Bavir Tablets and Oral Solution

BAVIR is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children.

Posology

Adults and adolescents over 12 years: The recommended dose of BAVIR is one tablet of 300 mg or 15 ml twice daily.

Paediatric population

Children from 3 months to 12 years: The recommended dosage is 8 mg/kg twice daily up to a maximum of 600 mg daily. Children less than 3 months: There are no data available on the use of BAVIR in this age group.

BAVIR can be taken with or without food. An oral dosing syringe is provided for accurate measurement of the prescribed dose of oral solution. Therapy should be initiated by a medical practitioner experienced in the management of HIV-infection.

Special populations

Renal impairment: No dosage adjustment of BAVIR is necessary in patients with renal dysfunction (see section 5.2).

Hepatic impairment: Abacavir is metabolised primarily by the liver. There is insufficient data to recommend the use of BAVIR in patients with impaired hepatic function.

Method of administration

To be taken orally.

BAVIR is contra-indicated:

• in patients with known hypersensitivity to abacavir or any ingredient of the formulations,
• in patients with a hereditary fructose intolerance,
• in patients with liver function impairment,
• in pregnancy and lactation,
• in infants under 3 months of age.

Hypersensitivity: Approximately 4 % of subjects receiving BAVIR develop a hypersensitivity reaction which in rare cases has proved fatal. This is characterised by the appearance of symptoms indicating multi-organ/body-system involvement. Patients who develop a hypersensitivity reaction must discontinue BAVIR and MUST not be re-challenged with BAVIR (see section 4.8).

Lactic acidosis/severe hepatomegaly with steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including abacavir, in the treatment of HIV infection (see section 4.8). A majority of these cases have been in women. Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia, and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea). Caution should be exercised when administering BAVIR, particularly to those with known risk factors for liver disease. Treatment with BAVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis with or without hepatitis (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients receiving BAVIR may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases. Patients should be advised that antiretroviral therapy with BAVIR 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.

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.

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. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Appropriate treatment of the opportunistic disease should be instituted or continued 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.

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.

The risk of HIV transmission to others: Patients should be advised that current antiretroviral therapy, including BAVIR, 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 BAVIR 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/u2113) and the serum bicarbonate and respond as follows:

• Lactate 2-5 mmol/u2113 with minimum symptoms: switch to agents that are less likely to cause lactic acidosis.
• Lactate 5-10 mmol/u2113 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/u2113: STOP all therapy (80 % mortality).

The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering BAVIR to patients with known risk factors for liver disease.

Treatment with BAVIR 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 BAVIR. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of BAVIR until diagnosis of pancreatitis is excluded.

Liver disease: Use of BAVIR can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of BAVIR 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 package inserts 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 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 package inserts for these medicines. Patients co-infected with HIV and HBV who discontinue BAVIR 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.

Sorbitol: BAVIR contains sorbitol which may cause abdominal pains and diarrhoea. BAVIR contains sorbitol which is metabolized to fructose and is therefore unsuitable for patients who have hereditary fructose intolerance (see section 4.3).

Abacavir was not mutagenic in bacterial tests, but showed activity in vitro in the human lymphocyte chromosome aberration assay, the mouse lymphoma assay, and the in vivo micronucleus test. This is consistent with the known activity of other nucleoside analogues. These results indicate that abacavir is a weak clastogen both in vitro and in vivo at high test concentrations. Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species, and in rats in the thyroid gland of males and the liver, urinary bladder, lymph nodes and the sub cutis of female rats. The majority of these tumours occurred at the highest dose levels equivalent to 24 to 32 times the expected systemic exposure in humans. The exception was the preputial gland tumour which occurred at a dose equivalent to 6 times the expected human systemic exposure. There is no structural counterpart of this gland in humans. While the carcinogenic potential in humans is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.

Mild myocardial degeneration: Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.

Cardiovascular events: Although the available data from clinical and observational studies with abacavir show inconsistent results, several studies suggest an increased risk of cardiovascular events (notably myocardial infarction) in patients treated with abacavir. Therefore, when prescribing BAVIR, action should be taken to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). In addition, alternative treatment option to the abacavir containing regimen should be considered when treating patients with a high cardiovascular risk.

Therapy experienced patients: In clinical trials patients with prolonged prior NRTI exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients with prolonged prior NRTI exposure, or who have HIV-1 isolates containing multiple mutations conferring resistance to NRTIs.

BAVIR contains sodium. This medicine contains less than 1 mmol sodium (23 mg) per tablet/ml, that is to say essentially u2018sodium freeu2019.

Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the potential for drug interactions involving abacavir is low. Abacavir shows limited potential to inhibit metabolism mediated by the cytochrome P450 3A4 enzyme. It has also been shown in vitro not to interact with medicines that are metabolized by CYP3A4, CYP2C9 or CYP2D6 enzymes. Induction of hepatic metabolism has not been observed in clinical studies. Therefore, there is little potential for medicine interactions with antiretroviral protease inhibitors and other medicines metabolised by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine.

Effect of abacavir on the pharmacokinetics of other agents: In vitro, abacavir demonstrates no or weak inhibition of the drug transporters organic anion transporter 1B1 (OATP1B1), OATP1B3, breast cancer resistance protein (BCRP) or P-glycoprotein (Pgp) and minimal inhibition of organic cation transporter 1 (OCT1), OCT2 and multidrug and toxin extrusion protein 2-K (MATE2-K). Abacavir is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters. Abacavir is an inhibitor of MATE1 in vitro, however abacavir has low potential to affect the plasma concentrations of MATE1 substrates at therapeutic drug exposures (up to 600 mg).

Effect of other agents on the pharmacokinetics of abacavir: In vitro, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, Multidrug resistance-associated protein 2 (MRP2) or MRP4, therefore drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Although abacavir is a substrate of BCRP and Pgp in vitro, clinical studies demonstrate no clinically significant changes in abacavir pharmacokinetics when co-administered with lopinavir/ritonovir (Pgp and BCRP inhibitors).

Ethanol: The metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41 %. No dose reduction of abacavir is necessary. Abacavir has no effect on the metabolism of ethanol.

Methadone: In a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with methadone showed a 35 % reduction in abacavir C max and a one hour delay in t max, but the AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study abacavir increased the mean methadone systemic clearance by 22 %. This change is not considered clinically relevant for the majority of patients, however occasionally methadone re-titration may be required.

Retinoids: Retinoid compounds such as isotretinoin, are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.

Pregnancy: BAVIR is contra-indicated in pregnancy.

Breastfeeding: BAVIR is contra-indicated in lactation.

No currently available data suggests that BAVIR affects the ability to drive or operate machinery.

a) Summary of the safety profile: Hypersensitivity: In clinical studies, approximately 4 % of subjects receiving BAVIR developed a hypersensitivity reaction which in rare cases proved fatal. This is characterised by the appearance of symptoms indicating multi-organ/body-system involvement. Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. Symptoms can occur at any time while being treated with BAVIR, but usually appear within the first 6 weeks of initiation of treatment with BAVIR (median time to onset 11 days).

b) Tabulated list of adverse reactions: The signs and symptoms of this hypersensitivity reaction are tabulated below:

Some patients with hypersensitivity reactions were initially thought to have respiratory disease (pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis or reactions to other medications. This delay in diagnosis of hypersensitivity has resulted in BAVIR being continued or re-introduced, leading to more severe hypersensitivity reactions or death. Therefore, the diagnosis of hypersensitivity reactions should be carefully considered for patients presenting with symptoms of these diseases. Symptoms worsen with continued therapy, and usually resolve upon discontinuation of BAVIR. Restarting BAVIR following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction may be more severe than on initial presentation, and may include life-threatening hypotension and death. Patients who develop this hypersensitivity reaction MUST discontinue BAVIR and MUST NOT be re-challenged. An Alert Card with information for the patient about the hypersensitivity reaction is included in the BAVIR pack (see section 4.4).

The adverse events reported during therapy for HIV disease with BAVIR were similar in adults and children.

c) Description of selected adverse reactions: Gastrointestinal disorders: Pancreatitis has been reported but a causal relationship to BAVIR treatment is uncertain. In general, adverse events have been transient and not treatment-limiting. Hepatobiliary disorders: Lactic acidosis/severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including abacavir, in the treatment of HIV infection. A majority of these cases have been in women. Caution should be exercised when administering BAVIR to any patient, and particularly to those with known risk factors for liver disease. Treatment with BAVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Single doses up to 1 200 mg and daily doses up to 1 800 mg of abacavir have been administered to patients in clinical studies. No unexpected adverse reactions were reported. The effects of higher doses are not known. If overdosage occurs the patient should be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.