Leitlinien & Arzneimittelsicherheit

HOS-093944 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The adverse reactions reported for Kivexa were consistent with the known safety profiles of abacavir and lamivudine when given as separate medicinal products. For many of these adverse reactions it is unclear whether they are related to the active substance, the wide range of other medicinal products used in the management of HIV infection, or whether they are a result of the underlying disease process. Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these 11 symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). 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. Tabulated list of adverse reactions The adverse reactions considered at least possibly related to abacavir or lamivudine 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). 12  Body system Abacavir Lamivudine Blood and lymphatic systems Uncommon: Neutropenia and disorders anaemia (both occasionally severe), thrombocytopenia Very rare: Pure red cell aplasia Immune system disorders Common: hypersensitivity Metabolism and nutrition Common: anorexia Very rare: lactic acidosis disorders Very rare: lactic acidosis Nervous system disorders Common: headache Common: Headache, insomnia. Very rare: Cases of peripheral neuropathy (or paraesthesia)

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HOS-093940 · 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.

HOS-093939 · has-indication-information · PDF-Seite 2

Kivexa is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults, adolescents and children weighing at least 25 kg (see sections 4.4 and 5.1). 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-093942 · has-interaction-information · PDF-Seite 7

Kivexa contains abacavir and lamivudine, therefore any interactions identified for these individually are relevant to Kivexa. Clinical studies have shown that there are no clinically significant interactions between abacavir and lamivudine. 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. 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 and lamivudine 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 does 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. Kivexa should not be taken with any other medicinal products containing lamivudine (see section 4.4). The list below should not be considered exhaustive but is representative of the classes studied. Drugs by Therapeutic Area Interaction Recommendation concerning Geometric mean change (%) co-administration (Possible mechanism) ANTIRETROVIRAL MEDICINAL PRODUCTS Didanosine /Abacavir Interaction not studied. No dosage adjustment Didanosine/Lamivudine Interaction not studied. necessary. Zidovudine/Abacavir Interaction not studied Zidovudine/Lamivudine Lamivudine: AUC  Zidovudine 300 mg single dose Zidovudine : AUC  Lamivudine 150 mg single dose Emtricitabine/Lamivudine Due to similarities, Kivexa should not be administered concomitantly with other

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HOS-093943 · has-pregnancy-information · PDF-Seite 10

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, the animal data as well as the clinical experience in pregnant women should be taken into account. Animal studies with abacavir have shown toxicity to the developing embryo and foetus in rats, but not in rabbits. Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats. (see section 5.3). The active ingredients of Kivexa may inhibit cellular DNA replication and 10 abacavir has been shown to be carcinogenic in animal models (see section 5.3). The clinical relevance of these findings is unknown. Placental transfer of abacavir and lamivudine has been shown to occur in humans. In pregnant women treated with abacavir, more than 800 outcomes after first trimester exposure and more than 1000 outcomes after second and third trimester exposure indicate no malformative and foetal/neonatal effect. In pregnant women treated with lamivudine, more than 1000 outcomes from first trimester and more than 1000 outcomes from second and third trimester exposure indicate no malformative and foeto/neonatal effect. There are no data on the use of Kivexa in pregnancy, however the malformative risk is unlikely in humans based on those data. For patients co-infected with hepatitis who are being treated with a lamivudine containing medicinal product such as Kivexa 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 progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on th

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HOS-093941 · has-warning-information · PDF-Seite 3

The special warnings and precautions relevant to abacavir and lamivudine are included in this section. There are no additional precautions and warnings relevant to Kivexa. Hypersensitivity reactions (see also section 4.8 ) Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section 4.8) 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: 3  • HLA-B*5701 status must always be documented prior to initiating therapy. • Kivexa 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. Ziagen, Trizivir, Triumeq) • Kivexa 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 Kivexa after the onset of hypersensitivity may result in a life-threatening reaction. • After stopping treatment with Kivexa for reasons of a suspected HSR, Kivexa or any other medicinal product containing abacavir (e.g. Ziagen, 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 Kivexa 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

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