Zeffix · 4.6 Fertility, pregnancy and lactation · 2

HOS-083962 · has-adverse-reaction-information · PDF-Seite 23

Summary of the safety profile The incidence of adverse reactions and laboratory abnormalities (with the exception of elevations of ALT and CPK, see below) were similar between placebo and lamivudine treated patients. The most common adverse reactions reported were malaise and fatigue, respiratory tract infections, throat and tonsil discomfort, headache, abdominal discomfort and pain, nausea, vomiting and diarrhoea. Tabulated list of adverse reactions Adverse reactions are listed below by system organ class and frequency. Frequency categories are only assigned to those adverse reactions considered to be at least possibly causally related to lamivudine. 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) and not known (cannot be estimated from the available data). The frequency categories assigned to the adverse reactions are mainly based on experience from clinical trials including a total of 1 171 patients with chronic hepatitis B receiving lamivudine at 100 mg. Blood and lymphatic system disorders Not known Thrombocytopenia Metabolism and nutrition disorders Very rare Lactic acidosis 23  Immune system disorders Rare Angioedema Hepatobiliary disorders Very common ALT elevations (see section 4.4) Exacerbations of hepatitis, primarily detected by serum ALT elevations, have been reported ‘on-treatment’ and following lamivudine withdrawal. Most events have been self-limited, however fatalities have been observed very rarely (see section 4.4). Skin and subcutaneous tissue disorders Common Rash, pruritus Musculoskeletal and connective tissue disorders Common Elevations of CPK Common Muscle disorders, including myalgia and cramps* Not known Rhabdomyolysis * In Phase III studies frequency observed in the lamivudine treatment group was not greater than observed in the placebo group Paediatric population Based on limited data in children aged 2 to 17 years, there were no new safety issues identified compared to adults. Other special populations In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paraesthesia) have been reported. In patients with chronic hepatitis B there was no observed difference in incidence of these event

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HOS-083956 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The incidence of adverse reactions and laboratory abnormalities (with the exception of elevations of ALT and CPK, see below) were similar between placebo and lamivudine treated patients. The most common adverse reactions reported were malaise and fatigue, respiratory tract infections, throat and tonsil discomfort, headache, abdominal discomfort and pain, nausea, vomiting and diarrhoea. Tabulated list of adverse reactions Adverse reactions are listed below by system organ class and frequency. Frequency categories are only assigned to those adverse reactions considered to be at least possibly causally related to lamivudine. 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) and not known (cannot be estimated from the available data). The frequency categories assigned to the adverse reactions are mainly based on experience from clinical trials including a total of 1 171 patients with chronic hepatitis B receiving lamivudine at 100 mg. Blood and lymphatic system disorders Not known Thrombocytopenia Metabolism and nutrition disorders Very rare Lactic acidosis Immune system disorders Rare Angioedema Hepatobiliary disorders Very common ALT elevations (see section 4.4) Exacerbations of hepatitis, primarily detected by serum ALT elevations, have been reported ‘on-treatment’ and following lamivudine withdrawal. Most events have been self-limited, however fatalities have been observed very rarely (see section 4.4). Skin and subcutaneous tissue disorders Common Rash, pruritus Musculoskeletal and connective tissue disorders Common Elevations of CPK Common Muscle disorders, including myalgia and cramps* Not known Rhabdomyolysis * In Phase III studies frequency observed in the lamivudine treatment group was not greater than observed in the placebo group 8 Paediatric population Based on limited data in children aged 2 to 17 years, there were no new safety issues identified compared to adults. Other special populations In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paraesthesia) have been reported. In patients with chronic hepatitis B there was no observed difference in incidence of

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HOS-083958 · has-contraindication-information · PDF-Seite 19

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

HOS-083952 · has-contraindication-information · PDF-Seite 4

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

HOS-083957 · has-indication-information · PDF-Seite 17

Zeffix is indicated for the treatment of chronic hepatitis B in adults with: ▪ compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and/or fibrosis. Initiation of lamivudine treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier is not available or appropriate (see section 5.1). ▪ decompensated liver disease in combination with a second agent, without cross-resistance to lamivudine (see section 4.2).

HOS-083951 · has-indication-information · PDF-Seite 2

Zeffix is indicated for the treatment of chronic hepatitis B in adults with: ▪ compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and/or fibrosis. Initiation of lamivudine treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier is not available or appropriate (see section 5.1). ▪ decompensated liver disease in combination with a second agent without cross-resistance to lamivudine (see section 4.2).

HOS-083960 · 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 elimination of unchanged substance. Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when their 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. 21 Substances shown to be predominately excreted either via the active organic anionic pathway, or by glomerular filtration are unlikely to yield clinically significant interactions with lamivudine. Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg increased lamivudine exposure by about 40 %. Lamivudine had no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine had no effect on the pharmacokinetics of lamivudine (see section 5.2). Lamivudine has no pharmacokinetic interaction with alpha-interferon when the two medicinal products are concurrently administered. There were no observed clinically significant adverse interactions in patients taking lamivudine concurrently with commonly used immunosuppressant medicinal products (e.g. cyclosporin A). However, formal interaction studies have not been performed. Emtricitabine Due to similarities, Zeffix should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Zeffix should not be taken with any other medicinal products containing lamivudine (see section 4.4). Cladribine 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

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HOS-083954 · 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 elimination of unchanged substance. Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when their 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. Substances shown to be predominately excreted either via the active organic anionic pathway, or by glomerular filtration are unlikely to yield clinically significant interactions with lamivudine. Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg increased lamivudine exposure by about 40 %. Lamivudine had no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine had no effect on the pharmacokinetics of lamivudine (see section 5.2). Lamivudine has no pharmacokinetic interaction with alpha-interferon when the two medicinal products are concurrently administered. There were no observed clinically significant adverse interactions in patients taking lamivudine concurrently with commonly used immunosuppressant medicinal products (e.g. cyclosporin A). However, formal interaction studies have not been performed. 6 Emtricitabine Due to similarities, Zeffix should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Zeffix should not be taken with any other medicinal products containing lamivudine (see section 4.4). Cladribine 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

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HOS-083961 · has-pregnancy-information · PDF-Seite 22

Pregnancy 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. Available human data from the Antiretroviral Pregnancy Registry reporting more than 1 000 outcomes from first trimester and more than 1 000 outcomes from second and third trimester exposure in pregnant women indicate no malformative and foeto/neonatal effect. Less than 1 % of these women have been treated for HBV, whereas the majority was treated for HIV at higher doses and with other concomitant medications. Zeffix can be used during pregnancy if clinically needed. For patients 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. 22 Breast-feeding 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 (less than 4 % of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. The total amount of lamivudine ingested by a breastfed infant is very low and is therefore likely to result in exposures exerting a sub-optimal antiviral effect. Maternal hepatitis B is not a contraindication to breast-feeding if the newborn is adequately managed for hepatitis B prevention at birth, and there is no evidence that the low concentration of lamivudine in human milk leads to adverse reactions in breastfed infants. Therefore, breastfeeding may be considered in breast-feeding mothers being treated with lamivudine for HBV taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of HBV, despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding to reduce the risk of the emergence of lamivudine resistant mutants in the infant. Fertility Reproductive studies in animals have shown no effect on male or female fertility (see section 5.3). 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 post-natally to nucleoside analogue

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HOS-083955 · has-pregnancy-information · PDF-Seite 7

Pregnancy 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. Available human data from the Antiretroviral Pregnancy Registry reporting more than 1 000 outcomes from first trimester and more than 1 000 outcomes from second and third trimester exposure in pregnant women indicate no malformative and foeto/ neonatal effect. Less than 1 % of these women have been treated for HBV, whereas the majority was treated for HIV at higher doses and with other concomitant medications. Zeffix can be used during pregnancy if clinically needed. For patients 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. Breast-feeding 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 (less than 4 % of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. The total amount of lamivudine ingested by a breastfed infant is very low and is therefore likely to result in exposures exerting a sub-optimal antiviral effect. Maternal hepatitis B is not a contraindication to breast-feeding if the newborn is adequately managed for hepatitis B prevention at birth, and there is no evidence that the low concentration of lamivudine in human milk leads to adverse reactions in breastfed infants. Therefore, breastfeeding may be considered in breast-feeding mothers being treated with lamivudine for HBV taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of HBV, despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding to reduce the risk of the emergence of lamivudine resistant mutants in the infant. Fertility Reproductive studies in animals have shown no effect on male or female fertility (see section 5.3). 7 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 post-natally to nucleoside analogu

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HOS-083953 · has-warning-information · PDF-Seite 4

Exacerbations of hepatitis Exacerbations on treatment Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline. In patients with compensated liver disease, these increases in serum ALT were generally not accompanied by an increase in serum bilirubin concentrations or signs of hepatic decompensation. HBV viral subpopulations with reduced susceptibility to lamivudine (YMDD mutant HBV) have been identified with extended therapy. In some patients the development of YMDD mutant HBV can lead to exacerbation of hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV DNA (see section 4.2). In patients who have YMDD mutant HBV, a switch to or addition of an alternative agent without cross resistance to lamivudine based on therapeutic guidelines should be considered (see section 5.1). Exacerbations after treatment discontinuation Acute exacerbation of hepatitis has been observed in patients who have discontinued hepatitis B therapy and is usually detected by serum ALT elevations and re-emergence of HBV DNA. In the controlled Phase III trials with no-active-treatment follow-up, the incidence of post-treatment ALT elevations (more than 3 times baseline) was higher in lamivudine-treated patients (21 %) compared with those receiving placebo (8 %). However, the proportion of patients who had post-treatment elevations associated with bilirubin elevations was low and similar in both treatment arms (see Table 3 in section 5.1). For lamivudine-treated patients, the majority of post-treatment ALT elevations occurred between 8 and 12 weeks post-treatment. Most events have been self-limiting, however some fatalities have been observed. If Zeffix is discontinued, patients should be periodically monitored both clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least four months, and then as clinically indicated. Exacerbations in patients with decompensated cirrhosis Transplantation recipients and patients with decompensated cirrhosis are at greater risk from active viral replication. Due to the marginal liver function in these patients, hepatitis reactivation at 4 discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal decompensation. Th

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HOS-083959 · has-warning-information · PDF-Seite 19

Exacerbations of hepatitis Exacerbations on treatment Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline. In patients with compensated liver disease, these increases in serum ALT were generally not accompanied by an increase in serum bilirubin concentrations or signs of hepatic decompensation. HBV viral subpopulations with reduced susceptibility to lamivudine (YMDD mutant HBV) have been identified with extended therapy. In some patients the development of YMDD mutant HBV can lead to exacerbation of hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV DNA (see section 4.2). In patients who have YMDD mutant HBV, a switch to or addition of an alternative agent without cross-resistance to lamivudine based on therapeutic guideline should be considered (see section 5.1). Exacerbations after treatment discontinuation Acute exacerbation of hepatitis has been observed in patients who have discontinued hepatitis B therapy and is usually detected by serum ALT elevations and re-emergence of HBV DNA. In the controlled Phase III trials with no-active-treatment follow-up, the incidence of post-treatment ALT elevations (more than 3 times baseline) was higher in lamivudine-treated patients (21 %) compared with those receiving placebo (8 %). However, the proportion of patients who had post-treatment elevations associated with bilirubin elevations was low and similar in both treatment arms (see Table 3 in section 5.1). For lamivudine-treated patients, the majority of post-treatment ALT elevations occurred between 8 and 12 weeks post-treatment. Most events have been self-limiting, however some fatalities have been observed. If Zeffix is discontinued, patients should be periodically monitored both 19 clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least four months, and then as clinically indicated. Exacerbations in patients with decompensated cirrhosis Transplantation recipients and patients with decompensated cirrhosis are at greater risk from active viral replication. Due to the marginal liver function in these patients, hepatitis reactivation at discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal decompensation. The

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