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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.
Embryo-Fetal Toxicity: Preliminary data from an observational study showed that dolutegravir was associated with increased risk of neural tube defects when administered at the time of conception and in early pregnancy. As there is limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, avoid use of dolutegravir at the time of conception through the first trimester of pregnancy.
If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on dolutegravir, if possible, switch to an alternative regimen.
Perform pregnancy testing before initiation of dolutegravir in adolescents and adults of childbearing potential to exclude use of dolutegravir during the first trimester of pregnancy.
Advise adolescents and adults of childbearing potential to consistently use effective contraception.
General: As a fixed combination, Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should not be administered concomitantly with other medicinal products containing any of the same active components, Dolutegravir, lamivudine or tenofovir disoproxil fumarate. Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should not be administered concomitantly with other cytidine analogues such as emtricitabine. (see Interactions). Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should not be administered concomitantly with adefovir dipivoxil.
Transmission of HIV: Treatment with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets has not been shown to eliminate the risk of transmission of HIV infection by sexual contact or by blood transfer, although the risk may be reduced. Patients should continue to use appropriate precautions to prevent transmission of HIV.
Liver disease: The safety and pharmacokinetics of Dolutegravir has not been investigated in patients with severe liver disease. Therefore Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should only be used in this group of patients if the benefits are considered to outweigh the risks, and with close safety monitoring.
Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection: Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.
Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with HBV.
Lamivudine and tenofovir disoproxil fumarate are also active against HBV. Therefore, discontinuation of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets must be closely monitored with both clinical and laboratory follow-up for at least four months after stopping treatment with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets. If appropriate, resumption of specific anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see Adverse Reactions).
Integrase class resistance of particular concern: The decision to use Dolutegravir in the presence of integrase class resistance should take into account that the activity of Dolutegravir is considerably compromised for viral strains harbouring Q148+≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I (see Pharmacology: Pharmacodynamics under Actions). To what extent Dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain (see Pharmacology: Pharmacokinetics under Actions).
Hypersensitivity reactions: Hypersensitivity reactions have been reported with Dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and other suspect agents should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with Dolutegravir or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction.
Renal function: Tenofovir is primarily excreted by the kidneys through a combination of glomerular filtration and active tubular secretion. Thus, clearance is decreased in patients with impaired renal function. There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with impaired renal function (< 80 ml/min). In such patients, Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should only be used if the potential benefits of treatment are considered to outweigh the potential risks.
In patients with moderate to severe renal impairment, the plasma half-life of lamivudine is increased due to decreased clearance. Decreased doses are recommended for patients with creatinine clearance <50 ml/min.
The use of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets is not recommended in patients with creatinine clearance < 50 ml/min, since appropriate dose reductions cannot be achieved with the combination tablet (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see Interactions). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets. Routine monitoring of calculated creatinine clearance and serum phosphate should be performed in patients at risk for renal impairment.
In patients receiving tenofovir disoproxil fumarate renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations, if serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance decreases below 50 ml/min (see Proximal tubulopathy under Adverse Reactions).
Consideration should also be given to interrupting treatment with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets in patients whose creatinine clearance falls below 50 ml/min or whose serum phosphate decreases below 1.0 mg/dl (0.32 mmol/l).
Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should be avoided with concurrent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents is unavoidable, renal function should be monitored weekly.
Bone effects: In a controlled clinical study decreases in bone mineral density of spine and changes in bone biomarkers from baseline were observed in both treatment groups, but were significantly greater in the tenofovir disoproxil fumarate treatment group than in the comparator group treated with stavudine (each in combination with lamivudine and efavirenz) at 144 weeks. Decreases in bone mineral density of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.
Tenofovir was studied in HIV-1 infected paediatric subjects 12 years of age and older. Under normal circumstances, bone mineral density increases rapidly in this age group. In this study, the mean rate of bone gain was less in the tenofovir-treated group compared to the placebo group. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in tenofovir-treated paediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults. Due to the possible effects of tenofovir on bone metabolism, Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should only be used in adolescents under the age of 18 if the benefits are considered to exceed the risk (see also Adverse Reactions).
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see Adverse Reactions). If bone abnormalities are suspected then appropriate consultation should be obtained.
Lactic acidosis: Lactic acidosis is a rare but severe, potentially life-threatening complication associated with use of nucleoside reverse transcriptase inhibitors (NRTI). Several other agents of this class are known to cause lactic acidosis. Preclinical and clinical data suggest that the risk of occurrence of lactic acidosis, considered a putative class effect of nucleoside analogues, is very low for tenofovir disoproxil fumarate and lamivudine. However, this risk cannot be excluded. Lactic acidosis may occur after a few to several months of NRTI treatment. Patients with hyperlactataemia may be asymptomatic, critically ill, or may have non-specific symptoms such as dyspnoea, fatigue, nausea, vomiting, diarrhoea and abdominal pain. Risk factors for NRTI-related lactic acidosis include female gender and obesity. Patients at increased risk should be closely monitored clinically. Screening for hyperlactataemia in asymptomatic patients treated with NRTIs, however, is not recommended. Symptomatic patients usually have levels > 5 mmol/l and require discontinuation of all NRTIs. Lactic acid levels > 10 mmol/l usually are a medical emergency.
Lipodystrophy and metabolic disorders: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV-infected patients. Whereas for some other antiretrovirals there is considerable evidence for this adverse reaction, the evidence for tenofovir, lamivudine and Dolutegravir as causative agents is weak; indeed switching from a thymidine analogue (e.g. stavudine) to tenofovir has been shown to increase limb fat in patients with lipoatrophy. A higher risk of lipodystrophy has been associated e.g. with older age of the patient, longer duration of antiretroviral therapy and related metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Measurement of fasting serum lipids and blood glucose as well as appropriate management of lipid disorders should be considered (see Adverse Reactions).
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see Adverse Reactions).
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated, in vitro and in vivo, to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Pancreatitis: Treatment with Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur (see Adverse Reactions).
Opportunistic infections: Patients receiving antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians or health care providers experienced in the treatment of HIV infection.
Drug interactions: Factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. This includes co-administration with medicinal products that reduce dolutegravir exposure (e.g. magnesium/aluminium-containing antacid, iron and calcium supplements, multivitamins and inducing agents, etravirine (without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John's wort and certain antiepileptic drugs) (see Interactions).
Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control (see Interactions). Metformin is eliminated renally and therefore it is of importance to monitor renal function when co-treated with dolutegravir. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45-59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered.
Co-administration of Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets and didanosine is not recommended since exposure to didanosine is significantly increased following co-administration with tenofovir disoproxil fumarate (see Interactions).
Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Excipients: Dolutegravir (as sodium)/Lamivudine/Tenofovir Disoproxil Fumarate 50mg/300mg/300mg Tablets contain 136.00 mg of lactose per maximum recommended daily dose. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on the Ability to Drive and Use Machine: There have been no studies to investigate the effect of dolutegravir on driving performance or the ability to operate machines. However, patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical4 status of the patient and the adverse reaction profile of dolutegravir should be borne in mind when considering the patient's ability to drive or operate machinery.
Use in the Elderly: Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with tenofovir disoproxil fumarate
