Epivir · 4.1 Therapeutic indications · 1

HOS-083217 · has-adverse-reaction-information · PDF-Seite 23

The following adverse reactions have been reported during therapy for HIV disease with Epivir. 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 (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), 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 Metabolism and nutrition disorders Very rare: lactic acidosis Nervous system disorders Common: headache, insomnia Very rare: peripheral neuropathy (or paraesthesia) Respiratory, thoracic and mediastinal disorders Common: cough, nasal symptoms Gastrointestinal disorders Common: nausea, vomiting, abdominal pain or cramps, diarrhoea Rare: pancreatitis, elevations in serum amylase Hepatobiliary disorders Uncommon: transient elevations in liver enzymes (AST, ALT) Rare: hepatitis Skin and subcutaneous tissue disorders Common: rash, alopecia Rare: angioedema Musculoskeletal and connective tissue disorders Common: arthralgia, muscle disorders Rare: rhabdomyolysis General disorders and administration site conditions Common: fatigue, malaise, fever 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 23 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 combined antiretroviral exposure (CART). The frequency of which is unknown (see section 4.4). Paediatric population 1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW Trial (COL105677), 669 of whom received abacavir and lamivudi

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HOS-083211 · has-adverse-reaction-information · PDF-Seite 8

The following adverse reactions have been reported during therapy for HIV disease with Epivir. 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 (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), 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 Metabolism and nutrition disorders Very rare: lactic acidosis Nervous system disorders Common: headache, insomnia Very rare: peripheral neuropathy (or paraesthesia) Respiratory, thoracic and mediastinal disorders Common: cough, nasal symptoms Gastrointestinal disorders Common: nausea, vomiting, abdominal pain or cramps, diarrhoea Rare: pancreatitis, elevations in serum amylase Hepatobiliary disorders Uncommon: transient elevations in liver enzymes (AST, ALT) Rare: hepatitis Skin and subcutaneous tissue disorders Common: rash, alopecia Rare: angioedema Musculoskeletal and connective tissue disorders Common: arthralgia, muscle disorders Rare: rhabdomyolysis General disorders and administration site conditions Common: fatigue, malaise, fever 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). 8 Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term combined antiretroviral exposure (CART). The frequency of which is unknown (see section 4.4). Paediatric population 1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW study (COL105677), 669 of whom received abacavir and lamivudine eithe

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HOS-083207 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-083213 · has-contraindication-information · PDF-Seite 19

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-083206 · has-indication-information · PDF-Seite 2

Epivir is indicated as part of antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children.

HOS-083212 · has-indication-information · PDF-Seite 17

Epivir is indicated as part of antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children.

HOS-083209 · has-interaction-information · PDF-Seite 6

Interaction studies have only been performed in adults. The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding and almost complete renal clearance. Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did not interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary (see section 4.2). Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. When concomitant administration is warranted, patients should be monitored clinically. Co-administration of lamivudine with high doses of co-trimoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis should be avoided. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is active renal secretion via the organic cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine. The nucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and are unlikely to interact with lamivudine. A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine (see section 5.2). Due to similarities, Epivir should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Epivir should not be taken with any other medicinal products containing lamivudine (see section 4.4). 6 In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of lamivudine with cladribine is not recommended (see section 4.4). Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products metabolised by this system (e.g. PIs) unlikely. Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) wi

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HOS-083215 · has-interaction-information · PDF-Seite 21

Interaction studies have only been performed in adults. The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding and almost complete renal clearance. Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did not interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary (see section 4.2). Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. When concomitant administration is warranted, patients should be monitored clinically. Co-administration of lamivudine with high doses of co-trimoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis should be avoided. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is active renal secretion via the organic cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine. The nucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and are unlikely to interact with lamivudine. A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine (see section 5.2). 21 Due to similarities, Epivir should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Epivir should not be taken with any other medicinal products containing lamivudine (see section 4.4). In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of lamivudine with cladribine is not recommended (see section 4.4). Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products metabolised by this system (e.g. PIs) unlikely. Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g)

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HOS-083216 · has-pregnancy-information · PDF-Seite 22

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 lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (see section 5.3). Placental transfer of lamivudine has been shown to occur in humans. More than 1000 outcomes from first trimester and more than 1000 outcomes from second and third trimester exposure in pregnant women indicate no evidence of malformative or foeto/neonatal toxicity of Epivir. Epivir can be used during pregnancy if clinically needed. The malformative risk is unlikely in humans based on those data. For patients co-infected with hepatitis who are being treated with lamivudine 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 infants exposed in utero and/or postnatally to nucleoside analogues (see section 4.4). Breast-feeding Following oral administration lamivudine was 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. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility Studies in animals showed that lamivudine had no effect on fertility (see section 5.3). 22

HOS-083210 · has-pregnancy-information · PDF-Seite 7

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 lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (see section 5.3). Placental transfer of lamivudine has been shown to occur in humans. More than 1000 outcomes from first trimester and more than 1000 outcomes from second and third trimester exposure in pregnant women indicate no evidence of malformative or foeto/neonatal toxicity of Epivir. Epivir can be used during pregnancy if clinically needed. The malformative risk is unlikely in humans based on those data. For patients co-infected with hepatitis who are being treated with lamivudine 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 infants exposed in utero and/or postnatally to nucleoside analogues (see section 4.4). Breast-feeding Following oral administration lamivudine was 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. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility Studies in animals showed that lamivudine had no effect on fertility (see section 5.3).

HOS-083214 · has-warning-information · PDF-Seite 19

Epivir is not recommended for use as monotherapy. Renal impairment In patients with moderate –to- severe renal impairment, the terminal plasma half-life of lamivudine is increased due to decreased clearance, therefore the dose should be adjusted (see section 4.2). Triple nucleoside therapy There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when lamivudine was combined with tenofovir disoproxil fumarate and abacavir as well as with tenofovir disoproxil fumarate and didanosine as a once daily regimen. Opportunistic infections Patients receiving Epivir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases. Pancreatitis Cases of pancreatitis have occurred rarely. However, it is not clear whether these cases were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with Epivir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur. 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. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogues, these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV. Weight and metabolic parameters An increase in weight and in levels of blood lipids and glucose may occur durin

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HOS-083208 · has-warning-information · PDF-Seite 4

Epivir is not recommended for use as monotherapy. Renal impairment In patients with moderate to severe renal impairment, the terminal plasma half-life of lamivudine is increased due to decreased clearance, therefore the dose should be adjusted (see section 4.2). Triple nucleoside therapy There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when lamivudine was combined with tenofovir disoproxil fumarate and abacavir as well as with tenofovir disoproxil fumarate and didanosine as a once daily regimen. Opportunistic infections Patients receiving Epivir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases. Pancreatitis Cases of pancreatitis have occurred rarely. However, it is not clear whether these cases were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with Epivir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur. 4 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. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV. Weight and metabolic parameters An increase in weight and

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