Tribuss 200 mg, 300mg, 600mg FC tablet

TRIBUSS is indicated for use alone as a complete regimen or in combination with other antiretroviral medicines for the treatment of HIV-1 infection in adults.

The dose of TRIBUSS is one tablet taken orally, once daily, on an empty stomach. Dosing at bedtime may improve the tolerability to efavirenz with respect to undesirable effects on the nervous system.

TRIBUSS is contraindicated in:

• Patients with a known hypersensitivity to tenofovir, emtricitabine, efavirenz or any of the excipients of TRIBUSS (see COMPOSITION).
• Patients with moderate (creatinine clearance 30 to 50 ml/min) or severe renal impairment (creatinine clearance < 30 ml/min (CrCl)). Patients with moderate or severe renal impairment require dose adjustment of emtricitabine and tenofovir disoproxil fumarate that cannot be achieved with TRIBUSS (see WARNINGS AND SPECIAL PRECAUTIONS).
• Concomitant use with bepridil, cisapride, midazolam, pimozide, terfenadine, triazolam or ergot derivatives, because competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these medicines and create the potential for serious and/or life-threatening adverse events (e.g. cardiac dysrhythmias, prolonged sedation, or respiratory depression) (see INTERACTIONS).
• Concomitant use with voriconazole because efavirenz significantly decreases voriconazole plasma concentrations (see INTERACTIONS).
• Concomitant use with St Johnu2019s Wort (Hypericum perforatum).
• Patients with a history of previous liver injury/failure with efavirenz containing antiretroviral treatment (ART).
• Patients with severe hepatic impairment (see WARNINGS AND SPECIAL PRECAUTIONS).
• Children less than 18 years of age, due to lack of data on safety and efficacy.
• Pregnancy and lactation (see HUMAN REPRODUCTION).

Patients with hepatic impairment

Liver enzymes: In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medicines associated with liver toxicity, monitoring of liver enzymes is recommended. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with TRIBUSS needs to be weighed up against the unknown risks of significant liver toxicity (see SIDE EFFECTS).

Tenofovir disoproxil fumarate: 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.

Efavirenz: There is some evidence that efavirenz is associated with three clinical pathological patterns of medicine induced liver failure in HIV positive patients of which the sub massive necrosis histological pattern seems to be associated with a high morbidity/mortality risk and may present many months after therapy has been initiated or even stopped. Risk factors include younger age, CD4+ counts u2265 350 cells/u03bcl and female gender. Patients on TRIBUSS or efavirenz containing antiretroviral treatment (ART) should be regularly monitored for jaundice (including a laboratory bilirubin and liver enzymes) and bleeding tendencies. Early detection and treatment of the liver failure and the immediate discontinuation of TRIBUSS or efavirenz containing medicines should be stressed. Patients who discontinued treatment with TRIBUSS should be followed up for symptoms/signs of liver failure for up to 12 months. TRIBUSS is contraindicated in patients with moderate to severe hepatic impairment (see CONTRAINDICATIONS). The safety and efficacy of TRIBUSS in patients with both HIV and hepatitis B virus infection have not been established.

Emtricitabine: The pharmacokinetics of emtricitabine have 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 (see CONTRAINDICATIONS).

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 alone or in combination with other antiretrovirals, such as in TRIBUSS. 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 to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Early symptoms (symptomatic hyperlactatemia) 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 rate and may be associated with pancreatitis, liver failure or renal failure. Lactic acidosis generally occurred after a few or several months of treatment. Treatment with TRIBUSS 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). Routine testing of serum lactate levels in asymptomatic patients on ART is not recommended. Measurement of serum lactate levels is recommended only for patients presenting with clinical signs or symptoms consistent with lactic acidosis. Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/litre) and respond as follows:

• Lactate 2 to 5 mmol/l: monitor regularly, and be alert for clinical signs.
• Lactate 5 to 10 mmol/l without symptoms: monitor closely.
• Lactate 5 to 10 mmol/l with symptoms: STOP all therapy. Exclude other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis, and lymphoma).
• Lactate greater than or equal to 10 mmol/l: STOP all therapy (80 % mortality in case studies).

Co-administration with related medicines (see INTERACTIONS): As a fixed combination, TRIBUSS should not be administered concomitantly with other medicines containing any of the same active components, namely: tenofovir disoproxil fumarate, efavirenz or emtricitabine. Due to similarities with emtricitabine, TRIBUSS should not be administered concomitantly with other cytidine analogues, such as lamivudine, including the lamivudine/zidovudine combination, or the abacavir sulphate/lamivudine combination, or the abacavir sulphate/lamivudine/zidovudine combination.

Patients co-infected with HIV and Hepatitis B Virus: It is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. TRIBUSS is not indicated for the treatment of chronic HBV infection and the safety and efficacy of TRIBUSS have not been established in patients co-infected with HBV and HIV. Discontinuation of TRIBUSS therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and HIV and have discontinued the emtricitabine 200 mg/tenofovir 300 mg combination or tenofovir DF 300 mg alone. In some of these patients the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are co-infected with HIV and HBV and discontinue TRIBUSS. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Renal impairment: Tenofovir and emtricitabine are principally eliminated by the kidney; however, efavirenz is not. Since TRIBUSS is a combination medicine and the dose of the individual components cannot be altered, patients with creatinine clearance <50 ml/min should not receive TRIBUSS (see CONTRAINDICATIONS).

*eGFR (ml/min) = 140 - age (years) x weight (kg) / serum creatinine (u03bcmol/l)

*eGFR (estimated glomerular filtration rate) For females multiply the GFR by 0,85

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia), has been reported in association with the use of tenofovir DF (see CONTRAINDICATIONS and SIDE EFFECTS). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with TRIBUSS. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment (see CONTRAINDICATIONS and SIDE EFFECTS). TRIBUSS should be avoided with concurrent or recent use of a nephrotoxic medicine.

Psychiatric symptoms: Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. There have been post-marketing reports of severe depression, death by suicide, delusions and psychosis-like behaviour. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risk of continued therapy outweighs the benefits (see SIDE EFFECTS).

Nervous system symptoms: Fifty-three percent of patients receiving efavirenz in controlled trials reported central nervous system symptoms compared to 25 % of patients receiving control regimens. These symptoms included dizziness (28, 1 %), insomnia (16, 3 %), impaired concentration (8, 3 %), somnolence (7, 0 %), abnormal dreams (6, 2 %), and hallucinations (1, 2 %). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking and depersonalisation. The majority of these symptoms were mild-to-moderate (50, 7 %); symptoms were severe in 2, 0 % of patients. Overall 2, 1 % of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 to 4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5 % to 9 % in patients treated with regimens containing efavirenz and from 3 % to 5 % in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms (see WARNINGS AND SPECIAL PRECAUTIONS, Psychiatric symptoms).

Patients receiving TRIBUSS should be alerted to the potential for additive central nervous system effects when TRIBUSS is used concomitantly with alcohol or psychoactive medicines.

Convulsions: Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medicines primarily metabolised by the liver, such as phenytoin and phenobarbital may require periodic monitoring of plasma levels.

Animal Toxicology: Non-sustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4 to 13 fold greater than those in humans given the recommended dose.

No medicine interaction studies have been conducted using TRIBUSS film-coated tablets. As TRIBUSS contains tenofovir disoproxil fumarate, efavirenz, and emtricitabine, any interactions that have been identified with these medicines individually may occur with TRIBUSS.

Efavirenz: Efavirenz has been shown in vivo to induce CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co-administered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19 and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Co-administration of efavirenz with medicines primarily metabolised by these isozymes may result in altered plasma concentrations of the co-administered medicine. Therefore, appropriate dose adjustments may be necessary for these medicines. Medicines which induce CYP3A4 activity (e.g. phenobarbital, rifampicin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.

Emtricitabine and tenofovir disoproxil fumarate: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of TRIBUSS 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, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir and valganciclovir. Co-administration of tenofovir DF 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 (for didanosine dosing adjustment recommendations, see Table 2 in the INTERACTIONS section). Suppression of CD4 cell counts has been observed in patients receiving tenofovir DF with didanosine at a dose of 400 mg daily. Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving either atazanavir or lopinavir/ritonavir with tenofovir DF should be monitored for tenofovir-associated adverse events. TRIBUSS should be discontinued in patients who develop tenofovir-associated adverse events (for atazanavir dosing adjustment recommendations (see Table 2 in the INTERACTIONS section). Other important medicine interaction information for TRIBUSS is summarised in Table 1 and 2. The medicine interactions described are based on studies conducted with efavirenz, emtricitabine or tenofovir DF as individual medicines or are potential medicine interactions; no medicine interaction studies have been conducted using TRIBUSS.

Pregnancy: TRIBUSS should not be used in pregnancy (see CONTRAINDICATIONS). Efavirenz may cause foetal harm when administered during the first trimester of pregnancy. Pregnancy should be avoided in women receiving TRIBUSS. A reliable form of barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives) while on therapy with TRIBUSS. Women should be advised to notify their medical practitioner or health care professional if they plan to become pregnant while taking TRIBUSS. If TRIBUSS is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking TRIBUSS, she should be informed of the potential harm to the foetus.

Women of childbearing potential should undergo pregnancy testing before initiation of TRIBUSS. There are no adequate and well-controlled studies of TRIBUSS in pregnant women.

Lactation: Breast feeding mothers: HIV-infected mothers should not breast feed their infants, to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that both efavirenz and tenofovir are secreted in milk. It is not known whether tenofovir, emtricitabine or efavirenz is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in breast feeding infants, mothers should be instructed not to breast feed if they are receiving TRIBUSS.

TRIBUSS may cause dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Efavirenz: Immune system disorders: Less frequent: Allergic reactions. Frequency unknown: Immuno-allergic liver injury/failure. Endocrine disorders: Frequency unknown: Gynaecomastia. Metabolism and nutritional disorders: Less frequent: Anorexia, raised serum-cholesterol and triglyceride concentrations. Frequency unknown: Redistribution/accumulation of body fat, weight gain, weight loss, increased appetite. Psychiatric disorders: Frequent: Aggravated depression. Less frequent: Abnormal dreams, anxiety, agitation, amnesia, apathy, confusion, emotional lability, euphoria, hallucination, insomnia, somnolence. Nervous system disorders: Frequent: Dizziness, headache. Less frequent: Impaired concentration, abnormal coordination, ataxia, convulsions, hypoaesthesia, paraesthesia, neuralgia, peripheral neuropathy, speech disorder, tremor and vertigo, syncope. Eye disorder: Less frequent: Abnormal vision. Ear and labyrinth disorders: Less frequent: Tinnitus. Cardiac disorders: Less frequent: Palpitations and tachycardia. Respiratory, thoracic and mediastinal disorders: Less frequent: Asthma. Frequency unknown: Sinusitis, and upper respiratory tract infections. Gastrointestinal disorders: Frequent: Nausea. Less frequent: Vomiting, diarrhoea, dyspepsia, abdominal pain, taste perversion. Frequency unknown: Gastritis, gastroenteritis and gastro-oesophageal reflux, constipation, malabsorption. Hepato-biliary disorders: Less frequent: Hepatitis, hepatic enzyme increase. Frequency unknown: Hepatic failure. Skin and subcutaneous tissue disorders: Frequent: Rash and increased swelling. Less frequent: Erythema multiforme, Stevens-Johnson syndrome, alopecia, skin exfoliation, urticaria. Frequency unknown: Nail disorders, skin discolouration, acne, eczema, folliculosis, seborrhoea, photoallergic dermatitis. Musculoskeletal, connective tissue and bone disorders: Less frequent: Arthralgia, myalgia. Frequency unknown: Myopathy. Reproductive system and breast disorders: Frequency unknown: Impotence, decreased libido, increased libido. General disorders and administrative site conditions: Frequent: Fatigue. Less frequent: Asthenia, hot flushes, malaise. Frequency unknown: Influenza-like symptoms, pain.

The type and frequency of side effects in children was generally similar to that of adult patients, with the exception that rash was reported more frequently in children and was more often of a higher grade than in adults.

Emtricitabine (200 mg): Blood and lymphatic system disorders: Frequency unknown: Neutropenia, anaemia. Immune system disorders: Frequency unknown: Allergic reactions. Metabolism and nutrition disorders: Frequency unknown: Lactic acidosis u2013 usually associated with severe hepatomegaly and steatosis, hypophosphatemia, hypertriglyceridemia, hyperglycaemia. Psychiatric disorders: Frequency unknown: Sleep disturbances (abnormal dreams, insomnia), depressive disorder. Nervous system disorders: Frequent: Headache. Frequency unknown: Dizziness, neuropathy, peripheral neuritis, paraesthesia. Respiratory, thoracic and mediastinal disorders: Frequency unknown: Increased cough, rhinitis, dyspnoea. Gastrointestinal disorders: Frequent: Nausea, vomiting, diarrhoea. Frequency unknown: Abdominal pain, dyspepsia, increased amylase, pancreatitis. Hepato-biliary disorders: Frequency unknown: Raised liver enzyme concentrations, hepatitis, hyperbilirubinemia. Skin and subcutaneous tissue disorders: Frequent: Rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction). Frequency unknown: Skin discolouration u2013 manifested by hyperpigmentation on the palms and/or soles, but is generally mild. Musculoskeletal, connective tissue and bone disorders: Frequency unknown: Arthralgia, myalgia. Renal and urinary disorders: Frequent: Elevation of creatinine kinase. General disorders and administrative site conditions: Frequency unknown: Asthenia.

Tenofovir (300 mg): Blood and lymphatic system disorders: Frequency unknown: Neutropenia, haematuria. Immune system disorders: Frequency unknown: Allergy, allergic reactions. Metabolism and nutrition disorders: Frequent: Hypophosphatemia. Frequency unknown: Lactic acidosis u2013 usually associated with severe hepatomegaly and steatosis, hypertriglyceridemia, hyperglycaemia. Psychiatric disorders: Frequency unknown: Depression, insomnia, anxiety. Nervous system disorders: Frequency unknown: Headache, asthenia, dizziness, peripheral neuropathy (including peripheral neuritis and neuropathy). Respiratory, thoracic and mediastinal disorders: Frequency unknown: Chest pain, pneumonia, dyspnoea. Gastrointestinal disorders: Frequent: Nausea, vomiting, diarrhoea, abdominal pain, flatulence, dyspepsia and anorexia, weight loss. Less frequent: Raised serum amylase concentrations, pancreatitis. Frequency unknown: Abdominal pain. Hepato-biliary disorders: Frequency unknown: Raised liver enzymes, hepatitis. Skin and subcutaneous tissue disorders: Frequency unknown: Skin rashes (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash and pustular rash), sweating. Musculoskeletal connective tissue and bone disorders: Frequency unknown: Back pain, myalgia. Renal and urinary disorders: Frequency unknown: Increased creatinine kinase levels, increased creatinine, interstitial nephritis, nephrogenic diabetes insipidus, polyuria, proximal tubulopathy, proteinuria, renal impairment, renal failure, renal insufficiency, acute renal failure, acute tubular necrosis, and effects on the renal proximal tubules, including Fanconi syndrome. General disorders and administrative site conditions: Frequency unknown: Fever.

Symptoms: Efavirenz: Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms and involuntary muscle contractions. Tenofovir disoproxil fumarate: Limited clinical experience at doses higher than the therapeutic dose of tenofovir DF 300 mg is available. In one study, 600 mg tenofovir disoproxil fumarate was administered to 8 patients orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known. Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine (200 mg). In one clinical pharmacology study, single doses of emtricitabine 1 200 mg were administered to 11 patients. No severe adverse reactions were reported.

Treatment: If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Efavirenz: Treatment of overdose with efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patientu2019s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed medicine. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the medicine from the blood. Tenofovir: Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54 %. Following a single 300 mg dose of tenofovir DF, a 4-hour haemodialysis session removed approximately 10 % of the administered tenofovir dose. Emtricitabine: Haemodialysis treatment removes approximately 30 % of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 ml/min and a dialysate flow rate of 600 ml/min). It is not known whether emtricitabine can be removed by peritoneal dialysis. Treatment is symptomatic and supportive.