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SANDOZ DOLUTEGRAVIR is a brand name for Dolutegravir, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Sandoz Dolutegravir, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adults and in INSTI-naïve children at least 6 years of age and weighing ≥ 40kg. 1.1 Pediatrics Pediatrics (aged less than 6 years or weighing less than 40 kg or…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations As with all antiretroviral drugs, dolutegravir therapy should be initiated by a healthcare practitioner experienced in the management of HIV infection. Perform pregnancy testing before initiation of Sandoz Dolutegravir in individuals of childbearing potential.
Sandoz Dolutegravir (dolutegravir sodium) Product Monograph Page 5 of 60 The following should be considered prior to initiating treatment with dolutegravir: • Poor virologic response was observed in subjects treated with Sandoz Dolutegravir 50mg twice daily with an integrase strand transfer inhibitor (INSTI) -resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including, but not limited to T66A, L74I/M, E138A/K/T, G140A/C/S, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.
Dolutegravir tablets may be taken with or without food. Sandoz Dolutegravir is available as tablets. For dosing recommendations using tablets see the recommenced dose for adults and Table 2 for pediatric patients. 2 Recommended Dose and Dosage Adjustment Adult Patients Table 1 Recommended Dosing Regimen in Adults Patient Population Tablet Dose Regimen Treatment-naïvea 50 mg QD* Treatment-experienced, INSTI- naïvea 50 mg QD Treatment-experienced, INSTI- resistantb 50 mg BID** * QD – once daily ** BID – twice daily a The dose of dolutegravir is 50 mg twice daily when co-administered with potent UGT1A/CYP3A inducers, including efavirenz, tipranavir/ritonavir, fosamprenavir/ritonavir or rifampin (see 9 DRUG INTERACTIONS).
b Alternative combinations that do not include metabolic inducers should be used where possible for INSTI-resistant patients. The safety and efficacy of doses above 50 mg twice daily have not been evaluated (see 9 DRUG INTERACTIONS).
Geriatrics There are limited data available on the use of dolutegravir in patients aged 65 years and older. In general, caution should be exercised in the administration of Sandoz Dolutegravir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Pediatric Treatment-naive or Treatment-experienced INSTI-naive Sandoz Dolutegravir (dolutegravir sodium) Product Monograph Page 6 of 60 The recommended dose of Sandoz Dolutegravir in pediatric patients aged at least 6 years and weighing at least 40 kg is provided in Table 2.
1 Adverse Reaction Overview The overall safety profile of dolutegravir is based on over 1500 HIV-infected patients treated with a dolutegravir-based regimen in Phase 2 and 3 clinical studies. The overall safety profile was similar across the treatment-naïve, treatment-experienced (and integrase-naïve) and integrase-resistant patient populations.
The most common adverse reactions of moderate to severe intensity and incidence ≥ 2% (in those receiving dolutegravir in any one study) are insomnia, headache, fatigue, nausea, and diarrhea. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions.
The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from Sandoz Dolutegravir (dolutegravir sodium) Product Monograph Page 12 of 60 clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
Treatment-Naïve Patients The safety assessment of dolutegravir in HIV-1-infected treatment-naïve patients is based on the analyses of 48-week data from two randomized, ongoing, international, multicentre, double-blind studies, SPRING-2 (ING113086) and SINGLE (ING114467).
In SPRING-2, 822 adult patients were randomized and received at least one dose of either dolutegravir 50 mg once daily (QD) or ISENTRESS 400 mg twice daily (BID), both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [KIVEXA] or emtricitabine/tenofovir [TRUVADA]).
The rate of adverse events leading to discontinuation was 2% in both treatment arms. In SINGLE, 833 adult patients were randomized to receive at least one dose of either dolutegravir 50 mg with fixed-dose abacavir and lamivudine (KIVEXA) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily.
General Patients receiving Sandoz Dolutegravir or any other antiretroviral therapy may still develop Sandoz Dolutegravir (dolutegravir sodium) Product Monograph Page 8 of 60 opportunistic infections and other complications of HIV infection.
Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded Precautions to prevent transmission should be taken in accordance with national guidelines.
Driving and Operating Machinery Exercise caution when driving or operating a vehicle or potentially dangerous machinery. Hepatic/Biliary/Pancreatic Hepatoxicity Cases of hepatic toxicity including elevated serum liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors.
Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (dolutegravir/abacavir/lamivudine). Monitoring for hepatotoxicity is recommended. Liver chemistry changes in patients with hepatitis B or C co-infection Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of dolutegravir.
Liver chemistry elevations consistent with immune reconstitution inflammatory syndrome were observed in some hepatitis B and/or C co- infected patients at the start of dolutegravir therapy. Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection.
2 Clinical Trial Adverse Reactions, Co-infection with Hepatitis B or C). Hypersensitivity Reactions Hypersensitivity reactions have been reported with integrase inhibitors, including dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including liver injury.
• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. • Sandoz Dolutegravir is contraindicated in combination with drugs with narrow therapeutic windows, that are substrates of organic cation transporter 2 (OCT2), including but not limited to dofetilide, or fampridine (also known as dalfampridine) (see 9 DRUG INTERACTIONS).
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Safety and efficacy of dolutegravir have not been established in pediatric patients aged less than 6 years, or who are INSTI-experienced with suspected or confirmed INSTI-resistant HIV-1. Sandoz Dolutegravir is not recommended in patients weighing less than 40 kg because no dose adjustment can be made.
Table 2 Recommended Dosing Regimen in pediatric patients Body Weight (kg) Once Daily Dosing Regimena ≥ 40 50 mg (one 50 mg tablet) a If certain UGT1A or CYP3A inducers including efavirenz, tipranavir/ritonavir, fosamprenavir/ritonavir or rifampin are coadministered, then increase the weight-based dose of dolutegravir to twice daily (see 9 DRUG INTERACTIONS).
To reduce the risk of choking, do not swallow more than one tablet at a time. Hepatic Insufficiency No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child- Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied.
3 Pharmacokinetics, Special Populations and Conditions, Hepatic Insufficiency). Renal Insufficiency Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls.
No dosage adjustment is required in INSTI- naïve patients with mild, moderate or severe (CrCl<30 mL /min, not on dialysis) renal impairment. Caution is advised for INSTI-resistant patients with severe renal impairment as the decreased dolutegravir exposure may result in loss of therapeutic effect and development of resistance to dolutegravir.
3 Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency). 5 Missed Dose If a dose is missed, patients should take the missed dose as soon as possible unless it is within 4 hours of their next scheduled dose. If a dose is skipped, the patient should not double the next dose.
The rate of adverse events leading to discontinuation were 2% in patients receiving dolutegravir 50 mg once daily + KIVEXA and 10% in patients receiving ATRIPLA once daily. Treatment-emergent adverse reactions (adverse events assessed as causally related by the investigators) of moderate to severe intensity with a ≥ 2% frequency in either treatment arm in SPRING-2 and SINGLE studies are provided in Table 4.
The adverse drug reactions and laboratory abnormalities observed at 96 weeks in SPRING-2 and at 144 weeks in SINGLE were generally consistent with those seen at 48 weeks.
Table 4:
Treatment-Emergent Adverse Reactions of at Least Moderate Intensity (Grades 2-4) and ≥ 2% Frequency in Treatment-Naïve Patients in SPRING-2 and SINGLE Trials (Through 48 weeks) SPRING-2 SINGLE Body System/ Preferred Term Dolutegravir 50 mg QD + 2 NRTIs (N = 411) ISENTRESS 400 mg BID + 2 NRTIs (N = 411) Dolutegravir 50 mg + KIVEXA QD (N = 414) ATRIPLA QD (N = 419) Psychiatric Insomnia Abnormal dreams 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) 13 (3%) 2 (<1%) 9 (2%) 8 (2%) Nervous System Dizziness 1 (<1%) 1 (<1%) 2 (<1%) 19 (5%) Sandoz Dolutegravir (dolutegravir sodium) Product Monograph Page 13 of 60 SPRING-2 SINGLE Body System/ Preferred Term Dolutegravir 50 mg QD + 2 NRTIs (N = 411) ISENTRESS 400 mg BID + 2 NRTIs (N = 411) Dolutegravir 50 mg + KIVEXA QD (N = 414) ATRIPLA QD (N = 419) Headache 3 (<1%) 4 (<1%) 7 (2%) 9 (2%) Gastrointestinal Nausea Diarrhea 6 (1%) 2 (<1%) 5 (1%) 2 (<1%) 3 (<1%) 4 (<1%) 12 (3%) 7 (2%) Skin and Subcutaneous Tissue Rash 0 2 (<1%) 1 (<1%) 14 (3%) Ear and Labyrinth Vertigo 0 1 (<1%) 0 7 (2%) Antiretroviral-Experienced and Integrase Inhibitor-Naïve Patients In an international, multicentre, double-blind study (ING111762, SAILING), 719 HIV-1-infected, antiretroviral treatment-experienced adults were randomized to receive either dolutegravir 50 mg once daily or ISENTRESS 400 mg twice daily with investigator-selected background regimen (BR) consisting of up to 2 agents, including at least one fully active agent.
At 48 weeks, the rates of adverse events leading to discontinuation were 2% (7/357) in patients receiving dolutegravir 50 mg once daily + BR and 4% (13/362) in patients receiving ISENTRESS 400 mg twice daily + BR. Through 48 wks, the only treatment-emergent adverse reaction of moderate to severe intensity with a ≥ 2% frequency in either treatment group was diarrhea, 2% (6/357) in subjects receiving dolutegravir 50 mg once daily + BR and 1% (5/362) in subjects receiving ISENTRESS 400 mg twice daily + BR.
Integrase Inhibitor-Resistant Patients In a multicentre, open-label, single-arm study (ING112574, VIKING-3), 183 HIV-1-infected, antiretroviral treatment-experienced adults with virologic failure with current or historical evidence of raltegravir and/or elvitegravir resistance received dolutegravir 50 mg twice daily with the current failing background regimen for 7 days and with Optimized Background Therapy (OBT) from Day 8.
The rate of discontinuation due to adverse events was 4% of patients at the Week 48 analysis. Treatment-emergent adverse reactions (adverse events assessed as causally related by the investigator) of moderate to severe intensity with a ≥ 2% frequency are listed in Table 5.
Table 5:
Treatment-Emergent Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4) and ≥ 2% Frequency in Integrase Inhibitor-Resistant Patients in the VIKING-3 Study (Week 24 and Week 48 Analyses) Sandoz Dolutegravir (dolutegravir sodium) Product Monograph Page 14 of 60 Week 24 Week 48 Body System/ Preferred Term Dolutegravir 50 mg BID + OBT (N = 183) Dolutegravir 50 mg BID + OBT (N = 183) Gastrointestinal Diarrhea Nausea 4 (2%) 3 (2%) 4 (2%) 3 (2%) Nervous System Headache 3 (2%) 2 (1%) Co-infection with Hepatitis B or C In Phase III studies, patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN).
Overall, the […]
Discontinue Sandoz Dolutegravir and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema).
Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay Sandoz Dolutegravir (dolutegravir sodium) Product Monograph Page 9 of 60 in stopping treatment with Sandoz Dolutegravir or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.
Immune Immune Reconstitution Inflammatory Syndrome (IRIS) Immune reconstitution inflammatory syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including dolutegravir. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium- complex (MAC), cytomegalovirus (CMV), Pneumocystis jirovecii pneumonia (PCP), and tuberculosis (TB)], which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, autoimmune hepatitis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.
1 Pregnant Women Dolutegravir has not been studied in pregnant women. Sandoz Dolutegravir should not be used in pregnant women unless the potential benefits outweigh the potential risks to the fetus (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).
Women of childbearing potential (WOCBP) should be informed about the potential risk of neural tube defects with Sandoz Dolutegravir and counselled about the use of effective contraception. It is recommended that pregnancy testing is conducted prior to initiation of Sandoz Dolutegravir.
If there are plans to become pregnant, or if pregnancy is confirmed within the first trimester while on Sandoz Dolutegravir, the risks and benefits of continuing Sandoz Dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient.
Factors to consider should include feasibility of switching, tolerability, ability to maintain viral suppression, actual gestational age, risk of transmission to the infant and the available data around the potential risk of neural tube defects and other pregnancy outcomes for dolutegravir and alternative antiretroviral drugs.
In a birth outcome surveillance study in Botswana, a numerically higher rate of neural tube defects was identified with exposure to dolutegravir compared to non-dolutegravir-containing antiretroviral regimens at the time of conception, however, the difference was not statistically significant.
30). In the same study, an increased risk of neural tube defects was not identified in women who started dolutegravir during pregnancy. 04%) to mothers who started dolutegravir during pregnancy had a neural tube […]