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Film Coated Tablets
60 X 300 mg
Ziagen can be taken with or without food. To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.
Alternatively, for patients who are unable to swallow tablets, the tablet(s) may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately.
Adults, adolescents and children (weighing at least 25 kg): The recommended dose of Ziagen is 600 mg daily. This may be administered as either 300 mg (one tablet) twice daily or 600 mg (two tablets) once daily.
Children (weighing less than 25 kg): Dosing according to weight bands is recommended for Ziagen tablets.
Children weighing ≥ 20 kg to < 25 kg: The recommended dose is 450 mg daily. This may be administered as either one 150 mg (one half of a tablet) taken in the morning and 300 mg (one whole tablet) taken in the evening, or 450 mg (one and a half tablets) taken once daily.
Children weighing 14 to< 20 kg: The recommended dose is 300 mg daily. This may be administered as either 150 mg (one half of a tablet) twice daily or 300 mg (one whole tablet) once daily.
Children less than three months of age: The clinical experience in children aged less than three months is limited and are insufficient to propose specific dosage recommendations.
Patients changing from the twice daily dosing regimen to the once daily dosing regimen should take the recommended once daily dose (as described above) approximately 12 hours after the last twice daily dose, and then continue to take the recommended once daily dose (as described above) approximately every 24 hours. When changing back to a twice daily regimen, patients should take the recommended twice daily dose approximately 24 hours after the last once daily dose.
Renal impairment: No dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen is not recommended for patients with end-stage renal disease.
Hepatic impairment: Abacavir is primarily metabolised by the liver. No definitive dose recommendation can be made in patients with mild hepatic impairment (Child-Pugh score 5-6). In patients with moderate or severe hepatic impairment, no clinical data are available, therefore the use of abacavir is not recommended unless judged necessary. If abacavir is used in patients with mild hepatic impairment, then close monitoring is required, including monitoring of abacavir plasma levels if feasible.
Elderly: No pharmacokinetic data are currently available in patients over 65 years of age.
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 with a twice daily regimen, in treatment-naïve adult patients on combination therap.
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. Abacavir should not be used in patients known to carry the HLA-B*5701 allele.
Hypersensitivity to abacavir or to any of the excipients.
Hypersensitivity reaction: Abacavir is associated with a risk for hypersensitivity reactions (HSR) characterised by fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have been observed with abacavir, some of which have been lifethreatening, and in rare cases fatal, when not managed appropriately.
The risk for abacavir HSR to occur is high for patients who test positive for the HLAB*5701 allele. However, abacavir HSRs have been reported at a lower frequency in patients who do not carry this allele.
Therefore the following should be adhered to:
• HLA-B*5701 status must always be documented prior to initiating therapy.
• Ziagen should never be initiated in patients with a positive HLA-B*5701 status, nor in patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-containing regimen. (e.g. Kivexa, Trizivir, Triumeq)
• Ziagen must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an HSR is suspected. Delay in stopping treatment with Ziagen after the onset of hypersensitivity may result in a life-threatening reaction.
• After stopping treatment with Ziagen for reasons of a suspected HSR, Ziagen or any other medicinal product containing abacavir (e.g. Kivexa, Trizivir,
Triumeq) must never be re-initiated.
• Restarting abacavir containing products following a suspected abacavir HSR can result 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.
• In order to avoid restarting abacavir, patients who have experienced a suspected HSR should be instructed to dispose of their remaining Ziagen tablets
Mitochondrial dysfunction following exposure in utero: Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine.
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.
Liver disease: The safety and efficacy of Ziagen has not been established in patients with significant underlying liver disorders. Ziagen is not recommended in patients with moderate or severe hepatic impairment.
Patients co-infected with chronic hepatitis B or C virus: 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.
Renal disease: Ziagen should not be administered to patients with end-stage renal disease.
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: While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
See prescribing information for full details.
For many 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 the adverse reactions listed at the attached doctor’s leaflet 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. 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.
See prescribing information for full details.
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, co-administration 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 and Lactation
Pregnancy: As a general rule, when deciding to use antiretroviral agents for the treatment HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, both animal data as well as clinical experience in pregnant women should be taken into account. Animal studies have shown toxicity to the developing embryo and foetus in rats, but not in rabbits. Abacavir has been shown to be carcinogenic in animal models. Clinical relevance in human of these data is unknown. Placental transfer of abacavir and/or its related metabolites has been shown to occur in human.
In pregnant women, more than 800 outcomes after first trimester exposure and more than 1000 outcomes after second and third trimester exposure indicate no malformative and foeto/neonatal effect of abacavir. The malformative risk is unlikely in humans based on those data.
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.
Breast-feeding: Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into human milk. 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.
Fertility: Studies in animals showed that abacavir had no effect on fertility.
Single doses up to 1200 mg and daily doses up to 1800 mg of Ziagen have been administered to patients in clinical studies. No additional adverse reactions to those reported for normal doses were reported. The effects of higher doses are not known. If overdose occurs the patient should be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.
Storage: Do not store above 30°C.