Ziagen · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-083976 · has-adverse-reaction-information · PDF-Seite 26

For many adverse reactions reported, it is unclear whether they are related to Ziagen, to the wide range of medicinal products used in the management of HIV infection or as a result of the disease process. Many of the adverse reactions listed below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these 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. Many of the adverse reactions have not been treatment limiting. The following convention has been used for their classification: 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). Metabolism and nutrition disorders Common: anorexia Very rare: lactic acidosis Nervous system disorders Common: headache Gastrointestinal disorders Common: nausea, vomiting, diarrhoea Rare: pancreatitis Skin and subcutaneous tissue disorders Common: rash (without systemic symptoms) Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis General disorders and administration site conditions Common: fever, lethargy, fatigue Description of Selected Adverse Reactions Abacavir hypersensitivity reactions The signs and symptoms of this HSR are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text. Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise. 26 Skin Rash (usually maculopapular or urticarial) Gastrointestinal tract Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration Respiratory tract Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory

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HOS-083970 · has-adverse-reaction-information · PDF-Seite 7

For many adverse reactions reported, it is unclear whether they are related to Ziagen, to the wide range of medicinal products used in the management of HIV infection or as a result of the disease process. Many of the adverse reactions listed below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these 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. Many of the adverse reactions have not been treatment limiting. The following convention has been used for their classification: 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). 7 Metabolism and nutrition disorders Common: anorexia Very rare: lactic acidosis Nervous system disorders Common: headache Gastrointestinal disorders Common: nausea, vomiting, diarrhoea Rare: pancreatitis Skin and subcutaneous tissue disorders Common: rash (without systemic symptoms) Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis General disorders and administration site conditions Common: fever, lethargy, fatigue Description of Selected Adverse Reactions Abacavir hypersensitivity reactions The signs and symptoms of this HSR are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text. Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise. Skin Rash (usually maculopapular or urticarial) Gastrointestinal tract Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration Respiratory tract Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory

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HOS-083966 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to abacavir or to any of the excipients listed in section 6.1. See sections 4.4 and 4.8.

HOS-083972 · has-contraindication-information · PDF-Seite 21

Hypersensitivity to abacavir or to any of the excipients listed in section 6.1. See sections 4.4 and 4.8.

HOS-083965 · has-indication-information · PDF-Seite 2

Ziagen is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults, adolescents and children (see sections 4.4 and 5.1). The demonstration of the benefit of Ziagen is mainly based on results of studies performed with a twice daily regimen, in treatment-naïve adult patients on combination therapy (see section 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-083971 · has-indication-information · PDF-Seite 20

Ziagen is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults, adolescents and children (see sections 4.4 and 5.1). The demonstration of the benefit of Ziagen is mainly based on results of studies performed in treatment-naïve adult patients on combination therapy with a twice daily regimen (see section 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-083974 · has-interaction-information · PDF-Seite 24

The potential for P450 mediated interactions with other medicinal products involving abacavir is low. In vitro studies have shown that abacavir has potential to inhibit cytochrome P450 1A1 (CYP1A1). P450 does not play a major role in the metabolism of abacavir, and abacavir shows limited potential to inhibit metabolism mediated by CYP 3A4. Abacavir has also been shown in vitro not to inhibit CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism 24 has not been observed in clinical studies. Therefore, there is little potential for interactions with antiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine. Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir. Ethanol: the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. These findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol. Methadone: in a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with methadone showed a 35% reduction in abacavir Cmax and a one hour delay in tmax but the AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study abacavir increased the mean methadone systemic clearance by 22%. The induction of drug metabolising enzymes cannot therefore be excluded. Patients being treated with methadone and abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as occasionally methadone re-titration may be required. Retinoids: retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied. Riociguat: In vitro, abacavir inhibits CYP1A1. Concomitant administration of a single dose of riociguat (0.5 mg) to HIV patients receiving the combination of abacavir/dolutegravir/lamivudine (600 mg/50 mg/300 mg once daily) led to an approximately three-fold higher riociguat AUC(0-∞) when compared to historical riociguat AUC(0-∞) reported in healthy subjects. Riociguat dose may need to be reduced. Consult the riociguat prescribing information for dosing

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HOS-083968 · has-interaction-information · PDF-Seite 6

The potential for P450 mediated interactions with other medicinal products involving abacavir is low. In vitro studies have shown that abacavir has potential to inhibit cytochrome P450 1A1 (CYP1A1). P450 does not play a major role in the metabolism of abacavir, and abacavir shows limited potential to inhibit metabolism mediated by CYP 3A4. Abacavir has also been shown in vitro not to inhibit, CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism has not been observed in clinical studies. Therefore, there is little potential for interactions with antiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine. Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir. Ethanol: the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. These findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol. Methadone: in a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with methadone showed a 35% reduction in abacavir Cmax and a one hour delay in tmax but the AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study abacavir increased the mean methadone systemic clearance by 22%. The induction of drug metabolising enzymes cannot therefore be excluded. Patients being treated with methadone and abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as occasionally methadone re-titration may be required. Retinoids: retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied. 6 Riociguat: In vitro, abacavir inhibits CYP1A1. Concomitant administration of a single dose of riociguat (0.5 mg) to HIV patients receiving the combination of abacavir/dolutegravir/lamivudine (600 mg/50 mg/300 mg once daily) led to an approximately three-fold higher riociguat AUC(0-∞) when compared to historical riociguat AUC(0-∞) reported in healthy subjects. Riociguat dose may need to be reduced. Consult the riociguat prescribing information for dosing

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HOS-083975 · has-pregnancy-information · PDF-Seite 25

Pregnancy As a general rule, when deciding to use antiretroviral agents for the treatment HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, both animal data as well as clinical experience in pregnant women should be taken into account. Animal studies have shown toxicity to the developing embryo and foetus in rats, but not in rabbits (see section 5.3). Abacavir has been shown to be carcinogenic in animal models (see section 5.3). Clinical relevance in human of these data is unknown. Placental transfer of abacavir and/or its related metabolites has been shown to occur in human. In pregnant women, 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 of abacavir. The malformative risk is unlikely in humans based on those data. 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. There are no data available on the safety of abacavir when administered to babies less 25 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 abacavir had no effect on fertility (see section 5.3).

HOS-083969 · has-pregnancy-information · PDF-Seite 7

Pregnancy As a general rule, when deciding to use antiretroviral agents for the treatment HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, both animal data as well as clinical experience in pregnant women should be taken into account. Animal studies have shown toxicity to the developing embryo and foetus in rats, but not in rabbits (see section 5.3). Abacavir has been shown to be carcinogenic in animal models (see section 5.3). Clinical relevance in human of these data is unknown. Placental transfer of abacavir and/or its related metabolites has been shown to occur in human. In pregnant women, 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 of abacavir. The malformative risk is unlikely in humans based on those data. 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. There are no data available on the safety of abacavir 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 abacavir had no effect on fertility (see section 5.3).

HOS-083967 · has-warning-information · PDF-Seite 3

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. • Ziagen 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, Trizivir, Triumeq) • Ziagen 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 Ziagen after the onset of hypersensitivity may result in a life-threatening reaction. • After stopping treatment with Ziagen for reasons of a suspected HSR, Ziagen or any other medicinal product containing abacavir (e.g. Kivexa, 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 Ziagen 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 to abacavir include fever and/or rash. Other signs and symptoms that have been observed as part of abacavir HSR are described in detail in section 4.8 (Description of selected a

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HOS-083973 · has-warning-information · PDF-Seite 21

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: 21  • HLA-B*5701 status must always be documented prior to initiating therapy. • Ziagen 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, Trizivir, Triumeq) • Ziagen 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 Ziagen after the onset of hypersensitivity may result in a life-threatening reaction. • After stopping treatment with Ziagen for reasons of a suspected HSR, Ziagen or any other medicinal product containing abacavir (e.g. Kivexa, 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 Ziagen oral solution. • 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 to abacavir include fever and/or rash. Other signs and symptoms that have been observed as part of abacavir HSR are described in d

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