medication_name stringlengths 6 170 | section_title stringclasses 42 values | text stringlengths 0 47.1k |
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Daptomycin Dr. Reddy's 350 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - List of excipients | List of excipients
Sodium hydroxide
6.2 |
Daptomycin Dr. Reddy's 350 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Daptomycin is not physically or chemically compatible with glucose-containing solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 |
Daptomycin Dr. Reddy's 350 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Shelf life | Shelf life
2 years
After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial has been demonstrated for 12 hours at 25°C and up to 48 hours at 2°C – 8°C. Chemical and physical stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours at 2°C – 8°C.
For the 30-minute intravenous infusion, the combined storage time (reconstituted solution in vial and diluted solution in infusion bag; see section 6.6) at 25°C must not exceed 12 hours (or 24 at 2°C – 8°C).
For the 2-minute intravenous injection, the storage time of the reconstituted solution in the vial (see section 6.6) at 25°C must not exceed 12 hours (or 48 at 2°C – 8°C).
However, from a microbiological point of view the product should be used immediately. No preservative or bacteriostatic agent is present in this product. If not used immediately, in-use storage times are the responsibility of the user and would not normally be longer than 24 hours at 2°C – 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
6.4 |
Daptomycin Dr. Reddy's 350 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in a refrigerator (2°C – 8°C).
For storage conditions after reconstitution and after reconstitution and dilution of the medicinal product see section 6.3.
6.5 |
Daptomycin Dr. Reddy's 350 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Single use 15 ml type I glass vials with bromobutyl rubber stoppers and sealed with 20 mm flip-off seal yellow.
Pack size: 1 vial.
6.6 |
Daptomycin Dr. Reddy's 350 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
In adults, daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over 2 minutes. Daptomycin should not be administered as a 2-minute injection to paediatric patients. Paediatric patients 7 to 17 years old should receive daptomycin infused over 30 minutes. In paediatric patients under 7 years old receiving a 9-12 mg/kg dose, daptomycin should be administered over 60 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional dilution step as detailed below.
Daptomycin given as 30 or 60-minute intravenous infusion
A 50 mg/ml concentration of Daptomycin 350 mg powder for solution for injection/infusion is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Daptomycin for intravenous infusion, please adhere to the following instructions: Aseptic technique should be used throughout to reconstitute or dilute lyophilised Daptomycin.
For Reconstitution:
1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin range in colour from pale yellow to light brown.
5. The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical volume 50 ml).
For Dilution:
1. Slowly remove the appropriate reconstituted liquid (50 mg daptomycin/ml) from the vial using a sterile needle that is 21 gauge or smaller in diameter by inverting the vial in order to allow the solution to drain towards the stopper. Using a syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove the required solution from the inverted vial.
2. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
3. Transfer the required reconstituted dose into 50 ml sodium chloride 9 mg/ml (0.9%).
4. The reconstituted and diluted solution should then be infused intravenously over 30 or 60 minutes as directed in section 4.2.
The following have been shown to be compatible when added to daptomycin containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.
Daptomycin given as 2-minute intravenous injection (adult patients only)
Water should not be used for reconstitution of Daptomycin for intravenous injection. Daptomycin should only be reconstituted with sodium chloride 9 mg/ml (0.9%).
A 50 mg/ml concentration of Daptomycin 350 mg powder for solution for injection/ infusion is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Daptomycin for intravenous injection, please adhere to the following instructions: Aseptic technique should be used throughout to reconstitute lyophilised Daptomycin.
1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin range in colour from pale yellow to light brown.
5. Slowly remove the reconstituted liquid (50 mg daptomycin/ml) from the vial using a sterile needle that is 21 gauge or smaller in diameter.
6. Invert the vial in order to allow the solution to drain towards the stopper. Using a syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
7. Replace needle with a new needle for the intravenous injection.
8. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9. The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.
Daptomycin vials are for single-use only.
From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Daptomycin Dr. Reddy's 350 mg Powder for Solution for Injection/Infusion | Marketing authorisation holder | Dr. Reddy's Laboratories (UK) Ltd.
410 Cambridge Science Park
Milton Road
Cambridge
CB4 0PE
United Kingdom
8. Marketing authorisation number(s)
PL 08553/0580
9. |
Daptomycin Dr. Reddy's 350 mg Powder for Solution for Injection/Infusion | Date of first authorisation/renewal of the authorisation | 15/08/2017
10. |
Daptomycin Dr. Reddy's 350 mg Powder for Solution for Injection/Infusion | Date of revision of the text | 24/11/2022 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Name of the medicinal product | Daptomycin Dr. Reddy's 500 mg Powder For Solution For Injection/Infusion
2. |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Qualitative and quantitative composition | Each vial contains 500 mg daptomycin.
One ml provides 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml (0.9%) solution.
For the full list of excipients, see section 6.1
3. |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Pharmaceutical form | Powder for solution for injection/infusion
A pale yellow to light brown lyophilised cake or powder.
4. |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Clinical particulars - Therapeutic indications | Therapeutic indications
Daptomycin is indicated for the treatment of the following infections (see sections 4.4 and 5.1).
- Adult and paediatric (1 to 17 years of age) patients with complicated skin and soft-tissue infections (cSSTI).
- Adult patients with right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It is recommended that the decision to use daptomycin should take into account the antibacterial susceptibility of the organism and should be based on expert advice. See sections 4.4 and 5.1.
- Adult and paediatric (1 to 17 years of age) patients with Staphylococcus aureus bacteraemia (SAB) .In adults, use in bacteraemia should be associated with RIE or with cSSTI, while in paediatric patients, use in bacteraemia should be associated with cSSTI.
Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, Daptomycin should be coadministered with appropriate antibacterial agent(s).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Clinical particulars - Posology and method of administration | Posology and method of administration
Clinical studies in patients employed infusion of daptomycin over at least 30 minutes. There is no clinical experience in patients with the administration of daptomycin as an injection over 2 minutes. This mode of administration was only studied in healthy subjects. However, when compared with the same doses given as intravenous infusions over 30 minutes there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).
Posology
Adults
- cSSTI without concurrent SAB: Daptomycin 4 mg/kg is administered once every 24 hours for 7-14 days or until the infection is resolved (see section 5.1).
- cSSTI with concurrent SAB: Daptomycin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient.
- Known or suspected RIE due to Staphylococcus aureus: Daptomycin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy should be in accordance with available official recommendations.
Daptomycin is administered intravenously in 0.9% sodium chloride (see section 6.6).
Daptomycin should not be used more frequently than once a day
Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least weekly) during treatment (see section 4.4).
Renal impairment
Daptomycin is eliminated primarily by the kidney.
Due to limited clinical experience (see table and footnotes below) daptomycin should only be used in adult patients with any degree of renal impairment (CrCl < 80 ml/min) when it is considered that the expected clinical benefit outweighs the potential risk. The response to treatment, renal function and creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of renal impairment (see also sections 4.4 and 5.2). The dosage regimen for daptomycin in paediatric patients with renal impairment has not been established.
Dose adjustments in adult patients with renal impairment by indication and creatinine clearance
Indication for use
Creatinine clearance
Dose recommendation
Comments
cSSTI without SAB
≥ 30 ml/min
4 mg/kg once daily
See section 5.1
< 30 ml/min
4 mg/kg every 48 hours
(1, 2)
RIE or cSSTI associated with SAB
≥ 30 ml/min
6 mg/kg once daily
See section 5.1
< 30 ml/min
6 mg/kg every 48 hours
(1, 2)
cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia
(1) The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see sections 4.4 and 5.2).
(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK modelling results, are recommended for patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Daptomycin should be administered following the completion of dialysis on dialysis days (see section 5.2).
Hepatic impairment
No dose adjustment is necessary when administering Daptomycin to patients with mild or moderate hepatic impairment (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic impairment (Child-Pugh Class C). Therefore caution should be exercised if Daptomycin is given to such patients.
Elderly patients
The recommended doses should be used in elderly patients except those with severe renal impairment (see above and section 4.4).
Paediatric population (1 to 17 years of age) The recommended dosage regimens for paediatric patients based on age and indication are shown below.
Age Group
Indication
cSSTI without SAB
cSSTI associated with SAB
Dosage Regimen
Duration of Therapy
Dosage Regimen
Duration of Therapy
12 to 17 years
5 mg/kg once every 24 hours infused over 30 minutes
Up to 14 days
7 mg/kg once every 24 hours infused over 30 minutes
(1)
7 to 11 years
7 mg/kg once every 24 hours infused over 30 minutes
9 mg/kg once every 24 hours infused over 30 minutes
2 to 6 years
9 mg/kg once every 24 hours infused over 60 minutes
12 mg/kg once every 24 hours infused over 60 minutes
1 to < 2 years
10 mg/kg once every 24 hours infused over 60 minutes
12 mg/kg once every 24 hours infused over 60 minutes
cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia;
(1) Minimum duration of daptomycin for paediatric SAB should be in accordance with the perceived risk of complications in the individual patient. The duration of daptomycin may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient. In the paediatric SAB study, the mean duration of IV daptomycin was 12 days, with a range of 1 to 44 days. The duration of therapy should be in accordance with available official recommendations.
Daptomycin is administered intravenously in 0.9 % sodium chloride (see section 6.6). Daptomycin should not be used more frequently than once a day.
Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least weekly) during treatment (see section 4.4).
Paediatric patients below the age of one year should not be given daptomycin due to the risk of potential effects on muscular, neuromuscular and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see section 5.3).
Method of administration
In adults, Daptomycin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period or by intravenous injection (see section 6.6) and administered over a 2-minute period.
In paediatric patients aged 7 to 17 years, Daptomycin is given by intravenous infusion over a 30-minute period (see section 6.6). In paediatric patients aged 1 to 6 years, Daptomycin is given by intravenous infusion over a 60-minute period (see section 6.6).
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
4.3 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
General
If a focus of infection other than cSSTI or RIE is identified after initiation of Daptomycin therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.
Anaphylaxis/hypersensitivity reactions
Anaphylaxis/hypersensitivity reactions have been reported with daptomycin. If an allergic reaction to Daptomycin occurs, discontinue use and institute appropriate therapy.
Pneumonia
It has been demonstrated in clinical studies that daptomycin is not effective in the treatment of pneumonia. Daptomycin is therefore not indicated for the treatment of pneumonia.
RIE due to
Staphylococcus aureus
Clinical data on the use of daptomycin to treat RIE due to Staphylococcus aureus are limited to 19 adult patients (see “Clinical efficacy in adults” in section 5.1).
The safety and efficacy of daptomycin in children and adolescents aged below 18 years with right-sided infective endocarditis (RIE) due to Staphylococcus aureus have not been established.
The efficacy of daptomycin in patients with prosthetic valve infections or with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated.
Deep-seated infections
Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay.
Enterococcal infections
There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of daptomycin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).
Non-susceptible micro-organisms
The use of antibacterials may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken.
Clostridoides difficile-associated diarrhoea
Clostridoides difficile-associated diarrhoea (CDAD) has been reported with daptomycin (see section 4.8). If CDAD is suspected or confirmed, Daptomycin may need to be discontinued and appropriate treatment instituted as clinically indicated.
Drug/laboratory test interactions
False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see also section 4.5).
Creatine phosphokinase and myopathy
Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with daptomycin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred more commonly in daptomycin-treated patients (1.9%) than in those that received comparators (0.5%). Therefore, it is recommended that:
• Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.
• CPK should be measured more frequently (e.g. every 2-3 days at least during the first two weeks of treatment) in patients who are at higher risk of developing myopathy. For example, patients with any degree of renal impairment (creatinine clearance < 80 ml/min; see also section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).
• It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be at increased risk of further increases during daptomycin therapy. This should be taken into account when initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently than once weekly.
• Daptomycin should not be administered to patients who are taking other medicinal products associated with myopathy unless it is considered that the benefit to the patient outweighs the risk.
• Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.
• Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Daptomycin should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.
Peripheral neuropathy
Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with Daptomycin should be investigated and consideration should be given to discontinuation of daptomycin (see sections 4.8 and 5.3).
Paediatric population
Paediatric patients below the age of one year should not be given daptomycin due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs (see section 5.3).
Eosinophilic pneumonia
Eosinophilic pneumonia has been reported in patients receiving Daptomycin (see section 4.8). In most reported cases associated with Daptomycin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organising pneumonia. The majority of cases occurred after more than 2 weeks of treatment with daptomycin and improved when daptomycin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Daptomycin should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products). Daptomycin should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.
Severe cutaneous adverse reactions Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and vesiculobullous rash with or without mucous membrane involvement (Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN)), which could be life-threatening or fatal, have been reported with daptomycin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. If signs and symptoms suggestive of these reactions appear, daptomycin should be discontinued immediately and an alternative treatment should be considered. If the patient has developed a severe cutaneous adverse reaction with the use of daptomycin, treatment with daptomycin must not be restarted in this patient at any time.
Tubulointerstitial nephritis Tubulointerstitial nephritis (TIN) has been reported in post-marketing experience with daptomycin. Patients who develop fever, rash, eosinophilia and/or new or worsening renal impairment while receiving daptomycin should undergo medical evaluation. If TIN is suspected, daptomycin should be discontinued promptly and appropriate therapy and/or measures should be taken.
Renal impairment
Renal impairment has been reported during treatment with daptomycin. Severe renal impairment may in itself also pre- dispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).
An adjustment of daptomycin dose interval is needed for patients whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Daptomycin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.
Caution is advised when administering daptomycin to patients who already have some degree of renal impairment (creatinine clearance < 80 ml/min) before commencing therapy with Daptomycin. Regular monitoring of renal function is advised (see also section 5.2).
In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents, regardless of the patient's pre-existing renal function (see also section 4.5).
The dosage regimen for daptomycin in paediatric patients with renal impairment has not been established.
Obesity
In obese subjects with Body Mass Index (BMI) > 40 kg/m2 but with creatinine clearance > 70 ml/min, the AUC0 -∞ daptomycin was significantly increased (mean 42% higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).
Sodium This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.
4.5 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Daptomycin undergoes little to no Cytochrome P450 (CYP450) -mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.
Interaction studies for daptomycin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.
Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration by intravenous infusion over a 30-minute period using a daptomycin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Daptomycin is unknown. Caution is warranted when daptomycin is co-administered with tobramycin.
Experience with the concomitant administration of daptomycin and warfarin is limited. Studies of daptomycin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving daptomycin and warfarin should be monitored for the first several days after therapy with daptomycin is initiated.
There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in adult patients taking one of these medicinal products at the same time as daptomycin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with daptomycin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.
Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal filtration.
During post–marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported. This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin (see section 4.4).
4.6 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
Daptomycin should not be used during pregnancy unless clearly necessary i.e., only if the expected benefit outweighs the possible risk.
Breast-feeding
In a single human case study, daptomycin was intravenously administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 µg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when daptomycin is administered to nursing women.
Fertility
No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).
4.7 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
On the basis of reported adverse drug reactions, daptomycin is presumed to be unlikely to produce an effect on the ability to drive or use machinery.
4.8 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
In clinical studies, 2,011 adult subjects received daptomycin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. In paediatric studies, 372 patients received daptomycin, of whom 61 received a single dose and 311 received a therapeutic regimen for cSSTI or SAB (daily doses ranged from 4 mg/kg to 12 mg/kg). Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for daptomycin and comparator regimens.
The most frequently reported adverse reactions (frequency common (≥ 1/100 to < 1/10)) are:
Fungal infections, urinary tract infection, candida infection, anaemia, anxiety, insomnia, dizziness, headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension, liver function tests abnormal (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)), rash, pruritus, limb pain, serum creatine phosphokinase (CPK) increased, infusion site reactions, pyrexia, asthenia.
Less frequently reported, but more serious, adverse reactions include hypersensitivity reactions, eosinophilic pneumonia (occasionally presenting as organizing pneumonia), drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.
Tabulated list of adverse reactions
The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data):
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1 Adverse reactions from clinical studies and post-marketing reports
System organ class
Frequency
Adverse reactions
Infections and infestations
Common:
Fungal infections, urinary tract infection, candida infection
Uncommon:
Fungaemia
Not known*:
Clostridioides difficile-associated diarrhoea**
Blood and lymphatic system disorders
Common:
Anaemia
Uncommon:
Thrombocythaemia, eosinophilia, international normalised ratio (INR) increased, leukocytosis
Rare:
Prothrombin time (PT) prolonged
Not known*
Thrombocytopaenia
Immune system disorders
Not known*:
Hypersensitivity**, manifested by isolated spontaneous reports including, but not limited to angioedema, pulmonary eosinophilia, sensation of oropharyngeal swelling, anaphylaxis**, infusion reactions including the following symptoms: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste
Metabolism and nutrition disorders
Uncommon:
Decreased appetite, hyperglycaemia, electrolyte imbalance
Psychiatric disorders
Common:
Anxiety, insomnia
Nervous system disorders
Common:
Dizziness, headache
Uncommon:
Paraesthesia, taste disorder, tremor, eye irritation
Not known*:
Peripheral neuropathy**
Ear and labyrinth disorders
Uncommon:
Vertigo
Cardiac disorders
Uncommon:
Supraventricular tachycardia, extrasystole
Vascular disorders
Common:
Hypertension, hypotension
Uncommon:
Flushes
Respiratory, thoracic and mediastinal disorders
Not known*:
Eosinophilic pneumonia1 **, cough
Gastrointestinal disorders
Common:
Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension
Uncommon:
Dyspepsia, glossitis
Hepatobiliary disorders
Common:
Liver function tests abnormal2 (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP))
Rare:
Jaundice
Skin and subcutaneous tissue disorders
Common:
Rash, pruritus
Uncommon:
Urticaria
Not known*
Acute generalised exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS)**, vesiculobullous rash with or without mucous membrane involvement (SJS or TEN)**
Musculoskeletal and connective tissue disorders
Common:
Limb pain, serum creatine phosphokinase (CPK)2 increased
Uncommon:
Myositis, increased myoglobin, muscular weakness, muscle pain, arthralgia, serum lactate dehydrogenase (LDH) increased, muscle cramps
Not known*:
Rhabdomyolysis3 **
Renal and urinary disorders
Uncommon:
Renal impairment, including renal failure and renal insufficiency, serum creatinine increased
Not known*
Tubulointerstitial nephritis (TIN)**
Reproductive system and breast disorders
Uncommon:
Vaginitis
General disorders and administration site conditions
Common:
Infusion site reactions, pyrexia, asthenia
Uncommon:
Fatigue, pain
* Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.
** See section 4.4.
1 While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the reporting rate of spontaneous reports is very low (< 1/10,000).
2 In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3 toxicity and resolved upon discontinuation of treatment.
3 When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal impairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.
The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy adult volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
4.9 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Clinical particulars - Overdose | Overdose
In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by haemodialysis (approximately 15% of the administered dose is removed over 4 hours) or by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours).
5. Pharmacological properties
5.1 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy adult volunteers. Steady-state concentrations are achieved by the third daily dose.
Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and Cmax) was demonstrated in healthy adult subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous injection.
Animal studies showed that daptomycin is not absorbed to any significant extent after oral administration.
Distribution
The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetrate the blood-brain barrier and the placental barrier following single and multiple doses.
Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy adult volunteers and adult patients treated with daptomycin, protein binding averaged about 90% including subjects with renal impairment.
Biotransformation
In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.
After infusion of 14C-daptomycin in healthy adults, the plasma radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.
Elimination
Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin.
Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 ml/hr/kg and its renal clearance is 4 to 7 ml/hr/kg.
In a mass balance study using radiolabelled material, 78% of the administered dose was recovered from the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin was approximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.
Special populations
Elderly
Following administration of a single 4 mg/kg intravenous dose of daptomycin over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0 -∞ was approximately 58% higher in elderly subjects (≥ 75 years of age) compared with those in healthy young subjects (18 to 30 years of age). There were no differences in Cmax. The differences noted are most likely due to the normal reduction in renal function observed in the geriatric population.
No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should be reduced if there is evidence of severe renal impairment.
Children and adolescents (1 to 17 years of age)
The pharmacokinetics of daptomycin in paediatric subjects was evaluated in 3 single-dose pharmacokinetic studies. After a single 4 mg/kg dose of daptomycin, total clearance normalised by weight and elimination half-life of daptomycin in adolescents (12-17 years of age) with Gram-positive infection were similar to adults. After a single 4 mg/kg dose of daptomycin, total clearance of daptomycin in children 7-11 years of age with Gram-positive infection was higher than in adolescents, whereas elimination half-life was shorter. After a single 4, 8, or 10 mg/kg dose of daptomycin, total clearance and elimination half-life of daptomycin in children 2-6 years of age were similar at different doses; total clearance was higher and elimination half-life was shorter than in adolescents. After a single 6 mg/kg dose of daptomycin, the clearance and elimination half-life of daptomycin in children 13-24 months of age were similar to children 2-6 years of age who received a single 4-10 mg/kg dose. The results of these studies show that exposures (AUC) in paediatric patients across all doses are generally lower than those in adults at comparable doses.
Paediatric patients with cSSTI
A Phase 4 study (DAP-PEDS-07-03) was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with cSSTI caused by Grampositive pathogens. Daptomycin pharmacokinetics in patients in this study are summarised in Table 2. Following administration of multiple doses, daptomycin exposure was similar across different age groups after dose adjustment based on body weight and age. Plasma exposures achieved with these doses were consistent with those achieved in the adult cSSTI study (following 4 mg/kg once daily in adults).
Mean (Standard Deviation) of Daptomycin Pharmacokinetics in Paediatric cSSTI Patients (1 to 17 Years of Age) in Study DAP-PEDS-07-03
Age Range
12-17 years
(N=6)
7-11 years
(N=2)a
2-6 years
(N=7)
1 to <2 years
(N=30)b
Dose
Infusion Time
5 mg/kg
30 minutes
7 mg/kg
30 minutes
9 mg/kg
60 minutes
10 mg/kg
60 minutes
AUC0-24hr (µg×hr/ml)
387 (81)
438
439 (102)
466
Cmax (µg/ml)
62.4 (10.4)
64.9, 74.4
81.9 (21.6)
79.2
Apparent t1/2 (hr)
5.3 (1.6)
4.6
3.8 (0.3)
5.04
CL/wt (ml/hr/kg)
13.3 (2.9)
16.0
21.4 (5.0)
21.5
Pharmacokinetic parameter values estimated by noncompartmental analysis
aIndividual values reported as only two patients in this age group provided pharmacokinetic samples to enable pharmacokinetic analysis; AUC, apparent t1/2 and CL/wt could be determined for only one of the two patients
bPharmacokinetic analysis conducted on the pooled pharmacokinetic profile with mean concentrations across subjects at each time point
Paediatric patients with SAB
A Phase 4 study (DAP-PEDBAC-11-02) was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with SAB. Daptomycin pharmacokinetics inpatients in this study are summarised in Table 3. Following administration of multiple doses, daptomycin exposure was similar across different age groups after dose adjustment based on body weight and age. Plasma exposures achieved with these doses were consistent with those achieved in the adult SAB study (following 6 mg/kg once daily in adults).
Table 3
Mean (Standard Deviation) of Daptomycin Pharmacokinetics in Paediatric SAB Patients (1 to 17 Years of Age) in Study DAP-PEDBAC-11-02
Age Range
12-17 years
(N=13)
7-11 years
(N=19)
1 to 6 years
(N=19)*
Dose
Infusion Time
7 mg/kg
30 minutes
9 mg/kg
30 minutes
12 mg/kg
60 minutes
AUC 0-24hr (μg×hr/ml)
656 (334)
579 (116)
620 (109)
Cmax (μg/ml)
104 (35.5)
104 (14.5)
106 (12.8)
Apparent t1/2 (hr)
7.5 (2.3)
6.0 (0.8)
5.1 (0.6)
CL/wt (ml/hr/kg)
12.4 (3.9)
15.9 (2.8)
19.9 (3.4)
Pharmacokinetic parameter values estimated using a model-based approach with sparsely collected pharmacokinetic samples from individual patients in the study.
*Mean (Standard Deviation) calculated for patients 2 to 6 years of age, since no patients 1 to <2 years of age were enrolled in the study. Simulation using a population pharmacokinetic model demonstrated that the AUCss (area under the concentration time curve at steady state) of daptomycin in paediatric patients 1 to <2 years of age receiving 12 mg/kg once daily would be comparable to that in adult patients receiving 6 mg/kg once daily.
Obesity
Relative to non-obese subjects daptomycin systemic exposure measured by AUC was about 28% higher in moderately obese subjects (Body Mass Index of 25-40 kg/m2 ) and 42% higher in extremely obese subjects (Body Mass Index of > 40 kg/m2 ). However, no dose adjustment is considered to be necessary based on obesity alone.
Gender
No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.
Renal impairment
Following administration of a single 4 mg/kg or 6 mg/kg intravenous dose of daptomycin over a 30-minute period to adult subjects with various degrees of renal impairment, total daptomycin clearance (CL) decreased and systemic exposure (AUC) increased as renal function (creatinine clearance) decreased.
Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after administration of a 6 mg/kg dose to adult patients on HD or CAPD was 2-fold higher than that observed in adult patients with normal renal function who received the same dose. On the second day after administration of a 6 mg/kg dose to HD and CAPD adult patients the daptomycin AUC was approximately 1.3 -fold higher than that observed after a second 6 mg/kg dose in adult patients with normal renal function. On this basis, it is recommended that adult patients on HD or CAPD receive daptomycin once every 48 hours at the dose recommended for the type of infection being treated (see section 4.2).
The dosage regimen for daptomycin in paediatric patients with renal impairment has not been established.
Hepatic impairment
The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic impairment (Child-Pugh B classification of hepatic impairment) compared with healthy volunteers matched for gender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary when administering daptomycin in patients with moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh C classification) have not been evaluated.
5.3 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Daptomycin administration was associated with minimal to mild degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopic changes in skeletal muscle were minimal (approximately 0.05% of myofibres affected) and at the higher doses were accompanied by elevations in CPK. No fibrosis or rhabdomyolysis was observed. Depending on the study duration, all muscle effects, including microscopic changes, were fully reversible within 1-3 months following cessation of dosing. No functional or pathological changes in smooth or cardiac muscle were observed.
The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels of 0.8 to 2.3-fold the human therapeutic levels at 6 mg/kg (30-minute intravenous infusion) for patients with normal renal function. As the pharmacokinetics (see section 5.2) is comparable, the safety margins for both methods of administration are very similar.
A study in dogs demonstrated that skeletal myopathy was reduced upon once daily administration as compared to fractionated dosing at same total daily dose, suggesting that myopathic effects in animals were primarily related to time between doses.
Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscle effects in adult rats and dogs, and were primarily related to plasma Cmax. Peripheral nerve changes were characterised by minimal to slight axonal degeneration and were frequently accompanied by functional changes. Reversal of both the microscopic and functional effects was complete within 6 months post-dose. Safety margins for peripheral nerve effects in rats and dogs are 8- and 6-fold, respectively, based on comparison of Cmax values at the No Observed Effect Level (NOEL) with the Cmax achieved on dosing with 30-minute intravenous infusion of 6 mg/kg once daily in patients with normal renal function.
The findings of in vitro and some in vivo studies designed to investigate the mechanism of daptomycin myotoxicity indicate that the plasma membrane of differentiated spontaneously contracting muscle cells is the target of toxicity. The specific cell surface component directly targeted has not been identified. Mitochondrial loss/damage was also observed; however the role and significance of this finding in the overall pathology are unknown. This finding was not associated with an effect on muscle contraction.
In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions as compared to skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doses lower than those associated with skeletal muscle toxicity.
In neonatal dogs, daptomycin caused marked clinical signs of twitching, muscle rigidity in the limbs, and impaired use of limbs, which resulted in decreases in body weight and overall body condition at doses ≥50 mg/kg/day and necessitated early discontinuation of treatment in these dose groups. At lower dose levels (25 mg/kg/day), mild and reversible clinical signs of twitching and one incidence of muscle rigidity were observed without any effects on body weight. There was no histopathological correlation in the peripheral and central nervous system tissue, or in the skeletal muscle, at any dose level, and the mechanism and clinical relevance for the adverse clinical signs are therefore unknown.
Reproductive toxicity testing showed no evidence of effects on fertility, embryofoetal, or postnatal development. However, daptomycin can cross the placenta in pregnant rats (see section 5.2). Excretion of daptomycin into milk of lactating animals has not been studied.
Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic or clastogenic in a battery of in vivo and in vitro genotoxicity tests.
6. |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - List of excipients | List of excipients
Sodium hydroxide
6.2 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Daptomycin is not physically or chemically compatible with glucose-containing solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Shelf life | Shelf life
2 years
After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial has been demonstrated for 12 hours at 25°C and up to 48 hours at 2°C – 8°C. Chemical and physical stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours at 2°C – 8°C.
For the 30-minute intravenous infusion, the combined storage time (reconstituted solution in vial and diluted solution in infusion bag; see section 6.6) at 25°C must not exceed 12 hours (or 24 at 2°C – 8°C).
For the 2-minute intravenous injection, the storage time of the reconstituted solution in the vial (see section 6.6) at 25°C must not exceed 12 hours (or 48 at 2°C – 8°C).
However, from a microbiological point of view the product should be used immediately. No preservative or bacteriostatic agent is present in this product. If not used immediately, in-use storage times are the responsibility of the user and would not normally be longer than 24 hours at 2°C – 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
6.4 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in a refrigerator (2°C – 8°C).
For storage conditions after reconstitution and after reconstitution and dilution of the medicinal product see section 6.3.
6.5 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Single use 15 ml type I glass vials with bromobutyl rubber stoppers and sealed with 20 mm flip-off seal blue.
Pack size: 1 vial.
6.6 |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
In adults, daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over 2 minutes. Daptomycin should not be administered as a 2-minute injection to paediatric patients. Paediatric patients 7 to 17 years old should receive daptomycin infused over 30 minutes. In paediatric patients under 7 years old receiving a 9-12 mg/kg dose, daptomycin should be administered over 60 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional dilution step as detailed below.
Daptomycin given as 30 or 60-minute intravenous infusion
A 50 mg/ml concentration of Daptomycin 500 mg powder for solution for injection/infusion is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Daptomycin for intravenous infusion, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute or dilute lyophilised Daptomycin.
For Reconstitution:
1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin range in colour from pale yellow to light brown.
5. The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical volume 50 ml).
For Dilution:
1. Slowly remove the appropriate reconstituted liquid (50 mg daptomycin/ml) from the vial using a sterile needle that is 21 gauge or smaller in diameter by inverting the vial in order to allow the solution to drain towards the stopper. Using a syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove the required solution from the inverted vial.
2. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
3. Transfer the required reconstituted dose into 50 ml sodium chloride 9 mg/ml (0.9%).
4. The reconstituted and diluted solution should then be infused intravenously over 30 or 60 minutes as directed in section 4.2.
The following have been shown to be compatible when added to daptomycin containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.
Daptomycin given as 2-minute intravenous injection (adult patients only)
Water should not be used for reconstitution of Daptomycin for intravenous injection. Daptomycin should only be reconstituted with sodium chloride 9 mg/ml (0.9%).
A 50 mg/ml concentration of Daptomycin 500 mg powder for solution for injection/infusion is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Daptomycin for intravenous injection, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Daptomycin.
1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin range in colour from pale yellow to light brown.
5. Slowly remove the reconstituted liquid (50 mg daptomycin/ml) from the vial using a sterile needle that is 21 gauge or smaller in diameter.
6. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
7. Replace needle with a new needle for the intravenous injection.
8. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9. The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.
Daptomycin vials are for single-use only.
From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Marketing authorisation holder | Dr. Reddy's Laboratories (UK) Ltd.
410 Cambridge Science Park
Milton Road
Cambridge
CB4 0PE
United Kingdom
8. Marketing authorisation number(s)
PL 08553/0581
9. |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Date of first authorisation/renewal of the authorisation | 15/08/2017
10. |
Daptomycin Dr. Reddy's 500 mg Powder for Solution for Injection/Infusion | Date of revision of the text | 24/11/2022 |
Delofine XL 5 mg Prolonged-Release Tablets | Name of the medicinal product | Felodipine 5 mg Prolonged-Release Tablets
Delofine XL 5 mg Prolonged-Release Tablets
2. |
Delofine XL 5 mg Prolonged-Release Tablets | Qualitative and quantitative composition | Each tablet contains 5 mg felodipine.
Excipients with known effect:
Each tablet contains 190 mg lactose and 30 mg macrogolglycerol hydroxystearate.
For the full list of excipients, see section 6.1.
3. |
Delofine XL 5 mg Prolonged-Release Tablets | Pharmaceutical form | Prolonged-release tablet
Light yellow circular, biconvex film-coated tablets debossed with 'L27' on one side and plain on the other side.
4. |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Hypertension.
Stable angina pectoris.
4.2 |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Hypertension
The dose should be adjusted individually. Treatment can be started with 5 mg once daily. Depending on the patient's response, the dosage can, where applicable, be decreased to 2.5 mg or increased to 10 mg daily. If necessary, another antihypertensive agent may be added. The standard maintenance dose is 5 mg once daily.
Angina pectoris
The dose should be adjusted individually. Treatment should be initiated with 5 mg once daily and, if needed, increased to 10 mg once daily.
Elderly population
Initial treatment with lowest available dose should be considered.
Renal impairment
Dose adjustment is not needed in patients with impaired renal function.
Hepatic impairment
Patients with impaired hepatic function may have elevated plasma concentrations of felodipine and may respond to lower doses (see section 4.4).
Paediatric population
There is limited clinical trial experience of the use of felodipine in hypertensive paediatric patients (see sections 5.1 and 5.2).
Method of administration
The tablets should be taken in the morning and be swallowed with water. In order to keep the prolonged-release properties, the tablets must not be divided, crushed or chewed. The tablets can be administered without food or following a light meal not rich in fat or carbohydrate.
4.3 |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Contraindications | Contraindications
• Pregnancy.
• Hypersensitivity to felodipine or any of the excipients listed in section 6.1.
• Decompensated heart failure.
• Acute myocardial infarction.
• Unstable angina pectoris.
• Haemodynamically significant cardiac valvular obstruction.
• Dynamic cardiac outflow obstruction.
4.4 |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
The efficacy and safety of felodipine in the treatment of hypertensive emergencies has not been studied.
Felodipine may cause significant hypotension with subsequent tachycardia. This may lead to myocardial ischaemia in susceptible patients.
Felodipine is cleared by the liver. Consequently, higher therapeutic concentrations and response can be expected in patients with clearly reduced liver function (see section 4.2).
Concomitant administration of drugs that strongly induce or inhibit CYP3 A4 enzymes result in extensively decreased or increased plasma levels of felodipine, respectively. Therefore, such combinations should be avoided (see section 4.5).
Felodipine/Delofine XL tablets contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Felodipine/Delofine XL tablets contains castor oil, which may cause stomach upset and diarrhoea.
Mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful oral hygiene.
Sodium content: Felodipine/Delofine XL tablets contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
4.5 |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Felodipine is metabolised in the liver by cytochrome P450 3A4 (CYP3A4). Concomitant administration of substances which interfere with CYP3A4 enzyme system may affect plasma concentrations of felodipine.
Enzyme interactions
Enzyme inhibiting and enzyme inducing substances of cytochrome P450 isoenzyme 3A4 may exert an influence on the plasma level of felodipine.
Interactions leading to increased plasma concentration of felodipine
CYP3A4 enzyme inhibitors have been shown to cause an increase in felodipine plasma concentrations. Felodipine Cmax and AUC increased 8-fold and 6-fold, respectively, when felodipine was coadministered with the strong CYP3A4 inhibitor itraconazole. When felodipine and erythromycin were coadministered, the Cmax and AUC of felodipine were increased by about 2.5-fold. Cimetidine increased the felodipine Cmax and AUC by approximately 55%. The combination with strong CYP3A4 inhibitors should be avoided.
In case of clinically significant adverse events due to elevated felodipine exposure when combined with strong CYP3A4 inhibitors, adjustment of felodipine dose and/or discontinuation of the CYP3A4 inhibitor should be considered.
Examples:
• Cimetidine
• Erythromycin
• Itraconazole
• Ketoconazole
• Anti-HIV/protease inhibitors (e.g. ritonavir)
• Certain flavonoids present in grapefruit juice
Felodipine tablets should not be taken together with grapefruit juice.
Interactions leading to decreased plasma concentration of felodipine
Enzyme inducers of the cytochrome P450 3A4 system have been shown to cause a decrease in plasma concentrations of felodipine. When felodipine was co-administered with carbamazepine, phenytoin or phenobarbital, the Cmax and AUC of felodipine were decreased by 82% and 96% respectively. The combination with strong CYP3A4 inducers should be avoided.
In case of lack of efficacy due to decreased felodipine exposure when combined with potent inducers of CYP3A4, adjustment of felodipine dose and/or discontinuation of the CYP3A4 inducer should be considered.
Examples:
• Phenytoin
• Carbamazepine
• Rifampicin
• Barbiturates
• Efavirenz
• Nevirapine
• Hypericum perforatum (St. John's wort)
Additional interactions
Tacrolimus: Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.
Cyclosporin: Felodipine does not affect plasma concentrations of cyclosporin.
4.6 |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
Felodipine should not be given during pregnancy. In non-clinical reproductive toxicity studies there were foetal developmental effects, which are considered to be due to the pharmacological action of felodipine.
Breast-feeding
Felodipine has been detected in breast milk, and due to insufficient data on potential effect on the infant, treatment is not recommended during breast-feeding.
Fertility
There are no data on the effects of felodipine on patient fertility. In a non-clinical reproductive study in the rat (see section 5.3), there were effects on foetal development but no effect on fertility at doses approximating to therapeutic.
4.7 |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Felodipine has minor or moderate influence on the ability to drive and use machines. If patients taking felodipine suffer from headache, nausea, dizziness or fatigue and ability to react may be impaired. Caution is recommended especially at the start of treatment.
4.8 |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
Felodipine can cause flushing, headache, palpitations, dizziness and fatigue. Most of these adverse reactions are dose- dependent and appear at the start of treatment or after a dose increase. Should such adverse reactions occur, they are usually transient and diminish with time.
Dose-dependent ankle swelling can occur in patients treated with felodipine. This results from precapillary vasodilatation and is not related to any generalised fluid retention.
Mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful oral hygiene.
Tabulated list of adverse reactions
The adverse reactions listed below have been identified from clinical trials and from post marketing surveillance. The following definitions of frequencies are used:
Very common ≥1/10
Common ≥1/100 to <1/10
Uncommon ≥1/1,000 to <1/100
Rare ≥1/10,000 to <1/1,000
Very rare <1/10,000
Table 1: |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Overdose | Undesirable effects
System organ class
Frequency
Adverse reaction
Nervous system disorders
Common
Uncommon
Headache
Dizziness, paraesthesia
Cardiac disorders
Uncommon
Tachycardia, palpitations
Vascular disorders
Common
Uncommon
Rare
Flush
Hypotension
Syncope
Gastrointestinal disorders
Uncommon
Rare
Very rare
Nausea, abdominal pain
Vomiting
Gingival hyperplasia, gingivitis
Hepatobiliary disorders
Very rare
Increased liver enzymes
Skin and subcutaneous tissue disorders
Uncommon
Rare
Very rare
Rash, pruritus
Urticaria
Photosensitivity reactions, leukocytoclastic vasculitis
Musculoskeletal and connective tissue disorders
Rare
Arthralgia, myalgia
Renal and urinary disorders
Very rare
Pollakisuria
Reproductive system and breast disorders
Rare
Impotence/sexual dysfunction
General disorders and administration site conditions
Very common
Uncommon
Very rare
Peripheral oedema
Fatigue
Hypersensitivity reactions, e.g. angio-oedema, fever
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Delofine XL 5 mg Prolonged-Release Tablets | Clinical particulars - Subsection 10 | Overdose
Symptoms
Overdosage may cause excessive peripheral vasodilatation with marked hypotension and sometimes bradycardia.
Management
If justified: activated charcoal, gastric lavage if performed within one hour after ingestion. If severe hypotension occurs, symptomatic treatment should be instituted.
The patient should be placed supine with the legs elevated. In case of accompanying bradycardia, atropine 0.5-1 mg should be administered intravenously. If this is not sufficient, plasma volume should be increased by infusion of e.g. glucose, saline, or dextran. Sympathomimetic medicinal products with predominant effect on the α1-adrenoceptor may be given if the above-mentioned measures are insufficient.
5. Pharmacological properties
5.1 |
Delofine XL 5 mg Prolonged-Release Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
Felodipine is administered as extended-release tablets, from which it is completely absorbed in the gastrointestinal tract. The systemic availability of felodipine is approximately 15% and is independent of dose in the therapeutic dose range.
The extended-release tablets produce a prolonged absorption phase of felodipine. This results in even felodipine plasma concentrations within the therapeutic range for 24 hours. Maximum blood plasma levels (tmax) are achieved with the prolonged-release form after 3 to 5 hours. The rate but not the extent of absorption of felodipine is increased when taken simultaneously with food with a high fat content.
Distribution
The plasma protein binding of felodipine is approximately 99%. It is bound pre-dominantly to the albumin fraction. Volume of distribution at steady state is 10 L/kg.
Biotransformation
Felodipine is extensively metabolised in the liver by cytochrome P450 3A4 (CYP3A4) and all identified metabolites are inactive. Felodipine is a high clearance medicinal product with an average blood clearance of 1200 ml/min. There is no significant accumulation during long-term treatment.
Elderly patients and patients with reduced liver function have on average higher plasma concentrations of felodipine than younger patients. The pharmacokinetics of felodipine is not changed in patients with renal impairment, including those treated with haemodialysis.
Elimination
The half-life of felodipine in the elimination phase is approximately 25 hours and steady state is reached after 5 days. There is no risk of accumulation during long-term treatment. About 70% of a given dose is excreted as metabolites in the urine; the remaining fraction is excreted in the faeces. Less than 0.5% of a dose is recovered unchanged in urine.
Linearity/non-linearity
Plasma concentrations are directly proportional to dose within the therapeutic dose range 2.5–10 mg.
Paediatric population
In a single dose (felodipine prolonged-release 5 mg) pharmacokinetic study with a limited number of children aged between 6 and 16 years (n=12) there was no apparent relationship between the age and AUC, Cmax or half-life of felodipine.
5.3 |
Delofine XL 5 mg Prolonged-Release Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Reproduction toxicity
In a study on fertility and general reproductive performance in rats treated with felodipine, a prolongation of parturition resulting in difficult labour/increased foetal deaths and early postnatal deaths was observed in the medium and high dose groups. These effects were attributed to the inhibitory effect of felodipine in high doses on uterine contractility. No disturbances of fertility were observed when doses within the therapeutic range were given to rats.
Reproduction studies in rabbits have shown a dose-related reversible enlargement of the mammary glands of the parent animals and dose-related digital anomalies in the foetuses. The anomalies in the foetuses were induced when felodipine was administered during early foetal development (before day 15 of pregnancy). In a reproduction study in monkeys, an abnormal position of the distal phalange(s) was noticed.
There were no other pre-clinical findings considered to be of concern and the reproductive findings are considered to be related to the pharmacological action of felodipine, when given to normotensive animals. The relevance of these findings for patients receiving felopidine is unknown. However, there have been no reported clinical incidences of phalangeal changes in foetus/neonate exposed to felodipine in-utero, from the information maintained within the internal patient safety databases.
6. |
Delofine XL 5 mg Prolonged-Release Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core:
Hydroxypropylcellulose (E463)
Hypromellose (E464)
Lactose monohydrate
Macrogolglycerol hydroxystearate
Aluminium magnesium silicate
Sodium stearyl fumarate
Tablet coating:
Hypromellose (E464), titanium dioxide (E171), macrogol and iron oxide yellow (E172).
6.2 |
Delofine XL 5 mg Prolonged-Release Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Delofine XL 5 mg Prolonged-Release Tablets | Pharmaceutical particulars - Shelf life | Shelf life
2 years
6.4 |
Delofine XL 5 mg Prolonged-Release Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Delofine XL 5 mg Prolonged-Release Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
PVC/PE/PVDC/Aluminium blister in packs of 14, 20, 28, 30, 50, 90, 98 and 100 tablets are available.
Not all pack sizes may be marketed.
6.6 |
Delofine XL 5 mg Prolonged-Release Tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Delofine XL 5 mg Prolonged-Release Tablets | Marketing authorisation holder | Morningside Healthcare Limited
Unit C, Harcourt Way
Leicester LE19 1WP
UK
8. Marketing authorisation number(s)
PL 20117/0398
9. |
Delofine XL 5 mg Prolonged-Release Tablets | Date of first authorisation/renewal of the authorisation | 04/01/2022
10. |
Delofine XL 5 mg Prolonged-Release Tablets | Date of revision of the text | 04/01/2022 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Introduction | This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.1. |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Name of the medicinal product | Delstrigo® 100 mg/300 mg/245 mg film-coated tablets.
2. |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Qualitative and quantitative composition | Each film-coated tablet contains 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate equivalent to 245 mg of tenofovir disoproxil.
Excipient with known effect
Each film-coated tablet contains 8.6 mg lactose (as monohydrate).
For the full list of excipients, see section 6.1.
3. |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Pharmaceutical form | Film-coated tablet.
Yellow, oval-shaped, tablet of dimensions 21.59 mm x 11.30 mm, debossed with the corporate logo and 776 on one side and plain on the other side.
4. |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Delstrigo is indicated for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class, lamivudine, or tenofovir (see sections 4.4 and 5.1).
Delstrigo is also indicated for the treatment of adolescents aged 12 years and older weighing at least 35 kg who are infected with HIV-1 without past or present evidence of resistance to the NNRTI class, lamivudine, or tenofovir and who have experienced toxicities which preclude the use of other regimens that do not contain tenofovir disoproxil (see sections 4.4 and 5.1).
4.2 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Therapy should be initiated by a physician experienced in the management of HIV infection.
Posology
The recommended dose of Delstrigo is one 100/300/245 mg tablet taken orally once daily with or without food.
Dose adjustment
If Delstrigo is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily. This is achieved by adding one 100 mg tablet of doravirine (as a single agent), to be taken approximately 12 hours apart from the dose of Delstrigo (see section 4.5).
Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, one 100 mg tablet of doravirine should be taken daily, approximately 12 hours after the dose of Delstrigo (see section 4.5).
Missed dose
If the patient misses a dose of Delstrigo within 12 hours of the time it is usually taken, the patient should take Delstrigo as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Delstrigo by more than 12 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not take 2 doses at one time.
Special populations
Elderly
There are limited data available on the use of doravirine, lamivudine, and tenofovir disoproxil in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see section 5.2). Special care is advised in this age group due to age associated changes such as decreases in renal function (see section 4.4).
Renal impairment
No dose adjustment of Delstrigo is required in adults with estimated creatinine clearance (CrCl) ≥ 50 mL/min.
Delstrigo should not be initiated in patients with estimated CrCl < 50 mL/min (see sections 4.4 and 5.2). Delstrigo should be discontinued if estimated CrCl declines below 50 mL/min (see section 4.4). Patients with moderate or severe renal impairment require a dose interval adjustment of lamivudine and tenofovir disoproxil that cannot be achieved with the combination tablet (see sections 4.4 and 5.2).
Hepatic impairment
No dose adjustment of doravirine/lamivudine/tenofovir disoproxil is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). It is not known whether the exposure to doravirine will increase in patients with severe hepatic impairment. Therefore, caution is advised when doravirine/lamivudine/tenofovir disoproxil is administered to patients with severe hepatic impairment (see section 5.2).
Paediatric population
Safety and efficacy of Delstrigo in children aged less than 12 years or weighing less than 35 kg have not been established.
Method of administration
Delstrigo must be taken orally, once daily with or without food and swallowed whole (see section 5.2).
4.3 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Co-administration with medicinal products that are strong cytochrome P450 CYP3A enzyme inducers is contraindicated as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of Delstrigo (see sections 4.4 and 4.5). These medicinal products include, but are not limited to the following:
• carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• rifampicin, rifapentine
• St. John's wort (Hypericum perforatum)
• mitotane
• enzalutamide
• lumacaftor
4.4 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
NNRTI substitutions and use of doravirine
Doravirine has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. NNRTI-associated mutations detected at screening were part of exclusion criteria in the Phase 2b/3-studies. A breakpoint for a reduction in susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinical efficacy has not been established (see section 5.1). There is not sufficient clinical evidence to support the use of doravirine in patients infected with HIV-1 with evidence of resistance to the NNRTI class.
Severe acute exacerbation of hepatitis B in patients co-infected with HIV-1 and HBV
All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy.
Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in patients who are co-infected with HIV-1 and HBV, and have discontinued lamivudine or tenofovir disoproxil, two of the components of Delstrigo. Patients who are co-infected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with Delstrigo. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
New onset or worsening renal impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia), has been reported with the use of tenofovir disoproxil, a component of Delstrigo.
Delstrigo should be avoided with concurrent or recent use of nephrotoxic medicinal products (e.g., high-dose or multiple nonsteroidal anti-inflammatory medicinal products [NSAIDs]) (see section 4.5). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir disoproxil. Some patients required hospitalisation and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.
Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at risk patients.
It is recommended that estimated CrCl be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with Delstrigo. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, it is recommended that estimated CrCl, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of Delstrigo and more frequent renal function monitoring should be assessed as appropriate per the patient's medical condition during Delstrigo therapy.
Lamivudine and tenofovir disoproxil are primarily excreted by the kidney. Delstrigo should be discontinued if estimated CrCl declines below 50 mL/min as dose interval adjustment required for lamivudine and tenofovir disoproxil cannot be achieved with the fixed dose combination tablet (see section 4.2).
Bone loss and mineralisation defects
Bone mineral density
In clinical trials in HIV-1 infected adults, tenofovir disoproxil was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir disoproxil. In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor.
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy.
The effects of tenofovir disoproxil associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for HIV-1 infected adult patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and Vitamin D was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.
Mineralisation defects
Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir disoproxil. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphataemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir disoproxil (see section 4.4).
Co-administration with other antiviral products
Doravirine/lamivudine/tenofovir disoproxil must not be co-administered with other medicinal products containing lamivudine, or with medicinal products containing tenofovir disoproxil, or tenofovir alafenamide, or with adefovir dipivoxil (see section 4.5). Doravirine/lamivudine/tenofovir disoproxil should not be administered with doravirine unless needed for dose adjustment (e.g., with rifabutin) (see sections 4.2 and 4.5).
Use with CYP3A inducers
Caution should be given to prescribing doravirine with medicinal products that may reduce the exposure of doravirine (see sections 4.3 and 4.5).
Immune reactivation syndrome
Immune reactivation syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, autoimmune hepatitis, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reactivation; however, the time to onset is more variable and can occur many months after initiation of treatment.
Lactose
Delstrigo contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Delstrigo is a complete regimen for the treatment of HIV-1 infection; therefore, Delstrigo should not be administered with other antiretroviral medicinal products. Information regarding potential medicinal product interactions with other antiretroviral medicines is not provided. Interaction studies have only been performed in adults.
Delstrigo contains doravirine, lamivudine, and tenofovir disoproxil, therefore any interactions identified for these individually are relevant to Delstrigo and are presented in Table 1.
Effects of other medicinal products on doravirine, lamivudine, and tenofovir disoproxil
Doravirine
Doravirine is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A are expected to affect the clearance of doravirine (see section 5.2). Doravirine/lamivudine/tenofovir disoproxil should not be co-administered with medicinal products that are strong CYP3A enzyme inducers as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of doravirine/lamivudine/tenofovir disoproxil (see sections 4.3 and 5.2).
Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations (see Table 1). When Delstrigo is co-administered with rifabutin, a 100 mg dose of doravirine should be given daily, approximately 12 hours after doravirine/lamivudine/tenofovir disoproxil dose (see section 4.2).
Co-administration of doravirine/lamivudine/tenofovir disoproxil with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., debrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, a 100 mg dose of doravirine should be administered daily, approximately 12 hours after the administration of doravirine/lamivudine/tenofovir disoproxil dose (see section 4.2).
Co-administration of doravirine/lamivudine/tenofovir disproxil and medicinal products that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. However, no dose adjustment is needed when doravirine is co-administered with CYP3A inhibitors.
Lamivudine
Because lamivudine is primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion (see section 5.2), co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of lamivudine.
Tenofovir disoproxil
Because tenofovir is primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion (see section 5.2), co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via OAT1, OAT3 or MRP4 may increase serum concentrations of tenofovir.
Due to the tenofovir disoproxil component of doravirine/lamivudine/tenofovir disoproxil, use of the product should be avoided with concurrent or recent use of nephrotoxic medicinal products. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs (see section 4.4).
Effects of doravirine, lamivudine, and tenofovir disoproxil on other medicinal products
Doravirine
Doravirine at a dose of 100 mg once daily is not likely to have a clinically relevant effect on the plasma concentrations of medicinal products that are dependent on transport proteins for absorption and/or elimination or that are metabolised by CYP enzymes.
However, co-administration of doravirine and the sensitive CYP3A substrate midazolam resulted in a 18 % decrease in midazolam exposure, suggesting that doravirine may be a weak CYP3A inducer. Therefore, caution should be used when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that also have a narrow therapeutic window (e.g., tacrolimus and sirolimus).
Lamivudine
Lamivudine does not inhibit or induce CYP enzymes.
Tenofovir
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low.
Interaction table
Table 1 shows the established and other potential medicinal product interactions with the individual components of Delstrigo but is not all inclusive (increase is indicated as ↑, decrease is indicated as ↓, and no change as ↔). For potential medicine product interactions with tenofovir disoproxil or lamivudine, (see sections 4.4 and 5.2).
Table 1: Interactions between the individual components of Delstrigo and other medicinal products
Medicinal Product by Therapeutic Area
Effects on Medicinal Product Levels
Geometric Mean Ratio (90 % CI)*
Recommendation Concerning Co-administration with doravirine/lamivudine/tenofovir disoproxil
Acid-Reducing Agents
antacid (aluminium and magnesium hydroxide oral suspension)
(20 mL SD, doravirine 100 mg SD)
↔ doravirine
AUC 1.01 (0.92, 1.11)
Cmax 0.86 (0.74, 1.01)
C24 1.03 (0.94, 1.12)
No dose adjustment is required.
pantoprazole
(40 mg QD, doravirine 100 mg SD)
↓ doravirine
AUC 0.83 (0.76, 0.91)
Cmax 0.88 (0.76, 1.01)
C24 0.84 (0.77, 0.92)
No dose adjustment is required.
omeprazole
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ doravirine
No dose adjustment is required.
Angiotensin Converting Enzyme Inhibitors
lisinopril
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ lisinopril
No dose adjustment is required.
Antiandrogens
enzalutamide
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration is contraindicated.
Antibiotics
nafcillin
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.
Anticonvulsants
carbamazepine
oxcarbazepine
phenobarbital
phenytoin
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration is contraindicated.
Antidiabetics
metformin
(1000 mg SD, doravirine 100 mg QD)
↔ metformin
AUC 0.94 (0.88, 1.00)
Cmax 0.94 (0.86, 1.03)
No dose adjustment is required.
canagliflozin
liraglutide
sitagliptin
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ canagliflozin
↔ liraglutide
↔ sitagliptin
No dose adjustment is required.
Antidiarrhoeals
telotristat ethyl
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, 12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.
Antigout and Uricosuric Agents
lesinurad
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately 12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.
Antimycobacterials
Single dose rifampicin
(600 mg SD, doravirine 100 mg SD)
Multiple dose rifampicin
(600 mg QD, doravirine 100 mg SD)
↔ doravirine
AUC 0.91 (0.78, 1.06)
Cmax 1.40 (1.21, 1.63)
C24 0.90 (0.80, 1.01)
↓ doravirine
AUC 0.12 (0.10, 0.15)
Cmax 0.43 (0.35, 0.52)
C24 0.03 (0.02, 0.04)
(Induction of CYP3A)
Co-administration is contraindicated.
rifapentine
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration is contraindicated.
rifabutin
(300 mg QD, doravirine 100 mg SD)
↓ doravirine
AUC 0.50 (0.45, 0.55)
Cmax 0.99 (0.85, 1.15)
C24 0.32 (0.28, 0.35)
(Induction of CYP3A)
If doravirine/ lamivudine/ tenofovir disoproxil is co-administered with rifabutin, a 100 mg dose of doravirine should be taken daily, approximately 12 h after dose of doravirine/lamivudine/tenofovir disoproxil.
Antineoplastics
mitotane
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration is contraindicated.
Antipsychotics
thioridazine
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately 12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.
Azole Antifungal Agents
ketoconazole
(400 mg QD, doravirine 100 mg SD)
↑ doravirine
AUC 3.06 (2.85, 3.29)
Cmax 1.25 (1.05, 1.49)
C24 2.75 (2.54, 2.98)
(Inhibition of CYP3A)
No dose adjustment is required.
fluconazole
itraconazole
posaconazole
voriconazole
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↑ doravirine
(Inhibition of CYP3A)
No dose adjustment is required.
Calcium Channel Blockers
diltiazem
verapamil
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↑ doravirine
(Inhibition of CYP3A)
No dose adjustment is required.
Cystic Fibrosis Treatment
lumacaftor
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration is contraindicated.
Endothelin Receptor Antagonists
bosentan
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.
Hepatitis C Antiviral Agents
elbasvir + grazoprevir
(50 mg elbasvir QD + 200 mg grazoprevir QD, doravirine 100 mg QD)
↑ doravirine
AUC 1.56 (1.45, 1.68)
Cmax 1.41 (1.25, 1.58)
C24 1.61 (1.45, 1.79)
(Inhibition of CYP3A)
↔ elbasvir
AUC 0.96 (0.90, 1.02)
Cmax 0.96 (0.91, 1.01)
C24 0.96 (0.89, 1.04)
↔ grazoprevir
AUC 1.07 (0.94, 1.23)
Cmax 1.22 (1.01, 1.47)
C24 0.90 (0.83, 0.96)
No dose adjustment is required.
ledipasvir + sofosbuvir
(90 mg ledipasvir SD + 400 mg sofosbuvir SD, doravirine 100 mg SD)
↑ doravirine
AUC 1.15 (1.07, 1.24)
Cmax 1.11 (0.97, 1.27)
C24 1.24 (1.13, 1.36)
↔ ledipasvir
AUC 0.92 (0.80, 1.06)
Cmax 0.91 (0.80, 1.02)
↔ sofosbuvir
AUC 1.04 (0.91, 1.18)
Cmax 0.89 (0.79, 1.00)
↔ GS-331007
AUC 1.03 (0.98, 1.09)
Cmax 1.03 (0.97, 1.09)
Expected:
↑ tenofovir
Patients receiving doravirine/lamivudine/tenofovir disoproxil concomitantly with ledipasvir/sofosbuvir should be monitored for adverse reactions associated with tenofovir disoproxil.
sofosbuvir/velpatasvir
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ doravirine
↑ tenofovir
Patients receiving doravirine/lamivudine/tenofovir disoproxil concomitantly with sofosbuvir/velpatasvir should be monitored for adverse reactions associated with tenofovir disoproxil.
sofosbuvir
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ doravirine
No dose adjustment is required.
daclatasvir
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ doravirine
No dose adjustment is required.
ombitasvir/paritaprevir/ ritonavir and dasabuvir +/- ritonavir
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↑ doravirine
(Inhibition of CYP3A due to ritonavir)
No dose adjustment is required.
dasabuvir
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ doravirine
No dose adjustment is required.
glecaprevir, pibrentasvir
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↑ doravirine
(inhibition of CYP3A)
No dose adjustment is required.
ribavirin
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ doravirine
No dose adjustment is required.
Herbal Supplements
St John's wort
(Hypericum perforatum)
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration is contraindicated.
HIV Antiviral Agents
tenofovir disoproxil
(300 mg QD, doravirine 100 mg SD)
↔ doravirine
AUC 0.95 (0.80, 1.12)
Cmax 0.80 (0.64, 1.01)
C24 0.94 (0.78, 1.12)
No dose adjustment is required.
lamivudine + tenofovir disoproxil
(300 mg lamivudine SD + 245 mg tenofovir disoproxil SD, doravirine 100 mg SD)
↔ doravirine
AUC 0.96 (0.87, 1.06)
Cmax 0.97 (0.88, 1.07)
C24 0.94 (0.83, 1.06)
↔lamivudine
AUC 0.94 (0.88, 1.00)
Cmax 0.92 (0.81, 1.05)
↔ tenofovir
AUC 1.11 (0.97, 1.28)
Cmax 1.17 (0.96, 1.42)
No dose adjustment is required.
Immunosuppressants
tacrolimus
sirolimus
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ doravirine
↓ tacrolimus, sirolimus
(Induction of CYP3A)
Monitor blood concentrations of tacrolimus and sirolimus as the dose of these agents may need to be adjusted.
Kinase Inhibitors
dabrafenib
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately 12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.
Miscellaneous
sorbitol solution (3.2 g, 10.2 g, 13.4 g)/lamivudine
Single dose lamivudine oral solution 300 mg
lamivudine
AUC ↓ 14 %; 32 %; 35 %
Cmax ↓ 28 %; 52 %; 55 %
When possible, avoid chronic co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products containing sorbitol or other osmotic acting poly-alcohols (e.g., xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic co-administration cannot be avoided.
Opioid Analgesics
methadone
(20-200 mg QD individualised dose, doravirine 100 mg QD)
↓ doravirine
AUC 0.74 (0.61, 0.90)
Cmax 0.76 (0.63, 0.91)
C24 0.80 (0.63, 1.03)
↔ R-methadone
AUC 0.95 (0.90, 1.01)
Cmax 0.98 (0.93, 1.03)
C24 0.95 (0.88, 1.03)
↔ S-methadone
AUC 0.98 (0.90, 1.06)
Cmax 0.97 (0.91, 1.04)
C24 0.97 (0.86, 1.10)
No dose adjustment is required.
buprenorphine
naloxone
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ buprenorphine
↔ naloxone
No dose adjustment is required.
Oral Contraceptives
0.03 mg ethinyl oestradiol/ 0.15 mg levonorgestrel SD, doravirine 100 mg QD
↔ ethinyl oestradiol
AUC 0.98 (0.94, 1.03)
Cmax 0.83 (0.80, 0.87)
↑ levonorgestrel
AUC 1.21 (1.14, 1.28)
Cmax 0.96 (0.88, 1.05)
No dose adjustment is required.
norgestimate/ethinyl oestradiol
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ norgestimate/ethinyl oestradiol
No dose adjustment is required.
Psychostimulants
modafinil
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↓ doravirine
(Induction of CYP3A)
Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.
Sedatives/Hypnotics
midazolam
(2 mg SD, doravirine 120 mg QD)
↓ midazolam
AUC 0.82 (0.70, 0.97)
Cmax 1.02 (0.81, 1.28)
No dose adjustment is required.
Statins
atorvastatin
(20 mg SD, doravirine 100 mg QD)
↔ atorvastatin
AUC 0.98 (0.90, 1.06)
Cmax 0.67 (0.52, 0.85)
No dose adjustment is required.
rosuvastatin
simvastatin
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
Expected:
↔ rosuvastatin
↔ simvastatin
No dose adjustment is required.
↑ = increase, ↓ = decrease, ↔ = no change
CI = Confidence Interval; SD = Single Dose; QD = Once Daily; BID = Twice Daily
*AUC0-∞ for single dose, AUC0-24 for once daily.
4.6 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of doravirine in pregnant women. A large amount of data on pregnant women (more than 3,000 outcomes from first trimester) taking the individual active component lamivudine in combination with other antiretrovirals indicates no malformative toxicity. A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil.
Antiretroviral pregnancy registry
To monitor maternal-foetal outcomes in patients exposed to antiretroviral medicinal products while pregnant, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.
Animal studies with doravirine do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
Animal studies with tenofovir disoproxil do not indicate direct or indirect harmful effects of tenofovir disoproxil with respect to reproductive toxicity (see section 5.3).
Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (see section 5.3). Placental transfer of lamivudine has been shown to occur in humans. Lamivudine may inhibit cellular DNA replication (see section 5.3). The clinical relevance of this finding is unknown.
As a precautionary measure, it is preferable to avoid the use of Delstrigo during pregnancy.
Breast-feeding
It is unknown whether doravirine is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk (see section 5.3).
Lamivudine has been identified in breast-fed newborns/infants of treated women. Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breast-fed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and progressively decrease to undetectable levels when breast-fed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old.
Tenofovir is excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants.
It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.
Fertility
No human data on the effect of Delstrigo on fertility are available. Animal studies do not indicate harmful effects of doravirine, lamivudine, or tenofovir disoproxil on fertility at exposure levels higher than the exposure in humans at the recommended clinical dose (see section 5.3).
4.7 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Delstrigo may have a minor influence on the ability to drive and use machines. Patients should be informed that fatigue, dizziness, and somnolence have been reported during treatment with Delstrigo (see section 4.8). This should be considered when assessing a patient's ability to drive or operate machinery.
4.8 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions considered possibly or probably related to doravirine were nausea (4 %) and headache (3 %).
Tabulated summary of adverse reactions
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), or very rare (< 1/10,000).
Table 2: Tabulated summary of adverse reactions associated with doravirine/lamivudine/tenofovir disoproxil
Frequency
Adverse reactions
Blood and lymphatic systems disorders
Uncommon
neutropenia*, anaemia*, thrombocytopenia*
Very rare
pure red cell aplasia*
Infections and infestations
Rare
rash pustular
Metabolism and nutrition disorders
Uncommon
hypophosphataemia, hypokalaemia*
Rare
hypomagnesaemia, lactic acidosis*
Psychiatric disorders
Common
abnormal dreams, insomnia1,
Uncommon
nightmare, depression2, anxiety3, irritability, confusional state, suicidal ideation
Rare
aggression, hallucination, adjustment disorder, mood altered, somnambulism
Nervous system disorders
Common
headache, dizziness, somnolence
Uncommon
disturbance in attention, memory impairment, paraesthesia, hypertonia, poor quality sleep
Very rare
peripheral neuropathy (or paraesthesia)*
Vascular disorders
Uncommon
hypertension
Respiratory, thoracic and mediastinal disorders
Common
cough*, nasal symptoms*
Rare
dyspnoea, tonsillar hypertrophy
Gastrointestinal disorders
Common
nausea, diarrhoea, abdominal pain4, vomiting, flatulence
Uncommon
constipation, abdominal discomfort5, abdominal distension, dyspepsia, faeces soft6, gastrointestinal motility disorder7, pancreatitis*
Rare
rectal tenesmus
Hepatobiliary disorders
Rare
hepatic steatosis*, hepatitis*
Skin and subcutaneous tissue disorders
Common
alopecia*, rash8
Uncommon
pruritus
Rare
dermatitis allergic, rosacea, angioedema*
Musculoskeletal and connective tissue disorders
Common
muscle disorders*
Uncommon
myalgia, arthralgia, rhabdomyolysis*†, muscular weakness*†
Rare
musculoskeletal pain, osteomalacia (manifested as bone pain and infrequently contributing to fractures)*, myopathy*
Renal and urinary disorders
Uncommon
increased creatinine*, proximal renal tubulopathy (including Fanconi syndrome)*
Rare
acute kidney injury, renal disorder, calculus urinary, nephrolithiasis, acute renal failure*, renal failure*, acute tubular necrosis*, nephritis (including acute interstitial)*, nephrogenic diabetes insipidus*
General disorders and administration site conditions
Common
fatigue, fever*
Uncommon
asthenia, malaise
Rare
chest pain, chills, pain, thirst
Investigations
Common
alanine aminotransferase increased9
Uncommon
aspartate aminotransferase increased, lipase increased, amylase increased, haemoglobin decreased
Rare
blood creatine phosphokinase increased
*This adverse reaction was not identified as an adverse reaction associated with doravirine from the Phase 3 clinical studies (DRIVE-FORWARD, DRIVE-AHEAD, DRIVE-SHIFT), but is included in this table as an adverse reaction based on the Summary of Product Characteristics of 3TC and/or TDF. The highest frequency category reported in the 3TC or TDF Summary of Product Characteristics is used.
†This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition.
1insomnia includes: insomnia, initial insomnia and sleep disorder.
2depression includes: depression, depressed mood, major depression, and persistent depressive disorder.
3anxiety includes: anxiety and generalised anxiety disorder.
4abdominal pain includes: abdominal pain, and abdominal pain upper.
5abdominal discomfort includes: abdominal discomfort, and epigastric discomfort.
6faeces soft includes: faeces soft and abnormal faeces.
7gastrointestinal motility disorder includes: gastrointestinal motility disorder, and frequent bowel movements.
8rash includes: rash, rash macular, rash erythematous, rash generalised, rash maculo-papular, rash papular, and urticarial.
9alanine aminotransferase increased includes: alanine aminotransferase increased and hepatocellular injury.
Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
Lactic acidosis
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.
Paediatric population
The safety of doravirine/lamivudine/tenofovir disoproxil was evaluated in 45 HIV-1 infected virologically suppressed or treatment-naïve paediatric patients 12 to less than 18 years of age through Week 48 in an open-label trial (IMPAACT 2014 (Protocol 027)). The safety profile in paediatric subjects was similar to that in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Clinical particulars - Overdose | Overdose
Doravirine
There is no information on potential acute symptoms and signs of overdose with doravirine.
Lamivudine
Because a negligible amount of lamivudine was removed via (4-hour) haemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous haemodialysis would provide clinical benefit in a lamivudine overdose event.
Tenofovir disoproxil
Tenofovir disoproxil is efficiently removed by haemodialysis with an extraction coefficient of approximately 54 %. Following a single 245 mg dose of tenofovir disoproxil, a 4-hour haemodialysis session removed approximately 10 % of the administered tenofovir dose.
5. Pharmacological properties
5.1 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Single-dose administration of one doravirine/lamivudine/tenofovir disoproxil tablet to healthy subjects (N = 24) under fasted conditions provided comparable exposures of doravirine, lamivudine, and tenofovir to administration of doravirine tablets (100 mg) plus lamivudine tablets (300 mg) plus tenofovir disoproxil tablets (245 mg). The administration of a single Delstrigo tablet with a high-fat meal to healthy subjects resulted in a 26 % increase in doravirine C24, while AUC and Cmax were not significantly affected. Lamivudine Cmax decreased by 19 % with a high fat meal, while AUC was not significantly affected. Tenofovir Cmax decreased by 12 % and AUC increased by 27 % with a high fat meal. These differences in pharmacokinetics are not clinically relevant.
Doravirine
The pharmacokinetics of doravirine were studied in healthy subjects and HIV-1-infected subjects. Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Steady state was generally achieved by Day 2 of once daily dosing, with accumulation ratios of 1.2 to 1.4 for AUC0-24, Cmax, and C24. Doravirine steady state pharmacokinetics following administration of 100 mg once daily to HIV-1 infected subjects, based on a population pharmacokinetics analysis are provided below.
Parameter
GM ( %CV)
AUC0-24
μg•h/mL
Cmax
μg/mL
C24
μg/mL
Doravirine
100 mg
once daily
16.1 (29)
0.962 (19)
0.396 (63)
GM: Geometric mean, %CV: Geometric coefficient of variation
Absorption
Following oral dosing, peak plasma concentrations are achieved 2 hours after dosing. Doravirine has an estimated absolute bioavailability of approximately 64 % for the 100 mg tablet.
Distribution
Based on administration of an IV microdose, the volume of distribution of doravirine is 60.5 L. Doravirine is approximately 76 % bound to plasma proteins.
Biotransformation
Based on in vitro data, doravirine is primarily metabolised by CYP3A.
Elimination
DoravirineDoravirine has a terminal half-life (t1/2) of approximately 15 hours. Doravirine is primarily eliminated via oxidative metabolism mediated by CYP3A4. Biliary excretion of unchanged medicinal product may contribute to the elimination of doravirine, but this elimination route is not expected to be significant. Excretion of unchanged medicinal product via urinary excretion is minor.
Lamivudine Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 microgram per mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hour per mL. Binding to plasma protein is low. Approximately 71 % of an intravenous dose of lamivudine is recovered as unchanged medicinal product in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulphoxide metabolite (approximately 5 % of an oral dose after 12 hours). In most single-dose trials in HIV-1 infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1 infected subjects, total clearance was 398.5 ± 69.1 mL/min (mean ± SD).
Tenofovir disoproxil
Following oral administration of a single 245 mg dose of tenofovir disoproxil to HIV-1-infected subjects in the fasted state, Cmax was achieved in one hour. Cmax and AUC values were 0.30 ± 0.09 micrograms per mL and 2.29 ± 0.69 µg•hr per mL, respectively. The oral bioavailability of tenofovir from tenofovir disoproxil in fasted subjects is approximately 25 %. Less than 0.7 % of tenofovir binds to human plasma proteins in vitro over the range of 0.01 to 25 micrograms per mL. Approximately 70-80 % of the intravenous dose of tenofovir is recovered as unchanged medicinal product in the urine within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with CrCl greater than 80 mL per minute of 243.5 ± 33.3 mL per minute (mean ± SD). Following oral administration, the terminal half-life of tenofovir is approximately 12 to 18 hours. In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYP450 enzymes.
Renal impairment
Doravirine
Renal excretion of doravirine is minor. In a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 31 % higher in subjects with severe renal impairment. In a population pharmacokinetic analysis, which included subjects with CrCl between 17 and 317 mL/min, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. No dose adjustment is required in patients with mild, moderate or severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis (see section 4.2).
Lamivudine
Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. Based on the lamivudine data, Delstrigo is not recommended for patients with CrCl of < 50 mL/min.
Tenofovir disoproxil
Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV infected adult subjects with varying degrees of renal impairment defined according to baseline CrCl (normal renal function when CrCl > 80 mL/min; mild with CrCl = 50-79 mL/min; moderate with CrCl = 30-49 mL/min and severe with CrCl = 10-29 mL/min). Compared with subjects with normal renal function, the mean (% CV) tenofovir exposure increased from 2,185 (12 %) ng·h/mL in subjects with CrCl > 80 mL/min to respectively 3,064 (30 %) ng·h/mL, 6,009 (42 %) ng·h/mL and 15,985 (45 %) ng·h/mL in subjects with mild, moderate, and severe renal impairment.
The pharmacokinetics of tenofovir in non-haemodialysis adult subjects with CrCl < 10 mL/min and in subjects with end-stage renal disease managed by peritoneal or other forms of dialysis have not been studied.
Hepatic impairment
Doravirine
Doravirine is primarily metabolised and eliminated by the liver. There was no clinically relevant difference in the pharmacokinetics of doravirine in a study comparing 8 subjects with moderate hepatic impairment (classified as Child-Pugh score B primarily due to increased encephalopathy and ascites scores) to 8 subjects without hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) (see section 4.2).
LamivudineThe pharmacokinetic properties of lamivudine have been determined in subjects with moderate to severe hepatic impairment. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.
Tenofovir disoproxilThe pharmacokinetics of tenofovir following a 245 mg dose of tenofovir disoproxil have been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.
Paediatric population
Mean doravirine exposures were similar in 54 paediatric patients aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or doravirine/lamivudine/tenofovir disoproxil IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or doravirine/lamivudine/tenofovir disoproxil. Exposures of lamivudine and tenofovir in paediatric subjects following the administration of doravirine/lamivudine/tenofovir disoproxil were similar to those in adults following administration of lamivudine and tenofovir disoproxil (Table 6).
Table 6: Steady state pharmacokinetics for doravirine, lamivudine, and tenofovir following administration of doravirine or doravirine/lamivudine/tenofovir disoproxil in HIV infected paediatric patients aged 12 to less than 18 years and weighing at least 35 kg
Parameter*
Doravirine†
Lamivudine‡
Tenofovir‡
AUC0-24
(µg•h/mL)
16.4 (24)
11.3 (28)
2.55 (14)
Cmax
(µg/mL)
1.03 (16)
2.1 (24)
0.293 (37)
C24
(µg/mL)
0.379 (42)
0.0663 (55)
0.0502 (9)
*Presented as geometric mean (%CV: geometric coefficient of variation)
†From population PK analysis (n=54)
‡From intensive PK analysis (n=10)
Abbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours
Elderly
Although a limited number of subjects aged 65 years and over has been included (n = 36), no clinically relevant differences in the pharmacokinetics of doravirine have been identified in subjects at least 65 years of age compared to subjects less than 65 years of age in a Phase 1 trial or in a population pharmacokinetic analysis. The pharmacokinetics of lamivudine and tenofovir have not been studied in subjects older than 65 years. No dose adjustment is required.
Gender
No clinically relevant pharmacokinetic differences have been identified between men and women for doravirine, lamivudine, and tenofovir.
Race
Doravirine
No clinically relevant racial differences in the pharmacokinetics of doravirine have been identified based on a population pharmacokinetic analysis of doravirine in healthy and HIV-1-infected subjects.
Lamivudine
There are no significant or clinically relevant racial differences in pharmacokinetics of lamivudine.
Tenofovir disoproxil
There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of tenofovir disoproxil.
5.3 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Reproductive toxicity
Doravirine
Reproduction studies with orally administered doravirine have been performed in rats and rabbits at exposures approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the recommended human dose (RHD) with no effects on embryo-foetal (rats and rabbits) or pre/postnatal (rats) development. Studies in pregnant rats and rabbits showed that doravirine is transferred to the foetus through the placenta, with foetal plasma concentrations of up to 40 % (rabbits) and 52 % (rats) that of maternal concentrations observed on gestation Day 20.
Doravirine was excreted into the milk of lactating rats following oral administration, with milk concentrations approximately 1.5 times that of maternal plasma concentrations.
Lamivudine
Lamivudine was not teratogenic in animal studies but there were indications of an increase in early embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in humans. A similar effect was not seen in rats even at very high systemic exposure.
Tenofovir disoproxil
Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in a peri-postnatal toxicity study at maternally toxic doses.
Carcinogenesis
Doravirine
Long-term oral carcinogenicity studies of doravirine in mice and rats showed no evidence of carcinogenic potential at estimated exposures up to 6 times (mice) and 7 times (rats) the human exposures at the RHD.
Lamivudine
Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the RHD.
Tenofovir disoproxil
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high-dose in mice. These tumours are unlikely to be of relevance to humans.
Mutagenesis
Doravirine
Doravirine was not genotoxic in a battery of in vitro or in vivo assays.
Lamivudine
Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.
Tenofovir disoproxil
Tenofovir disoproxil was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil was negative when administered to male mice.
Impairment of fertility
Doravirine
There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at up to 7 times the exposure in humans at the RHD.
Lamivudine
Lamivudine did not affect male or female fertility in rats.
Tenofovir disoproxil
Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters.
Repeat dose toxicity
Doravirine
Administration of doravirine in animal toxicity studies was not associated with toxicity.
Lamivudine
Administration of lamivudine in animal toxicity studies at high doses was not associated with any major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney function were seen together with occasional reductions in liver weight. The clinically relevant effects noted were a reduction in red blood cell count and neutropenia.
Tenofovir disoproxil
Findings in repeat-dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use included kidney and bone changes and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs). The bone toxicity in young adult rats and dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold the exposure in patients). Findings in the rat and monkey studies indicated that there was a substance related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD.
6. |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Croscarmellose sodium (E468)
Hypromellose acetate succinate
Magnesium stearate (E470b)
Microcrystalline cellulose (E460)
Silica, colloidal anhydrous (E551)
Sodium stearyl fumarate
Film-coating
Carnauba wax (E903)
Hypromellose (E464)
Iron oxide yellow (E172)
Lactose monohydrate
Titanium dioxide (E171)
Triacetin (E1518)
6.2 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
30 months
6.4 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in the original bottle and keep the bottle tightly closed to protect from moisture. Do not remove the desiccant. This medicinal product does not require any special temperature storage conditions.
6.5 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Each carton contains a high density polyethylene (HDPE) bottle with a polypropylene child-resistant closure with silica gel desiccants.
The following pack sizes are available:
• 1 bottle with 30 film-coated tablets
• 90 film-coated tablets (3 bottles of 30 film-coated tablets)
Not all pack sizes may be marketed.
6.6 |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Marketing authorisation holder | Merck Sharp & Dohme (UK) Limited
120 Moorgate
London
EC2M 6UR
United Kingdom
8. Marketing authorisation number(s)
PLGB 53095/0015
9. |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 01 January 2021
10. |
Delstrigo 100 mg /300 mg /245 mg film-coated tablets | Date of revision of the text | 19 December 2022
© 2022 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved.
SPC.DEL.22.GB.8237.II-008.RCN024698 |
Demeclocycline Hydrochloride 150mg Capsules | Name of the medicinal product | Ledermycin Capsules 150mg
Demeclocycline Hydrochloride 150mg Capsules
2. |
Demeclocycline Hydrochloride 150mg Capsules | Qualitative and quantitative composition | LEDERMYCIN capsules each contain 150mg of demeclocycline hydrochloride.
3. |
Demeclocycline Hydrochloride 150mg Capsules | Pharmaceutical form | capsule, hard
4. |
Demeclocycline Hydrochloride 150mg Capsules | Clinical particulars - Therapeutic indications | Therapeutic indications
For the treatment of infections caused by tetracycline-sensitive organisms. For example, LEDERMYCIN is highly effective in the treatment of infections caused by Borrelia recurrentis (relapsing fever), Calymmatobacterium granulinatis (granuloma inguinale), Chlamydia species (psittacosis, lymphogranuloma vereneum, trachoma, inclusion conjunctivitis), Francisella tularensis (tularaemia), Haemophilus ducreyi (chancroid), Leptospira (meningitis, jaundice), Mycoplasma pneumoniae (non-gonococcal urethritis), Pseumomonas mallei and pseudomallei (glanders and melioidosis), Rickettsiae (typhus fever, Q fever, rocky mountain spotted fever), Vibrio species (cholera). It is also highly effective, alone or in combination with streptomycin, in the treatment of infections due to Brucella species (brucellosis) and Yersinia pestis (bubonic plague). Severe acne vulgaris.
Other sensitive organisms include: Actinomyces israelii, Bacillus anthracis (pneumonia), Clostridium species (gas gangrene, tetanus), Entamoeba histolytica (dysentery), Neisseria gonorrhoeae and anaerobic species, Treponema pallidum and pertenue (syphilis and yaws).
For the treatment of chronic hyponatraemia associated with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) secondary to malignant disease, where water restriction is ineffective and the patient does not have concomitant cirrhosis.
4.2 |
Demeclocycline Hydrochloride 150mg Capsules | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
For Antibiotic Use
Adults
(Capsules) - 600mg daily in 2 or 4 divided doses. For primary atypical pneumonia, the average daily dose is 900mg in 3 divided doses for 6 days.
Elderly
Use with caution in elderly patients. (See Section 4.3 Contra-indications and Section 4.4 Special warnings and special precautions for use)
Paediatric population
Not recommended for children under 12 years of age.
For the treatment of Chronic Hyponatraemia due to SIADH
Adults only
Initially: 900mg-l200mg daily in divided doses
Maintenance dose: 600-900mg daily in divided doses
LEDERMYCIN should be swallowed whole with plenty of fluid while sitting or standing. Doses should be taken an hour before or 2 hours after meals as absorption of LEDERMYCIN is impaired by milk and food. Antibiotic therapy should be continued for one to three days after characteristic symptoms of fever have subsided. The incidence of rheumatic fever or glomerulonephritis following streptococcal infections suggests that therapy of a streptococcal infection should be continued for 8 full days even though symptoms have subsided.
LEDERMYCIN therapy in the treatment of chronic hyponatraemia due to SIADH should not be withdrawn without commencing other methods of control.
Method of administration
Oral administration.
4.3 |
Demeclocycline Hydrochloride 150mg Capsules | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
The use of LEDERMYCIN is contraindicated in patients with acute porphyria, patients who are pregnant or breast-feeding, children under 12 years of age, patients with a history of hypersensitivity to tetracyclines and patients with renal impairment.
4.4 |
Demeclocycline Hydrochloride 150mg Capsules | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
LEDERMYCIN should be used with caution in patients with renal or hepatic dysfunction, or in conjunction with other potentially hepatotoxic or nephrotoxic drugs. Concurrent use with the anaesthetic methoxyflurane increases the risk of kidney failure. The anti-anabolic action of the tetracyclines may cause an increase in BUN. The treatment of chronic hyponatraemia may necessitate the administration of high doses of LEDERMYCIN for prolonged periods, so increasing the potential for nephrotoxicity (manifested by rises in plasma urea and creatinine) and photoallergic reactions. Cross-resistance between tetracyclines may develop in micro-organisms and cross sensitisation in patients. LEDERMYCIN should be discontinued if there are signs/symptoms of overgrowth of resistant organisms including candida, enteritis, glossitis, stomatitis, vaginitis, pruritis ani or staphylococcal enterocolitis.
Lower doses are indicated in cases of renal impairment to avoid excessive systemic accumulation and if therapy is prolonged, serum level determinations are advisable. Patients who have known liver disease should not receive more than 1g daily. In long term therapy, periodic laboratory evaluation of organ systems, including haematopoietic, renal and hepatic studies should be performed.
LEDERMYCIN has the greatest potential of the tetracycline analogues for causing photo-allergic reactions in hypersensitive persons. Such patients should be warned to avoid direct exposure to natural or artificial sunlight and to discontinue therapy at the first sign of skin discomfort. Exacerbation of pre-existing SLE has been reported with tetracyclines.
LEDERMYCIN may increase muscle weakness in patients with myasthenia gravis.
4.5 |
Demeclocycline Hydrochloride 150mg Capsules | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
LEDERMYCIN should not be used with penicillins.
Tetracyclines depress plasma prothrombin activity and reduced doses of concomitant anti-coagulants such as Coumarins and phenindione may be required.
Absorption of LEDERMYCIN is impaired by the concomitant administration of milk and dairy products, food, iron, calcium, zinc, magnesium and particularly aluminium salts commonly used as antacids.
Absorption of tetracyclines is possibly reduced by kaolin, quinapril tablets (quinapril tablets contain magnesium carbonate), strontium ranelate, sucralfate, tripotassium dicitratobismuthate.
There is a possible increased risk of benign intracranial hypertension with concomitant use of tetracyclines and retinoids, e.g. acitretin, isotretinoin, tretinoin. There is increased risk of ergotism when tetracyclines given with ergotamine and methysergide.
Typhoid Vaccine (oral): Antibacterials inactivate oral typhoid vaccine and therefore Ledermycin should be avoided for 3 days before and after oral typhoid vaccine.
4.6 Pregnancy and lactation
LEDERMYCIN is contra-indicated during pregnancy and lactation.
Pregnancy
Results of animal studies indicate that tetracyclines cross the placenta, are found in foetal tissues and can have toxic effects on the developing foetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy.
The use of tetracyclines during tooth development (last half of pregnancy and children to the age of 12 years) may cause permanent discoloration of the teeth (yellow-grey-brown). This adverse reaction is more common during long term use of the drugs but has been observed following repeated short term courses. Enamel hypoplasia has also been reported.
Breast-feeding
Tetracyclines have been found in the milk of lactating women who are taking a drug in this class. Permanent tooth discoloration may occur in the developing infant and enamel hypoplasia has been reported. Therefore, LEDERMYCIN should not be administered to lactating women.
4.7 |
Demeclocycline Hydrochloride 150mg Capsules | Clinical particulars - Fertility, pregnancy and lactation | Effects on ability to drive and use machines
Headache, dizziness, visual disturbances and rarely impaired hearing have been reported with tetracyclines and patients should be warned about the possible hazards of driving or operating machinery during treatment.
4.8 |
Demeclocycline Hydrochloride 150mg Capsules | Clinical particulars - Effects on ability to drive and use machines | Undesirable effects
The following undesirable effects have been reported for Demeclocycline hydrochloride.
The undesirable effects are listed according to their frequency:
Not known (cannot be estimated from the available data)
System organ class
Frequency |
Demeclocycline Hydrochloride 150mg Capsules | Clinical particulars - Undesirable effects | Undesirable effects
Blood and lymphatic system disorders
Not Known
Haemolytic anaemia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and eosinophiliaa
Immune system disorders
Not Known
Hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, angioneurotic oedema, anaphylaxis, anaphylactoid purpura, pericarditis and exacerbation of systemic lupus erythematosus
Nervous system disorders
Not Known
Headache, dizziness, bulging fontanelles (in infants), benign intracranial hypertension (in juveniles and adults), raised intracranial pressure (such as severe or persistent headache or blurred vision) b, myasthenia
Eye disorders
Not Known
Visual disturbances
Ear and labyrinth disorders
Not Known
Impaired hearing
Gastrointestinal disorders
Not Known
Nausea, vomiting, diarrhoea, dysphagia, oesophagitis, oesphageal ulceration,c candidiasis, pseudomembranous colitis (Clostridium difficile overgrowth) glossitis, stomatitis, vaginitis, or staphylococcal enterocolitis, pancreatitis
Skin and subcutaneous tissue disorders
Not Known
Photosensitivity, erythematous, maculo-papular rashes, pruritus, bullous dermatoses, exfoliative dermatitis, skin discolouration, serious skin reactions
Renal and urinary disorders
Not Known
Renal dysfunction, especially in patients with pre-existing renal impairment, acute renal failure or nephritis, reversible nephrogenic diabetes insipidus (prolonged and/or at high dosages)
Hepatobiliary disorders
Not Known
Hepatitis, jaundice, hepatic failure
Investigations
Not Known
Transient increases in liver function test values
a. When given over prolonged periods, tetracyclines have been reported to produce brown-black discoloration of the thyroid gland. No abnormalities of thyroid function are known to occur.
b. While the condition and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility of permanent sequelae exists.
c. In patients taking oral tetracyclines in solid dose form, usually where medication was taken immediately before retiring or with inadequate fluids.
Reporting of Adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Demeclocycline Hydrochloride 150mg Capsules | Clinical particulars - Overdose | Overdose
Management
No specific antidote. Gastric lavage plus oral administration of milk or antacids. Maintain fluid and electrolyte balance.
5. Pharmacological properties
5.1 |
Demeclocycline Hydrochloride 150mg Capsules | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
Tetracyclines are incompletely and irregularly absorbed from the gastrointestinal tract. Absorption is affected by the soluble salts of divalent and trivalent metals, milk and food.
Distribution
Plasma concentrations of up to 2.4mg per ml have been reported 3 to 4 hours after an oral dose of 300mg, only falling to about 1mg per ml after 24 hours. 41-90% of circulating demeclocycline is bound to plasma proteins.
Tetracyclines are widely distributed throughout the body tissue and fluids, and are retained at sites of new bone formation and recent calcification. The biological half life of demeclocycline is 12 hours.
Elimination
Tetracyclines are excreted in the urine and faeces.
5.3 |
Demeclocycline Hydrochloride 150mg Capsules | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
There are no other preclinical safety data of relevance to the prescriber apart from those already detailed in the SPC.
6. |
Demeclocycline Hydrochloride 150mg Capsules | Pharmaceutical particulars - List of excipients | List of excipients
Powdered Cellulose, magnesium stearate, Colloidal Anhydrous Silica.
Capsule body and cap: titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (El72), erythrosine (El27), gelatin.
Printing on capsule: Shellac NF E904, Purified water, Propylene glycol (E1520), Dehydrated Alcohol, Strong ammonia solution, Potassium Hydroxide, Isopropyl Alcohol and black iron oxide (E172)
6.2 |
Demeclocycline Hydrochloride 150mg Capsules | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None.
6.3 |
Demeclocycline Hydrochloride 150mg Capsules | Pharmaceutical particulars - Shelf life | Shelf life
36 months
6.4 |
Demeclocycline Hydrochloride 150mg Capsules | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C.
Blister pack-Store in original package in order to protect from light and moisture.
Container/Bottle - Keep the container/bottle tightly closed in the outer carton in order to protect from light and moisture
6.5 |
Demeclocycline Hydrochloride 150mg Capsules | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Polypropylene containers - 20, 28 or 100 capsules.
Screw capped glass bottles - 100 capsules.
Blister pack - 20 capsules.
HDPE ø 45 mm round 50 ml plastic container containing 28 capsules
6.6 |
Demeclocycline Hydrochloride 150mg Capsules | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements.
7. |
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