Combivir

HOS-083670 · has-adverse-reaction-information · PDF-Seite 11

Adverse reactions have been reported during therapy for HIV disease with lamivudine and zidovudine separately or in combination. For many of these events, it is unclear whether they are related to lamivudine, zidovudine, the wide range of medicinal products used in the management of HIV disease, or as a result of the underlying disease process. As Combivir contains lamivudine and zidovudine, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no evidence of added toxicity following concurrent administration of the two compounds. Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of zidovudine (see section 4.4). Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving Combivir should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Combivir should not be continued (see section 4.4). Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4) 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. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4). Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4). Lamivudine The adverse reactions considered at least possibly related to the treatment are listed below 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Blood and lymphatic systems disorders Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia Very rare: Pure red cell aplasia Metabolis

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HOS-083666 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Zidovudine 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). Combivir is therefore contraindicated in these patients (see section 4.4).

HOS-083665 · has-indication-information · PDF-Seite 2

Combivir is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection (see section 4.2).

HOS-083668 · has-interaction-information · PDF-Seite 7

Combivir contains lamivudine and zidovudine, therefore any interactions identified for these individually are relevant to Combivir. Clinical studies have shown that there are no clinically significant interactions between lamivudine and zidovudine. 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 or nephrotoxic drugs may increase lamivudine exposure. Lamivudine and zidovudine are not significantly metabolised by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. 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- (Possible mechanism) administration ANTIRETROVIRAL MEDICINAL PRODUCTS Didanosine/Lamivudine Interaction not studied. No dosage adjustment necessary. Didanosine /Zidovudine Interaction not studied. Stavudine/Lamivudine Interaction not studied. Combination not Stavudine/Zidovudine In vitro antagonism of anti-HIV recommended. activity between stavudine and zidovudine could result in decreased efficacy of both drugs. ANTI-INFECTIVE PRODUCTS Atovaquone/Lamivudine Interaction not studied. As only limited data available Atovaquone/Zidovudine Zidovudine AUC 33% the clinical significance is (750 mg twice daily with Atovaquone AUC  unknown. food/200 mg thrice daily) Clarithromycin/Lamivudine Interaction not studied. Se

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HOS-083669 · 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. 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. 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). The malformative risk is unlikely in humans based on the mentioned large amount of data. The active ingredients of Combivir may inhibit cellular DNA replication and zidovudine has been shown to be transplacental carcinogen in one animal study (see section 5.3). The clinical relevance of these findings is unknown. For patients co-infected with hepatitis who are being treated with lamivudine containing medicinal products such as Combivir 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 Both lamivudine and zidovudine are excreted in breast milk at similar concentrations to those found in serum. 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 the safety of lamivudine when administered to babies less than three months old. After administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility Neither zidovudine nor lamivudin

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HOS-083667 · has-warning-information · PDF-Seite 3

The special warnings and precautions relevant to both lamivudine and zidovudine are included in this section. There are no additional precautions and warnings relevant to the combination Combivir. 3 It is recommended that separate preparations of lamivudine and zidovudine should be administered in cases where dosage adjustment is necessary (see section 4.2). In these cases, the physician should refer to the individual prescribing information for these medicinal products. The concomitant use of stavudine with zidovudine should be avoided (see section 4.5). Opportunistic infections Patients receiving Combivir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of HIV infection. Haematological adverse reactions Anaemia, neutropenia and leukopenia (usually secondary to neutropenia) can be expected to occur in patients receiving zidovudine. These occurred more frequently at higher zidovudine dosages (1200- 1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease. Haematological parameters should therefore be carefully monitored (see section 4.3) in patients receiving Combivir. These haematological effects are not usually observed before four to six weeks therapy. For patients with advanced symptomatic HIV disease, it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter. In patients with early HIV disease haematological adverse reactions are infrequent. Depending on the overall condition of the patient, blood tests may be performed less often, for example every one to three months. Additionally dosage adjustment of zidovudine may be required if severe anaemia or myelosuppression occurs during treatment with Combivir, or in patients with pre-existing bone marrow compromise e.g. haemoglobin <9 g/dL (5.59 mmol/L) or neutrophil count <1.0 x 109/L (see section 4.2). As dosage adjustment of Combivir is not possible separate preparations of zidovudine and lamivudine should be used. Physicians should refer to the individual prescribing information for these medicinal products. Pancreatitis Cases of pancreatitis have occurred rarely in patients treated with lamivudine an

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