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Drug details for : ZIAGEN Oral Solution (HIV)
| Drug class description : | Nucleoside Reverse Transcriptase Inhibitors(NRTI's) |
| Generic Name : | Abacavir |
| Drug description : | Oral solution The oral solution is clear to slightly opalescent yellowish, aqueous solution with strawberry and banana flavouring. |
| Presentation : | Oral solution containing 20 mg/ml of abacavir as abacavir sulfate. |
| Indications : | 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. |
| Adult Dosage : | Ziagen should be prescribed by physicians experienced in the management of HIV infection. Adults and adolescents over 12 years: 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 (See Special Precautions). 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 (See Contraindications and Special Precautions). |
| Child Dosage : | 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. |
| Elderly Dosage : | No pharmacokinetic data is currently available in patients over 65 years of age. |
| Contra Indications : | 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. |
| Special Precautions : | Hypersensitivity Reaction (See Adverse Reactions): In clinical studies approximately 5% of subjects receiving abacavir develop a hypersensitivity reaction; some of these cases were life-threatening and resulted in a fatal outcome despite taking precautions. •Description Hypersensitivity reactions are characterised by the appearance of symptoms indicating multi-organ system involvement. Almost all hypersensitivity reactions will have fever and/or rash as part of the syndrome. Other signs and symptoms may include respiratory signs and symptoms such as dyspnoea, sore throat, cough and abnormal chest x-ray findings (predominantly infiltrates, which can be localised), gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain, and may lead to misdiagnosis of hypersensitivity as respiratory disease (pneumonia, bronchitis, pharyngitis), or gastroenteritis. Other frequently observed signs or symptoms of the hypersensitivity reaction may include lethargy or malaise and musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia). The symptoms related to this hypersensitivity reaction worsen with continued therapy and can be life-threatening. These symptoms usually resolve upon discontinuation of Ziagen. •Management Hypersensitivity reaction symptoms usually appear within the first six weeks of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Patients should be monitored closely, especially during the first two months of treatment with Ziagen, with consultation every two weeks. Patients who are diagnosed with a hypersensitivity reaction whilst on therapy MUST discontinue Ziagen immediately. Ziagen, or any other medicinal product containing abacavir (i.e. Kivexa, Trizivir), MUST NEVER be restarted in patients who have stopped therapy due to a hypersensitivity reaction. Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death. To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, Ziagen must be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). Special care is needed for those patients simultaneously starting treatment with Ziagen and other medicinal products known to induce skin toxicity (such as non-nucleoside reverse transcriptase inhibitors - NNRTIs). This is because it is currently difficult to differentiate between rashes induced by these products and abacavir related hypersensitivity reactions. •Management after an interruption of Ziagen therapy If therapy with Ziagen has been discontinued for any reason and restarting therapy is under consideration, the reason for discontinuation must be established to assess whether the patient had any symptoms of a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, Ziagen or any other medicinal product containing abacavir (i.e. Kivexa, Trizivir ) must not be restarted. Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting Ziagen in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping Ziagen. The most common isolated symptom of a hypersensitivity reactionwas a skin rash. Moreover, on very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy, and who had no preceding symptoms of a hypersensitivity reaction. In both cases, if a decision is made to restart Ziagen this must be done in a setting where medical assistance is readily available. •Essential patient information Prescribers must ensure that patients are fully informed regarding the following information on the hypersensitivity reaction: - patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that may result in a life-threatening reaction or death. - patients developing signs or symptoms possibly linked with a hypersensitivity reaction MUST CONTACT their doctor IMMEDIATELY. - patients who are hypersensitive to abacavir should be reminded that they must never take Ziagen or any other medicinal product containing abacavir (i.e. Kivexa, Trizivir) - in order to avoid restarting Ziagen, patients who have experienced a hypersensitivity reaction should be asked to return the remaining Ziagen tablets or oral solution to the pharmacy. - patients who have stopped Ziagen for any reason, and particularly due to possible adverse reactions or illness, must be advised to contact their doctor before restarting. - patients should be advised of the importance of taking Ziagen regularly. - each patient should be reminded to read the Package Leaflet included in the Ziagen pack. They should be reminded of the importance of removing the Alert Card included in the pack, and keeping it with them at all times. Lactic acidosis:lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. 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 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 nucleoside analogues should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely. 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 events 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 (See Adverse Reactions). Pancreatitis: pancreatitis has been reported, but a causal relationship to Ziagen 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. Once daily administration (abacavir 600 mg): the benefit of abacavir as a once daily regimen is mainly based on a study performed in combination with efavirenz and lamivudine, in antiretroviral-naïve adult patients. 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 (See Contraindications). 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 events. 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. For patients with severe hepatic impairment, Ziagen is contraindicated (See Contraindications). 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. 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. 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. |
| Interactions : | 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 Cmax and a one hour delay in tmax 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. Pregnancy:Ziagen is not recommended during pregnancy. The safe use of abacavir in human pregnancy has not been established. Placental transfer of abacavir and/or its related metabolites has been shown to occur in animals. Toxicity to the developing embryo and foetus occurred in rats, but not in rabbits. The teratogenic potential of abacavir could not be established from studies in animals. Lactation:abacavir and its metabolites are secreted into the milk of lactating rats. It is expected that these will also be secreted into human milk, although this has not been confirmed. There are no data available on the safety of abacavir when administered to babies less than three months old. It is therefore recommended that mothers do not breast-feed their babies while receiving treatment with abacavir. Additionally, it is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV. |
| Adverse Reactions : | 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 Cmax and a one hour delay in tmax 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. Pregnancy:Ziagen is not recommended during pregnancy. The safe use of abacavir in human pregnancy has not been established. Placental transfer of abacavir and/or its related metabolites has been shown to occur in animals. Toxicity to the developing embryo and foetus occurred in rats, but not in rabbits. The teratogenic potential of abacavir could not be established from studies in animals. Lactation:abacavir and its metabolites are secreted into the milk of lactating rats. It is expected that these will also be secreted into human milk, although this has not been confirmed. There are no data available on the safety of abacavir when administered to babies less than three months old. It is therefore recommended that mothers do not breast-feed their babies while receiving treatment with abacavir. Additionally, it is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV. |
| Manufacturer : | GlaxoSmithKline |
| Drug Availability : | (POM) |
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