Dolamvir 50 mg/300 mg Tablets

DOLAMVIR is a triple combination therapy which is indicated for the treatment of human immunodeficiency virus (HIV) infection in adults aged 18 years and older.

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

Adults: The dose of DOLAMVIR is one tablet taken orally, once daily, without regard to food.

Special Populations:

Renal impairment: Significantly increased exposure occurred when tenofovir, as in DOLAMVIR, was administered to patients with moderate to severe renal impairment (see section 4.3). The pharmacokinetics of tenofovir, as in DOLAMVIR, have not been evaluated in non-haemodialysis patients with creatinine clearance u02c2 80 mL/min); therefore, no dosing recommendations is available for these patients. For treatment-nau00efve and treatment-experienced patients the recommended dose of DOLAMVIR is one tablet once daily. DOLAMVIR is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3). DOLAMVIR is contraindicated in patients with renal impairment with creatinine clearance less than 80 mL/min. Rifampicin decreases the blood levels of dolutegravir. A supplementary dose dolutegravir should be given in patients taking DOLAMVIR. Paediatric Population: DOLAMVIR is not recommended for use in patients younger than 18 years of age.

Method of administration: For oral use.

• Hypersensitivity reaction to dolutegravir, lamivudine or tenofovir disoproxil fumarate or to any of the excipients listed in section 6.1.
• Impairment of renal function (see section 4.4).
• Pregnancy and lactation (see section 4.6).
• Women of child-bearing age not using highly effective contraception.
• Concomitant use with adefovir dipivoxil.
• Co-administration with dofetilide and pilsicainide.
• Co-administration with didanosine.
• Co-administration with metformin.
• Patients younger than 18 years of age.
• Moderate and severe hepatic impairment.

Safety and efficacy of the individual active ingredients in various antiretroviral combination regimens with similar dosages as contained in DOLAMVIR have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed-drug combination as in DOLAMVIR for the treatment of HIV have not been established in clinical studies. The complete professional information of the other medicines used in combination should be consulted before initiation of therapy.

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

Lipodystrophy: Combination antiretroviral therapy, including DOLAMVIR 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. 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. Patients with evidence of lipodystrophy should 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, cytomegalovirus retinitis, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted, 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. Autoimmune disorders (such as Graves' disease) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

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.

Opportunistic infections: Patients receiving DOLAMVIR 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 DOLAMVIR, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Lactic acidosis / hyperlactataemia: Use of DOLAMVIR 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 - 5 mmol/L with minimum symptoms: switch to medicines that are less likely to cause lactic acidosis.
• Lactate 5 - 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 DOLAMVIR to patients with known risk factors for liver disease. Treatment with DOLAMVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

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 post-natally to nucleoside analogues. 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 sign and symptoms.

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

Liver disease: Use of DOLAMVIR can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of DOLAMVIR has not been established in patients with significant underlying liver disorders/diseases. In case of concomitant antiviral therapy for hepatitis B or C, please also consult the relevant professional information for these medicines. 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.

Patients with renal impairment: In patients with moderate to severe renal impairment, the terminal half-life of DOLAMVIR is increased due to decreased clearance. DOLAMVIR is a combination medicine and the dose of the individual components cannot be altered. Since DOLAMVIR is primarily eliminated by the kidneys, co-administration of DOLAMVIR with medicines that reduce renal function or compete for active tubular secretion may increase serum concentrations of DOLAMVIR and/or increase the concentrations of other renally eliminated medicines. Some examples include, but are not limited to adefovir dipivoxil, cidofovir, aciclovir, valaciclovir, ganciclovir and valganciclovir. DOLAMVIR is not recommended for patients with creatinine clearance < 80 mL/min or patients who require haemodialysis. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported in association with the use of tenofovir disoproxil fumarate in clinical practice. Careful monitoring of renal function (serum creatinine and serum phosphate) is therefore recommended before taking DOLAMVIR. Renal safety with tenofovir has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance < 80 mL/min).

Renal monitoring: It is recommended that renal function (creatinine clearance and serum phosphate) is assessed in all patients prior to initiating therapy with tenofovir disoproxil fumarate and that it is also monitored every four weeks during the first year of tenofovir disoproxil fumarate therapy, and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.

Co-administration and risk of renal toxicity: Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent of a nephrotoxic medicine (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic medicines is unavoidable, renal function should be monitored weekly. Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicines which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicine). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicines, which are secreted by the same renal pathway, including transport proteins hOAT 1 and 3 or MRP 4, might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicines which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly. DOLAMVIR should be avoided with concurrent or recent use of a nephrotoxic medicine. Patients at risk of, or with a history of renal dysfunction and patients receiving concomitant nephrotoxic substances should be carefully monitored for changes in serum creatinine and phosphorus.

K65R mutation: DOLAMVIR should be avoided in antiretroviral experienced patients with HIV-1 harbouring the K65R mutation.

Bone mineral density: Decreases in bone mineral density of the spine and changes in bone biomarkers from baseline are significantly greater with tenofovir disoproxil fumarate, as contained in DOLAMVIR. Decreases in bone mineral density of the hip are significantly greater. Clinically relevant bone fractures are reported. If bone abnormalities are suspected, then appropriate consultation should be obtained. Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk of osteopenia. DOLAMVIR may cause a reduction in bone mineral density. The effects of tenofovir disoproxil fumarate associated changes in bone mineral density on long-term bone health and future fracture risk are currently unknown. Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although 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. Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy.

Patients with HIV and hepatitis B or C virus co-infection: 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. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant professional information for these medicines.

Patients co-infected with HIV and HBV who discontinue DOLAMVIR should be closely monitored with both clinical and laboratory follow-up after stopping treatment. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Discontinuation of DOLAMVIR therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.

Exacerbations of hepatitis: Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy. Flares after treatment discontinuation: Acute exacerbations of hepatitis have been reported in patients after the discontinuation of hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of 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 flares are especially serious, and sometimes fatal in patients with decompensated liver disease.

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 DOLAMVIR 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, angioedema). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with DOLAMVIR, or other suspect medicines, after the onset of hypersensitivity may result in a life-threatening reaction.

Caution should be given to co-administering medications (prescription and non-prescription) that may change the exposure of dolutegravir or medications that may have their exposure changed by dolutegravir (see sections 4.3 and 4.5). The co-administration of dolutegravir with etravirine (ETR) is not recommended unless the patient is also receiving concomitant atazanavir + ritonavir (ATV + RTV), lopinavir + ritonavir (LPV + RTV) or darunavir + ritonavir (DRV + RTV) (see section 4.5). The recommended dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see section 4.5).

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 medicines (see section 4.5).

Metformin concentrations may be increased by dolutegravir. Metformin is contra-indicated in patients taking dolutegravir (see section 4.3).

Women of child-bearing potential: DOLAMVIR should not be prescribed in women who plan to become pregnant. Women of child-bearing age should not use DOLAMVIR unless they are reliably using highly effective contraception. Treatment with DOLAMVIR should not be initiated without a medically supervised negative pregnancy test. This test should be repeated at frequent intervals during treatment with DOLAMVIR, and especially in the event that pregnancy is suspected.

Pregnancy: DOLAMVIR 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 in utero such as tenofovir and lamivudine, (see section 4.4).

Breastfeeding: Mothers breastfeeding their infants should not use DOLAMVIR. 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.

Fertility: There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility.

Patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical status of the patient and the adverse reaction profile of DOLAMVIR should be borne in mind when considering the patient's ability to drive or operate machinery.

Table 5: Tabulated summary of adverse reactions associated with the individual components of DOLAMVIR.

Lamivudine

System organ class Frequent Less frequent Frequency unknown Blood and the lymphatic system disorders Neutropenia, anaemia, thrombocytopenia Pure red cell aplasia Endocrine disorders Hyperglycaemia Metabolism and nutrition disorders Hyperlactataemia Lactic acidosis, lipodystrophy (redistribution/ accumulation of body fat) (see section 4.4) Nervous system disorders Headache, insomnia Peripheral neuropathy (or paraesthesia), late onset neurological disorders in children exposed in utero Gastrointestinal disorders Nausea, vomiting, diarrhoea, upper abdominal pain or cramps, stomatitis Pancreatitis, elevations in serum amylase. Hepato-biliary disorders Transient rises in liver enzymes (AST, ALT) Hepato-biliary disorders Hepatic steatosis, hepatitis Skin and subcutaneous tissue disorders Rash, alopecia Anaphylaxis, urticaria, pruritus Musculoskeletal, connective tissue and bone disorders Arthralgia, muscle disorders Rhabdomyolysis, decrease in bone mineral density, osteopenia, fractures Myasthenia, CPK elevation General disorders and administration site conditions Fatigue, malaise, fever

Tenofovir disoproxil fumarate

System organ class Frequent Less frequent Frequency unknown Immune system disorders Allergic reactions, including angioedema Metabolism and nutrition disorders Hypophosphatemia, lactic acidosis, hypokalaemia Respiratory, thoracic and mediastinal disorders Dyspnoea Gastrointestinal disorders Anorexia, dyspepsia, flatulence, abdominal pain Pancreatitis, increased amylase Hepato-biliary disorders Increased liver enzymes, hepatitis Hepatic steatosis Skin and subcutaneous tissue disorders Rash Musculoskeletal, connective tissue and bone disorders Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), myasthenia, myopathy Renal and urinary disorders Renal insufficiency, renal failure, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus Interstitial nephritis (including acute cases), polyuria General disorders and administration site conditions Asthenia

Dolutegravir

System organ class Frequent Less frequent Frequency unknown Immune system disorder Hypersensitivity, immune reconstitution syndrome Endocrine disorders Hyperglycaemia Psychiatric disorders Insomnia, depression 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 Headache, dizziness, abnormal dreams Ear and labyrinth disorders Vertigo Gastrointestinal disorders Nausea, diarrhoea Vomiting, flatulence, upper abdominal pain Abdominal pain and discomfort Hepato-biliary disorders Transient rises in liver enzymes (AST, ALT) Hepatitis Skin and subcutaneous tissue disorders Rash, pruritus Musculoskeletal and connective tissue disorders Myositis Arthralgia, myalgia Renal and urinary disorders Renal impairment, increase in serum creatinine General disorders and administration site conditions Fatigue

Tenofovir disoproxil fumarate: If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 mL/min. The elimination of tenofovir by peritoneal dialysis has not been studied.

Lamivudine: Limited data are available on the consequences of ingestion of acute overdose in humans. If overdosage occurs, the patient should be monitored, and palliative supportive treatment applied as required.

Dolutegravir: Management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of dolutegravir as contained in DOLAMVIR. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.