Altaeda Tablet

ALTAEDA is indicated:

• for use alone as a complete regimen for the treatment of human immunodeficiency virus - 1 (HIV-1) infection in adults and paediatric patients weighing at least 40 kg.

ALTAEDA therapy should be initiated by a medical practitioner experienced in the management of HIV infection. Prior to initiation of ALTAEDA, patients should be tested for hepatitis B virus infection (see section 4.4). Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating ALTAEDA therapy and should be monitored during therapy in all patients (see section 4.4). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in all individuals.

Posology:

Treatment of HIV-1 infection in adults and paediatric patients weighing at least 40 kg

The dose of ALTAEDA is one tablet once daily taken with or without food. (See section 4.5)

Special Populations

Elderly patients

Dolutegravir Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure. Pharmacokinetic data for dolutegravir in subjects of > 65 years old are limited. In general, caution should be exercised in the administration of dolutegravir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicine therapy. (See section 4.4 and 4.5)

Emtricitabine and Tenofovir

Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly. (> 65 years). (See section 4.4).

Clinical studies of emtricitabine and tenofovir disoproxil fumarate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be done with caution, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicine therapy. In clinical trials, 80 subjects out of the 97 subjects enrolled aged 65 years and over received emtricitabine (FTC), tenofovir alafenamide (TAF), elvitegravir (EVG) and cobicistat (COBI). No differences in safety or efficacy have been observed between elderly subjects and adults between 18 and less than 65 years of age.

Renal Impairment

ALTAEDA tablets are not recommended for patients with severe renal impairment (estimated creatinine clearance below 30 mL per min) because ALTAEDA tablets are a fixed-dose combination, and the dosage of the individual components cannot be adjusted. No dosage adjustment of ALTAEDA 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

Dolutegravir

No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh grade A). ALTAEDA is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).

Tenofovir

The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir disoproxil fumarate have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. No change in tenofovir disoproxil fumarate dosing is required in patients with hepatic impairment.

Emtricitabine and Tenofovir

The pharmacokinetics of tenofovir and emtricitabine or emtricitabine has not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited. No dosage adjustment of dolutegravir, emtricitabine and tenofovir alafenamide tablets is recommended in patients with mild (Child-Pugh Class A) hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of dolutegravir, emtricitabine and tenofovir alafenamide has not been studied. Therefore, ALTAEDA tablets are not recommended for use in patients with moderate or severe hepatic impairment (see section 4.3).

Paediatric Population

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

Method of administration

ALTAEDA film coated tablets is a fixed dose combination that cannot be adjusted. ALTAEDA is taken orally with or without food.

• ALTAEDA is contraindicated in patients with previously demonstrated hypersensitivity to dolutegravir, emtricitabine and tenofovir alafenamide or any of the components of ALTAEDA (see section 6.1).
• ALTAEDA is contraindicated in combination with dofetilide. (See section 4.5)
• ALTAEDA is contraindicated in combination with pilsicainide. (See section 4.5)
• ALTAEDA is contraindicated in patients taking metformin (See section 4.5)
• ALTAEDA should not be co-administered with other tenofovir-containing medicines, or with other emtricitabine-containing medicines.
• ALTAEDA should not be administered with lamivudine-containing medicines due to similarities between emtricitabine and lamivudine.
• ALTAEDA is contraindicated in moderate and severe hepatic impairment.
• ALTAEDA is contraindicated in severe renal impairment, creatinine clearance < 30 mL/min (renal impairment).
• Antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation
• ALTAEDA is contraindicated in Pregnancy and lactation.

Hypersensitivity reactions

Hypersensitivity reactions have been reported with integrase inhibitors, including dolutegravir. and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue ALTAEDA 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, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia and angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping treatment with ALTAEDA or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.

Risk of Adverse Reactions or Loss of Virologic Response Due to Interactions

The concomitant use of ALTAEDA tablets and other medicines may result in known or potentially significant interactions, some of which may lead to loss of therapeutic effect of ALTAEDA tablets and possible development of resistance and possible clinically significant adverse reactions from greater exposures of concomitant medicine (see section 4.3 and section 4.8). Consider the potential for interactions prior to and during therapy with ALTAEDA tablets; review concomitant medicines during therapy with ALTAEDA tablets; and monitor for the adverse reactions associated with the concomitant medicines.

Lipodystrophy and metabolic abnormalities

Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Lactic acidosis/severe hepatomegaly with steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including emtricitabine, a component of ALTAEDA tablets, and tenofovir disoproxil fumurate, another prodrug of tenofovir, alone or in combination with other antiretrovirals.

WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Tenofovir alafenamide, one component of ALTAEDA tablets, is approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued medicines containing tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of ALTAEDA tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue ALTAEDA tablets. If appropriate, initiation of anti-hepatitis B therapy may be warranted. This is caused by mitochondrial dysfunction. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues such as ALTAEDA to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with ALTAEDA film coated tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 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 to 5 mmol/L with minimum symptoms: Switch to medicines that are less likely to cause lactic acidosis.
• Lactate 5 to 10 mmol/L with symptoms and/or with reduced standard bicarbonate: Stop ALTAEDA 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 ALTAEDA to patients with known risk factors for liver disease. Treatment with ALTAEDA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Mitochondrial dysfunction

Nucleoside and nucleotide analogues such as emtricitabine and tenofovir disoproxil fumarate 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 post-natally to nucleoside analogues, these have predominantly concerned treatment with regimens containing zidovudine and may be the case with ALTAEDA. Apart from lactic acidosis/hyperlactataemia (see above), other manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), and peripheral neuropathy. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and nucleotide analogues, even HIV negative infants/children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs and symptoms.

Immune Reconstitution Syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections 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 ART and occurs more commonly in patients with low CD4 counts. Relevant examples are tuberculosis, cytomegalovirus retinitis, generalised and/or focal atypical mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Auto-immune disorders (such as Graves' disease, polymyositis 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. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C coinfected patients at the start of dolutegravir therapy. Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C coinfection. 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 coinfected patients (see section 4.8).

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). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Hepatoxicity

The unbound fraction of dolutegravir in the blood is doubled in patients with moderate hepatic impairment. Dolutegravir is not recommended in patients with moderate or hepatic impairment (see section 4.3) Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of dolutegravir, emtricitabine and tenofovir alafenamide tablets. 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. Medicine-induced liver injury leading to liver transplant has been reported with fixed-dose abacavir, dolutegravir, and lamivudine. Monitoring for hepatotoxicity is recommended. The use of emtricitabine and tenofovir disoproxil fumarate can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of emtricitabine and tenofovir disoproxil fumarate has not been established in patients with significant underlying liver disorders/diseases. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored. If there is evidence of worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.

Coinfection with Hepatitis B or C

Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy.

Dolutegravir

In Phase III studies, patients with hepatitis B and/or C coinfection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients coinfected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C coinfection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C coinfection for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C coinfection at the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn. This may occur with ALTAEDA as dolutegravir is a component thereof.

Emtricitabine and Tenofovir

Tenofovir alafenamide, one component of ALTAEDA film coated tablets, is approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing tenofovir disoproxil fumarate (TDF) or emtricitabine and may occur with ALTAEDA film coated tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients coinfected with HIV-1 and HBV who discontinue emtricitabine or tenofovir, which are components of ALTAEDA film coated tablets. 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.

Opportunistic infections

Patients receiving ALTAEDA may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by medical practitioners experienced in the treatment of these associated HIV diseases. Regular monitoring of viral load and CD4 counts needs to be done.

Transmission of infection

Patients should be advised that current antiretroviral therapy, including ALTAEDA, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken. ALTAEDA are not indicated for use as preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.

Pancreatitis

Pancreatitis has been observed in some patients receiving emtricitabine and tenofovir disoproxil fumarate and may occur in ALTAEDA. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting, or elevated biochemical markers. Discontinue use of ALTAEDA until diagnosis of pancreatitis is excluded.

Renal impairment

Emtricitabine and tenofovir disoproxil fumarate are principally eliminated by the kidney. In patients with moderate to severe renal impairment, the terminal half-life of tenofovir disoproxil fumarate is increased due to decreased clearance. Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating ALTAEDA film coated tablets therapy. All patients should be monitored during therapy with ALTAEDA. 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 (see section 4.3). Calculated creatinine clearance and serum phosphorus should be routinely monitored in patients with chronic kidney disease because these patients are at greater risk of developing Fanconi syndrome on tenofovir prodrugs (see section 4.3). Discontinue ALTAEDA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. ALTAEDA should be avoided with concurrent or recent use of nephrotoxic medicines including non-steroidal anti-inflammatory medicines are at increased risk of developing renal-related adverse reactions. ALTAEDA should not be administered to patients with creatinine clearance below 50 mL/min or patients requiring haemodialysis (see section 4.3).

Renal impairment in adults can be determined using the South African Renal Society modification of the Cockroft and Gault formula for calculation of creatinine clearance: Use the eCrCl mL/min=[(140-age) x weight (kg) x 0.85 (if female)] divided by serum creatinine (micromoles/litre). Renal impairment is classified accordingly:

• mild renal impairment: CrCl u2265 50-80 mL/min
• moderate renal impairment CrCl > 30-50 mL/min
• severe renal impairment CrCl < 30 mL/min.

Bone effects

Bone mineral density monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Tenofovir combination therapy is associated with decreased bone mineral density. During therapy with emtricitabine and tenofovir disoproxil fumarate 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, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained. 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 or renal function in at-risk patients. These manifest as bone pain or pain in extremities and which may contribute to fractures, and have been reported in association with the use of tenofovir disoproxil fumarate and may occur in ALTAEDA (see section 4.8).

Dolutegravir

Caution should be given to co-administering medications (prescription and non-prescription) that may change the exposure of dolutegravir which is a component of ALTAEDA or medications that may have their exposure changed by dolutegravir, which is a component of ALTAEDA (see section 4.3). Dolutegravir should not be co-administered with polyvalent cation-containing antacids. Dolutegravir is recommended to be administered 2 hours before or 6 hours after these agents.

Emtricitabine or tenofovir

ALTAEDA should not be co-administered with other medicines containing emtricitabine or tenofovir (see section 4.3).

Due to similarities between emtricitabine and lamivudine, ALTAEDA should not be co-administered with other medicines containing lamivudine, including lamivudine and zidovudine co-formulation, lamivudine for HIV, lamivudine for HBV, abacavir sulfate and lamivudine co-formulation or abacavir sulfate, lamivudine and zidovudine co-formulation (see section 4.3).

Co-administration of didanosine buffered tablet formulation with ALTAEDA should be under fasted conditions. Co-administration of ALTAEDA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine associated adverse events (see section 4.8).

Patients receiving atazanavir and lopinavir/ritonavir and ALTAEDA should be monitored for ALTAEDA-associated adverse events. ALTAEDA should be discontinued in patients who develop ALTAEDA-associated adverse events (see section 4.8).

Tenofovir decreases the AUC and C min of atazanavir. When co-administered with ALTAEDA, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be co-administered with ALTAEDA. Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of ALTAEDA with medicines that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated medicines. Some examples include, but are not limited to adefovir dipivoxil, cidofovir, aciclovir, valaciclovir, ganciclovir and valganciclovir.

The concomitant use of dolutegravir, emtricitabine and tenofovir alafenamide tablets and other medicines may result in known or potentially significant medicine interactions, some of which may lead to (see section 4.3):

• Loss of therapeutic effect of dolutegravir, emtricitabine and tenofovir alafenamide tablets and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of concomitant medicines.

For concomitant medicines for which the interaction can be mitigated, please see Table 6 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 dolutegravir, emtricitabine and tenofovir alafenamide tablets; review concomitant medications during therapy with dolutegravir, emtricitabine and tenofovir alafenamide tablets; and monitor for the adverse reactions associated with the concomitant medicines.

Dolutegravir, emtricitabine and tenofovir alafenamide tablets ALTAEDA alone are not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in ALTAEDA film coated tablets is insufficient in these subpopulations. Dolutegravir, emtricitabine and tenofovir alafenamide tablets ALTAEDA are not indicated for use as preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.

Women of childbearing potential

A reliable method of contraception should be used to avoid pregnancy while taking ALTAEDA.

Pregnancy

ALTAEDA is contraindicated in pregnancy (see section 4.3). A urine pregnancy test should be carried out within 24 hours before commencing treatment with dolutegravir containing medicines. Once treatment has started, pregnancy testing should be repeated every 4 weeks. Pregnancy testing and counselling should be performed if a patient misses her periods or if there are any abnormalities in the menstrual bleeding. Nucleotide analogues, as in ALTAEDA may impact on mitochondrial function to a variable degree. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or post-natally to nucleotide analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) peripheral neuropathy and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is unknown. These findings should be considered and investigated for any baby/ infant/ child exposed in utero to nucleos(t)ide analogues who present with severe clinical findings of unknown aetiology, particularly neurologic findings.

Breastfeeding

HIV infected women should not breastfeed their infants in order to avoid transmission of HIV. It is expected that dolutegravir and emtricitabine, which are components of ALTAEDA will be secreted into human milk. Breastfeeding while taking ALTAEDA is contraindicated. (See section 4.3)

Fertility

No fertility data is available for humans. No adverse effects on fertility and reproductive performance of male and female rats have been observed.

No studies on the effects of either ALTAEDA on the ability to drive and use machines have been performed. The clinical status of the patient and the adverse event profile of ALTAEDA should be borne in mind (see section 4.8). Dizziness has been reported during treatment with either tenofovir disoproxil fumarate and emtricitabine as well as tenofovir alafenamide fumarate and emtricitabine. Dizziness has also been reported with the use of dolutegravir. Therefore patients are advised not use machinery or drive whilst on treatment with ALTAEDA as ALTAEDA contains dolutegravir, emtricitabine and tenofovir alafenamide fumarate. (See section 4.8).

a) Summary of the safety profile

Serious adverse reaction may occur with the use of ALTAEDA and are listed below:

• Hepatotoxicity
• Hypersensitivity Reactions
• Severe Acute Exacerbation of Hepatitis B
• Immune Reconstitution Syndrome
• New Onset or Worsening Renal Impairment
• Lactic Acidosis and Severe Hepatomegaly with Steatosis

The most frequently reported adverse reactions are separated according to the individual component in ALTAEDA and is stated below.

Dolutegravir

The most frequent adverse reactions of moderate to severe intensity and incidence at least 2 % (in those receiving dolutegravir in any one adult trial) are insomnia, fatigue, and headache.

Emtricitabine and Tenofovir Alafenamide

Most common adverse reaction (incidence greater than or equal to 10 %, all grades) is nausea.

b) Structured listing summary of adverse reactions

List of adverse reactions The following adverse reactions are reported corresponding to: Frequent, Less Frequent and Frequency Unknown:

Undesirable effects as a result of all three components in ALTAEDA, Dolutegravir, Emtricitabine and Tenofovir alafenamide fumarate

Immune System Disorders

Less Frequent: Hypersensitivity, immune reconstitution syndrome

Psychiatric Disorders

Frequent: Insomnia

Less Frequent: 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

Gastrointestinal Disorders

Less Frequent: Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting.

Hepatobiliary disorders

Less Frequent: Hepatitis

Skin and Subcutaneous Tissue Disorders

Less Frequent: Pruritus

Musculoskeletal and connective tissue Disorders

Less Frequent: Myositis

Renal and urinary disorders

Less Frequent: Renal impairment

General disorders and administration site conditions

Frequent: Fatigue

Undesirable effects as a result of one component in ALTAEDA, Dolutegravir

Immune System Disorders

Less Frequent: Hypersensitivity, immune reconstitution syndrome

Psychiatric Disorders

Frequent: Insomnia

Frequency Unknown: Anxiety

Nervous System Disorders

Frequent: Headache, dizziness and abnormal dreams

Gastrointestinal Disorders

Frequent: Nausea, diarrhoea, vomiting, flatulence and upper abdominal pain

Less Frequent: Abdominal pain and abdominal discomfort

Hepatobiliary disorders

Less Frequent: Hepatitis

Frequency Unknown: Acute liver failure, hepatotoxicity

Skin and Subcutaneous Tissue Disorders

Frequent: Rash and pruritus

Frequency Unknown: Arthralgia, myalgia

General disorders and administration site conditions

Frequent: Fatigue

Undesirable effects as a result of two component in ALTAEDA, Emtricitabine and Tenofovir

Blood and lymphatic system disorders

Frequent: Neutropenia

Less Frequent: Anaemia

Immune System Disorders

Frequent: Allergic reaction including angioedema

Metabolism and nutrition disorders

Frequent: Hypertriglyceridemia and hyperglycaemia

Frequency Unknown: Hypophosphataemia, lactic acidosis and hypokalaemia

Psychiatric Disorders

Frequent: Insomnia and abnormal dreams

Nervous System Disorders

Frequent: Dizziness and headache

Respiratory, thoracic and mediastinal disorders

Frequent: Dyspnoea

Gastrointestinal Disorders

Frequent: Diarrhoea, nausea, vomiting, flatulence, abdominal pain, amylase elevation, lipase elevation

Less Frequent: Dyspepsia

Frequency Unknown: Pancreatitis

Hepatobiliary disorders

Frequent: Hyperbilirubinemia, increased liver enzymes (including increased AST, increased ALT and/or gamma GT)

Frequency Unknown: Hepatitis and hepatic steatosis

Skin and Subcutaneous Tissue Disorders

Frequent: Rash event (rash, maculopapular rash, vesiculobullous rash, pustular rash), skin discoloration

Less Frequent: Angioedema, pruritus and urticaria

Musculoskeletal and connective tissue Disorders

Frequent: Creatine kinase elevation

Less Frequent: Arthralgia

Frequency Unknown: Myopathy, osteomalacia (both associated with proximal renal tubulopathy), rhabdomyolysis, muscular weakness.

Renal and urinary disorders

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 (including acute cases)

General disorders and administration site conditions

Frequent: Pain, asthenia and fatigue

There is known specific treatment for overdose with ALTAEDA. In overdose, side effects can be precipitated and/or be of increased severity, the patient should be monitored, and standard supportive treatment applied as required (see section 4.8).

Dolutegravir

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

Emtricitabine (FTC)

Limited clinical experience is available at doses higher than the recommended dose of FTC. In one clinical pharmacology study, single doses of FTC 1200 mg (6 times the recommended dose of FTC) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known. Haemodialysis treatment removes approximately 30 % of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis.

Tenofovir Alafenamide (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 200 mg/25 mg fixed-dose combination emtricitabine and tenofovir alafenamide) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54 %.