Avonza Special Precautions

General: As a fixed combination, Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets should not be administered concomitantly with other medicinal products containing any of the same active components, efavirenz, lamivudine or tenofovir disoproxil fumarate. Efavirenz Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets should not be administered concomitantly with other cytidine analogues such as emtricitabine (see Interactions). Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets should not be administered concomitantly with adefovir dipivoxil.
Convulsions: Convulsions have been observed in patients receiving EFV, generally in the presence of known medical history of seizures. Caution should be taken in any patient with a history of seizures.
Transmission of HIV: Treatment with Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets has not been shown to eliminate the risk of transmission of HIV infection by sexual contact or by blood transfer, although the risk may be reduced. Patients should continue to use appropriate precautions to prevent transmission of HIV.
Didanosine: Co-administration of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets and didanosine is not recommended since exposure to didanosine is significantly increased following co-administration with tenofovir disoproxil fumarate (see Interactions).
Liver disease: The safety and pharmacokinetics of efavirenz has not been investigated in patients with severe liver disease. Therefore, Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets should only be used in this group of patients if the benefits are considered to outweigh the risks, and with close safety monitoring.
Liver toxicity: Increased transaminase levels may occur months after starting efavirenz and may be more frequent in patients with HBV- and/or HCV co-infection. Discontinuation is recommended if hepatoxicity is symptomatic, or if the transaminase levels are > 10 times the upper limit of normal.
Hepatic failure has occurred in patients with no preexisting hepatic disease or other identifiable risk factors (see Adverse Reactions). Liver enzyme monitoring should be considered for patients without pre-existing hepatic dysfunction or other risk factors.
Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection: Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.
Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with HBV.
Lamivudine and tenofovir disoproxil fumarate are also active against HBV. Therefore, discontinuation of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets therapy inpatients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets must be closely monitored with both clinical and laboratory follow-up for at least four months after stopping treatment with Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets. If appropriate, resumption of specific anti-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.
Rash: A mild-to-moderate rash very commonly develops within two weeks after starting efavirenz and does not require treatment discontinuation. The rash usually resolves within two weeks. Severe rash or erythema, including Stevens-Johnson syndrome, requires immediate discontinuation (see Adverse Reactions).
Central nervous system and psychiatric effects: Central nervous system and psychiatric side effects are very common after starting efavirenz (see Adverse Reactions). These symptoms typically occur within the first week of treatment and usually resolve within 4 weeks of treatment. There is a potential additive effect with alcohol and other psychoactive drugs. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation they should contact their doctor or health care provider immediately to determine whether the benefits outweigh the risks of continued therapy.
Renal function: Tenofovir is primarily excreted by the kidneys through a combination of glomerular filtration and active tubular secretion. Thus, clearance is decreased in patients with impaired renal function. There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with impaired renal function (< 80 ml/min). In such patients, Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets should only be used if the potential benefits of treatment are considered to outweigh the potential risks.
In patients with moderate to severe renal impairment, the plasma half-life of lamivudine is increased due to decreased clearance. Decreased doses are recommended for patients with creatinine clearance <50 ml/min.
The use of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets is not recommended in patients with creatinine clearance < 50 ml/min, since appropriate dose reductions cannot be achieved with the combination tablet (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see Adverse Reactions). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets. Routine monitoring of calculated creatinine clearance and serum phosphate should be performed in patients at risk for renal impairment.
In patients receiving tenofovir disoproxil fumarate renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations, if serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance decreases below 50 ml/min (see Renal tubulopathy under Adverse Reactions).
Consideration should also be given to interrupting treatment with Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets in patients whose creatinine clearance falls below 50 ml/min or whose serum phosphate decreases below 1.0 mg/dl (0.32 mmol/l).
Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets should be avoided with concurrent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents is unavoidable, renal function should be monitored weekly.
Bone effects: In a controlled clinical study decreases in bone mineral density of spine and changes in bone biomarkers from baseline were observed in both treatment groups, but were significantly greater in the tenofovir disoproxil fumarate treatment group than in the comparator group treated with stavudine (each in combination with lamivudine and efavirenz) at 144 weeks. Decreases in bone mineral density of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.
Tenofovir was studied in HIV-1 infected paediatric subjects 12 years of age and older. Under normal circumstances, bone mineral density increases rapidly in this age group. In this study, the mean rate of bone gain was less in the tenofovir-treated group compared to the placebo group. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in tenofovir-treated paediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults. Due to the possible effects of tenofovir on bone metabolism, Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets should only be used in adolescents under the age of 18 if the benefits are considered to exceed the risk (see also Adverse Reactions).
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see Adverse Reactions). If bone abnormalities are suspected then appropriate consultation should be obtained.
Lactic acidosis: Lactic acidosis is a rare but severe, potentially life-threatening complication associated with use of nucleoside reverse transcriptase inhibitors (NRTI). Several other agents of this class are known to cause lactic acidosis. Preclinical and clinical data suggest that the risk of occurrence of lactic acidosis, considered a putative class effect of nucleoside analogues, is very low for tenofovir disoproxil fumarate and lamivudine. However, this risk cannot be excluded. Lactic acidosis may occur after a few to several months of NRTI treatment. Patients with hyperlactataemia may be asymptomatic, critically ill, or may have non-specific symptoms such as dyspnoea, fatigue, nausea, vomiting, diarrhoea and abdominal pain. Risk factors for NRTI-related lactic acidosis include female gender and obesity. Patients at increased risk should be closely monitored clinically. Screening for hyperlactataemia in asymptomatic patients treated with NRTIs, however, is not recommended. Symptomatic patients usually have levels > 5 mmol/l and require discontinuation of all NRTIs. Lactic acid levels > 10 mmol/l usually are a medical emergency.
Lipodystrophy and metabolic disorders: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV-infected patients. Whereas for some other antiretrovirals there is considerable evidence for this adverse reaction, the evidence for tenofovir, lamivudine and efavirenz as causative agents is weak; indeed switching from a thymidine analogue (e.g. stavudine) to tenofovir has been shown to increase limb fat in patients with lipoatrophy. A higher risk of lipodystrophy has been associated e.g. with older age of the patient, longer duration of antiretroviral therapy and related metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Measurement of fasting serum lipids and blood glucose as well as appropriate management of lipid disorders should be considered (see Adverse Reactions).
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 postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Pancreatitis: Treatment with Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 300 mg/300 mg/400 mg Tablets should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur (see Adverse Reactions).
Opportunistic infections: Patients receiving antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians or health care providers experienced in the treatment of HIV infection.
Immune Reactivation Syndrome: In HIV infected patients with pre-existing severe immune deficiency, typically in the first few weeks or months after initiation of combination ART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens (e.g. CMV retinitis, mycobacterial infections, Pneumocystis pneumonia) may arise and cause serious clinical conditions or aggravation of symptoms. Treatment should be instituted when necessary.
Osteonecrosis: Although the etiology 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. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Excipients: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. However, dizziness has been reported during treatment with efavirenz and tenofovir disoproxil fumarate. Efavirenz may also cause impaired concentration and/or somnolence. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and operating machinery.
Use in the Elderly: Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with tenofovir disoproxil fumarate (see Interactions).