Envuteg 300 mg. 25 mg. 50 mg Tablets

ENVUTEG is indicated for use alone as a complete regimen for the treatment of human immunodeficiency virus type I (HIV-1) infection in adults and children weighing at least 40 kg.

Limitation of use: ENVUTEG alone is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of ENVUTEG is insufficient in these subpopulations. See the full prescribing information for dolutegravir.

Posology

Therapy should be initiated by a medical practitioner experienced in the management of HIV infection.

Testing prior to initiation and during treatment with ENVUTEG

• Perform pregnancy testing before initiation of ENVUTEG in adolescents and adults of childbearing potential (see section 4.4).
• Prior to or when initiating ENVUTEG, test patients for hepatitis B virus (HBV) infection (see section 4.4).
• Prior to initiation and during treatment with ENVUTEG, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus (see section 4.4).

Recommended dosage

ENVUTEG is a fixed-dose combination medicine containing 50 mg of dolutegravir, 300 mg of lamivudine (3TC), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage regimen of ENVUTEG in adults and children weighing at least 40 kg is one tablet once daily orally with or without food.

Special populations

Dosage adjustment for special population

Because ENVUTEG is a fixed-dose combination formulation and cannot be dose adjusted, it is not recommended in patients requiring dosage adjustment.

Paediatric use

ENVUTEG tablets should only be administered to paediatric patients with a body weight of at least 40 kg because they are a fixed-dose combination that cannot be adjusted. The safety and efficacy have been established for the individual components in this weight group.

Elderly use

Clinical trials of individual components of ENVUTEG did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Caution should be exercised in the administration of ENVUTEG in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicine therapy (see section 5.1).

Renal impairment

ENVUTEG tablets are not recommended for patients with severe renal impairment (estimated creatinine clearance below 30 mL) because ENVUTEG is a fixed-dose combination, and the dosage of the individual components cannot be adjusted. No dosage adjustment of ENVUTEG tablets is recommended in patients with mild or moderate renal impairment (estimated creatinine clearance greater than or equal to 30 mL per minute).

Hepatic Impairment

No dosage adjustment of ENVUTEG tablets is recommended in patients with mild (Child - Pugh Class A) hepatic impairment. The effect of moderate or severe hepatic impairment (Child-Pugh Class B or C) on the pharmacokinetics of dolutegravir, lamivudine and tenofovir alafenamide has not been studied. Therefore, ENVUTEG tablets are not recommended for use in patients with severe hepatic impairment (see sections 4.3 and 5.1).

• Known hypersensitivity to lamivudine, tenofovir alafenamide, dolutegravir, or any of the excipients of ENVUTEG (listed in section 6.1).
• Patients receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• Co-administration with metformin, adefovir, pilsicainide or didanosine.
• Woman of childbearing age.
• Patients younger than 18 years.
• Moderate and severe hepatic impairment.
• Uncontrolled renal failure.

Metabolic abnormalities

Combination antiretroviral therapy, including ENVUTEG has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.

Lipodystrophy

Combination antiretroviral therapy, including ENVUTEG, has also been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting and breast enlargement in HIV patients. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicine related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Fasting serum lipids and blood glucose levels should be monitored. Lipid disorders should be managed as clinically appropriate. Patients with evidence of lipodystrophy should also have a thorough cardiovascular risk assessment.

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, atypical mycobacterial infections, cytomegalovirus retinitis, pneumocystis jerovecii and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued, and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (cART) including components of ENVUTEG. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness, or difficulty in movement.

Mitochondrial dysfunction

Nucleoside and nucleotide analogues as contained in ENVUTEG 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), metabolic disorders (hyperlactataemia, hyperlipidaemia). 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 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 of symptoms.

Severe acute exacerbation of hepatitis B in patients with HBV infection

All patients should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating ENVUTEG. Discontinuation of anti-HBV therapy, including 3TC and TAF, two components of ENVUTEG, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue dolutegravir, lamivudine and tenofovir alafenamide tablets should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Hypersensitivity reactions

Hypersensitivity reactions have been reported and were characterised by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1 % of subjects receiving dolutegravir in Phase 3 clinical trials. Discontinue ENVUTEG and other suspect medicines 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 or peeling of the skin, oral blisters or lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with ENVUTEG or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.

Hepatotoxicity

Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of ENVUTEG (see section 4.8). In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with combination abacavir, dolutegravir, and lamivudine. Monitoring for hepatotoxicity is recommended.

Embryo-foetal toxicity

Preliminary data from an observational study showed that dolutegravir, a component of ENVUTEG, 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 ENVUTEG at the time of conception through the first trimester of pregnancy (see section 4.6). If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on ENVUTEG, if possible, switch to an alternative regimen. Perform pregnancy testing before initiation of ENVUTEG in adolescents and adults of childbearing potential to exclude use of ENVUTEG during the first trimester of pregnancy (see section 4.6). Advise adolescents and adults of childbearing potential to consistently use effective contraception (see section 4.6).

Risk of adverse reactions or loss of virologic response due to interactions

The concomitant use of ENVUTEG and other medicines may result in known or potentially significant interactions, some of which may lead to (see sections 4.3 and 4.5):

• Loss of therapeutic effect of ENVUTEG and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of concomitant medicines.

See Table 4 for steps to prevent or manage these possible and known significant medicine interactions, including dosing recommendations. Consider the potential for medicine interactions prior to and during therapy with ENVUTEG; review concomitant medicines during therapy with ENVUTEG; and monitor for the adverse reactions associated with the concomitant medicines.

New onset or worsening renal impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of TAF with emtricitabine (FTC), elvitegravir (EVG), and cobicistat (COBI), there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT), and renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1 % of participants with eGFRs greater than 50 mL/minute who received TAF. ENVUTEG is not recommended in patients with estimated creatinine clearance below 50 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic medicines including non-steroidal anti-inflammatory medicines are at increased risk of developing renal-related adverse reactions. Prior to initiation and during treatment with ENVUTEG, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue ENVUTEG in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Lactic acidosis and severe hepatomegaly with steatosis

Use of ENVUTEG can result in potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue, and weight loss. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/L) and the serum bicarbonate and respond as follows:

• Lactate 2 u2013 5 mmol/L with minimum symptoms: Switch to medicines that are less likely to cause lactic acidosis.
• Lactate 5 u2013 10 mmol/L with symptoms and/or with reduced standard bicarbonate: Stop NRTIs and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism.
• Lactate > 10 mmol/L: STOP all therapy (80 % mortality).

The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering ENVUTEG to patients with known risk factors for liver disease. Treatment with ENVUTEG should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Pancreatitis

Pancreatitis has been observed in some patients receiving ENVUTEG. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of ENVUTEG until diagnosis of pancreatitis is excluded.

Opportunistic infections

Patients receiving ENVUTEG should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

The risk of HIV transmission to others

Patients should be advised that current antiretroviral therapy, including ENVUTEG, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Bone mineral density

During therapy with ENVUTEG, assessment of bone mineral density (BMD) should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. The effect of supplementation with calcium and vitamin D was not studied. If bone abnormalities are suspected then appropriate consultation should be obtained.

Bone mineral density effects:

In the pooled analysis of two 48-week trials of antiretroviral treatment-nau00efve HIV-1 infected adult subjects, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 u22121,30 % with FTC+TAF with EVG+COBI at the lumbar spine and u22120,66 % at the total hip. BMD declines of 5 % or greater at the lumbar spine were experienced by 10 % of FTC+TAF with EVG+COBI subjects. BMD declines of 7 % or greater at the femoral neck were experienced by 7 % of FTC+TAF with EVG+COBI subjects. The long-term clinical significance of these BMD changes is not known.

In 799 virologically-suppressed TDF-treated adult subjects that switched to FTC+TAF with EVG+COBI, at Week 48 mean BMD increased (1,86 % lumbar spine, 1,95 % total hip). BMD declines of 5 % or greater at the lumbar spine were experienced by 1 % of FTC+TAF with EVG+COBI subjects. BMD declines of 7 % or greater at the femoral neck were experienced by 1 % of FTC+TAF with EVG+COBI subjects.

Paediatric use

Safety and effectiveness in paediatric patients and patients < 18 years of age have not been established.

Elderly use

Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Excipient warnings

Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, total lactase deficiency, or glucose-galactose malabsorption or fructose intolerance should not take ENVUTEG.

Effect of dolutegravir on the pharmacokinetics of other medicines

Dolutegravir

In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC 50 = 1,93 microM) and multidrug and toxin extrusion transporter (MATE)l (IC 50 = 6,34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATEl. Dolutegravir may increase plasma concentrations of medicines eliminated via OCT2 or MATEl (dofetilide and metformin, Table 1) (see section 4.3).

In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT)1 (IC 50 = 2,12 microM) and OAT3 (IC 50 = 1,97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OATl and OAT3.

In vitro, dolutegravir did not inhibit (IC 50 greater than 50 microM) the following: Cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2Cl9, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP) 1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of interaction trials, dolutegravir is not expected to affect the pharmacokinetics of medicines that are substrates of these enzymes or transporters.

Effect of other medicines on the pharmacokinetics of dolutegravir, 3TC, or TAF

Dolutegravir

Dolutegravir is metabolised by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Medicines that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Co-administration of dolutegravir and other medicines that inhibit these enzymes may increase dolutegravir plasma concentration. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by co-administration of lopinavir/ritonavir or darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir (Table 1) (see section 5.1).

In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.

TAF

TAF is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Medicines that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption (see Table 6). Medicines that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of ENVUTEG and development of resistance. Co-administration of ENVUTEG with other medicines that inhibit P-gp and BCRP may increase the absorption and plasma concentration of TAF. TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. TAF is a weak inhibitor of CYP3A in vitro. TAF is not an inhibitor or inducer of CYP3A in vivo.

Significant interactions for dolutegravir, 3TC, or TAF

There were no interaction trials conducted with fixed-dose ENVUTEG. ENVUTEG is intended as a complete regimen. Dolutegravir and TAF

Table 1 provides clinical recommendations as a result of interactions with dolutegravir and/or TAF. These recommendations are based on either interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy (see section 5.1).

Women of childbearing potential /Contraception in males and females

Pregnancy testing

Perform pregnancy testing in adolescents and adults of childbearing potential before initiation of ENVUTEG.

Contraception

Adolescents and adults of childbearing potential should avoid use of ENVUTEG at the time of conception through the first trimester of pregnancy because of the potential risk of neural tube defects.

Advise adolescents and adults of childbearing potential who are taking ENVUTEG to consistently use effective contraception.

Pregnancy

ENVUTEG is contraindicated in pregnancy and lactation. Neural tube defects have been noted in an observational study in humans, where DTG-based regimens were used at the time of conception and early pregnancy (see section 4.3). Tenofovir, dolutegravir and lamivudine were shown to cross the placenta in reproductive toxicity studies in animals. Late onset neurological disorders, including seizures, have been observed in children who have been exposed to nucleoside analogues such as tenofovir and lamivudine (see Mitochondrial Dysfunction under section 4.4). ENVUTEG should not be prescribed in women who plan to become pregnant. Woman of childbearing age should not use ENVUTEG unless they are reliably using highly effective contraception. Treatment with ENVUTEG should not be initiated without a medically supervised negative pregnancy test. This test should be repeated at frequent intervals during treatment with ENVUTEG, and especially in the event that pregnancy is suspected.

If there are plans to become pregnant or if pregnancy is confirmed while on dolutegravir during the first trimester, the patient must be switched to an alternative regimen.

Breastfeeding

Mothers breastfeeding their infants should not use ENVUTEG. Lamivudine is excreted in human milk at similar concentrations to those found in serum; tenofovir is excreted in breast milk and it is not known whether dolutegravir is excreted in human milk.

ENVUTEG causes dizziness and fatigue which may affect the ability to drive and use machines. Patients should ensure that they do not engage in driving or using machines until they know how ENVUTEG affects them.

Adverse reactions identified in an analysis of pooled data from clinical studies are listed below by system organ class and by frequency.

Tabulated list of adverse reactions

Blood and lymphatic system disorders

• Frequent Neutropenia.
• Frequency unknown Anaemia.

Immune system disorders

• Frequent Allergic reaction, including angioedema.
• Less frequent Hypersensitivity, Immune Reconstitution Syndrome (see section 4.4).
• Frequent Hypertriglyceridaemia, hyperglycaemia.

Metabolism and nutrition disorders

• Frequency unknown Hypophosphataemia, lactic acidosis, hypokalaemia.

Psychiatric disorders

• Frequent Insomnia, abnormal dreams, suicidal ideation, attempt, behaviour, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness.

Nervous system disorders

• Frequent Headache, dizziness.

Respiratory, thoracic and mediastinal disorders

• Frequent Dyspnoea.

Gastrointestinal disorders

• Frequent Nausea, diarrhoea, vomiting, flatulence, upper abdominal pain, dyspepsia, amylase elevation, lipase elevation.
• Less frequent Abdominal pain, abdominal discomfort.
• Frequency unknown Pancreatitis.

Hepatobiliary disorders

• Frequent Hyperbilirubinaemia, increased liver enzymes (including increased AST, increased ALT and/or gamma GT).
• Less frequent Hepatitis.
• Frequency unknown Hepatic steatosis.

Skin and subcutaneous tissue disorders

• Frequent Rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, skin discolouration.

Musculoskeletal, connective tissue and bone disorders

• Frequent Creatine kinase elevation, myositis, arthralgia.
• Frequency unknown Myopathy, osteomalacia, rhabdomyolysis, muscular weakness.

Renal and urinary disorders

• Frequent Renal impairment.
• Frequency unknown Increased creatinine, renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, nephrogenic diabetes insipidus, proteinuria, acute tubular necrosis, polyuria, interstitial nephritis.

General disorders and administration site conditions

• Frequent Fatigue, pain, asthenia.

Description of selected adverse reactions

Changes in laboratory chemistries

Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 48 weeks. In treatment-nau00efve patients a mean change from baseline of 9,96 mmol/L (range: -53 mmol/L to 54,8 mmol/L) was observed after 48 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced patients. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.

Small increases in total bilirubin (without clinical jaundice) were observed with dolutegravir. These changes are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1).

Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy.

Hepatitis B and/or hepatitis C virus co-infection

In Phase 3 trials, subjects with hepatitis B and/or C virus co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving dolutegravir were observed in 18 % vs. 3 % with the 50 mg once-daily dose and 13 % vs. 8 % with the 50 mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C at the start of therapy with dolutegravir, particularly in the setting where anti-hepatitis therapy was withdrawn (see section 4.4).

Not for use in subjects < 40 kg.

Post-marketing experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post-marketing use.

Psychiatric disorders: Frequency unknown: Anxiety.

Hepatobiliary disorders: Frequency unknown: Acute liver failure, hepatotoxicity.

Musculoskeletal disorders: Frequency unknown: Arthralgia, myalgia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

There is no known specific treatment for overdose with dolutegravir, lamivudine and tenofovir alafenamide tablets. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.

Dolutegravir: As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

3TC: Because a negligible amount of 3TC was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a 3TC overdose event.

TAF: Limited clinical experience is available at doses higher than the recommended dose of TAF. A single dose of 125 mg TAF (5 times the TAF dose in dolutegravir, lamivudine and tenofovir alafenamide tablets) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54 %.