Trilated 50 mg/300 mg Film-Coated Tablets

TRILATED is indicated for the treatment of HIV - 1 infection in adults aged 18 years and older.

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

Adults: The dose of TRILATED is one tablet taken orally, once a day, without regards to food.

Paediatric population: TRILATED is not recommended for use in patients younger than 18 years of age.

Dose adjustment for renal impairment Significantly increased exposure occurred when tenofovir, as in TRILATED, was administered to patients with moderate to severe renal impairment (see section 4.3). The pharmacokinetics of tenofovir, as in TRILATED, have not been evaluated in non-haemodialysis patients with creatinine clearance < 50 mL/min; therefore, no dosing recommendations is available for these patients. TRILATED is not suitable for use in patients with renal impairment with creatinine clearance less than 50 mL/min. Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking TRILATED.

Method of administration The dose of TRILATED is one tablet taken orally, once daily, without regard to food.

• TRILATED is contraindicated in patients with known hypersensitivity to dolutegravir, lamivudine, tenofovir disoproxil fumarate or any of the components of TRILATED.
• Uncontrolled renal failure (see section 4.4).
• Pregnancy and lactation (see section 4.6).
• Women of childbearing 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 TRILATED have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed-drug combination as in TRILATED for the treatment of HIV have not been established in clinical studies. The complete patient information leaflets of the other medicines used in combination should be consulted before initiation of therapy.

Depression (Including suicidal ideation) TRILATED can cause depression and suicidal ideation behaviour, particularly in patients with a pre-existing history or psychiatric illness. Patients should inform their medical practitioner if they notice any symptoms of depression during treatment.

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

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Lactic acidosis/severe hepatomegaly with steatosis Lactic acidosis, usually associated with hepatic steatosis, including fatal cases, has been reported with the use of nucleoside analogues, such as in TRILATED. Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal failure. Lactic acidosis generally occurs after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

The likelihood of interactions is low due to the limited metabolism as plasma protein binding and almost complete renal clearance. Zidovudine plasma levels are not significantly altered when co-administered with lamivudine. Zidovudine has no effect on the pharmacokinetics of lamivudine. Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicines are used concurrently. Lamivudine is therefore not recommended to be used in combination with zalcitabine.

Administration of trimethoprim, a constituent of co-trimoxazole causes an increase in lamivudine plasma levels. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of co-trimoxazole.

The possibility of interactions with other drugs administered concurrently should be considered, particularly when the main route is renal. No medicine interaction studies have been conducted using TRILATED. As TRILATED contains tenofovir disoproxil fumarate and lamivudine, any interactions that have been identified with these individual medicines may occur with TRILATED.

Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir (see below), including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of TRILATED in women of childbearing potential to exclude inadvertent (unintentional) use of TRILATED during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and risks of starting or continuing treatment with dolutegravir versus using another antiretroviral regimen should be discussed with her.

Pregnancy As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir, as in TRILATED, from the time of conception through the first 6 weeks of gestation are at potential risk. In addition, 2 of the 5 birth defects (encephalocele and iniencephaly), which have been observed with dolutegravir use, although often termed neural tube defects, may occur post-neural tube closure, the time period of which may be later than 6 weeks of gestation, but within the first trimester.

TRILATED cause dizziness, impaired concentration and/or drowsiness and 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 TRILATED affects them.

TRILATED can have side effects. a. Summary of the safety profile b. Tabulated summary of adverse reactions Dolutegravir: System organ class Frequency Adverse reactions Immune system disorders Less frequent Hypersensitivity, Immune Reconstitution Syndrome Psychiatric disorders Frequent Insomnia Nervous system disorders Frequent Headache, dizziness, abnormal dreams Gastrointestinal disorders Frequent Nausea, diarrhoea Less frequent Vomiting, flatulence, upper abdominal pain Frequency unknown Abdominal pain, abdominal discomfort Hepato-biliary disorders Less frequent Hepatitis Skin and subcutaneous tissue disorders Frequent Rash, pruritus Lamivudine: The following side effects have been reported during therapy for HIV disease with TRILATED tablets alone and in combination with other antiretrovirals: System organ class Frequency Adverse reactions Blood and lymphatic system disorders Less frequent Neutropenia, anaemia, thrombocytopenia Less frequent Pure red cell aplasia Metabolism and nutrition disorders Frequent Hyperlactataemia Less frequent Lactic acidosis, lipodystrophy (redistribution/ accumulation of body fat) (see section 4.4) Frequent Headache, insomnia Nervous system disorders Less frequent Peripheral neuropathy (or paraesthesia), late onset neurological disorders in children exposed in utero Gastrointestinal disorders Frequent Nausea, vomiting, upper abdominal pain or cramps, diarrhoea Less frequent Pancreatitis, elevations in serum amylase Hepatobiliary disorders Frequent ALT (SGPT) elevation AST (SGOT) elevation Less frequent Transient elevations in liver enzymes (AST ALT) Hepato-biliary disorders Less frequent Transient elevations in liver enzymes (AST ALT) Skin and subcutaneous tissue disorders Frequent Rash, alopecia Musculoskeletal, connective tissue and bone disorders Frequent Arthralgia, muscle disorders Less frequent Rhabdomyolysis, decrease in bone mineral density, osteopenia, fractures General disorders and administration site condition Frequent Fatigue, malaise, fever Tenofovir: System organ class Frequency Adverse reactions Immune system disorders Less frequent Allergic reactions Metabolism and nutrition disorders Less frequent Hypophosphataemia, lactic acidosis Respiratory, thoracic and mediastinal disorders Less frequent Dyspnoea Gastrointestinal disorders Frequent Anorexia, dyspepsia, flatulence, abdominal pain Less frequent Increased amylase, pancreatitis Hepato-biliary disorders Frequent Increased liver enzymes, hepatitis Renal and urinary disorders Frequent Renal insufficiency, increased creatinine, proximal renal tubulopathy, renal failure, acute tubular necrosis, nephrogenic diabetes insipidus, proteinuria.

If overdose occurs the patients must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. 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 TRILATED. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As TRILATED is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. 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. Tenofovir disoproxil fumarate If overdose occurs the patient must be monitored for evidence of toxicity and palliative supportive treatment be 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.