Trizivir · 4.3 Contraindications · 1

HOS-093054 · has-adverse-reaction-information · PDF-Seite 14

Summary of the safety profile Adverse reactions have been reported with abacavir, lamivudine and zidovudine used separately or in combination for therapy of HIV disease. Because Trizivir contains abacavir, lamivudine and zidovudine, the adverse reactions associated with these compounds may be expected. Tabulated list of adverse reactions reported with the individual substances The adverse reactions reported with abacavir, lamivudine and zidovudine are presented in Table 2. They are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000). Care must be taken to eliminate the possibility of a hypersensitivity reaction if any of these symptoms occur. Table 1: Adverse reactions reported with the individual components of Trizivir Abacavir Lamivudine Zidovudine IMPORTANT: for information on abacavir hypersensitivity see the information below, under the Description of selected adverse reactions Abacavir hypersensitivity Blood and lymphatic system disorders Uncommon: neutropenia, Common: anaemia, neutropenia anaemia (both occasionally and leukopenia severe), thrombocytopenia Uncommon: thrombocytopenia Very rare: pure red cell aplasia and pancytopenia with marrow hypoplasia Rare: pure red cell aplasia Very rare: aplastic anaemia Immune system disorders Common: hypersensitivity Metabolism and nutrition disorders Very Rare : lactic acidosis Common: anorexia Rare: anorexia, lactic acidosis in the absence of hypoxaemia Very Rare : lactic acidosis Psychiatric disorders Rare: anxiety, depression Nervous system disorders Common: headache, insomnia Very common: headache Com

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HOS-093050 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. See sections 4.4 and 4.8. Patients with end-stage renal disease. Due to the active substance zidovudine, Trizivir is contraindicated in patients with abnormally low neutrophil counts (< 0.75 x 109/l), or abnormally low haemoglobin levels (< 7.5 g/dl or 4.65 mmol/l) (see section 4.4).

HOS-093049 · has-indication-information · PDF-Seite 2

Trizivir is indicated for the treatment of Human Immunodeficiency Virus (HIV) infection in adults (see sections 4.4 and 5.1). This fixed combination replaces the three components (abacavir, lamivudine and zidovudine) used separately in similar doses. It is recommended that treatment is started with abacavir, lamivudine, and zidovudine separately for the first 6-8 weeks (see section 4.4). The choice of this fixed combination should be based not only on potential adherence criteria, but mainly on expected efficacy and risk related to the three nucleoside analogues. The demonstration of the benefit of Trizivir is mainly based on results of studies performed in treatment naive patients or moderately antiretroviral experienced patients with non-advanced disease. In patients with high viral load (> 100,000 copies/mL) choice of therapy needs special consideration (see section 5.1). Overall, the virologic suppression with this triple nucleoside regimen could be inferior to that obtained with other multitherapies notably including boosted Protease inhibitors or non-nucleoside reverse transcriptase inhibitors, therefore the use of Trizivir should only be considered under special circumstances (e.g. co-infection with tuberculosis). 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(see section 4.4). Abacavir should not be used in patients known to carry the HLA-B*5701 allele.

HOS-093052 · has-interaction-information · PDF-Seite 8

Trizivir contains abacavir, lamivudine and zidovudine, therefore any interactions identified for these individually are relevant to Trizivir. Clinical studies have shown that there are no clinically significant interactions between abacavir, lamivudine and zidovudine. Abacavir is metabolised by UDP-glucuronyltransferase (UGT) enzymes and alcohol dehydrogenase; co-administration of inducers or inhibitors of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure. Zidovudine is primarily metabolised by UGT enzymes; co-administration of inducers or inhibitors of UGT enzymes could alter zidovudine exposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through organic cation transporters (OCTs); co-administration of lamivudine with OCT inhibitors may increase lamivudine exposure. Abacavir, lamivudine and zidovudine are not significantly metabolised by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they induce this enzyme system. Lamivudine and zidovudine do not inhibit cytochrome P450 enzymes. Abacavir shows limited potential to inhibit metabolism mediated by CYP3A4 and has been shown in vitro not to inhibit CYP2C9 or CYP 2D6 enzymes. In vitro studies have shown that abacavir has potential to inhibit cytochrome P450 1A1 (CYP1A1). Therefore, there is little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal products metabolised by major P450 enzymes. Interaction studies have only been performed in adults. The list below should not be considered exhaustive but is representative of the classes studied. Drugs by Therapeutic Area Interaction Recommendation Geometric mean change concerning co- (%) administration (Possible mechanism) ANTIRETROVIRAL MEDICINAL PRODUCTS Didanosine/Abacavir Interaction not studied. No dosage adjustment Didanosine/Lamivudine Interaction not studied. necessary. Didanosine/Zidovudine Interaction not studied. Stavudine/Abacavir Interaction not studied. Combination not Stavudine/Lamivudine Interaction not studied. recommended.

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HOS-093053 · has-pregnancy-information · PDF-Seite 12

Pregnancy As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 12 the animal data as well as the clinical experience in pregnant women should be taken into account. In the present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV. There are no data on the use of Trizivir in pregnancy. A moderate amount of data on pregnant women taking the individual actives abacavir, lamivudine and zidovudine in combination indicates no malformative toxicity (more than 300 outcomes from first trimester exposures). A large amount of data on pregnant women taking lamivudine or zidovudine indicate no malformative toxicity (more than 3000 outcomes from first trimester exposure each, of which over 2000 outcomes involved exposure to both lamivudine and zidovudine). Moderate amount of data (more than 600 outcomes from first trimester) indicates no malformative toxicity for abacavir. The malformative risk is unlikely in humans based on the mentioned moderate amount of data. The active ingredients of Trizivir may inhibit cellular DNA replication, zidovudine has been shown to be transplacental carcinogen in one animal study and abacavir has been shown to be carcinogenic in animal models (see section 5.3). The clinical relevance of these findings is unknown. For patients co-infected with hepatitis who are being treated with a lamivudine containing medicinal product such as Trizivir and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine. 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 (see section 4.4). Breast-feeding Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into human milk. Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (<4% of maternal serum concentrations) and pr

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HOS-093051 · has-warning-information · PDF-Seite 3

The special warnings and precautions relevant to abacavir, lamivudine and zidovudine are included in this section. There are no additional precautions or warnings relevant to the combination Trizivir. 3 Hypersensitivity Reactions (see also section 4.8 ) Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section4.8) characterised by fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have been observed with abacavir, some of which have been life-threatening, 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 HLA-B*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. • Trizivir 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, Ziagen, Triumeq) • Trizivir 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 Trizivir after the onset of hypersensitivity may result in a life-threatening reaction. • After stopping treatment with Trizivir for reasons of a suspected HSR, Trizivir or any other medicinal product containing abacavir (e.g. Kivexa, Ziagen, 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 Trizivir tablets Clinical description of abacavir HSR Abacavir HSR has been well characterised through clinical studies and during post marketing follow- up. Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Almost all HSR

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