local injection site reactions may be accompanied by systemic reactions like arthralgia, fever, headache, myalgia, nausea, vomiting, abdominal pain, or asthma. Rare infections with Yersinia and Mucormycosis have been reported in association with Desferal use (see PRECAUTIONS). Cardiovascular: Tachycardia, hypotension, shock. Digestive: Abdominal discomfort, diarrhea, nausea, vomiting. Hematologic: Blood dyscrasia (e.g., cases of thrombocytopenia and/or leukopenia have been reported. A causal relationship has not been clearly established). Musculoskeletal: Leg cramps. Growth retardation and bone changes (e.g., metaphyseal dysplasia) are common in chelated patients given doses above 60 mg/kg, especially those who begin iron chelation in the first three years of life. If doses are kept to 40 mg/kg or below, the risk may be reduced (see WARNINGS, PRECAUTIONS/Pediatric Use). Nervous System: Neurological disturbances including dizziness, peripheral sensory, motor, or mixed neuropathy, paresthesias; exacerbation or precipitation of aluminum-related dialysis encephalopathy (see PRECAUTIONS/Information for Patients). Special Senses: High-frequency sensorineural hearing loss and/or tinnitus are uncommon if dosage guidelines are not exceeded and if dose is reduced when ferritin levels decline. Visual disturbances are rare if dosage guidelines are not exceeded. These may include decreased acuity, blurred vision, loss of vision, dyschromatopsia, night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration), optic neuritis, and cataracts (see WARNINGS). Respiratory: Acute respiratory distress syndrome (with dyspnea, cyanosis, and/or interstitial infiltrates) (see WARNINGS). Skin: Very rare generalized rash. Urogenital: Dysuria, impaired renal function (see CONTRAINDICATIONS). OVERDOSAGE Acute Toxicity Intravenous LD50s (mg/kg): mice, 287; rats, 329. Signs and Symptoms Inadvertent administration of an overdose or inadvertent intravenous bolus administration/rapid intravenous infusion may be associated with hypotension, tachycardia and gastrointestinal disturbances; acute but transient loss of vision, aphasia, agitation, headache, nausea, pallor, CNS depression including coma, bradycardia and acute renal failure have been reported. Treatment There is no specific antidote. Desferal should be discontinued and appropriate symptomatic measures undertaken. Desferal is readily dialyzable. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-267/S-045 Page 8 DOSAGE AND ADMINISTRATION Acute Iron Intoxication Intramuscular Administration This route is preferred and should be used for ALL PATIENTS NOT IN SHOCK. A dose of 1000 mg should be administered initially. This may be followed by 500 mg every 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered every 4-12 hours. The total amount administered should not exceed 6000 mg in 24 hours. For reconstitution instructions for intramuscular administration see Table 1 below. Table 1: Preparation for Intramuscular Administration RECONSTITUTE DESFERAL WITH STERILE WATER FOR INJECTION Vial Size Amount of Sterile Water for Injection Required for Reconstitution Total Drug Content after Reconstitution Final Concentration per mL after Reconstitution 500 mg 2 mL 500 mg/2.35 mL 213 mg/mL 2 grams 8 mL 2 grams/9.4 mL 213 mg/mL The reconstituted Desferal solution is a yellow-colored solution. The drug should be completely dissolved before the solution is withdrawn. Desferal reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion. Intravenous Administration THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN A STATE OF CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW INFUSION. THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR FOR THE FIRST 1000 MG ADMINISTERED. SUBSEQUENT IV DOSING, IF NEEDED, MUST BE AT A SLOWER RATE, NOT TO EXCEED 125 MG/HR. The reconstituted solution is added to physiologic saline, (e.g., 0.9% sodium chloride, 0.45% sodium chloride), glucose in water, or Ringer’s lactate solution. An initial dose of 1000 mg should be administered at a rate NOT TO EXCEED 15 mg/kg/hr. This may be followed by 500 mg over 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered over 4-12 hours. The total amount administered should not exceed 6000 mg in 24 hours. As soon as the clinical condition of the patient permits, intravenous administration should be discontinued and the drug should be administered intramuscularly. For reconstitution instructions for intravenous administration see Table 2 below. Table 2: Preparation for Intravenous Administrations RECONSTITUTE DESFERAL WITH STERILE WATER FOR INJECTION Vial Size Amount of Sterile Water for Injection Required for Reconstitution Total Drug Content after Reconstitution Final Concentration per mL after Reconstitution 500 mg 5 mL 500 mg/5.3 mL 95 mg/mL 2 grams 20 mL 2 grams/21.1 mL 95 mg/mL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-267/S-045 Page 9 The reconstituted Desferal solution is an isotonic, clear and colorless to slightly- yellowish solution. The drug should be completely dissolved before the solution is withdrawn. Desferal reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion. Chronic Iron Overload The more effective of the following routes of administration must be chosen on an individual basis for each patient. Intramuscular Administration A daily dose of 500-1000 mg should be administered intramuscularly. In addition, 2000 mg should be administered intravenously with each unit of blood transfused; however, Desferal should be administered separately from the blood. The rate of intravenous infusion must not exceed 15 mg/kg/hr. The total daily dose should not exceed 1000 mg in the absence of a transfusion, or 6000 mg even if transfused three or more units of blood or packed red blood cells. For reconstitution instructions for intramuscular administration see Table 3 below. Table 3: Preparation for Intramuscular Administration RECONSTITUTE DESFERAL WITH STERILE WATER FOR INJECTION Vial Size Amount of Sterile Water for Injection Required for Reconstitution Total Drug Content after Reconstitution Final Concentration per mL after Reconstitution 500 mg 2 mL 500 mg/2.35 mL 213 mg/mL 2 grams 8 mL 2 grams/9.4 mL 213 mg/mL The reconstituted Desferal solution is a yellow-colored solution. The drug should be completely dissolved before the solution is withdrawn. Desferal reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion. Subcutaneous Administration A daily dose of 1000-2000 mg (20-40 mg/kg/day) should be administered over 8-24 hours, utilizing a small portable pump capable of providing continuous mini-infusion. The duration of infusion must be individualized. In some patients, as much iron will be excreted after a short infusion of 8-12 hours as with the same dose given over 24 hours. For reconstitution instructions for subcutaneous administration see Table 4 below. Table 4: Preparation for Subcutaneous Administration RECONSTITUTE DESFERAL WITH STERILE WATER FOR INJECTION Vial Size Amount of Sterile Water for Injection Required for Reconstitution Total Drug Content after Reconstitution Final Concentration per mL after Reconstitution 500 mg 5 mL 500 mg/5.3 mL 95 mg/mL 2 grams 20 mL 2 grams/21.1 mL 95 mg/mL The reconstituted Desferal solution is an isotonic, clear and colorless to slightly- yellowish solution. The drug should be completely dissolved before the solution is withdrawn. Desferal reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY. Discard unused portion. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-267/S-045 Page 10 Stability after Reconstitution The product should be used immediately after reconstitution (commencement of treatment within 3 hours) for microbiological safety. When reconstitution is carried out under validated aseptic conditions (in a sterile laminar flow hood using aseptic technique), the product may be stored at room temperature for a maximum period of 24 hours before use. Do not refrigerate reconstituted solution. Reconstituting Desferal in solvents or under conditions other than indicated may result in precipitation. Turbid solutions should not be used. HOW SUPPLIED Vials - each containing 500 mg of sterile, lyophilized deferoxamine mesylate Cartons of 4 vials……………………………………………NDC 0078-0467-91 Vials - each containing 2 g of sterile, lyophilized deferoxamine mesylate Cartons of 4 vials……………………………………………NDC 0078-0347-51 Do not store above 25°C (77°F). REV: SEPTEMBER 2008 T2008-68 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:58.056239	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016267s045lbl.pdf', 'application_number': 16267, 'submission_type': 'SUPPL ', 'submission_number': 45}
10,879	NDA 16-295/S-037 Page 3 Rx only HYDREA (hydroxyurea capsules, USP) DESCRIPTION HYDREA® (hydroxyurea capsules, USP) is an antineoplastic agent, available for oral use as capsules providing 500 mg hydroxyurea. Inactive ingredients: citric acid, colorants (D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red 40 and D&C Red 28), gelatin, lactose, magnesium stearate, sodium phosphate, and titanium dioxide. Hydroxyurea occurs as an essentially tasteless, white crystalline powder. Its structural formula is: CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects. Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 4 Pharmacokinetics Absorption Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea. Distribution Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes. Metabolism Up to 50% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. In one minor pathway, hydroxyurea may be degraded by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea. Excretion Excretion of hydroxyurea in humans is a nonlinear process occurring through two pathways. One is saturable, probably hepatic metabolism; the other is first-order renal excretion. Special Populations Geriatric, Gender, Race No information is available regarding pharmacokinetic differences due to age, gender or race. Pediatric No pharmacokinetic data are available in pediatric patients treated with hydroxyurea. Renal Insufficiency There are no data that support specific guidance for dosage adjustment in patients with renal impairment. As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. Close monitoring of hematologic parameters is advised in these patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 5 Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. Drug Interactions There are no data on concomitant use of hydroxyurea with other drugs in humans. Animal Pharmacology and Toxicology The oral LD50 of hydroxyurea is 7330 mg/kg in mice and 5780 mg/kg in rats, given as a single dose. In subacute and chronic toxicity studies in the rat, the most consistent pathological findings were an apparent dose-related mild to moderate bone marrow hypoplasia as well as pulmonary congestion and mottling of the lungs. At the highest dosage levels (1260 mg/kg/day for 37 days then 2520 mg/kg/day for 40 days), testicular atrophy with absence of spermatogenesis occurred; in several animals, hepatic cell damage with fatty metamorphosis was noted. In the dog, mild to marked bone marrow depression was a consistent finding except at the lower dosage levels. Additionally, at the higher dose levels (140 to 420 mg or 140 to 1260 mg/kg/week given 3 or 7 days weekly for 12 weeks), growth retardation, slightly increased blood glucose values, and hemosiderosis of the liver or spleen were found; reversible spermatogenic arrest was noted. In the monkey, bone marrow depression, lymphoid atrophy of the spleen, and degenerative changes in the epithelium of the small and large intestines were found. At the higher, often lethal, doses (400 to 800 mg/kg/day for 7 to 15 days), hemorrhage and congestion were found in the lungs, brain, and urinary tract. Cardiovascular effects (changes in heart rate, blood pressure, orthostatic hypotension, EKG changes) and hematological changes (slight hemolysis, slight methemoglobinemia) were observed in some species of laboratory animals at doses exceeding clinical levels. INDICATIONS AND USAGE Significant tumor response to HYDREA has been demonstrated in melanoma, resistant chronic myelocytic leukemia, and recurrent, metastatic, or inoperable carcinoma of the ovary. Hydroxyurea used concomitantly with irradiation therapy is intended for use in the local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip. CONTRAINDICATIONS Hydroxyurea is contraindicated in patients with marked bone marrow depression, i.e., leukopenia (<2500 WBC) or thrombocytopenia (<100,000), or severe anemia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 6 HYDREA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. WARNINGS Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed (see CONTRAINDICATIONS). Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. However, the recovery from myelosuppression is rapid when therapy is interrupted. It should be borne in mind that bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; hydroxyurea should be used cautiously in such patients. Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema. Fatal and nonfatal pancreatitis have occurred in HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine. Hepatotoxicity and hepatic failure resulting in death have been reported during post-marketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Severe anemia must be corrected before initiating therapy with hydroxyurea. Erythrocytic abnormalities: megaloblastic erythropoiesis, which is self-limiting, is often seen early in the course of hydroxyurea therapy. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. Hydroxyurea may also delay plasma iron clearance and reduce the rate of iron utilization by erythrocytes, but it does not appear to alter the red blood cell survival time. Hydroxyurea should be used with caution in patients with marked renal dysfunction. Elderly patients may be more sensitive to the effects of hydroxyurea, and may require a lower dose regimen (see PRECAUTIONS: Geriatric Use). In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or associated with the patient’s underlying disease. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 7 Carcinogenesis and Mutagenesis Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125-250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype. Pregnancy Drugs which affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. The physician should carefully consider this possibility before administering this drug to male or female patients who may contemplate conception. HYDREA can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. 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 harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 8 PRECAUTIONS Therapy with hydroxyurea requires close supervision. The complete status of the blood, including bone marrow examination, if indicated, as well as kidney function and liver function should be determined prior to, and repeatedly during, treatment. The determination of the hemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of hydroxy- urea therapy. If the white blood cell count decreases to less than 2500/mm3, or the platelet count to less than 100,000/mm3, therapy should be interrupted until the values rise significantly toward normal levels. Severe anemia, if it occurs, should be managed without interrupting hydroxyurea therapy. Hydroxyurea is not indicated for the treatment of HIV infection; however, if HIV-infected patients are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis and hepatotoxicity is recommended. Patients who develop signs and symptoms of pancreatitis or hepatotoxicity should permanently discontinue therapy with hydroxyurea. (See WARNINGS and ADVERSE REACTIONS.) Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS for Carcinogenesis and Mutagenesis information. Impairment of Fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females. Pregnancy Pregnancy Category D. (See WARNINGS.) Nursing Mothers Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 9 Geriatric Use Elderly patients may be more sensitive to the effects of hydroxyurea, and may require a lower dose regimen. This drug is known to be 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: Renal Insufficiency). Drug Interactions Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse events. (See WARNINGS and ADVERSE REACTIONS.) Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary. Information for Patients HYDREA is a medication that must be handled with care. People who are not taking HYDREA should not be exposed to it. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets. ADVERSE REACTIONS Adverse reactions have been primarily bone marrow depression (leukopenia, anemia, and occasionally thrombocytopenia), and less frequently gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis - like skin changes, peripheral and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with HYDREA. Skin cancer has been reported. Dysuria and alopecia occur very rarely. Large doses may produce moderate drowsiness. Neurological disturbances have occurred extremely rarely and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. HYDREA (hydroxyurea capsules, USP) occasionally may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 10 and creatinine levels. Abnormal BSP retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported. Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea or radiation treatment alone. These effects primarily include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred rarely and only in the presence of marked leukopenia. HYDREA may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis. The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnea has been rarely reported. Pulmonary fibrosis also has been reported rarely. Fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in Study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3. (See WARNINGS and PRECAUTIONS.) OVERDOSAGE Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have also been observed. DOSAGE AND ADMINISTRATION Procedures for proper handling and disposal of antineoplastic drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Because of the rarity of melanoma, resistant chronic myelocytic leukemia, carcinoma of the ovary, and carcinomas of the head and neck in pediatric patients, dosage regimens have not been established. All dosage should be based on the patient’s actual or ideal weight, whichever is less. Concurrent use of HYDREA with other myelosuppressive agents may require adjustment of dosages. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 11 Solid Tumors Intermittent Therapy 80 mg/kg administered orally as a single dose every third day Continuous Therapy 20 to 30 mg/kg administered orally as a single dose daily Concomitant Therapy with Irradiation Carcinoma of the head and neck—80 mg/kg administered orally as a single dose every third day Administration of hydroxyurea should begin at least seven days before initiation of irradiation and continued during radiotherapy as well as indefinitely afterwards provided that the patient may be kept under adequate observation and evidences no unusual or severe reactions. Resistant Chronic Myelocytic Leukemia Until the intermittent therapy regimen has been evaluated, CONTINUOUS therapy (20 to 30 mg/kg administered orally as a single dose daily) is recommended. An adequate trial period for determining the antineoplastic effectiveness of hydroxyurea is six weeks of therapy. When there is regression in tumor size or arrest in tumor growth, therapy should be continued indefinitely. Therapy should be interrupted if the white blood cell count drops below 2500/mm3, or the platelet count below 100,000/mm3. In these cases, the counts should be re-evaluated after three days, and therapy resumed when the counts return to acceptable levels. Since the hematopoietic rebound is prompt, it is usually necessary to omit only a few doses. If prompt rebound has not occurred during combined HYDREA and irradiation therapy, irradiation may also be interrupted. However, the need for postponement of irradiation has been rare; radiotherapy has usually been continued using the recommended dosage and technique. Severe anemia, if it occurs, should be corrected without interrupting hydroxyurea therapy. Because hematopoiesis may be compromised by extensive irradiation or by other antineoplastic agents, it is recommended that hydroxyurea be administered cautiously to patients who have recently received extensive radiation therapy or chemotherapy with other cytotoxic drugs. Pain or discomfort from inflammation of the mucous membranes at the irradiated site (mucositis) is usually controlled by measures such as topical anesthetics and orally administered analgesics. If the reaction is severe, hydroxyurea therapy may be temporarily interrupted; if it is extremely severe, irradiation dosage may, in addition, be temporarily postponed. However, it has rarely been necessary to terminate these therapies. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 12 Severe gastric distress, such as nausea, vomiting, and anorexia, resulting from combined therapy may usually be controlled by temporary interruption of hydroxyurea administration. Renal Insufficiency There are no data that support specific guidance for dosage adjustments in patients with renal impairment. As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of HYDREA in patients with renal impairment. Close monitoring of hematologic parameters is advised in these patients. Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. HOW SUPPLIED HYDREA® (hydroxyurea capsules, USP) 500 mg capsules in bottles of 100 (NDC 0003-0830-50). Capsule identification number: 830. The cap is opaque green and the body is opaque pink. They are imprinted on both sections in black ink with “HYDREA” and “830”. Storage Store at 25º C (77º F); excursions permitted to 15°-30º C (59°-86º F) [see USP Controlled Room Temperature]. Keep tightly closed. REFERENCES 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publications No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402. 2. AMA Council Report: Guidelines for Handling Parenteral Antineoplastics. JAMA 1985; 253 (11): 1590-1592. 3. National Study Commission on Cytotoxic Exposure—Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-037 Page 13 4. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428. 5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center, CA- A Cancer Journal for Clinicians 1983; (Sept./Oct.) 258-263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049. 7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685. A Bristol-Myers Squibb Company Princeton, New Jersey, 08543 USA Made in Italy TBD Revised TBD This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:58.313363	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/16295slr037_hydrea_lbl.pdf', 'application_number': 16295, 'submission_type': 'SUPPL ', 'submission_number': 37}
10,878	NDA 16-295/S-036 Page 3 Rx only DROXIA (hydroxyurea capsules, USP) DESCRIPTION DROXIA® (hydroxyurea capsules, USP) is available for oral use as capsules providing 200 mg, 300 mg and 400 mg hydroxyurea. Inactive ingredients: citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide and capsule colorants; FD&C Blue #1 and FD&C Green #3 (200 mg capsules); D&C Red #28, D&C Red #33 and FD&C Blue #1 (300 mg capsules); D&C Red #28, D&C Red #33 and D&C Yellow #10 (400 mg capsules). Hydroxyurea is an essentially tasteless, white crystalline powder. Its structural formula is: WARNING Treatment of patients with DROXIA may be complicated by severe, sometimes life- threatening, adverse effects. DROXIA should be administered under the supervision of a physician experienced in the use of this medication for the treatment of sickle cell anemia. Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation to a tumorigenic phenotype. Hydroxyurea is thus unequivocally genotoxic and a presumed transspecies carcinogen which implies a carcinogenic risk to humans. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemias have been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patients’ underlying disease. The physician and patient must very carefully consider the potential benefits of DROXIA relative to the undefined risk of developing secondary malignancies. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 4 CLINICALPHARMACOLOGY Mechanism of Action The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. The mechanisms by which DROXIA (hydroxyurea capsules, USP) produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of DROXIA that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium. Pharmacokinetics Absorption Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea. Distribution Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes. Metabolism Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea. Excretion Excretion of hydroxyurea in humans is likely a linear first-order renal process. In adults with SCA, mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose. Special Populations Geriatric, Gender, Race No information is available regarding pharmacokinetic differences due to age, gender or race. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 5 Pediatric No pharmacokinetic data are available in pediatric patients treated with hydroxyurea for SCA. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open- label, non-randomized, single dose, multi-center study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance (CrCl) > 80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15mg/kg, achieved by using combinations of the 200mg, 300mg, or 400mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study the mean exposure (AUC) in patients whose creatinine clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION). The table below describes the recommended dosage modification. Creatinine Clearance (mL/min) Recommended Droxia® Initial Dose (mg/kg daily) ≥ 60 < 60 or ESRD* 15 7.5 On dialysis days, hydroxyurea should be administered to patients with ESRD following hemodialysis. Close monitoring of hematologic parameters is advised in these patients. Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. Drug Interactions There are no data on concomitant use of hydroxyurea with other drugs in humans. Clinical Studies The efficacy of hydroxyurea in sickle cell anemia was assessed in a large clinical study (Multicenter Study of Hydroxyurea in Sickle Cell Anemia)1. The study was a randomized, double-blind, placebo-controlled trial that evaluated 299 adult patients (≥18 years) with moderate to severe disease (≥3 painful crises yearly). The trial was This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 6 stopped by the Data Safety Monitoring Committee, after accrual was completed but before the scheduled 24 months of follow-up was completed in all patients, based on observations of fewer painful crises among patients receiving hydroxyurea. Compared to placebo treatment, treatment with hydroxyurea resulted in a significant decrease in the yearly rate of painful crises, the yearly rate of painful crises requiring hospitalization, the incidence of chest syndrome, the number of patients transfused, and units of blood transfused. Hydroxyurea treatment significantly increased the median time to both first and second painful crises. Although patients with 3 or more painful crises during the preceding 12 months were eligible for the study, most of the benefit in crisis reduction was seen in the patients with 6 or more painful crises during the preceding 12 months. HYDROXYUREA PLACEBO PERCENT CHANGE EVENT (N=152) (N=147) VS PLACEBO P-VALUE Median yearly rate of painful crises 2.5 4.6 -46 =0.001 Median yearly rate of painful crises requiring hospitalization 1.0 2.5 -60 =0.0027 Median time to first painful crisis (months) 2.76 1.35 +104 =0.014 Median time to second painful crisis (months) 6.58 4.13 +59 =0.0024 Incidence of chest syndrome (# episodes) 56 101 -45 =0.003 Number of patients transfused 55 79 -30 =0.002 Number of units of blood transfused 423 670 -37 =0.003 A painful crisis was defined in the study as acute sickling-related pain that resulted in a visit to a medical facility, that lasted more than 4 hours, and that required treatment with a parenteral narcotic or NSAID. Chest syndrome, priapism, and hepatic sequestration were also included in this definition. No deaths were attributed to treatment with hydroxyurea, and none of the patients developed neoplastic disorders during the study. Treatment was permanently stopped for medical reasons in 14 hydroxyurea-treated (2 patients with myelotoxicity) and 6 placebo-treated patients. (See ADVERSE REACTIONS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 7 Fetal Hemoglobin In patients with SCA treated with hydroxyurea, fetal hemoglobin (HbF) increases 4 to 12 weeks after initiation of treatment. In general, average HbF levels correlate with dose and plasma level with possible plateauing at higher dosages. A clear relation between reduction in crisis frequency and increased HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive effects of hydroxyurea, particularly on neutrophils, was the factor most strongly correlated with reduced crisis frequency. INDICATIONS AND USAGE DROXIA (hydroxyurea capsules, USP) is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe painful crises (generally at least 3 during the preceding 12 months). CONTRAINDICATIONS DROXIA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. WARNINGS DROXIA is a cytotoxic and myelosuppressive agent. DROXIA should not be given if bone marrow function is markedly depressed, as indicated by neutrophils below 2000 cells/mm3; a platelet count below 80,000/mm3; a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm3 when the hemoglobin concentration is below 9 g/dL. Neutropenia is generally the first and most common manifestation of hematologic suppression. (See DOSAGE AND ADMINISTRATION.) Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. Recovery from myelosuppression is usually rapid when therapy is interrupted. DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended. Fatal and nonfatal pancreatitis have occurred in HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine. Hepatotoxicity and hepatic failure resulting in death have been reported during post-marketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Carcinogenesis and Mutagenesis (See Boxed WARNING.) Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 8 hydroxyurea or is associated with the patients’ underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Conventional long-term studies to evaluate the carcinogenic potential of DROXIA have not been performed. However, intraperitoneal administration of 125-250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype. Pregnancy DROXIA (hydroxyurea capsules, USP) can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malforma- tions (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. 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 harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. PRECAUTIONS Therapy with DROXIA requires close supervision. Some patients treated at the recommended initial dose of 15 mg/kg/day have experienced severe or life-threatening myelosuppression, requiring interruption of treatment and dose reduction. The hematologic status of the patient, as well as kidney and liver function should be determined prior to, and repeatedly during treatment. Treatment should be interrupted if neutrophil levels fall to <2000/mm3; platelets fall to <80,000/mm3; hemoglobin declines to less than 4.5 g/dL; or if reticulocytes fall below 80,000/mm3 when the hemoglobin concentration is below 9 g/dL. Following recovery, treatment may be resumed at lower doses (see DOSAGE AND ADMINISTRATION). Hydroxyurea should be used with caution in patients with renal dysfunction. Data from a single dose study of the pharmacokinetics of hydroxyurea in patients with sickle cell anemia suggest that the initial dose of hydroxyurea should be reduced in patients with renal impairment. (See CLINICAL PHARMACOLOGY, Special Populations and 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 16-295/S-036 Page 9 Patients must be able to follow directions regarding drug administration and their monitoring and care. Hydroxyurea is not indicated for the treatment of HIV infection; however, if HIV-infected patients are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis and hepatotoxicity is recommended. Patients who develop signs and symptoms of pancreatitis or hepatotoxicity should permanently discontinue therapy with hydroxyurea. (See WARNINGS and ADVERSE REACTIONS sections.) Carcinogenesis, Mutagenesis, and Impairment of Fertility See WARNINGS and Boxed WARNING for Carcinogenesis and Mutagenesis information. Impairment of Fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females. Pregnancy Pregnancy Category D. (See WARNINGS.) Nursing Mothers Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, a decision should be made either 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. Drug Interactions Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Information for Patients (See Patient Information at end of labeling). Patients should be reminded that this medication must be handled with care. People who are not taking DROXIA should not be exposed to it. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets. The necessity of monitoring blood counts every two weeks, throughout the duration of therapy, should be emphasized. For additional information, see the accompanying Patient In- formation leaflet. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 10 ADVERSE REACTIONS Sickle Cell Anemia In patients treated for sickle cell anemia in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia1, the most common adverse reactions were hematologic, with neutropenia, and low reticulocyte and platelet levels necessitating temporary cessation in almost all patients. Hematologic recovery usually occurred in two weeks. Non-hematologic events that possibly were associated with treatment include hair loss, skin rash, fever, gastrointestinal disturbances, weight gain, bleeding and parvovirus B-19 infection; however, these non-hematologic events occurred with similar frequencies in the hydroxyurea and placebo treatment groups. Melanonychia has also been reported in patients receiving DROXIA (hydroxyurea capsules, USP) for SCA. Other Adverse events associated with the use of hydroxyurea in the treatment of neoplastic diseases, in addition to hematologic effects include: gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculo-papular rash, skin ulceration, dermatomyositis-like skin changes, peripheral erythema and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea. Skin cancer has been reported. Dysuria and alopecia occur very rarely. Large doses may produce moderate drowsiness. Neurological disturbances have occurred extremely rarely and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea occasionally may cause temporary impairment of renal tubular function accom-panied by elevations in serum uric acid, BUN, and creatinine levels. Abnormal BSP retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported. The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnea has been rarely reported. Pulmonary fibrosis also has been reported rarely. Fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3. (See WARNINGS and PRECAUTIONS.) OVERDOSAGE Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been observed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 11 DOSAGE AND ADMINISTRATION Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of DROXIA is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. (See WARNINGS section.) If blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic** blood counts over 24 consecutive weeks), or 35mg/kg/day, is reached. If blood counts are between the acceptable range* and toxic, the dose is not increased. If blood counts are considered toxic, DROXIA should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. DROXIA may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day increments, until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again. acceptable range = neutrophils ≥2500 cells/mm3, platelets ≥95,000/mm3, hemoglobin >5.3 g/dL and reticulocytes ≥95,000/mm3 if the hemoglobin concentration <9 g/dL. toxic = neutrophils <2000 cells/mm3, platelets <80,000/mm3, hemoglobin <4.5 g/dL and reticulocytes <80,000/mm3 if the hemoglobin concentration <9 g/dL. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of DROXIA in patients with renal impairment. The results of a single dose study of the influence of renal function on the pharmacokinetics of hydroxyurea in adults with sickle cell disease suggest that the initial dose of hydroxyurea should be reduced by 50%, to 7.5 mg/kg/d, when used to treat patients with renal impairment. (See PRECAUTIONS and CLINICAL PHARMACOLOGY). Close monitoring of hematologic parameters is advised in these patients. Creatinine Clearance (mL/min) Recommended Droxia® Initial Dose (mg/kg daily) ≥ 60 < 60 or ESRD 15 7.5 *On dialysis days, hydroxyurea should be administered to patients with ESRD following hemodialysis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 12 Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published 2-8. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. HOW SUPPLIED DROXIA (hydroxyurea capsules, USP). 200 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003- 6335-17). The cap and body are opaque blue-green. The capsule is marked in black ink on both the cap and body with DROXIA and 6335. 300 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003- 6336-17). The cap and body are opaque purple. The capsule is marked in black ink on both the cap and body with DROXIA and 6336. 400 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003- 6337-17). The cap and body are opaque reddish-orange. The capsule is marked in black ink on both the cap and body with DROXIA and 6337. Storage Store at 25° C (77° F); excursions permitted to 15–30° C (59–86° F) [see USP Controlled Room Temperature]. Keep tightly closed. REFERENCES 1. Charache S, et al; Hydroxyurea and Sickle Cell Anemia: Clinical Utility of a Myelo- suppressive “Switching” Agent. Medicine. 1996; 75:300-326. 2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publications. No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402. 3. AMA Council Report: Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985;253 (11):1590-1592. 4. National Study Commission on Cytotoxic Exposure–Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences. 179 Longwood Avenue, Boston, MA 02115. 5. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Hand- ling of Antineoplastic Agents. Med J Australia. 1983;1:426-428. 6. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center, CA- A Cancer Journal for Clinicians. 1983;(Sept./Oct.) 258-263. 7. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990;47:1033-1049. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 13 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines), Am J Health-Syst Pharm. 1996;53:1669-1685. A Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Made in Italy Revised September 2002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 14 Patient Information About DROXIA Capsules (generic name = hydroxyurea) What is DROXIA? DROXIA is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in adults with sickle cell anemia. How DROXIA works is not certain but it may work by reducing the number of white blood cells and/or increasing red blood cells that carry fetal hemoglobin (HbF). Fetal hemoglobin may prevent sickling. What is Sickle Cell Anemia? Sickle cell anemia is an inherited disorder of the red blood cells. Red blood cells carry oxygen to all parts of the body by using a protein called hemoglobin. Normal red blood cells contain only normal hemoglobin and are shaped like indented disks. These cells are very flexible and move easily through small blood vessels. In sickle cell anemia, the red blood cells contain sickle hemoglobin, which causes them to change to a rigid, spiked shape (sickle shape) after oxygen is released. Sickled cells get stuck and form plugs What is the most important information I should know about DROXIA? DROXIA (pronounced drock-SEE-yuh) capsules are used to treat sickle cell anemia in adults. DROXIA reduces the frequency of painful crises and reduces the need for blood transfusions. • It is VERY IMPORTANT that you have regular blood counts so that your doctor can decrease or increase the DROXIA dose as needed to avoid serious complications. • The most serious side effects of DROXIA involve the blood and may include severely low white blood cell counts (leukopenia, neutropenia), which can decrease your resistance to infections, severely low red blood cell counts (anemia), or severely low platelet counts (thrombocy- topenia), which can cause bleeding. Almost all patients who received DROXIA in clinical studies needed to have their medication stopped for a time to allow their low blood counts to return to acceptable levels. • If you get pregnant, DROXIA may harm or cause death to your unborn child. You should not become pregnant while taking DROXIA. Make sure you use a contraceptive method. Tell your doctor if you become pregnant or plan to become pregnant while taking DROXIA. • DROXIA may decrease the ability of men to father children and women to have children. • Laboratory tests and reports in humans suggest DROXIA may increase your risk of developing cancer, especially if it is taken for a long time. However, it is still uncertain whether DROXIA causes cancer. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 15 in small blood vessels. These plugs restrict blood flow, causing damage to surrounding tissues resulting in a painful crisis. Because there are blood vessels in all parts of the body, painful crises can occur anywhere in your body. In addition, sickle cells are trapped and destroyed in the liver and spleen. This results in a shortage of red blood cells (anemia). Will DROXIA cure my Sickle Cell Anemia? No. However, DROXIA may help you better control your sickle cell anemia, but it is important to follow your doctor’s instructions carefully. In a study of adults taking recommended doses, daily treatment with DROXIA resulted in fewer painful crises, fewer patients with “acute chest syndrome” (a pneumonia-like condition that leads to difficulty in breathing) and less need for blood transfusions. Who should not take DROXIA capsules? Do not take DROXIA capsules if you are allergic to any of the ingredients. Besides the active ingredient hydroxyurea, DROXIA capsules contain the following inactive ingredients: citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide and capsule colorants. Tell your doctor if you think you have ever had an allergic reaction. If you get pregnant, DROXIA may harm or cause death to your unborn child. You should not become pregnant while taking DROXIA. Make sure you use a contraceptive method. Tell your doctor if you become pregnant or plan to become pregnant while taking DROXIA. How do I take DROXIA capsules? Always follow your doctor’s instructions carefully when taking DROXIA capsules or any prescription medication. The usual dose of DROXIA may range from as few as one to several capsules per day. DROXIA is usually taken once a day. You should try to take it at the same time each day. Your doctor will determine the proper starting dose of DROXIA for you based on your weight and blood count. The dose will then be increased slowly to your maximum tolerated dose (maximum dose that does NOT produce severely low blood counts). Your doctor should measure your blood counts every two weeks after you begin treatment with DROXIA. Depending on the results, your dosage may be adjusted or the drug may be stopped for a while. DROXIA is a medication that must be handled with care. People who are not taking DROXIA should not be exposed to it. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. If you accidentally take an overdose of DROXIA capsules, seek medical attention immedi- ately. Contact your doctor, local poison control center, or emergency room. What if I miss a dose of DROXIA capsules? Try not to miss your dose of DROXIA, but if you do, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and resume your regular dosing schedule. Do not take two doses during the same day. If you miss more than one dose, call your doctor for instructions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 16 What should I avoid while taking DROXIA capsules? Some other medications can increase your risk of experiencing serious side effects from DROXIA. While you are taking DROXIA capsules, you should inform your doctor of all prescription and over-the-counter medicines that you are taking. In nursing mothers, DROXIA is present in breast milk. Because of the potential for side effects in the newborn, you should discontinue nursing your baby while taking DROXIA. What are the possible side effects of DROXIA capsules? As with other medicines, DROXIA may cause unwanted effects, although it is not always possible to tell whether such effects are caused by DROXIA, another medication you may be taking, or your sickle cell anemia. Any side effects or unusual symptoms that you experience should be reported to your doctor, particularly if they persist or are troublesome. The most serious side effects of DROXIA involve the blood, and may include severely low white blood cell counts (leukopenia, neutropenia), which can decrease your resistance to infect-ions, severely low red blood cell counts (anemia), or severely low platelet counts (thrombocy-topenia), which can cause bleeding. Almost all patients who received DROXIA in clinical studies needed to have their medication stopped for a time to allow their low blood counts to return to acceptable levels. The side effects reported most often by adults with sickle cell anemia participating in studies of DROXIA included hair loss, skin rash, fever, stomach and/or bowel disturbances, weight gain, bleeding, virus infection, and discolored nails (melanonychia), but these were equally common in people getting a placebo (sugar pill). Skin cancer and leukemia, which can be fatal, have been reported in patients receiving long-term hydroxyurea for conditions other than sickle cell anemia. In laboratory tests DROXIA causes changes in chromosomes and DNA (genetic material) that strongly suggest it can cause cancer in people, especially if it is taken for a long time. Are regular blood counts necessary while taking DROXIA capsules? Yes. Your doctor should measure your blood counts every two weeks while you are taking DROXIA. Your DROXIA dose will require adjustment based on these regular blood counts. Serious problems can occur if the DROXIA dose is not adjusted on time. What else should I know about DROXIA capsules? If you have kidney or liver disease, close monitoring of your blood count, kidney and liver function will be required. If you have kidney disease, your dose of DROXIA may be started at a lower level and increased gradually. Because it may not be possible to detect a deficiency of folic acid in patients taking DROXIA, your doctor may prescribe a folic acid supplement for you. What else should I do to control my sickle cell crises? Because painful crises can be brought on by factors such as infection, dehydration, worsening anemia, emotional stress, extreme temperature exposure, or ingestion of substances such as This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 17 alcohol or other recreational drugs, you should be aware of the following general guidelines that will help keep you pain-free: —Seek immediate medical attention when a fever develops or signs of infection appear. —Avoid smoking and drinking more than 1–2 alcoholic beverages a day. —Drink 8 to 10 glasses of water or other fluid each day. —Avoid any types of physical exertion that seem to bring on painful crises or other discomfort. —Avoid extreme temperature changes and dress appropriately in hot and cold weather. What should I know if I am HIV-positive? Because of serious, life-threatening side effects associated with DROXIA used in combination with certain medications for HIV, your doctor should closely monitor your pancreas and liver function with frequent physical examinations and laboratory blood tests. Some studies have shown a decrease in the number of CD4 (T-cells) for HIV-positive patients taking DROXIA. Although DROXIA is approved by the U.S. Food and Drug Administration for treating sickle cell anemia, it is not approved for treating HIV infection. This medicine was prescribed for your particular condition. Do not use DROXIA Capsules for another condition or give it to others. Keep DROXIA Capsules and all medicines out of the reach of children. Discard DROXIA Capsules when they are outdated or no longer needed by flushing the contents of your bottle down the toilet. This summary does not include everything there is to know about DROXIA Capsules. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. If you have questions or concerns, or want more information about DROXIA Capsules, your physician and pharmacist have the complete prescribing information upon which this guide is based. You may want to read it and discuss it with your doctor. Remember, no written summary can replace careful discussion with your doctor. This Patient Information has been approved by the U.S. Food and Drug Administration. A Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Made in Italy Revised September 2002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 18 Rx only HYDREA (hydroxyurea capsules, USP) DESCRIPTION HYDREA® (hydroxyurea capsules, USP) is an antineoplastic agent, available for oral use as capsules providing 500 mg hydroxyurea. Inactive ingredients: citric acid, colorants (D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red 40 and D&C Red 28), gelatin, lactose, magnesium stearate, sodium phosphate, and titanium dioxide. Hydroxyurea occurs as an essentially tasteless, white crystalline powder. Its structural formula is: CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects. Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 19 Pharmacokinetics Absorption Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea. Distribution Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes. Metabolism Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea. Excretion Excretion of hydroxyurea in humans is likely a linear first-order renal process. Special Populations Geriatric, Gender, Race No information is available regarding pharmacokinetic differences due to age, gender or race. Pediatric No pharmacokinetic data are available in pediatric patients treated with hydroxyurea. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open- label, non-randomized, single dose, multi-center study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance (CrCl) > 80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15mg/kg, achieved by using combinations of the 200mg, 300mg, or 400mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 20 given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study the mean exposure (AUC) in patients whose creatinine clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Close monitoring of hematologic parameters is advised in these patients. Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. Drug Interactions There are no data on concomitant use of hydroxyurea with other drugs in humans. Animal Pharmacology and Toxicology The oral LD50 of hydroxyurea is 7330 mg/kg in mice and 5780 mg/kg in rats, given as a single dose. In subacute and chronic toxicity studies in the rat, the most consistent pathological findings were an apparent dose-related mild to moderate bone marrow hypoplasia as well as pulmonary congestion and mottling of the lungs. At the highest dosage levels (1260 mg/kg/day for 37 days then 2520 mg/kg/day for 40 days), testicular atrophy with absence of spermatogenesis occurred; in several animals, hepatic cell damage with fatty metamorphosis was noted. In the dog, mild to marked bone marrow depression was a consistent finding except at the lower dosage levels. Additionally, at the higher dose levels (140 to 420 mg or 140 to 1260 mg/kg/week given 3 or 7 days weekly for 12 weeks), growth retardation, slightly increased blood glucose values, and hemosiderosis of the liver or spleen were found; reversible spermatogenic arrest was noted. In the monkey, bone marrow depression, lymphoid atrophy of the spleen, and degenerative changes in the epithelium of the small and large intestines were found. At the higher, often lethal, doses (400 to 800 mg/kg/day for 7 to 15 days), hemorrhage and congestion were found in the lungs, brain, and urinary tract. Cardiovascular effects (changes in heart rate, blood pressure, orthostatic hypotension, EKG changes) and hematological changes (slight hemolysis, slight methemoglo-binemia) were observed in some species of laboratory animals at doses exceeding clinical levels. INDICATIONS AND USAGE Significant tumor response to HYDREA (hydroxyurea capsules, USP) has been demonstrated in melanoma, resistant chronic myelocytic leukemia, and recurrent, metastatic, or inoperable carcinoma of the ovary. Hydroxyurea used concomitantly with irradiation therapy is intended for use in the local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip. CONTRAINDICATIONS Hydroxyurea is contraindicated in patients with marked bone marrow depression, i.e., leukopenia (<2500 WBC) or thrombocytopenia (<100,000), or severe anemia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 21 HYDREA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. WARNINGS Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed (see CONTRAINDICATIONS). Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. However, the recovery from myelosuppression is rapid when therapy is interrupted. It should be borne in mind that bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; hydroxyurea should be used cautiously in such patients. Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema. Fatal and nonfatal pancreatitis have occurred in HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine. Hepatotoxicity and hepatic failure resulting in death have been reported during post-marketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Severe anemia must be corrected before initiating therapy with hydroxyurea. Erythrocytic abnormalities: megaloblastic erythropoiesis, which is self-limiting, is often seen early in the course of hydroxyurea therapy. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. Hydroxyurea may also delay plasma iron clearance and reduce the rate of iron utilization by erythrocytes, but it does not appear to alter the red blood cell survival time. Elderly patients may be more sensitive to the effects of hydroxyurea, and may require a lower dose regimen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or associated with the patients’ underlying disease. Carcinogenesis and Mutagenesis Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patients’ underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125-250 mg/kg hydroxyurea (about 0.6-1.2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 22 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype. Pregnancy Drugs which affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. The physician should carefully consider this possibility before administering this drug to male or female patients who may contemplate conception. HYDREA (hydroxyurea capsules, USP) can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. 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 harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. PRECAUTIONS Therapy with hydroxyurea requires close supervision. The complete status of the blood, including bone marrow examination, if indicated, as well as kidney function and liver function should be determined prior to, and repeatedly during, treatment. The determination of the hemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of hydroxy- urea therapy. If the white blood cell count decreases to less than 2500/mm3, or the platelet count to less than 100,000/mm3, therapy should be interrupted until the values rise significantly toward normal levels. Severe anemia, if it occurs, should be managed without interrupting hydroxyurea therapy. Hydroxyurea should be used with caution in patients with marked renal dysfunction. (See CLINICAL PHARMACOLOGY, Special Populations; DOSAGE AND ADMINISTRATION.) Hydroxyurea is not indicated for the treatment of HIV infection; however, if HIV-infected patients are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis and hepatotoxicity is recommended. Patients who develop signs and symptoms of pancreatitis or hepatotoxicity should permanently discontinue therapy with hydroxyurea. (See WARNINGS and ADVERSE REACTIONS sections.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 23 Carcinogenesis, Mutagenesis, and Impairment of Fertility See WARNINGS for Carcinogenesis and Mutagenesis information. Impairment of Fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females. Pregnancy Pregnancy Category D. (See WARNINGS.) Nursing Mothers Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, 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. Drug Interactions Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse events. (See WARNINGS and ADVERSE REACTIONS.) Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary. Information for Patients HYDREA is a medication that must be handled with care. People who are not taking HYDREA should not be exposed to it. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets. ADVERSE REACTIONS Adverse reactions have been primarily bone marrow depression (leukopenia, anemia, and occasionally thrombocytopenia), and less frequently gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with HYDREA. Skin cancer has been reported. Dysuria and alopecia occur very rarely. Large doses may produce moderate drowsiness. Neurological This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 24 disturbances have occurred extremely rarely and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. HYDREA (hydroxyurea capsules, USP) occasionally may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, and creatinine levels. Abnormal BSP retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported. Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea or radiation treatment alone. These effects primarily include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred rarely and only in the presence of marked leukopenia. HYDREA may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis. The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnea has been rarely reported. Pulmonary fibrosis also has been reported rarely. Fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3. (See WARNINGS and PRECAUTIONS.) OVERDOSAGE Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have also been observed. DOSAGE AND ADMINISTRATION Procedures for proper handling and disposal of antineoplastic drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Because of the rarity of melanoma, resistant chronic myelocytic leukemia, carcinoma of the ovary, and carcinomas of the head and neck in pediatric patients, dosage regimens have not been established. All dosage should be based on the patient’s actual or ideal weight, whichever is less. Concurrent use of HYDREA with other myelosuppresive agents may require adjustment of dosages. SOLID TUMORS Intermittent Therapy 80 mg/kg administered orally as a single dose every third day This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 25 Continuous Therapy 20 to 30 mg/kg administered orally as a single dose daily Concomitant Therapy with Irradiation Carcinoma of the head and neck—80 mg/kg administered orally as a single dose every third day Administration of hydroxyurea should begin at least seven days before initiation of irradiation and continued during radiotherapy as well as indefinitely afterwards provided that the patient may be kept under adequate observation and evidences no unusual or severe reactions. RESISTANT CHRONIC MYELOCYTIC LEUKEMIA Until the intermittent therapy regimen has been evaluated, CONTINUOUS therapy (20 to 30 mg/kg administered orally as a single dose daily) is recommended. An adequate trial period for determining the antineoplastic effectiveness of hydroxyurea is six weeks of therapy. When there is regression in tumor size or arrest in tumor growth, therapy should be continued indefinitely. Therapy should be interrupted if the white blood cell count drops below 2500/mm3, or the platelet count below 100,000/mm3. In these cases, the counts should be re-evaluated after three days, and therapy resumed when the counts return to acceptable levels. Since the hematopoietic rebound is prompt, it is usually necessary to omit only a few doses. If prompt rebound has not occurred during combined HYDREA (hydroxyurea capsules, USP) and irradiation therapy, irradiation may also be interrupted. However, the need for postponement of irradiation has been rare; radiotherapy has usually been continued using the recommended dosage and technique. Severe anemia, if it occurs, should be corrected without interrupting hydroxyurea therapy. Because hematopoiesis may be compromised by extensive irradiation or by other antineoplastic agents, it is recommended that hydroxyurea be administered cautiously to patients who have recently received extensive radiation therapy or chemotherapy with other cytotoxic drugs. Pain or discomfort from inflammation of the mucous membranes at the irradiated site (mucositis) is usually controlled by measures such as topical anesthetics and orally administered analgesics. If the reaction is severe, hydroxyurea therapy may be temporarily interrupted; if it is extremely severe, irradiation dosage may, in addition, be temporarily postponed. However, it has rarely been necessary to terminate these therapies. Severe gastric distress, such as nausea, vomiting, and anorexia, resulting from combined therapy may usually be controlled by temporary interruption of hydroxyurea administration. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of HYDREA in patients with renal impairment. (See PRECAUTIONS and CLINICAL PHARMACOLOGY.) Close monitoring of hematologic parameters is advised in these patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-295/S-036 Page 26 Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. HOW SUPPLIED HYDREA® (hydroxyurea capsules, USP) 500 mg capsules in bottles of 100 (NDC 0003-0830-50). Capsule identification number: 830. The cap is opaque green and the body is opaque pink. They are imprinted on both sections in black ink with “HYDREA” and “830”. Storage Store at 25º C (77º F); excursions permitted to 15°-30º C (59°-86º F) [see USP Controlled Room Temperature]. Keep tightly closed. REFERENCES 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publications No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402. 2. AMA Council Report: Guidelines for Handling Parenteral Antineoplastics. JAMA 1985; 253 (11): 1590-1592. 3. National Study Commission on Cytotoxic Exposure—Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 4. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428. 5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center, CA- A Cancer Journal for Clinicians 1983; (Sept./Oct.) 258-263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049. 7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685. A Bristol-Myers Squibb Company Princeton, New Jersey, 08543 USA Made in Italy Revised July 2002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:58.365921	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/16295se2-036_droxia_lbl.pdf', 'application_number': 16295, 'submission_type': 'SUPPL ', 'submission_number': 36}
10,877	LASIX® (furosemide) Tablets 20, 40, and 80 mg WARNING LASIX® (furosemide) is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required and dose and dose schedule must be adjusted to the individual patient’s needs. (See DOSAGE AND ADMINISTRATION.) DESCRIPTION LASIX® is a diuretic which is an anthranilic acid derivative. LASIX tablets for oral administration contain furosemide as the active ingredient and the following inactive ingredients: lactose monohydrate NF, magnesium stearate NF, starch NF, talc USP, and colloidal silicon dioxide NF. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid. LASIX is available as white tablets for oral administration in dosage strengths of 20, 40 and 80 mg. Furosemide is a white to off-white odorless crystalline powder. It is practically insoluble in water, sparingly soluble in alcohol, freely soluble in dilute alkali solutions and insoluble in dilute acids. The CAS Registry Number is 54-31-9. The structural formula is as follows: structural formula CLINICAL PHARMACOLOGY Investigations into the mode of action of LASIX have utilized micropuncture studies in rats, stop flow experiments in dogs and various clearance studies in both humans and experimental animals. It has been demonstrated that LASIX inhibits primarily the absorption of sodium and chloride not only in the proximal and distal tubules but also in the loop of Henle. The high degree of efficacy is largely due to the unique site of action. The action on the distal tubule is independent of any inhibitory effect on carbonic anhydrase and aldosterone. Recent evidence suggests that furosemide glucuronide is the only or at least the major biotransformation product of furosemide in man. Furosemide is extensively bound to plasma proteins, mainly to albumin. Plasma concentrations ranging from 1 to 400 μg/mL are 91 to 99% bound in healthy individuals. The unbound fraction averages 2.3 to 4.1% at therapeutic concentrations. The onset of diuresis following oral administration is within 1 hour. The peak effect occurs within the first or second hour. The duration of diuretic effect is 6 to 8 hours. 1 Reference ID: 3896453 In fasted normal men, the mean bioavailability of furosemide from LASIX Tablets and LASIX Oral Solution is 64% and 60%, respectively, of that from an intravenous injection of the drug. Although furosemide is more rapidly absorbed from the oral solution (50 minutes) than from the tablet (87 minutes), peak plasma levels and area under the plasma concentration-time curves do not differ significantly. Peak plasma concentrations increase with increasing dose but times-to peak do not differ among doses. The terminal half-life of furosemide is approximately 2 hours. Significantly more furosemide is excreted in urine following the IV injection than after the tablet or oral solution. There are no significant differences between the two oral formulations in the amount of unchanged drug excreted in urine. Geriatric Population Furosemide binding to albumin may be reduced in elderly patients. Furosemide is predominantly excreted unchanged in the urine. The renal clearance of furosemide after intravenous administration in older healthy male subjects (60-70 years of age) is statistically significantly smaller than in younger healthy male subjects (20-35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects. (See PRECAUTIONS: Geriatric Use.) INDICATIONS AND USAGE Edema LASIX is indicated in adults and pediatric patients for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. LASIX is particularly useful when an agent with greater diuretic potential is desired. Hypertension Oral LASIX may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with LASIX alone. CONTRAINDICATIONS LASIX is contraindicated in patients with anuria and in patients with a history of hypersensitivity to furosemide. WARNINGS In patients with hepatic cirrhosis and ascites, LASIX therapy is best initiated in the hospital. In hepatic coma and in states of electrolyte depletion, therapy should not be instituted until the basic condition is improved. Sudden alterations of fluid and electrolyte balance in patients with cirrhosis may precipitate hepatic coma; therefore, strict observation is necessary during the period of diuresis. Supplemental potassium chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalemia and metabolic alkalosis. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, LASIX should be discontinued. 2 Reference ID: 3896453 Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported. Reports usually indicate that LASIX ototoxicity is associated with rapid injection, severe renal impairment, the use of higher than recommended doses, hypoproteinemia or concomitant therapy with aminoglycoside antibiotics, ethacrynic acid, or other ototoxic drugs. If the physician elects to use high dose parenteral therapy, controlled intravenous infusion is advisable (for adults, an infusion rate not exceeding 4 mg LASIX per minute has been used). (See PRECAUTIONS: Drug Interactions) PRECAUTIONS General Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in elderly patients. As with any effective diuretic, electrolyte depletion may occur during LASIX therapy, especially in patients receiving higher doses and a restricted salt intake. Hypokalemia may develop with LASIX, especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present, or during concomitant use of corticosteroids, ACTH, licorice in large amounts, or prolonged use of laxatives. Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially myocardial effects. All patients receiving LASIX therapy should be observed for these signs or symptoms of fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia, hypomagnesemia or hypocalcemia): dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, or gastrointestinal disturbances such as nausea and vomiting. Increases in blood glucose and alterations in glucose tolerance tests (with abnormalities of the fasting and 2-hour postprandial sugar) have been observed, and rarely, precipitation of diabetes mellitus has been reported. In patients with severe symptoms of urinary retention (because of bladder emptying disorders, prostatic hyperplasia, urethral narrowing), the administration of furosemide can cause acute urinary retention related to increased production and retention of urine. Thus, these patients require careful monitoring, especially during the initial stages of treatment. In patients at high risk for radiocontrast nephropathy LASIX can lead to a higher incidence of deterioration in renal function after receiving radiocontrast compared to high-risk patients who received only intravenous hydration prior to receiving radiocontrast. In patients with hypoproteinemia (e.g., associated with nephrotic syndrome) the effect of LASIX may be weakened and its ototoxicity potentiated. Asymptomatic hyperuricemia can occur and gout may rarely be precipitated. Patients allergic to sulfonamides may also be allergic to LASIX. The possibility exists of exacerbation or activation of systemic lupus erythematosus. As with many other drugs, patients should be observed regularly for the possible occurrence of blood dyscrasias, liver or kidney damage, or other idiosyncratic reactions. 3 Reference ID: 3896453 Information for Patients Patients receiving LASIX should be advised that they may experience symptoms from excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can usually be managed by getting up slowly. Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia. Patients with diabetes mellitus should be told that furosemide may increase blood glucose levels and thereby affect urine glucose tests. The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide. Hypertensive patients should avoid medications that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms. Laboratory Tests Serum electrolytes (particularly potassium), CO2, creatinine and BUN should be determined frequently during the first few months of LASIX therapy and periodically thereafter. Serum and urine electrolyte determinations are particularly important when the patient is vomiting profusely or receiving parenteral fluids. Abnormalities should be corrected or the drug temporarily withdrawn. Other medications may also influence serum electrolytes. Reversible elevations of BUN may occur and are associated with dehydration, which should be avoided, particularly in patients with renal insufficiency. Urine and blood glucose should be checked periodically in diabetics receiving LASIX, even in those suspected of latent diabetes. LASIX may lower serum levels of calcium (rarely cases of tetany have been reported) and magnesium. Accordingly, serum levels of these electrolytes should be determined periodically. In premature infants LASIX may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed. (See PRECAUTIONS: Pediatric Use) Drug Interactions LASIX may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function. Except in life-threatening situations, avoid this combination. LASIX should not be used concomitantly with ethacrynic acid because of the possibility of ototoxicity. Patients receiving high doses of salicylates concomitantly with LASIX, as in rheumatic disease, may experience salicylate toxicity at lower doses because of competitive renal excretory sites. There is a risk of ototoxic effects if cisplatin and LASIX are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if LASIX is not given in 4 Reference ID: 3896453 lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. LASIX has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine. Lithium generally should not be given with diuretics because they reduce lithium’s renal clearance and add a high risk of lithium toxicity. LASIX combined with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers may lead to severe hypotension and deterioration in renal function, including renal failure. An interruption or reduction in the dosage of LASIX, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. LASIX may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. Simultaneous administration of sucralfate and LASIX tablets may reduce the natriuretic and antihypertensive effects of LASIX. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of LASIX is achieved. The intake of LASIX and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of LASIX within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of LASIX concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of LASIX. There is evidence that treatment with phenytoin leads to decrease intestinal absorption of LASIX, and consequently to lower peak serum furosemide concentrations. Methotrexate and other drugs that, like LASIX, undergo significant renal tubular secretion may reduce the effect of LASIX. Conversely, LASIX may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both LASIX and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of LASIX. LASIX can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and LASIX is associated with increased risk of gouty arthritis secondary to LASIX-induced hyperurecemia and cyclosporine impairment of renal urate excretion. 5 Reference ID: 3896453 High doses (> 80 mg) of furosemide may inhibit the binding of thyroid hormones to carrier proteins and result in transient increase in free thyroid hormones, followed by an overall decrease in total thyroid hormone levels. One study in six subjects demonstrated that the combination of furosemide and acetylsalicylic acid temporarily reduced creatinine clearance in patients with chronic renal insufficiency. There are case reports of patients who developed increased BUN, serum creatinine and serum potassium levels, and weight gain when furosemide was used in conjunction with NSAIDs. Literature reports indicate that coadministration of indomethacin may reduce the natriuretic and antihypertensive effects of LASIX (furosemide) in some patients by inhibiting prostaglandin synthesis. Indomethacin may also affect plasma renin levels, aldosterone excretion, and renin profile evaluation. Patients receiving both indomethacin and LASIX should be observed closely to determine if the desired diuretic and/or antihypertensive effect of LASIX is achieved. Carcinogenesis, Mutagenesis, Impairment of Fertility Furosemide was tested for carcinogenicity by oral administration in one strain of mice and one strain of rats. A small but significantly increased incidence of mammary gland carcinomas occurred in female mice at a dose 17.5 times the maximum human dose of 600 mg. There were marginal increases in uncommon tumors in male rats at a dose of 15 mg/kg (slightly greater than the maximum human dose) but not at 30 mg/kg. Furosemide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested in the presence or absence of an in vitro metabolic activation system, and questionably positive for gene mutation in mouse lymphoma cells in the presence of rat liver S9 at the highest dose tested. Furosemide did not induce sister chromatid exchange in human cells in vitro, but other studies on chromosomal aberrations in human cells in vitro gave conflicting results. In Chinese hamster cells it induced chromosomal damage but was questionably positive for sister chromatid exchange. Studies on the induction by furosemide of chromosomal aberrations in mice were inconclusive. The urine of rats treated with this drug did not induce gene conversion in Saccharomyces cerevisiae. LASIX (furosemide) produced no impairment of fertility in male or female rats, at 100 mg/kg/day (the maximum effective diuretic dose in the rat and 8 times the maximal human dose of 600 mg/day). Pregnancy PREGNANCY CATEGORY C - Furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits at 2, 4 and 8 times the maximal recommended human dose. There are no adequate and well-controlled studies in pregnant women. LASIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Treatment during pregnancy requires monitoring of fetal growth because of the potential for higher birth weights. 6 Reference ID: 3896453 The effects of furosemide on embryonic and fetal development and on pregnant dams were studied in mice, rats and rabbits. Furosemide caused unexplained maternal deaths and abortions in the rabbit at the lowest dose of 25 mg/kg (2 times the maximal recommended human dose of 600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal recommended human dose of 600 mg/day) also caused maternal deaths and abortions when administered to rabbits between Days 12 and 17 of gestation. In a third study, none of the pregnant rabbits survived a dose of 100 mg/kg. Data from the above studies indicate fetal lethality that can precede maternal deaths. The results of the mouse study and one of the three rabbit studies also showed an increased incidence and severity of hydronephrosis (distention of the renal pelvis and, in some cases, of the ureters) in fetuses derived from the treated dams as compared with the incidence in fetuses from the control group. Nursing Mothers Because it appears in breast milk, caution should be exercised when LASIX is administered to a nursing mother. LASIX may inhibit lactation. Pediatric Use In premature infants LASIX may precipitate nephrocalcinosis/nephrolithiasis. Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no history of prematurity who have been treated chronically with LASIX. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving LASIX. If LASIX is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus Geriatric Use Controlled clinical studies of LASIX 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 the 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 PRECAUTIONS: General and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS Adverse reactions are categorized below by organ system and listed by decreasing severity. 7 Reference ID: 3896453 Gastrointestinal System Reactions 1. hepatic encephalopathy in patients with 6. oral and gastric irritation hepatocellular insufficiency 7. cramping 2. pancreatitis 8. diarrhea 3. jaundice (intrahepatic cholestatic jaundice) 9. constipation 4. increased liver enzymes 10. nausea 5. anorexia 11. vomiting Systemic Hypersensitivity Reactions 1. Severe anaphylactic or anaphylactoid 3. interstitial nephritis reactions (e.g. with shock) 4. necrotizing angiitis 2. systemic vasculitis Central Nervous System Reactions 1. tinnitus and hearing loss 4. dizziness 2. paresthesias 5. headache 3. vertigo 6. blurred vision 7. xanthopsia Hematologic Reactions 1. aplastic anemia 5. leukopenia 2. thrombocytopenia 6. anemia 3. agranulocytosis 7. eosinophilia 4. hemolytic anemia Dermatologic-Hypersensitivity Reactions 1. toxic epidermal necrolysis 7. bullous pemphigoid 2. Stevens-Johnson Syndrome 8. purpura 3. erythema multiforme 9. photosensitivity 4. drug rash with eosinophilia and systemic 10. rash symptoms 11. pruritis 5. acute generalized exanthematous pustulosis 12. urticaria 6. exfoliative dermatitis Cardiovascular Reaction 1. Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics. 2. Increase in cholesterol and triglyceride serum levels Other Reactions 1. hyperglycemia 6. restlessness 2. glycosuria 7. urinary bladder spasm 3. hyperuricemia 8. thrombophlebitis 4. muscle spasm 9. fever 5. weakness 8 Reference ID: 3896453 Whenever adverse reactions are moderate or severe, LASIX dosage should be reduced or therapy withdrawn. OVERDOSAGE The principal signs and symptoms of overdose with LASIX are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action. The acute toxicity of LASIX has been determined in mice, rats and dogs. In all three, the oral LD50 exceeded 1000 mg/kg body weight, while the intravenous LD50 ranged from 300 to 680 mg/kg. The acute intragastric toxicity in neonatal rats is 7 to 10 times that of adult rats. The concentration of LASIX in biological fluids associated with toxicity or death is not known. Treatment of overdosage is supportive and consists of replacement of excessive fluid and electrolyte losses. Serum electrolytes, carbon dioxide level and blood pressure should be determined frequently. Adequate drainage must be assured in patients with urinary bladder outlet obstruction (such as prostatic hypertrophy). Hemodialysis does not accelerate furosemide elimination. DOSAGE AND ADMINISTRATION Edema Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response. Adults -- The usual initial dose of LASIX is 20 to 80 mg given as a single dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hours later or the dose may be increased. The dose may be raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect has been obtained. The individually determined single dose should then be given once or twice daily (eg, at 8 am and 2 pm). The dose of LASIX may be carefully titrated up to 600 mg/day in patients with clinically severe edematous states. Edema may be most efficiently and safely mobilized by giving LASIX on 2 to 4 consecutive days each week. When doses exceeding 80 mg/day are given for prolonged periods, careful clinical observation and laboratory monitoring are particularly advisable. (See PRECAUTIONS: Laboratory Tests.) Geriatric patients -- In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range (see PRECAUTIONS: Geriatric Use). Pediatric patients -- The usual initial dose of oral LASIX in pediatric patients is 2 mg/kg body weight, given as a single dose. If the diuretic response is not satisfactory after the initial dose, 9 Reference ID: 3896453 dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hours after the previous dose. Doses greater than 6 mg/kg body weight are not recommended. For maintenance therapy in pediatric patients, the dose should be adjusted to the minimum effective level. Hypertension Therapy should be individualized according to the patient’s response to gain maximal therapeutic response and to determine the minimal dose needed to maintain the therapeutic response. Adults -- The usual initial dose of LASIX for hypertension is 80 mg, usually divided into 40 mg twice a day. Dosage should then be adjusted according to response. If response is not satisfactory, add other antihypertensive agents. Changes in blood pressure must be carefully monitored when LASIX is used with other antihypertensive drugs, especially during initial therapy. To prevent excessive drop in blood pressure, the dosage of other agents should be reduced by at least 50 percent when LASIX is added to the regimen. As the blood pressure falls under the potentiating effect of LASIX, a further reduction in dosage or even discontinuation of other antihypertensive drugs may be necessary. Geriatric patients -- In general, dose selection and dose adjustment for the elderly patient should be cautious, usually starting at the low end of the dosing range (see PRECAUTIONS: Geriatric Use). HOW SUPPLIED LASIX (furosemide) Tablets 20 mg are supplied as white, oval, monogrammed tablets in Bottles of 100 (NDC 0039-0067-10) and 1000 (NDC 0039-0067-70). The 20 mg tablets are imprinted with “Lasix®” on one side. LASIX Tablets 40 mg are supplied as white, round, monogrammed, scored tablets in Bottles of 100 (NDC 0039-0060-13), 500 (NDC 0039-0060-50), and 1000 (NDC 0039-0060-70). The 40 mg tablets are imprinted with “Lasix® 40” on one side. LASIX Tablets 80 mg are supplied as white, round, monogrammed, facetted edge tablets in Bottles of 50 (NDC 0039-0066-05) and 500 (NDC 0039-0066-50). The 80 mg tablets are imprinted with “Lasix® 80” on one side. Note: Dispense in well-closed, light-resistant containers. Exposure to light might cause a slight discoloration. Discolored tablets should not be dispensed. Tested by USP Dissolution Test 2 Store at 25º C (77º F); excursions permitted to 15 - 30º C (59 - 86º F). [See USP Controlled Room Temperature.] Revised March 2016 10 Reference ID: 3896453 Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY © 2016 sanofi-aventis U.S. LLC Reference ID: 3896453 11	custom-source	2025-02-12T13:43:58.446837	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016273s068lbl.pdf', 'application_number': 16273, 'submission_type': 'SUPPL ', 'submission_number': 68}
10,880	1 Rx only DROXIA® (hydroxyurea capsules, USP) WARNING Treatment of patients with DROXIA may be complicated by severe, sometimes life- threatening, adverse effects. DROXIA should be administered under the supervision of a physician experienced in the use of this medication for the treatment of sickle cell anemia. Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation to a tumorigenic phenotype. Hydroxyurea is thus unequivocally genotoxic and a presumed transspecies carcinogen which implies a carcinogenic risk to humans. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemias have been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. The physician and patient must very carefully consider the potential benefits of DROXIA relative to the undefined risk of developing secondary malignancies. DESCRIPTION DROXIA® (hydroxyurea capsules, USP) is available for oral use as capsules providing 200 mg, 300 mg, and 400 mg hydroxyurea. Inactive ingredients: citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide, and capsule colorants; FD&C Blue No. 1 and FD&C Green No. 3 (200 mg capsules); D&C Red No. 28, D&C Red No. 33, and FD&C Blue No. 1 (300 mg capsules); D&C Red No. 28, D&C Red No. 33, and D&C Yellow No. 10 (400 mg capsules). Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Hydroxyurea is an essentially tasteless, white crystalline powder. Its structural formula is: CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. The mechanisms by which DROXIA produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of DROXIA that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium. Pharmacokinetics Absorption Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea. Distribution Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Metabolism Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea. Excretion Excretion of hydroxyurea in humans is likely a linear first-order renal process. In adults with SCA, mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose. Special Populations Geriatric, Gender, Race No information is available regarding pharmacokinetic differences due to age, gender, or race. Pediatric No pharmacokinetic data are available in pediatric patients treated with hydroxyurea for SCA. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study, the mean exposure (AUC) in patients whose creatinine Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) The table below describes the recommended dosage modification. Creatinine Clearance (mL/min) Recommended DROXIA Initial Dose (mg/kg daily) ≥60 15 <60 or ESRD* 7.5 On dialysis days, hydroxyurea should be administered to patients with ESRD following hemodialysis. Close monitoring of hematologic parameters is advised in these patients. Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. Drug Interactions There are no data on concomitant use of hydroxyurea with other drugs in humans. Clinical Studies The efficacy of hydroxyurea in sickle cell anemia was assessed in a large clinical study (Multicenter Study of Hydroxyurea in Sickle Cell Anemia).1 The study was a randomized, double-blind, placebo-controlled trial that evaluated 299 adult patients (≥18 years) with moderate to severe disease (≥3 painful crises yearly). The trial was stopped by the Data Safety Monitoring Committee, after accrual was completed but before the scheduled 24 months of follow-up was completed in all patients, based on observations of fewer painful crises among patients receiving hydroxyurea. Compared to placebo treatment, treatment with hydroxyurea resulted in a significant decrease in the yearly rate of painful crises, the yearly rate of painful crises requiring hospitalization, the incidence of chest syndrome, the number of patients transfused, and Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 units of blood transfused. Hydroxyurea treatment significantly increased the median time to both first and second painful crises. Although patients with 3 or more painful crises during the preceding 12 months were eligible for the study, most of the benefit in crisis reduction was seen in the patients with 6 or more painful crises during the preceding 12 months. EVENT HYDROXYUREA (N=152) PLACEBO (N=147) PERCENT CHANGE VS PLACEBO P-VALUE Median yearly rate of painful crises 2.5 4.6 −46 =0.001 Median yearly rate of painful crises requiring hospitalization 1.0 2.5 −60 =0.0027 Median time to first painful crisis (months) 2.76 1.35 +104 =0.014 Median time to second painful crisis (months) 6.58 4.13 +59 =0.0024 Incidence of chest syndrome (# episodes) 56 101 −45 =0.003 Number of patients transfused 55 79 −30 =0.002 Number of units of blood transfused 423 670 −37 =0.003 A painful crisis was defined in the study as acute sickling-related pain that resulted in a visit to a medical facility, that lasted more than 4 hours, and that required treatment with a parenteral narcotic or NSAID. Chest syndrome, priapism, and hepatic sequestration were also included in this definition. No deaths were attributed to treatment with hydroxyurea, and none of the patients developed neoplastic disorders during the study. Treatment was permanently stopped for medical reasons in 14 hydroxyurea-treated (2 patients with myelotoxicity) and 6 placebo- treated patients. (See ADVERSE REACTIONS.) Fetal Hemoglobin In patients with SCA treated with hydroxyurea, fetal hemoglobin (HbF) increases 4 to 12 weeks after initiation of treatment. In general, average HbF levels correlate with dose and plasma level with possible plateauing at higher dosages. A clear relation between reduction in crisis frequency and increased HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive effects of hydroxyurea, Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 particularly on neutrophils, was the factor most strongly correlated with reduced crisis frequency. INDICATIONS AND USAGE DROXIA (hydroxyurea capsules, USP) is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe painful crises (generally at least 3 during the preceding 12 months). CONTRAINDICATIONS DROXIA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. WARNINGS DROXIA is a cytotoxic and myelosuppressive agent. DROXIA should not be given if bone marrow function is markedly depressed, as indicated by neutrophils below 2000 cells/mm3; a platelet count below 80,000/mm3; a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm3 when the hemoglobin concentration is below 9 g/dL. Neutropenia is generally the first and most common manifestation of hematologic suppression. (See DOSAGE AND ADMINISTRATION.) Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. Recovery from myelosuppression is usually rapid when therapy is interrupted. DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended. In HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in HIV- infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. Peripheral neuropathy, which was severe in some cases, has been reported in HIV- infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop. Carcinogenesis and Mutagenesis (See BOXED WARNING.) Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Conventional long-term studies to evaluate the carcinogenic potential of DROXIA have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype. Pregnancy DROXIA can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. 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 harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. PRECAUTIONS General Therapy with DROXIA requires close supervision. Some patients, treated at the recommended initial dose of 15 mg/kg/day, have experienced severe or life-threatening myelosuppression, requiring interruption of treatment and dose reduction. The hemato- logic status of the patient, as well as kidney and liver function should be determined prior to, and repeatedly during treatment. Treatment should be interrupted if neutrophil levels fall to <2000/mm3; platelets fall to <80,000/mm3; hemoglobin declines to less than 4.5 g/dL; or if reticulocytes fall below 80,000/mm3 when the hemoglobin concentration is below 9 g/dL. Following recovery, treatment may be resumed at lower doses (see DOSAGE AND ADMINISTRATION). Hydroxyurea should be used with caution in patients with renal dysfunction. Data from a single-dose study of the pharmacokinetics of hydroxyurea in patients with sickle cell anemia suggest that the initial dose of hydroxyurea should be reduced in patients with renal impairment. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) Patients must be able to follow directions regarding drug administration and their monitoring and care. Hydroxyurea is not indicated for the treatment of HIV infection; however, if HIV-infected patients are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Patients who develop signs and symptoms of pancreatitis should Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 permanently discontinue therapy with hydroxyurea. (See WARNINGS and ADVERSE REACTIONS.) An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with hydroxyurea, and in particular, in combination with didanosine and stavudine. This combination should be avoided. Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS and BOXED WARNING for Carcinogenesis and Mutagenesis information. Impairment of Fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females. Pregnancy Pregnancy Category D. (See WARNINGS.) Nursing Mothers Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, a decision should be made either 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. Drug Interactions Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Information for Patients (See Patient Information at end of labeling.) Patients should be reminded that this medication must be handled with care. People who are not taking DROXIA should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling DROXIA or bottles containing DROXIA. Anyone handling DROXIA should wash their hands before and after contact with the bottle or capsules. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules. The necessity of monitoring blood counts every two weeks, throughout the duration of therapy, should be emphasized. For additional information, see the accompanying Patient Information leaflet. ADVERSE REACTIONS Sickle Cell Anemia In patients treated for sickle cell anemia in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia,1 the most common adverse reactions were hematologic, with neutropenia, and low reticulocyte and platelet levels necessitating temporary cessation in almost all patients. Hematologic recovery usually occurred in two weeks. Non-hematologic events that possibly were associated with treatment include hair loss, skin rash, fever, gastrointestinal disturbances, weight gain, bleeding, and parvovirus B-19 infection; however, these non-hematologic events occurred with similar frequencies in the hydroxyurea and placebo treatment groups. Melanonychia has also been reported in patients receiving DROXIA for SCA. Other Adverse events associated with the use of hydroxyurea in the treatment of neoplastic diseases, in addition to hematologic effects include: gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral erythema, and facial erythema. Hyperpigmentation, atrophy of skin and nails, Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 scaling, and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea. Skin cancer has been reported. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy (see WARNINGS). Dysuria and alopecia have been reported. Large doses may produce drowsiness. Neurological disturbances have occurred and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels. Abnormal bromsulphalein (BSP) retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported. The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea has been reported. Pulmonary fibrosis also has been reported. In HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine, fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in Study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3. (See WARNINGS and PRECAUTIONS.) OVERDOSAGE Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been observed. DOSAGE AND ADMINISTRATION Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published.2-5 To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing DROXIA capsules. DROXIA capsules should not be opened. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Personnel should avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below. Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of DROXIA is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. (See WARNINGS.) If blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic** blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached. If blood counts are between the acceptable range* and toxic, the dose is not increased. If blood counts are considered toxic, DROXIA should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. DROXIA may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day increments, until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again. acceptable range = neutrophils ≥2500 cells/mm3 , platelets ≥95,000/mm3 , hemoglobin >5.3 g/dL and reticulocytes ≥95,000/mm3 if the hemoglobin concentration <9 g/dL. toxic = neutrophils <2000 cells/mm3 , platelets <80,000/mm3 , hemoglobin <4.5 g/dL and reticulocytes <80,000/mm3 if the hemoglobin concentration <9 g/dL. Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of DROXIA in patients with renal impairment. The results of a Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 single-dose study of the influence of renal function on the pharmacokinetics of hydroxyurea in adults with sickle cell disease suggest that the initial dose of hydroxyurea should be reduced by 50%, to 7.5 mg/kg/day, when used to treat patients with renal impairment. (See PRECAUTIONS and CLINICAL PHARMACOLOGY.) Close monitoring of hematologic parameters is advised in these patients. Creatinine Clearance (mL/min) Recommended DROXIA Initial Dose (mg/kg daily) ≥60 15 <60 or ESRD 7.5 *On dialysis days, hydroxyurea should be administered to patients with ESRD following hemodialysis. Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. HOW SUPPLIED DROXIA® (hydroxyurea capsules, USP). 200 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6335-17). The cap and body are opaque blue-green. The capsule is marked in black ink on both the cap and body with “DROXIA” and “6335”. 300 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6336-17). The cap and body are opaque purple. The capsule is marked in black ink on both the cap and body with “DROXIA” and “6336”. 400 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6337-17). The cap and body are opaque reddish-orange. The capsule is marked in black ink on both the cap and body with “DROXIA” and “6337”. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep tightly closed. REFERENCES 1. Charache S, Barton FB, Moore RD, et al; Hydroxyurea and sickle cell anemia: clinical utility of a myelosuppressive “switching” agent. Medicine. 1996;75:300- 326. 2. 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. 3. 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 4. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193. 5. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society. Manufactured for: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Made in Italy 1053547A8 Rev January 2012 Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Patient Information About DROXIA® Capsules (generic name = hydroxyurea) What is the most important information I should know about DROXIA? DROXIA (pronounced drock-SEE-yuh) capsules are used to treat sickle cell anemia in adults. DROXIA reduces the frequency of painful crises and reduces the need for blood transfusions. • It is VERY IMPORTANT that you have regular blood counts so that your doctor can decrease or increase the DROXIA dose as needed to avoid serious complications. • The most serious side effects of DROXIA involve the blood and may include severely low white blood cell counts (leukopenia, neutropenia), which can decrease your resistance to infections, severely low red blood cell counts (anemia), or severely low platelet counts (thrombocytopenia), which can cause bleeding. Almost all patients who received DROXIA in clinical studies needed to have their medication stopped for a time to allow their low blood counts to return to acceptable levels. • If you get pregnant, DROXIA may harm or cause death to your unborn child. You should not become pregnant while taking DROXIA. Make sure you use a contraceptive method. Tell your doctor if you become pregnant or plan to become pregnant while taking DROXIA. • DROXIA may decrease the ability of men to father children and women to have children. • Laboratory tests and reports in humans suggest DROXIA may increase your risk of developing cancer, especially if it is taken for a long time. However, it is still uncertain whether DROXIA causes cancer. What is DROXIA? DROXIA (hydroxyurea capsules, USP) is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in adults with sickle cell anemia. How DROXIA works is not certain but it may work by reducing the number of white blood cells and/or increasing red blood cells that carry fetal hemoglobin (HbF). Fetal hemoglobin may prevent sickling. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 What is Sickle Cell Anemia? Sickle cell anemia is an inherited disorder of the red blood cells. Red blood cells carry oxygen to all parts of the body by using a protein called hemoglobin. Normal red blood cells contain only normal hemoglobin and are shaped like indented disks. These cells are very flexible and move easily through small blood vessels. In sickle cell anemia, the red blood cells contain sickle hemoglobin, which causes them to change to a rigid, spiked shape (sickle shape) after oxygen is released. Sickled cells get stuck and form plugs in small blood vessels. These plugs restrict blood flow, causing damage to surrounding tissues resulting in a painful crisis. Because there are blood vessels in all parts of the body, painful crises can occur anywhere in your body. In addition, sickle cells are trapped and destroyed in the liver and spleen. This results in a shortage of red blood cells (anemia). Will DROXIA cure my Sickle Cell Anemia? No. However, DROXIA may help you better control your sickle cell anemia, but it is important to follow your doctor’s instructions carefully. In a study of adults taking recommended doses, daily treatment with DROXIA resulted in fewer painful crises, fewer patients with “acute chest syndrome” (a pneumonia-like condition that leads to difficulty in breathing) and less need for blood transfusions. Who should not take DROXIA capsules? Do not take DROXIA capsules if you are allergic to any of the ingredients. Besides the active ingredient hydroxyurea, DROXIA capsules contain the following inactive ingredients: citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide, and capsule colorants. Tell your doctor if you think you have ever had an allergic reaction. If you get pregnant, DROXIA may harm or cause death to your unborn child. You should not become pregnant while taking DROXIA. Make sure you use a contraceptive method. Tell your doctor if you become pregnant or plan to become pregnant while taking DROXIA. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 How do I take DROXIA capsules? Always follow your doctor’s instructions carefully when taking DROXIA capsules or any prescription medication. The usual dose of DROXIA may range from as few as one to several capsules per day. DROXIA is usually taken once a day. You should try to take it at the same time each day. Your doctor will determine the proper starting dose of DROXIA for you based on your weight and blood count. The dose will then be increased slowly to your maximum tolerated dose (maximum dose that does NOT produce severely low blood counts). Your doctor should measure your blood counts every two weeks after you begin treatment with DROXIA. Depending on the results, your dosage may be adjusted or the drug may be stopped for a while. If you accidentally take an overdose of DROXIA capsules, seek medical attention immediately. Contact your doctor, local Poison Control Center, or emergency room. How do I handle DROXIA capsules safely? DROXIA is a medication that must be handled with care. People who are not taking DROXIA should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling DROXIA or bottles containing DROXIA. Anyone handling DROXIA should wash their hands before and after contact with the bottle or capsules. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. DROXIA should be kept out of the reach of children and pets. Contact your doctor or pharmacist for instructions on how to dispose of outdated capsules. What if I miss a dose of DROXIA capsules? Try not to miss your dose of DROXIA, but if you do, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and resume your regular dosing schedule. Do not take two doses during the same day. If you miss more than one dose, call your doctor for instructions. What should I avoid while taking DROXIA capsules? Some other medications can increase your risk of experiencing serious side effects from DROXIA. While you are taking DROXIA capsules, you should inform your doctor of all prescription and over-the-counter medicines that you are taking. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 In nursing mothers, DROXIA is present in breast milk. Because of the potential for side effects in the newborn, you should discontinue nursing your baby while taking DROXIA. What are the possible side effects of DROXIA capsules? As with other medicines, DROXIA may cause unwanted effects, although it is not always possible to tell whether such effects are caused by DROXIA, another medication you may be taking, or your sickle cell anemia. Any side effects or unusual symptoms that you experience should be reported to your doctor, particularly if they persist or are troublesome. The most serious side effects of DROXIA involve the blood, and may include severely low white blood cell counts (leukopenia, neutropenia), which can decrease your resistance to infections, severely low red blood cell counts (anemia), or severely low platelet counts (thrombocytopenia), which can cause bleeding. Almost all patients who received DROXIA in clinical studies needed to have their medication stopped for a time to allow their low blood counts to return to acceptable levels. The side effects reported most often by adults with sickle cell anemia participating in studies of DROXIA included hair loss, skin rash, fever, stomach and/or bowel disturbances, weight gain, bleeding, virus infection, and discolored nails (melanonychia), but these were equally common in people getting a placebo (sugar pill). Skin cancer and leukemia, which can be fatal, have been reported in patients receiving long-term hydroxyurea for conditions other than sickle cell anemia. In laboratory tests, DROXIA causes changes in chromosomes and DNA (genetic material) that strongly suggest it can cause cancer in people, especially if it is taken for a long time. Skin ulcers have been seen in patients taking DROXIA therapy. Contact your doctor if skin ulcers develop while you are taking DROXIA. Are regular blood counts necessary while taking DROXIA capsules? Yes. Your doctor should measure your blood counts every two weeks while you are taking DROXIA. Your DROXIA dose will require adjustment based on these regular blood counts. Serious problems can occur if the DROXIA dose is not adjusted on time. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 What else should I know about DROXIA capsules? If you have kidney or liver disease, close monitoring of your blood count, kidney and liver function will be required. If you have kidney disease, your dose of DROXIA may be started at a lower level and increased gradually. Because it may not be possible to detect a deficiency of folic acid in patients taking DROXIA, your doctor may prescribe a folic acid supplement for you. What else should I do to control my sickle cell crises? Because painful crises can be brought on by factors such as infection, dehydration, worsening anemia, emotional stress, extreme temperature exposure, or ingestion of substances such as alcohol or other recreational drugs, you should be aware of the following general guidelines that will help keep you pain-free: • Seek immediate medical attention when a fever develops or signs of infection appear. • Avoid smoking and drinking more than 1 to 2 alcoholic beverages a day. • Drink 8 to 10 glasses of water or other fluid each day. • Avoid any types of physical exertion that seem to bring on painful crises or other discomfort. • Avoid extreme temperature changes and dress appropriately in hot and cold weather. What should I know if I am HIV-positive? Because of serious, life-threatening side effects associated with DROXIA used in combination with certain medications for HIV, your doctor should closely monitor your pancreas and liver function with frequent physical examinations and laboratory blood tests. The combination of DROXIA, ZERIT® (stavudine) and VIDEX® (didanosine) should be avoided. Some studies have shown a decrease in the number of CD4 (T-cells) for HIV-positive patients taking DROXIA. Although DROXIA is approved by the U.S. Food and Drug Administration for treating sickle cell anemia, it is not approved for treating HIV infection. This medicine was prescribed for your particular condition. Do not use DROXIA capsules for another condition or give it to others. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 This summary does not include everything there is to know about DROXIA capsules. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. If you have questions or concerns, or want more information about DROXIA capsules, your physician and pharmacist have the complete prescribing information upon which this guide is based. You may want to read it and discuss it with your doctor. Remember, no written summary can replace careful discussion with your doctor. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured for: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Made in Italy 1053547A8 Rev January 2012 Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Rx only HYDREA® (hydroxyurea capsules, USP) DESCRIPTION HYDREA® (hydroxyurea capsules, USP) is an antineoplastic agent available for oral use as capsules providing 500 mg hydroxyurea. Inactive ingredients: citric acid, colorants (D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, and D&C Red No. 28), gelatin, lactose, magnesium stearate, sodium phosphate, and titanium dioxide. Hydroxyurea is an essentially tasteless, white crystalline powder. Its structural formula is: CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects. Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Pharmacokinetics Absorption Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea. Distribution Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes. Metabolism Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea. Excretion Excretion of hydroxyurea in humans is likely a linear first-order renal process. Special Populations Geriatric, Gender, Race No information is available regarding pharmacokinetic differences due to age, gender, or race. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Pediatric No pharmacokinetic data are available in pediatric patients treated with hydroxyurea. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study, the mean exposure (AUC) in patients whose creatinine clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Close monitoring of hematologic parameters is advised in these patients. Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. Drug Interactions There are no data on concomitant use of hydroxyurea with other drugs in humans. Animal Pharmacology and Toxicology The oral LD50 of hydroxyurea is 7330 mg/kg in mice and 5780 mg/kg in rats, given as a single dose. In subacute and chronic toxicity studies in the rat, the most consistent pathological findings were an apparent dose-related mild to moderate bone marrow hypoplasia as well Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 as pulmonary congestion and mottling of the lungs. At the highest dosage levels (1260 mg/kg/day for 37 days, then 2520 mg/kg/day for 40 days), testicular atrophy with absence of spermatogenesis occurred; in several animals, hepatic cell damage with fatty metamorphosis was noted. In the dog, mild to marked bone marrow depression was a consistent finding except at the lower dosage levels. Additionally, at the higher dose levels (140 to 420 mg or 140 to 1260 mg/kg/week given 3 or 7 days weekly for 12 weeks), growth retardation, slightly increased blood glucose values, and hemosiderosis of the liver or spleen were found; reversible spermatogenic arrest was noted. In the monkey, bone marrow depression, lymphoid atrophy of the spleen, and degenerative changes in the epithelium of the small and large intestines were found. At the higher, often lethal, doses (400 to 800 mg/kg/day for 7 to 15 days), hemorrhage and congestion were found in the lungs, brain, and urinary tract. Cardiovascular effects (changes in heart rate, blood pressure, orthostatic hypotension, EKG changes) and hematological changes (slight hemolysis, slight methemoglobinemia) were observed in some species of laboratory animals at doses exceeding clinical levels. INDICATIONS AND USAGE Significant tumor response to HYDREA (hydroxyurea capsules, USP) has been demonstrated in melanoma, resistant chronic myelocytic leukemia, and recurrent, meta- static, or inoperable carcinoma of the ovary. Hydroxyurea used concomitantly with irradiation therapy is intended for use in the local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip. CONTRAINDICATIONS Hydroxyurea is contraindicated in patients with marked bone marrow depression, ie, leukopenia (<2500 WBC) or thrombocytopenia (<100,000), or severe anemia. HYDREA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. WARNINGS Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed (see CONTRAINDICATIONS). Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 anemia occur less often and are seldom seen without a preceding leukopenia. However, the recovery from myelosuppression is rapid when therapy is interrupted. It should be borne in mind that bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; hydroxyurea should be used cautiously in such patients. Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema. In HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. Peripheral neuropathy, which was severe in some cases, has been reported in HIV- infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Severe anemia must be corrected before initiating therapy with hydroxyurea. Erythrocytic abnormalities: megaloblastic erythropoiesis, which is self-limiting, is often seen early in the course of hydroxyurea therapy. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. Hydroxyurea may also delay plasma iron clearance and reduce the rate of iron utilization by erythrocytes, but it does not appear to alter the red blood cell survival time. Elderly patients may be more sensitive to the effects of hydroxyurea, and may require a lower dose regimen (see PRECAUTIONS: Geriatric Use). In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or associated with the patient’s underlying disease. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop and alternative cytoreductive agents should be initiated as indicated. Carcinogenesis and Mutagenesis Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype. Pregnancy Drugs which affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. The physician should carefully consider this possibility before administering this drug to male or female patients who may contemplate conception. HYDREA can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. 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 harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. PRECAUTIONS General Therapy with hydroxyurea requires close supervision. The complete status of the blood, including bone marrow examination, if indicated, as well as kidney function and liver function should be determined prior to, and repeatedly during, treatment. The determination of the hemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of hydroxyurea therapy. If the white blood cell count decreases to less than 2500/mm3, or the platelet count to less than 100,000/mm3, therapy should be interrupted until the values rise significantly toward normal levels. Severe anemia, if it occurs, should be managed without interrupting hydroxyurea therapy. Hydroxyurea should be used with caution in patients with marked renal dysfunction. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) Hydroxyurea is not indicated for the treatment of HIV infection; however, if HIV- infected patients are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Patients who develop signs and symptoms of pancreatitis should permanently discontinue therapy with hydroxyurea. (See WARNINGS and ADVERSE REACTIONS.) An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with hydroxyurea, and in particular, in combination with didanosine and stavudine. This combination should be avoided. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS for Carcinogenesis and Mutagenesis information. Impairment of Fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females. Pregnancy Pregnancy Category D. (See WARNINGS.) Nursing Mothers Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, 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 Elderly patients may be more sensitive to the effects of hydroxyurea, and may require a lower dose regimen. This drug is known to be 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: Renal Insufficiency). Drug Interactions Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse events. (See WARNINGS and ADVERSE REACTIONS.) Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea. Information for Patients HYDREA is a medication that must be handled with care. People who are not taking HYDREA should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling HYDREA or bottles containing HYDREA. Anyone handling HYDREA should wash their hands before and after contact with the bottle or capsules. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules. ADVERSE REACTIONS Reported adverse reactions are bone marrow depression (leukopenia, anemia, and thrombocytopenia), gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with HYDREA. Skin cancer has been reported. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy (see WARNINGS). Dysuria and alopecia have been reported. Large doses may produce moderate drowsiness. Neurological disturbances have occurred and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. HYDREA may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels. Abnormal Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 bromsulphalein (BSP) retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported. Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea or radiation treatment alone. These effects primarily include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred in the presence of marked leukopenia. HYDREA may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis. The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea has been reported. Pulmonary fibrosis also has been reported. In HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine, fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in Study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3. (See WARNINGS and PRECAUTIONS.) OVERDOSAGE Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have also been observed. DOSAGE AND ADMINISTRATION Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing HYDREA capsules. HYDREA capsules should not be opened. Personnel should avoid exposure to crushed or opened capsules. If contact with crushed Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below. Because of the rarity of melanoma, resistant chronic myelocytic leukemia, carcinoma of the ovary, and carcinomas of the head and neck in pediatric patients, dosage regimens have not been established. All dosage should be based on the patient’s actual or ideal weight, whichever is less. Concurrent use of HYDREA with other myelosuppressive agents may require adjustment of dosages. Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary. Solid Tumors Intermittent Therapy 80 mg/kg administered orally as a single dose every third day Continuous Therapy 20 to 30 mg/kg administered orally as a single dose daily Concomitant Therapy with Irradiation Carcinoma of the head and neck—80 mg/kg administered orally as a single dose every third day Administration of hydroxyurea should begin at least seven days before initiation of irradiation and continued during radiotherapy as well as indefinitely afterwards provided that the patient may be kept under adequate observation and evidences no unusual or severe reactions. Resistant Chronic Myelocytic Leukemia Until the intermittent therapy regimen has been evaluated, CONTINUOUS therapy (20-30 mg/kg administered orally as a single dose daily) is recommended. An adequate trial period for determining the antineoplastic effectiveness of hydroxyurea is six weeks of therapy. When there is regression in tumor size or arrest in tumor growth, therapy should be continued indefinitely. Therapy should be interrupted if the white Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 blood cell count drops below 2500/mm3, or the platelet count below 100,000/mm3. In these cases, the counts should be reevaluated after three days, and therapy resumed when the counts return to acceptable levels. Since the hematopoietic rebound is prompt, it is usually necessary to omit only a few doses. If prompt rebound has not occurred during combined HYDREA and irradiation therapy, irradiation may also be interrupted. However, the need for postponement of irradiation has been rare; radiotherapy has usually been continued using the recommended dosage and technique. Severe anemia, if it occurs, should be corrected without interrupting hydroxyurea therapy. Because hematopoiesis may be compromised by extensive irradiation or by other antineoplastic agents, it is recommended that hydroxyurea be administered cautiously to patients who have recently received extensive radiation therapy or chemotherapy with other cytotoxic drugs. Pain or discomfort from inflammation of the mucous membranes at the irradiated site (mucositis) is usually controlled by measures such as topical anesthetics and orally administered analgesics. If the reaction is severe, hydroxyurea therapy may be temporarily interrupted; if it is extremely severe, irradiation dosage may, in addition, be temporarily postponed. However, it has rarely been necessary to terminate these therapies. Severe gastric distress, such as nausea, vomiting, and anorexia, resulting from combined therapy may usually be controlled by temporary interruption of hydroxyurea administration. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of HYDREA in patients with renal impairment. (See PRECAUTIONS and CLINICAL PHARMACOLOGY.) Close monitoring of hematologic parameters is advised in these patients. Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 HOW SUPPLIED HYDREA® (hydroxyurea capsules, USP) 500 mg capsules in bottles of 100 (NDC 0003-0830-50). Capsule identification number: 830. The cap is opaque green and the body is opaque pink. They are imprinted on both sections in black ink with “HYDREA” and “830”. Storage Store at 25ºC (77ºF); excursions permitted to 15º-30ºC (59º-86ºF) [see USP Controlled Room Temperature]. Keep tightly closed. 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 JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society. Manufactured for: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Made in Italy 1053327A8 Rev January 2012 Approved Reference ID: 3077330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:58.595613	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016295s041s042lbl.pdf', 'application_number': 16295, 'submission_type': 'SUPPL ', 'submission_number': 41}
10,881	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use HYDREA safely and effectively. See full prescribing information for HYDREA. HYDREA (hydroxyurea) capsules, for oral use Initial U.S. Approval: 1967 ---------------------------RECENT MAJOR CHANGES-------------------------- Indications and Usage, melanoma (1) Removed 7/2015 Indications and Usage, carcinoma of the ovary (1) Removed 7/2015 Dosage and Administration (2) 7/2015 ---------------------------INDICATIONS AND USAGE--------------------------- HYDREA is an antimetabolite indicated for the treatment of:  Resistant chronic myeloid leukemia. (1)  Locally advanced squamous cell carcinomas of the head and neck, (excluding lip) in combination with concurrent chemoradiation. (1) -----------------------DOSAGE AND ADMINISTRATION----------------------  Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards. (2.1)  Renal impairment: Reduce the dose of HYDREA by 50% in patients with creatinine clearance less than 60 mL/min. (2.3, 8.6, 12.3) ---------------------DOSAGE FORMS AND STRENGTHS---------------------  Capsules: 500 mg (3) ------------------------------CONTRAINDICATIONS------------------------------  In patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------  Myelosuppression: Do not give if bone marrow function is markedly depressed. Monitor hematology labs and interrupt, reduce dose as appropriate. (5.1)  Malignancies: Advise protection from sun exposure and monitor for secondary malignancies. (5.2)  Embryo-fetal toxicity can cause fetal harm Advise of potential risk to a fetus and use of effective contraception. (5.3, 8.1)  Vasculitic toxicities: Discontinue HYDREA and initiate alternative management if this occurs. (5.4)  Risks with concomitant use of antiretroviral drugs: Pancreatitis, hepatotoxicity, and neuropathy have occurred. Monitor for signs and symptoms in patients with HIV infection using antiretroviral drugs; discontinue HYDREA, and implement treatment. (5.5)  Radiation recall: Monitor for skin erythema in patients who previously received radiation and manage symptomatically. (5.6) -------------------------------ADVERSE REACTIONS----------------------------- Most common adverse reactions (30%) are hematological, gastrointestinal symptoms, and anorexia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- Antiretroviral drugs (7) -----------------------USE IN SPECIFIC POPULATIONS-----------------------  Nursing Mothers: Hydroxyurea is excreted in human milk. Discontinue nursing during treatment with HYDREA. (8.3)  Geriatric Use: Care should be taken in dose selection and may require a lower dose regimen and monitoring of renal function. (8.5) See 17 for PATIENT COUNSELING INFORMATION Revised: 7/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Dose Modifications for Toxicity 2.3 Dose Modifications for Renal Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression 5.2 Malignancies 5.3 Embryo-Fetal Toxicity 5.4 Vasculitic Toxicities 5.5 Risks with Concomitant Use of Antiretroviral Drugs 5.6 Radiation Recall 5.7 Macrocytosis 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs 7.2 Test Interference 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 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 16.3 Handling and Disposal 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3793402 1 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 HYDREA is indicated for the treatment of:  Resistant chronic myeloid leukemia.  Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information HYDREA is used alone or in conjunction with other antitumor agents or radiation therapy to treat neoplastic diseases. Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards. Base all dosage on the patient’s actual or ideal weight, whichever is less. HYDREA is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)]. Prophylactic administration of folic acid is recommended [see Warnings and Precautions (5.7)]. 2.2 Dose Modifications for Toxicity Monitor for the following and reduce the dose or discontinue HYDREA accordingly:  Myelosuppression [see Warnings and Precautions (5.1)]  Cutaneous vasculitis [see Warnings and Precautions (5.4)] Monitor blood counts at least once a week during HYDREA therapy. Severe anemia must be corrected before initiating therapy with HYDREA. Consider dose modifications for other toxicities. 2.3 Dose Modifications for Renal Impairment Reduce the dose of HYDREA by 50% in patients with measured creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Creatinine Clearance (mL/min) Recommended HYDREA Initial Dose (mg/kg daily)  15 <60 or ESRD 7.5 * On dialysis days, administer HYDREA to patients following hemodialysis. Reference ID: 3793402 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Close monitoring of hematologic parameters is advised in these patients. 3 DOSAGE FORMS AND STRENGTHS Capsules: 500 mg opaque green cap and opaque pink body imprinted with “HYDREA” and “830.” 4 CONTRAINDICATIONS HYDREA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of the formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Hydroxyurea causes severe myelosuppression. Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often and are seldom seen without a preceding leukopenia. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; use hydroxyurea cautiously in such patients. Evaluate hematologic status prior to and during treatment with HYDREA. Provide supportive care and modify dose or discontinue HYDREA as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted. 5.2 Malignancies Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies. 5.3 Embryo-Fetal Toxicity Hydroxyurea may cause fetal harm when administered to a pregnant woman. Hydroxyurea is genotoxic. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations at 180 mg/kg/day in rats and at 30 mg/kg/day in rabbits. Single doses of 375 mg/kg to rats caused growth retardation and impaired learning ability. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and after treatment with HYDREA for at least 30 days after therapy. Females of reproductive potential should also ensure that their male partner, who is/has taken HYDREA, uses effective contraception during and after treatment for at least 1 year after Reference ID: 3793402 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda therapy. Advise males of reproductive potential to use effective contraception during and after treatment with HYDREA for at least 1 year after therapy [see Use in Specific Populations (8.1, 8.3)]. 5.4 Vasculitic Toxicities Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. If cutaneous vasculitic ulcers occur, institute treatment and discontinue of HYDREA. 5.5 Risks with Concomitant Use of Antiretroviral Drugs Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see Drug Interactions (7.1)]. 5.6 Radiation Recall Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema. Monitor for skin erythema in patients who previously received radiation and manage symptomatically. 5.7 Macrocytosis HYDREA may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections:  Myelosuppression [see Warnings and Precautions (5.1)]  Malignancies [see Warnings and Precautions (5.2)]  Embryo-fetal toxicity [see Warnings and Precautions (5.3)]  Vasculitic toxicities [see Warnings and Precautions (5.4)]  Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.5)]  Radiation recall [see Warnings and Precautions (5.6)]  Macrocytosis [see Warnings and Precautions (5.7)] Reference ID: 3793402 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Postmarketing Experience The following adverse reactions have been identified during postapproval use of HYDREA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.  Gastrointestinal disorders: stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation  Skin and subcutaneous tissue disorders: maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral and facial erythema, hyperpigmentation, atrophy of skin and nails, scaling, violet papules, and alopecia  Renal and urinary disorders: dysuria, elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels  Nervous system disorders: headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions  General Disorders: fever, chills, malaise, edema, and asthenia  Hepatobiliary disorders: elevation of hepatic enzymes  Respiratory disorders: diffuse pulmonary infiltrates, dyspnea, and pulmonary fibrosis Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea or radiation treatment alone. These effects primarily include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred in the presence of marked leukopenia. HYDREA may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis. 7 DRUG INTERACTIONS 7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs Pancreatitis In patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis. Hepatotoxicity Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral Reference ID: 3793402 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drugs. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination. Peripheral Neuropathy Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine. 7.2 Test Interference Interference with Uric Acid, Urea, or Lactic Acid Assays Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary HYDREA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. 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 harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Drugs which affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. The physician should carefully consider this possibility before administering this drug to male or female patients who may contemplate conception [see Warnings and Precautions (5.3)]. Animal Data Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of 375 mg/kg (about 1.7 times the maximum Reference ID: 3793402 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. 8.3 Nursing Mothers Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, discontinue nursing during treatment with HYDREA. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Elderly patients may be more sensitive to the effects of hydroxyurea, and may require a lower dose regimen. Hydroxyurea is excreted by the kidney, and the risk of adverse 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 (2.3)]. 8.6 Renal Impairment The exposure to hydroxyurea is higher in patients with creatinine clearance of less than 60 mL/min or in patients with end-stage renal disease (ESRD). Reduce dosage and closely monitor the hematologic parameters when HYDREA is to be administered to these patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. 10 OVERDOSAGE Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have also been observed. 11 DESCRIPTION HYDREA (hydroxyurea capsules, USP) is an antimetabolite available for oral use as capsules containing 500 mg hydroxyurea. Inactive ingredients include citric acid, colorants (D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, and D&C Red No. 28), gelatin, lactose, magnesium stearate, sodium phosphate, and titanium dioxide. Hydroxyurea is a white crystalline powder. It has a molecular weight of 76.05. Its structural formula is: Reference ID: 3793402 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects. Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells. It appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration. 12.3 Pharmacokinetics Absorption Following oral administration of HYDREA, hydroxyurea reaches peak plasma concentrations in 1 to 4 hours. Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose. There are no data on the effect of food on the absorption of hydroxyurea. Distribution Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water. Hydroxyurea concentrates in leukocytes and erythrocytes. Metabolism Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation by urease found in intestinal bacteria. Reference ID: 3793402 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Excretion In patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose. Specific Populations Renal Impairment The effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell disease and renal impairment. Patients with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30 <50 mL/min), or severe (<30 mL/min) renal impairment received a single oral dose of 15 mg/kg hydroxyurea. Patients with ESRD received two doses of 15 mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. The exposure to hydroxyurea (mean AUC) in patients with CrCl <60 mL/min and those with ESRD was 64% higher than in patients with normal renal function (CrCl >60 mL/min). Reduce the dose of HYDREA when it is administered to patients with creatinine clearance of <60 mL/min or with ESRD following hemodialysis [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility See Warnings and Precautions (5.2) for carcinogenesis and mutagenesis information. Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype. Impairment of Fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females. 15 REFERENCES OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. Reference ID: 3793402 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied HYDREA (hydroxyurea capsules, USP) is supplied as 500 mg capsules in HDPE bottles with a plastic safety screw cap. Each bottle contains 100 capsules. The cap is opaque green and the body is opaque pink. The capsules are imprinted on both sections with “HYDREA” and “830” in black ink (NDC 0003-0830-50). 16.2 Storage Store at 25C (77F); excursions permitted to 15C-30C (59F-86F) [see USP Controlled Room Temperature]. Keep tightly closed. 16.3 Handling and Disposal HYDREA is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)]. To decrease the risk of contact, advise caregivers to wear disposable gloves when handling HYDREA or bottles containing HYDREA. Wash hands with soap and water before and after contact with the bottle or capsules when handling HYDREA. Do not open HYDREA capsules. Avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs on the skin, wash affected area immediately and thoroughly with soap and water. If contact with crushed or opened capsules occurs on the eye(s), the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. If the powder from the capsule is spilled, immediately wipe it up with a damp disposable towel and discard in a closed container, such as a plastic bag; as should the empty capsules. The spill areas should then be cleaned three times using a detergent solution followed by clean water. Keep the medication away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules. 17 PATIENT COUNSELING INFORMATION  There is a risk of myelosuppression. Monitoring blood counts weekly throughout the duration of therapy should be emphasized to patients taking HYDREA [see Warnings and Precautions (5.1)]. Advise patients to report signs and symptoms of infection or bleeding immediately.  Advise patients that there is a risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia and skin cancers [see Warnings and Precautions (5.2, 5.4)].  Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females and males of reproductive potential to use contraception during and after treatment with HYDREA [see Warnings and Precautions 5.3 and Use in Specific Populations (8.1)]. Reference ID: 3793402 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Advise females to discontinue breastfeeding during treatment with HYDREA [see Use in Specific Populations (8.3)].  Patients with HIV infection should contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy [see Warnings and Precautions (5.5)].  Postirradiation erythema can occur in patients who have received previous irradiation therapy [see Warnings and Precautions (5.6)]. Manufactured for: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Product of Italy [print code] Reference ID: 3793402 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:58.752629	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/016295s045lbl.pdf', 'application_number': 16295, 'submission_type': 'SUPPL ', 'submission_number': 45}
10,882	1 MYAMBUTOL® Ethambutol Hydrochloride TABLETS 100 mg and 400 mg DESCRIPTION MYAMBUTOL ethambutol hydrochloride is an oral chemotherapeutic agent which is specifically effective against actively growing microorganisms of the genus Mycobacterium, including M. tuberculosis. The structural formula is: (+)-2,2'(Ethylenediimino)-di-1-butanol dihydrochloride MYAMBUTOL 100 and 400 mg tablets contain the following inactive ingredients: Gelatin, Hydroxypropyl Methylcellulose, Magnesium Stearate, Sodium Lauryl Sulfate, Sorbitol, Stearic Acid, Sucrose, Titanium Dioxide and other ingredients. CLINICAL PHARMACOLOGY MYAMBUTOL following a single oral dose of 25 mg/kg of body weight, attains a peak of 2 to 5 µg/mL in serum 2 to 4 hours after administration. When the drug is administered daily for longer periods of time at this dose, serum levels are similar. The serum level of MYAMBUTOL falls to undetectable levels by 24 hours after the last dose except in some patients with abnormal renal function. The intracellular concentrations of erythrocytes reach peak values approximately twice those of plasma and maintain this ratio throughout the 24 hours. During the 24-hour period following oral administration of MYAMBUTOL approximately 50 percent of the initial dose is excreted unchanged in the urine, while an additional 8 to 15 percent appears in the form of metabolites. The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. From 20 to 22 percent of the initial dose is excreted in the feces as unchanged drug. No drug accumulation has been observed with consecutive single daily doses of 25 mg/kg in patients with normal kidney function, although marked accumulation has been demonstrated in patients with renal insufficiency. MYAMBUTOL diffuses into actively growing mycobacterium cells such as tubercle bacilli. MYAMBUTOL appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated. MYAMBUTOL has been shown to be effective against strains of Mycobacterium tuberculosis but does not seem to be active against fungi, viruses, or other bacteria. Mycobacterium tuberculosis strains previously unexposed to MYAMBUTOL have been uniformly sensitive to CH 3CH 2 NHCH 2CH 2 NH CH 2CH 3 H CH 2OH C C 2HCl . H CH 2OH This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 concentrations of 8 or less µg/mL, depending on the nature of the culture media. When MYAMBUTOL has been used alone for treatment of tuberculosis, tubercle bacilli from these patients have developed resistance to MYAMBUTOL ethambutol hydrochloride by in vitro susceptibility tests; the development of resistance has been unpredictable and appears to occur in a step-like manner. No cross resistance between MYAMBUTOL and other antituberculous drugs has been reported. MYAMBUTOL has reduced the incidence of the emergence of mycobacterial resistance to isoniazid when both drugs have been used concurrently. An agar diffusion microbiologic assay, based upon inhibition of Mycobacterium smegmatis (ATCC 607) may be used to determine concentrations of MYAMBUTOL in serum and urine. This technique has not been published, but further information can be obtained upon inquiry to Lederle Laboratories. ANIMAL PHARMACOLOGY Toxicological studies in dogs on high prolonged doses produced evidence of myocardial damage and failure, and depigmentation of the tapetum lucidum of the eyes, the significance of which is not known. Degenerative changes in the central nervous system, apparently not dose-related, have also been noted in dogs receiving ethambutol hydrochloride over a prolonged period. In the rhesus monkey, neurological signs appeared after treatment with high doses given daily over a period of several months. These were correlated with specific serum levels of ethambutol hydrochloride and with definite neuroanatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received ethambutol hydrochloride in high doses for a prolonged period. INDICATIONS MYAMBUTOL is indicated for the treatment of pulmonary tuberculosis. It should not be used as the sole antituberculous drug, but should be used in conjunction with at least one other antituberculous drug. Selection of the companion drug should be based on clinical experience, considerations of comparative safety, and appropriate in vitro susceptibility studies. In patients who have not received previous antituberculous therapy, ie, initial treatment, the most frequently used regimens have been the following: MYAMBUTOL plus isoniazid MYAMBUTOL plus isoniazid plus streptomycin. In patients who have received previous antituberculous therapy, mycobacterial resistance to other drugs used in initial therapy is frequent. Consequently, in such retreatment patients, MYAMBUTOL should be combined with at least one of the second line drugs not previously administered to the patient and to which bacterial susceptibility has been indicated by appropriate in vitro studies. Antituberculous drugs used with MYAMBUTOL have included cycloserine, ethionamide, pyrazinamide, viomycin and other drugs. Isoniazid, aminosalicylic acid, and streptomycin have also been used in multiple drug regimens. Alternating drug regimens have also been utilized. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 CONTRAINDICATIONS MYAMBUTOL is contraindicated in patients who are known to be hypersensitive to this drug. It is also contraindicated in patients with known optic neuritis unless clinical judgement determines that it may be used. WARNINGS MYAMBUTOL may produce decreases in visual acuity which appear to be due to optic neuritis. This effect may be related to dose and duration of treatment. This effect is generally reversible when administration of the drug is discontinued promptly. However, irreversible blindness has been reported. (See PRECAUTIONS and ADVERSE REACTIONS). Liver toxicities including fatalities have been reported (see ADVERSE REACTIONS). Baseline and periodic assessment of hepatic function should be performed. PRECAUTIONS MYAMBUTOL ethambutol hydrochloride is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. Patients with decreased renal function need the dosage reduced as determined by serum levels of MYAMBUTOL, since the main path of excretion of this drug is by the kidneys. Because this drug may have adverse effects on vision, physical examination should include ophthalmoscopy, finger perimetry and testing of color discrimination. In patients with visual defects such as cataracts, recurrent inflammatory conditions of the eye, optic neuritis, and diabetic retinopathy, the evaluation of changes in visual acuity is more difficult, and care should be taken to be sure the variations in vision are not due to the underlying disease conditions. In such patients, consideration should be given to relationship between benefits expected and possible visual deterioration since evaluation of visual changes is difficult. (For recommended procedures, see next paragraphs under ADVERSE REACTIONS.) As with any potent drug, baseline and periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, should be performed. Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. There are reports of ophthalmic abnormalities occurring in infants born to women on antituberculous therapy that included ethambutol hydrochloride. MYAMBUTOL should be used during pregnancy only if the benefit justifies the potential risk to the fetus. MYAMBUTOL has been shown to be teratogenic in pregnant mice and rabbits when given in high doses. When pregnant mice or rabbits were treated with high doses of ethambutol hydrochloride, fetal mortality was slightly but not significantly (P>0.05) increased. Female rats This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 treated with ethambutol hydrochloride displayed slight but insignificant (P>0.05) decreases in fertility and litter size. In fetuses born of mice treated with high doses of MYAMBUTOL during pregnancy, a low incidence of cleft palate, exencephaly and abnormality of the vertebral column were observed. Minor abnormalities of the cervical vertebra were seen in the newborn of rats treated with high doses of ethambutol hydrochloride during pregnancy. Rabbits receiving high doses of MYAMBUTOL during pregnancy gave birth to two fetuses with monophthalmia, one with a shortened right forearm accompanied by bilateral wrist-joint contracture and one with hare lip and cleft palate. Geriatric Use There are limited data on the use of ethambutol in the elderly. One study of 101 patients, 65 years and older, on multiple drug antituberculosis regimens included 94 patients on ethambutol. No differences in safety or tolerability were observed in these patients compared with that reported in adults in general. 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. ADVERSE REACTIONS MYAMBUTOL may produce decreases in visual acuity, including irreversible blindness, which appear to be due to optic neuritis. Optic neuropathy including optic neuritis or retrobulbar neuritis occurring in association with ethambutol therapy may be characterized by one or more of the following events: decreased visual acuity, scotoma, color blindness, and/or visual defect. These events have also been reported in the absence of a diagnosis of optic or retrobulbar neuritis. Patients should be advised to report promptly to their physician any change of visual acuity. The change in visual acuity may be unilateral or bilateral and hence each eye must be tested separately and both eyes tested together. Testing of visual acuity should be performed before beginning MYAMBUTOL therapy and periodically during drug administration, except that it should be done monthly when a patient is on a dosage of more than 15 mg per kilogram per day. Snellen eye charts are recommended for testing of visual acuity. Studies have shown that there are definite fluctuations of one or two lines of the Snellen chart in the visual acuity of many tuberculous patients not receiving MYAMBUTOL. The following table may be useful in interpreting possible changes in visual acuity attributable to MYAMBUTOL. Initial Snellen Reading Reading Indicating Significant Decrease Significant Number of Lines Decrease Number of Points 20/13 20/25 3 12 20/15 20/25 2 10 20/20 20/30 2 10 20/25 20/40 2 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 20/30 20/50 2 20 20/40 20/70 2 30 20/50 20/70 1 20 In general, changes in visual acuity less than those indicated under “Significant Number of Lines” and “Decrease Number of Points” may be due to chance variation, limitations of the testing method, or physiologic variability. Conversely, changes in visual acuity equaling or exceeding those under “Significant Number of Lines” and “Decrease Number of Points” indicate need for retesting and careful evaluation of the patient’s visual status. If careful evaluation confirms the magnitude of visual change and fails to reveal another cause, MYAMBUTOL should be discontinued and the patient reevaluated at frequent intervals. Progressive decreases in visual acuity during therapy must be considered to be due to MYAMBUTOL. If corrective glasses are used prior to treatment, these must be worn during visual acuity testing. During 1 to 2 years of therapy, a refractive error may develop which must be corrected in order to obtain accurate test results. Testing the visual acuity through a pinhole eliminates refractive error. Patients developing visual abnormality during MYAMBUTOL treatment may show subjective visual symptoms before, or simultaneously with, the demonstration of decreases in visual acuity, and all patients receiving MYAMBUTOL should be questioned periodically about blurred vision and other subjective eye symptoms. Recovery of visual acuity generally occurs over a period of weeks to months after the drug has been discontinued. Some patients have received MYAMBUTOL ethambutol hydrochloride again after such recovery without recurrence of loss of visual acuity. Other adverse reactions reported include: anaphylactoid reactions, dermatitis, pruritus, and joint pain; anorexia, nausea, vomiting, gastrointestinal upset, and abdominal pain; fever, malaise, headache, and dizziness; mental confusion, disorientation, and possible hallucinations; thrombocytopenia and leukopenia. Numbness and tingling of the extremities due to peripheral neuritis have been reported. Elevated serum uric acid levels occur and precipitation of acute gout has been reported. Pulmonary infiltrates and eosinophilia also have been reported during MYAMBUTOL therapy. Liver toxicities, including fatalities, have been reported. (See WARNINGS.) Since MYAMBUTOL is recommended for therapy in conjunction with one or more other antituberculous drugs, these changes may be related to the concurrent therapy. DOSAGE and ADMINISTRATION MYAMBUTOL should not be used alone, in initial treatment or in retreatment. MYAMBUTOL should be administered on a once every 24-hour basis only. Absorption is not significantly altered by administration with food. Therapy, in general, should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occurred. MYAMBUTOL is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use 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 6 Initial Treatment: In patients who have not received previous antituberculous therapy, administer MYAMBUTOL 15 mg/kg (7 mg/lb) of body weight, as a single oral dose once every 24 hours. In the more recent studies, isoniazid has been administered concurrently in a single, daily, oral dose. Retreatment: In patients who have received previous antituberculous therapy, administer MYAMBUTOL 25 mg/kg (11 mg/lb) of body weight, as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculous drug to which the organisms have been demonstrated to be susceptible by appropriate in vitro tests. Suitable drugs usually consist of those not previously used in the treatment of the patient. After 60 days of MYAMBUTOL administration, decrease the dose to 15 mg/kg (7 mg/lb) of body weight, and administer as a single oral dose once every 24 hours. During the period when a patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised. See Table for easy selection of proper weight-dose tablet(s). Weight-Dose Table 15 mg/kg (7 mg/lb) Schedule Weight Range Daily Dose Pounds Kilograms In mg Under 85 lb. Under 37 Kg.....................500 85 – 94.5 37 – 43 .............................600 95 – 109.5 43 – 50..............................700 110 – 124.5 50 – 57..............................800 125 – 139.5 57 – 64..............................900 140 – 154.5 64 – 71............................1000 155 – 169.5 71 – 79............................1100 170 – 184.5 79 – 84............................1200 185 – 199.5 84 – 90............................1300 200 – 214.5 90 – 97............................1400 215 and Over Over 97...........................1500 25 mg/kg (11 mg/lb) Schedule Under 85 lbs. Under 38 kg......................900 85 – 92.5 38 – 42............................1000 93 – 101.5 42 – 45.5.........................1100 102 – 109.5 45.5 – 50.........................1200 110 – 118.5 50 – 54............................1300 119 – 128.5 54 – 58............................1400 129 – 136.5 58 – 62............................1500 137 – 146.5 62 – 67............................1600 147 – 155.5 67 – 71............................1700 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 156 – 164.5 71 – 75............................1800 165 – 173.5 75 – 79............................1900 174 – 182.5 79 – 83............................2000 183 – 191.5 83 – 87............................2100 192 – 199.5 87 – 91............................2200 200 – 209.5 91 – 95............................2300 210 – 218.5 95 – 99............................2400 219 and Over Over 99...........................2500 HOW SUPPLIED MYAMBUTOL® ethambutol hydrochloride Tablets 100 mg – round, convex, white, film coated tablets engraved M6 on one side and LL on the other, are supplied as follows: NDC 51479-046-01 - Bottle of 100 400 mg – round, convex, white, scored, film coated tablets engraved with LL on one side and M to the left and 7 to the right of the score on the other side, are supplied as follows: NDC 51479-047-01 - Bottle of 100 NDC 51479-047-10 - Bottle of 1000 NDC 51479-047-04 - Unit Dose 10 (2 X 5) Strips Store at controlled room temperature 20°C to 25°C (68° to 77°F). Rx only Manufactured by LEDERLE PHARMACEUTICAL DIVISION of American Cyanamid Company Pearl River, NY 10965 For DURA PHARMACEUTICALS, INC. San Diego, CA 92121 CI 4544-5 Revised September 26, 2001 MY001C01 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:58.765052	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/16320slr057_Myambutol_lbl.pdf', 'application_number': 16320, 'submission_type': 'SUPPL ', 'submission_number': 57}
10,884	______________________________________________________________________________________________ Myambutol® (Ethambutol HCl USP) Tablets, 100 mg & 400 mg 1.14.2.3 Final Labeling Text 1.14.2.3 Final Labeling Text The final labeling for Ethambutol HCl tablets 100 & 40mg can be found below: company logo Ethambutol Hydrochloride TABLETS USP 100 mg and 400 mg Rx DESCRIPTION ETHAMBUTOL HYDROCHLORIDE is an oral chemotherapeutic agent which is specifically effective against actively growing microorganisms of the genus Mycobacterium, including M. tuberculosis. The structural formula is: structural formula ETHAMBUTOL HYDROCHLORIDE (HCl) 100 and 400 mg tablets contain the following inactive ingredients: Gelatin, Hydroxypropyl Methylcellulose, Magnesium Stearate, Sodium Lauryl Sulfate, Sorbitol, Stearic Acid, Sucrose, Titanium Dioxide and other ingredients. CLINICAL PHARMACOLOGY ETHAMBUTOL HCL, following a single oral dose of 25 mg/kg of body weight, attains a peak of 2 to 5 mcg/mL in serum 2 to 4 hours after administration. When the drug is administered daily for longer periods of time at this dose, serum levels are similar. The serum level of ETHAMBUTOL HCL falls to undetectable levels by 24 hours after the last dose except in some patients with abnormal renal function. The intracellular concentrations of erythrocytes reach peak values approximately twice those of plasma and maintain this ratio throughout the 24 hours. During the 24-hour period following oral administration of ETHAMBUTOL HCl approximately 50 percent of the initial dose is excreted unchanged in the urine, while an additional 8 to 15 percent appears in the form of metabolites. The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. From 20 to 22 percent of the initial dose is excreted in the feces as unchanged drug. No drug accumulation has been observed with consecutive single daily doses of 25 mg/kg in patients NDA 16-320 1 of 8 Reference ID: 3265997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________________________________ Myambutol® (Ethambutol HCl USP) Tablets, 100 mg & 400 mg 1.14.2.3 Final Labeling Text with normal kidney function, although marked accumulation has been demonstrated in patients with renal insufficiency. ETHAMBUTOL HCl diffuses into actively growing Mycobacterium cells such as tubercle bacilli. ETHAMBUTOL HCl appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated. ETHAMBUTOL HCl has been shown to be effective against strains of Mycobacterium tuberculosis but does not seem to be active against fungi, viruses, or other bacteria. Mycobacterium tuberculosis strains previously unexposed to ETHAMBUTOL HCl have been uniformly sensitive to concentrations of 8 or less mcg/mL, depending on the nature of the culture media. When ETHAMBUTOL HCl has been used alone for treatment of tuberculosis, tubercle bacilli from these patients have developed resistance to ETHAMBUTOL HCl (ethambutol hydrochloride) by in vitro susceptibility tests; the development of resistance has been unpredictable and appears to occur in a step-like manner. No cross resistance between ETHAMBUTOL HCl and other antituberculous drugs has been reported. ETHAMBUTOL HCl has reduced the incidence of the emergence of mycobacterial resistance to isoniazid when both drugs have been used concurrently. An agar diffusion microbiologic assay, based upon inhibition of Mycobacterium smegmatis (ATCC 607) may be used to determine concentrations of ETHAMBUTOL HCl in serum and urine. ANIMAL PHARMACOLOGY Toxicological studies in dogs on high prolonged doses produced evidence of myocardial damage and failure, and depigmentation of the tapetum lucidum of the eyes, the significance of which is not known. Degenerative changes in the central nervous system, apparently not dose-related, have also been noted in dogs receiving ethambutol hydrochloride over a prolonged period. In the rhesus monkey, neurological signs appeared after treatment with high doses given daily over a period of several months. These were correlated with specific serum levels of ethambutol and with definite neuroanatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received ethambutol hydrochloride in high doses for a prolonged period. INDICATIONS ETHAMBUTOL HCl is indicated for the treatment of pulmonary tuberculosis. It should not be used as the sole antituberculous drug, but should be used in conjunction with at least one other antituberculous drug. Selection of the companion drug should be based on clinical experience, considerations of comparative safety, and appropriate in vitro susceptibility studies. In patients who have not received previous antituberculous therapy, ie, initial treatment, the most frequently used regimens have been the following: ETHAMBUTOL HCl plus isoniazid ETHAMBUTOL HCl plus isoniazid plus streptomycin. NDA 16-320 2 of 8 Reference ID: 3265997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________________________________ Myambutol® (Ethambutol HCl USP) Tablets, 100 mg & 400 mg 1.14.2.3 Final Labeling Text In patients who have received previous antituberculous therapy, mycobacterial resistance to other drugs used in initial therapy is frequent. Consequently, in such retreatment patients, ETHAMBUTOL HCl should be combined with at least one of the second line drugs not previously administered to the patient and to which bacterial susceptibility has been indicated by appropriate in vitro studies. Antituberculous drugs used with ETHAMBUTOL HCl have included cycloserine, ethionamide, pyrazinamide, viomycin and other drugs. Isoniazid, aminosalicylic acid, and streptomycin have also been used in multiple drug regimens. Alternating drug regimens have also been utilized. CONTRAINDICATIONS ETHAMBUTOL HCl is contraindicated in patients who are known to be hypersensitive to this drug. It is also contraindicated in patients with known optic neuritis unless clinical judgment determines that it may be used. ETHAMBUTOL HCl is contraindicated in patients who are unable to appreciate and report visual side effects or changes in vision (e.g., young children, unconscious patients). WARNINGS ETHAMBUTOL HCl may produce decreases in visual acuity which appear to be due to optic neuritis. This effect may be related to dose and duration of treatment. This effect is generally reversible when administration of the drug is discontinued promptly. However, irreversible blindness has been reported. (See PRECAUTIONS and ADVERSE REACTIONS). Liver toxicities including fatalities have been reported (see ADVERSE REACTIONS). Baseline and periodic assessment of hepatic function should be performed. PRECAUTIONS ETHAMBUTOL HCl ethambutol hydrochloride is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. Patients with decreased renal function need the dosage reduced as determined by serum levels of ETHAMBUTOL HCl, since the main path of excretion of this drug is by the kidneys. Because this drug may have adverse effects on vision, physical examination should include ophthalmoscopy, finger perimetry and testing of color discrimination. In patients with visual defects such as cataracts, recurrent inflammatory conditions of the eye, optic neuritis, and diabetic retinopathy, the evaluation of changes in visual acuity is more difficult, and care should be taken to be sure the variations in vision are not due to the underlying disease conditions. In such patients, consideration should be given to relationship between benefits expected and possible visual deterioration since evaluation of visual changes is difficult. (For recommended procedures, see next paragraphs under ADVERSE REACTIONS.) As with any potent drug, baseline and periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, should be performed. Drug Interactions NDA 16-320 3 of 8 Reference ID: 3265997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________________________________ Myambutol® (Ethambutol HCl USP) Tablets, 100 mg & 400 mg 1.14.2.3 Final Labeling Text The results of a study of coadministration of ETHAMBUTOL HCl (50mg/kg) with an aluminum hydroxide containing antacid to 13 patients with tuberculosis showed a reduction of mean serum concentrations and urinary excretion of ethambutol of approximately 20% and 13%, respectively, suggesting that the oral absorption of ethambutol may be reduced by these antacid products. It is recommended to avoid concurrent administration of ethambutol with aluminum hydroxide containing antacids for at least 4 hours following ethambutol administration. Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. There are reports of ophthalmic abnormalities occurring in infants born to women on antituberculous therapy that included ETHAMBUTOL HCl. ETHAMBUTOL HCl should be used during pregnancy only if the benefit justifies the potential risk to the fetus. ETHAMBUTOL HCl has been shown to be teratogenic in pregnant mice and rabbits when given in high doses. When pregnant mice or rabbits were treated with high doses of ethambutol hydrochloride, fetal mortality was slightly but not significantly (P>0.05) increased. Female rats treated with ethambutol hydrochloride displayed slight but insignificant (P>0.05) decreases in fertility and litter size. In fetuses born of mice treated with high doses of ETHAMBUTOL HCl during pregnancy, a low incidence of cleft palate, exencephaly and abnormality of the vertebral column were observed. Minor abnormalities of the cervical vertebra were seen in the newborn of rats treated with high doses of ethambutol hydrochloride during pregnancy. Rabbits receiving high doses of ETHAMBUTOL HCl during pregnancy gave birth to two fetuses with monophthalmia, one with a shortened right forearm accompanied by bilateral wrist- joint contracture and one with hare lip and cleft palate. Nursing Mothers ETHAMBUTOL HCl is excreted into breast milk. The use of ETHAMBUTOL HCl should be considered only if the expected benefit to the mother outweighs the potential risk to the infant. Pediatric Use ETHAMBUTOL HCl (ethambutol hydrochloride) is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. Geriatric Use There are limited data on the use of ETHAMBUTOL HCl in the elderly. One study of 101 patients, 65 years and older, on multiple drug antituberculosis regimens included 94 patients on ETHAMBUTOL HCl. No differences in safety or tolerability were observed in these patients compared with that reported in adults in general. 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. ADVERSE REACTIONS NDA 16-320 4 of 8 Reference ID: 3265997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________________________________ Myambutol® (Ethambutol HCl USP) Tablets, 100 mg & 400 mg 1.14.2.3 Final Labeling Text ETHAMBUTOL HCl may produce decreases in visual acuity, including irreversible blindness, which appear to be due to optic neuritis. Optic neuropathy including optic neuritis or retrobulbar neuritis occurring in association with ethambutol therapy may be characterized by one or more of the following events: decreased visual acuity, scotoma, color blindness, and/or visual defect. These events have also been reported in the absence of a diagnosis of optic or retrobulbar neuritis. Patients should be advised to report promptly to their physician any change of visual acuity. The change in visual acuity may be unilateral or bilateral and hence each eye must be tested separately and both eyes tested together. Testing of visual acuity should be performed before beginning ETHAMBUTOL HCl therapy and periodically during drug administration, except that it should be done monthly when a patient is on a dosage of more than 15 mg per kilogram per day. Snellen eye charts are recommended for testing of visual acuity. Studies have shown that there are definite fluctuations of one or two lines of the Snellen chart in the visual acuity of many tuberculous patients not receiving ETHAMBUTOL HCl. The following table may be useful in interpreting possible changes in visual acuity attributable to ETHAMBUTOL HCl. Initial Reading Significant Decrease Snellen Indicating Number of Number Reading Significant Lines of Points Decrease 20/13 20/25 3 12 20/15 20/25 2 10 20/20 20/30 2 10 20/25 20/40 2 15 20/30 20/50 2 20 20/40 20/70 2 30 20/50 20/70 1 20 In general, changes in visual acuity less than those indicated under “Significant Number of Lines” and “Decrease Number of Points” may be due to chance variation, limitations of the testing method, or physiologic variability. Conversely, changes in visual acuity equaling or exceeding those under “Significant Number of Lines” and “Decrease Number of Points” indicate need for retesting and careful evaluation of the patient’s visual status. If careful evaluation confirms the magnitude of visual change and fails to reveal another cause, ETHAMBUTOL HCl should be discontinued and the patient reevaluated at frequent intervals. Progressive decreases in visual acuity during therapy must be considered to be due to ETHAMBUTOL HCl. If corrective glasses are used prior to treatment, these must be worn during visual acuity testing. During 1 to 2 years of therapy, a refractive error may develop which must be corrected in order NDA 16-320 5 of 8 Reference ID: 3265997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________________________________ Myambutol® (Ethambutol HCl USP) Tablets, 100 mg & 400 mg 1.14.2.3 Final Labeling Text to obtain accurate test results. Testing the visual acuity through a pinhole eliminates refractive error. Patients developing visual abnormality during ETHAMBUTOL HCl treatment may show subjective visual symptoms before, or simultaneously with, the demonstration of decreases in visual acuity, and all patients receiving ETHAMBUTOL HCl should be questioned periodically about blurred vision and other subjective eye symptoms. Recovery of visual acuity generally occurs over a period of weeks to months after the drug has been discontinued. Some patients have received ETHAMBUTOL HCl (ethambutol hydrochloride) again after such recovery without recurrence of loss of visual acuity. Other adverse reactions reported include: hypersensitivity, anaphylactic/anaphylactoid reaction, dermatitis, erythema multiforme, pruritus, and joint pain; anorexia, nausea, vomiting, gastrointestinal upset, and abdominal pain; fever, malaise, headache, and dizziness; mental confusion, disorientation, and possible hallucinations; thrombocytopenia, leukopenia, and neutropenia. Numbness and tingling of the extremities due to peripheral neuritis have been reported. Elevated serum uric acid levels occur and precipitation of acute gout has been reported. Pulmonary infiltrates, with or without eosinophilia, also have been reported during ETHAMBUTOL HCl therapy. Liver toxicities, including fatalities, have been reported. (See WARNINGS). Since ETHAMBUTOL HCl is recommended for therapy in conjunction with one or more other antituberculous drugs, these changes may be related to the concurrent therapy. Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis. Fever and lymphadenopathy may be present. DOSAGE and ADMINISTRATION ETHAMBUTOL HCl should not be used alone, in initial treatment or in retreatment. ETHAMBUTOL HCl should be administered on a once every 24-hour basis only. Absorption is not significantly altered by administration with food. Therapy, in general, should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occurred. ETHAMBUTOL HCl is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. Initial Treatment: In patients who have not received previous antituberculous therapy, administer ETHAMBUTOL HCl 15 mg/kg (7 mg/lb) of body weight, as a single oral dose once every 24 hours. In the more recent studies, isoniazid has been administered concurrently in a single, daily, oral dose. Retreatment: In patients who have received previous antituberculous therapy, administer ETHAMBUTOL HCl 25 mg/kg (11 mg/lb) of body weight, as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculous drug to which the organisms have been demonstrated to be susceptible by appropriate in vitro tests. Suitable drugs usually consist of those not previously used in the treatment of the patient. After 60 days of ETHAMBUTOL HCl administration, decrease the dose to 15 mg/kg (7mg/lb) of body weight, and administer as a single oral dose once every 24 hours. NDA 16-320 6 of 8 Reference ID: 3265997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________________________________ Myambutol® (Ethambutol HCl USP) Tablets, 100 mg & 400 mg 1.14.2.3 Final Labeling Text During the period when a patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised. See Table for easy selection of proper weight-dose tablet(s). Weight-Dose Table 15 mg/kg (7 mg/lb) Schedule Weight Range Dose Pounds Kilograms In mg Under 85 lbs Under 37 Kg .............................. 500 85 – 94.5 37 – 43 ........................... 600 95 – 109.5 43 – 50 ............................700 110– 124.5 50 – 57 ........................... 800 125– 139.5 57 – 64 ........................... 900 140– 154.5 64 – 71 ......................... 1000 155– 169.5 71 – 79 ......................... 1100 170 – 184.5 79 – 84 ......................... 1200 185– 199.5 84 – 90 ......................... 1300 200– 214.5 90 – 97 ......................... 1400 215 and Over Over 97 .................................... 1500 25 mg/kg (11 mg/lb) Schedule Under 85 lbs. Under 38 kg .. ........................... 900 85 – 92.5 38 – 42 ........................ 1000 93 – 101.5 42 – 45.5 ..................... 1100 102– 109.5 45.5 – 50 ..................... 1200 110– 118.5 50 – 54 ........................ 1300 119– 128.5 54 – 58 ........................ 1400 129– 136.5 58 – 62 ........................ 1500 137– 146.5 62 – 67 ........................ 1600 147–155.5 67 – 71 ........................ 1700 156– 164.5 71 – 75 ........................ 1800 165– 173.5 75 – 79 ........................ 1900 174– 182.5 79 – 83 ........................ 2000 183– 191.5 83 – 87 ........................ 2100 192– 199.5 87 – 91 ........................ 2200 200– 209.5 91 – 95 ........................ 2300 210– 218.5 95 – 99 ........................ 2400 219 and Over Over 99 ....................... 2500 NDA 16-320 7 of 8 Reference ID: 3265997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________________________________ Myambutol® (Ethambutol HCl USP) Tablets, 100 mg & 400 mg 1.14.2.3 Final Labeling Text HOW SUPPLIED Ethambutol hydrochloride Tablets USP 100 mg – round, convex, white, film coated tablets engraved E6 on one side are supplied as follows: NDC 54879-001-01 - Bottle of 100 NDC 54879-001-00 - 10 Blister-packs x 10 tablets 400 mg – round, convex, white, scored, film coated tablets engraved with E to the left and 7 to the right of the score on one side are supplied as follows: NDC 54879-002-01 - Bottle of 100 NDC 54879-002-00 - 10 Blister-packs x 10 tablets Store at controlled room temperature 20° to 25°C (68° to 77°F). Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 Manufactured for & Distributed by: STI Pharma, LLC Langhorne, PA 19047. Revised April 2012 Code No.:MH/DRUGS/PD/182 NDA 16-320 8 of 8 Reference ID: 3265997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:58.959915	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016320s066lbl.pdf', 'application_number': 16320, 'submission_type': 'SUPPL ', 'submission_number': 66}

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