Nucleoside Reverse Transcriptase Inhibitors(NRTI's)

Abacavir

Ziagen 20 mg/ml oral solution

Oral solution. The oral solution is clear to slightly opalescent yellowish, aqueous solution

Ziagen is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection.

The demonstration of the benefit of Ziagen is mainly based on results of studies performed in treatment-naïve adult patients on combination therapy with a twice daily regimen.

Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. . Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir (see “Management after an interruption of Ziagen therapy”). Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing.

Ziagen should be prescribed by physicians experienced in the management of HIV infection.

Adults and adolescents: the recommended dose of Ziagen is 600 mg daily (30 ml). This may be administered as either 300 mg (15 ml) twice daily or 600 mg (30 ml) once daily.

Patients changing to the once daily regimen should take 300 mg (15 ml) twice a day and switch to 600 mg (30 ml) once a day the following morning. Where an evening once daily regimen is preferred, 300 mg (15 ml) of Ziagen should be taken on the first morning only, followed by 600 mg (30 ml) in the evening. When changing back to a twice daily regimen, patients should complete the day's treatment and start 300 mg (15 ml) twice a day the following morning.

Ziagen can be taken with or without food.

Ziagen is also available as a tablet formulation.

Renal impairment: no dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen should be avoided in patients with end-stage renal disease.

Hepatic impairment: abacavir is primarily metabolised by the liver. No dose recommendation can be made in patients with mild hepatic impairment. No data are available in patients with moderate hepatic impairment, therefore the use of abacavir is not recommended unless judged necessary. In patients with mild and moderate hepatic impairment close monitoring is required, and if feasible, monitoring of abacavir plasma levels is recommended. Abacavir is contraindicated in patients with severe hepatic impairment.

Children from three months to 12 years: the recommended dose is 8 mg/kg twice daily up to a maximum of 600 mg (30 ml) daily. Children less than three months: the data available on the use of Ziagen in this age group are very limited. Ziagen can be taken with or without food. Ziagen is also available as a tablet formulation.

No pharmacokinetic data is currently available in patients over 65 years of age.

Ziagen is contraindicated in patients with known hypersensitivity to abacavir or to any of the excipients of Ziagen oral solution.

See INFORMATION ON HYPERSENSITIVITY REACTIONS in Special Precautions and Adverse Reactions. Ziagen is contraindicated in patients with severe hepatic impairment.

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. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). 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.

Lipodystrophy: combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

Pancreatitis: pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain.

Triple nucleoside therapy: in patients with high viral load (>100,000 copies/ml) the choice of a triple combination with abacavir, lamivudine and zidovudine needs special consideration.

There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when abacavir was combined with tenofovir disoproxil fumarate and lamivudine as a once daily regimen.

Liver disease: the safety and efficacy of Ziagen has not been established in patients with significant underlying liver disorders. Ziagen is contraindicated in patients with severe hepatic impairment. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

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 according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

A pharmacokinetic study has been performed in patients with mild hepatic impairment. However, a definitive recommendation on dose reduction is not possible due to substantial variability of drug exposure in this patient population. The clinical safety data available with abacavir in hepatically impaired patients is very limited. Due to the potential increases in exposure (AUC) in some patients, close monitoring is required. No data are available in patients with moderate or severe hepatic impairment. Plasma concentrations of abacavir are expected to substantially increase in these patients. Therefore, the use of abacavir in patients with moderate hepatic impairment is not recommended unless judged necessary and requires close monitoring of these patients.

Renal disease: Ziagen should not be administered to patients with end-stage renal disease.

Excipients: Ziagen oral solution contains 340 mg/ml of sorbitol. When taken according to the dosage recommendations each 15 ml dose contains approximately 5 g of sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Sorbitol can have a mild laxative effect. The calorific value of sorbitol is 2.6 kcal/g.

Ziagen oral solution also contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

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 Ziagen or any other antiretroviral therapy 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.

Transmission: patients should be advised that current antiretroviral therapy, including Ziagen, have 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.

Mycoardial Infarction: Observational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk. Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction. To date, there is no established biological mechanism to explain a potential increase in risk. When prescribing Ziagen, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the potential for P450 mediated interactions with other medicinal products involving abacavir is low. P450 does not play a major role in the metabolism of abacavir, and abacavir does not inhibit metabolism mediated by CYP 3A4. Abacavir has also been shown in vitro not to inhibit CYP 3A4, CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism has not been observed in clinical studies. Therefore, there is little potential for interactions with antiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine.

Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.

Ethanol: the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. These findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol.

Methadone: in a pharmacokinetic study, coadministration 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%. The induction of drug metabolising enzymes cannot therefore be excluded. Patients being treated with methadone and abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as occasionally methadone re-titration may be required.

Retinoids: retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.

For many of the other adverse reactions reported, it is unclear whether they are related to Ziagen, to the wide range of medicinal products used in the management of HIV infection or as a result of the disease process.

Many of those listed below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. If Ziagen has been discontinued in patients due to experiencing any one of these symptoms and a decision is made to restart a medicinal product containing abacavir, this must be done in a setting where medical assistance is readily available. Very rarely cases of erythema multiforme, Stevens Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued.

Many of the adverse reactions have not been treatment limiting. The following convention has been used for their classification: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) very rare (<1/10,000).

Metabolism and nutrition disorders

Common: anorexia

Nervous system disorders

Common: headache

Gastrointestinal disorders

Common: nausea, vomiting, diarrhoea

Rare: pancreatitis

Skin and subcutaneous tissue disorders

Common: rash (without systemic symptoms)

Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

General disorders and administration site conditions

Common: fever, lethargy, fatigue

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues.

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

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

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART) an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.

Laboratory abnormalities

In controlled clinical studies laboratory abnormalities related to Ziagen treatment were uncommon, with no differences in incidence observed between Ziagen treated patients and the control arms.

GlaxoSmithKline

(POM)

04 March 2010