Norvir · 4.1 Therapeutic indications · 2

HOS-083291 · has-adverse-reaction-information · PDF-Seite 24

Summary of the safety profile Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the specific co-administered protease inhibitor. For information on adverse reactions refer to the SmPC of the specific co-administered protease inhibitor. Adverse reactions from clinical trials and post-marketing experience in adult patients The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhoea, nausea, 24 vomiting, abdominal pain (upper and lower)), neurological disturbances (including paraesthesia and oral paraesthesia) and fatigue/asthenia. Tabulated list of adverse reactions The following adverse reactions of moderate to severe intensity with possible or probable relationship to ritonavir have been reported. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: 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); not known (cannot be estimated from the available data). Events noted as having a frequency not known were identified via post-marketing surveillance Adverse reactions in clinical studies and post-marketing in adult patients System Order Class Frequency Adverse reaction Blood and lymphatic system Common Decreased white blood cells, decreased disorders haemoglobin, decreased neutrophils, increased eosinophils, thrombocytopenia Uncommon Increased neutrophils Immune system disorders Common Hypersensitivity, including urticaria and face oedema. Rare Anaphylaxis Metabolism and nutrition Common Hypercholesterolaemia, disorders hypertriglyceridaemia, gout, oedema and peripheral oedema, dehydration (usually associated with gastrointestinal symptoms) Unco

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HOS-083297 · has-adverse-reaction-information · PDF-Seite 57

Summary of the safety profile Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the specific co-administered protease inhibitor. For information on adverse reactions refer to the SmPC of the specific co-administered protease inhibitor. Adverse reactions from clinical trials and post-marketing experience in adult patients The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhoea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paraesthesia and oral paraesthesia) and fatigue/asthenia. Tabulated list of adverse reactions The following adverse reactions of moderate to severe intensity with possible or probable relationship to ritonavir have been reported. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: 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); not known (cannot be estimated from the available data). Events noted as having frequency not known were identified via post-marketing surveillance. 57  Adverse reactions in clinical studies and post-marketing in adult patients System Order Class Frequency Adverse reaction Blood and lymphatic system Common Decreased white blood cells, decreased disorders haemoglobin, decreased neutrophils, increased eosinophils, thrombocytopenia Uncommon Increased neutrophils Immune system disorders Common Hypersensitivity including urticaria, and face oedema Rare Anaphylaxis Metabolism and nutrition Common Hypercholesterolaemia, disorders hypertriglyceridaemia, gout, oedema and peripheral oedema, dehydration (usually associated with gastrointestinal symptoms) Uncommon Diabetes mellitus

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HOS-083293 · has-contraindication-information · PDF-Seite 35

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Ritonavir should not be given to patients with decompensated liver disease. In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and CYP2D6- mediated biotransformations. The enzyme-modulating effect of ritonavir may be dose dependent (see section 5.1). The following medicines are contraindicated when used with ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to inhibit metabolism of the co-administered medicinal product, resulting in increased exposure to the co-administered medicinal product and risk of clinically significant adverse effects: Medicinal Product Medicinal Products Rationale Class within Class Concomitant medicinal product levels increased or decreased 1-Adrenoreceptor Alfuzosin Increased plasma concentrations of alfuzosin Antagonist which may lead to severe hypotension (see section 4.5). 35 Analgesics Pethidine, Increased plasma concentrations of propoxyphene norpethidine and propoxyphene. Thereby, increasing the risk of serious respiratory depression or haematologic abnormalities, or other serious adverse effects from these agents. Antianginal Ranolazine Increased plasma concentrations of ranolazine which may increase the potential for serious and/or life-threatening reactions (see section 4.5). Anticancer Neratinib Increased plasma concentrations of neratinib which may increase the potential for serious and/or life-threatening reactions including hepatotoxicity (see section 4.5). Venetoclax Increased

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HOS-083287 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Ritonavir should not be given to patients with decompensated liver disease. In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and CYP2D6- mediated biotransformations. The enzyme-modulating effect of ritonavir may be dose dependent (see section 5.1). The following medicines are contraindicated when used with ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to inhibit 3 metabolism of the co-administered medicinal product, resulting in increased exposure to the co-administered medicinal product and risk of clinically significant adverse effects: Medicinal Product Medicinal Products Rationale Class within Class Concomitant medicinal product levels increased or decreased 1-Adrenoreceptor Alfuzosin Increased plasma concentrations of alfuzosin Antagonist which may lead to severe hypotension (see section 4.5). Analgesics Pethidine, Increased plasma concentrations of propoxyphene norpethidine and propoxyphene. Thereby, increasing the risk of serious respiratory depression or haematologic abnormalities, or other serious adverse effects from these agents. Antianginal Ranolazine Increased plasma concentrations of ranolazine which may increase the potential for serious and/or life-threatening reactions (see section 4.5). Anticancer Neratinib Increased plasma concentrations of neratinib which may increase the potential for serious and/or life-threatening reactions including hepatotoxicity (see section 4.5).

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HOS-083286 · has-indication-information · PDF-Seite 2

Ritonavir is indicated as a pharmacokinetic enhancer of co-administered protease inhibitors as part of antiretroviral combination therapy in human immunodeficiency virus-1 (HIV-1) infected patients (adults and children of 2 years of age and older) (see sections 4.2, 4.4, 5.1, 5.2).

HOS-083292 · has-indication-information · PDF-Seite 34

Ritonavir is indicated as a pharmacokinetic enhancer of co-administered protease inhibitors as part of antiretroviral combination therapy in human immunodeficiency virus-1 (HIV-1) infected patients (adults and children of 2 years of age and older) (see sections 4.2, 4.4, 5.1, 5.2).

HOS-083289 · has-interaction-information · PDF-Seite 9

Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Co-administration of ritonavir and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse effects. For selected 9 medicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over time. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease over time (e.g. digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinal products” below). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways, and may result in decreased systemic exposure to such medicinal products, which could decease or shorten their therapeutic effect. Important information regarding medicinal product interactions when ritonavir is used as a pharmacokinetic enhancer is also contained in the SmPC of the co-administered protease inhibitor. Medicinal products that affect ritonavir levels Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing St John’s wort (Hypericum perforatum). This is due to the induction of medicinal product metabolising enzymes by St John’s wort. Herbal preparations containing St John’s wort must not be used in combination with ritonavir. If a patient is already taking St John’s wort, St John’s wort should be stopped and if possible check viral levels. Ritonavir levels may increase on stopping St John’s wort. The dose of ritonavir may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John’s wort (see section 4.3). Serum levels of ritonavir may be affected by select co-administered medicinal products (e.g. phenytoin and rifampicin). These interactions are noted in the medicinal product interaction tables below. Medicinal product that are affected by the use of ritonavir Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal pr

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HOS-083295 · has-interaction-information · PDF-Seite 42

Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Co-administration of ritonavir and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse effects. For selected medicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over time. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease over time (e.g. digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinal products” below). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways, and may result in decreased systemic exposure to such medicinal products, which could decease or shorten their therapeutic effect. Important information regarding medicinal product interactions when ritonavir is used as a pharmacokinetic enhancer is also contained in the SmPC of the co-administered protease inhibitor. Medicinal products that affect ritonavir levels Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing St John’s wort (Hypericum perforatum). This is due to the induction of medicinal product metabolising enzymes by St John’s wort. Herbal preparations containing St John’s wort must not be used in combination with ritonavir. If a patient is already taking St John’s wort, St John’s wort should be stopped and if possible check viral levels. Ritonavir levels may increase on stopping St John’s wort. The dose of ritonavir may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John’s wort (see section 4.3). Serum levels of ritonavir may be affected by select co-administered medicinal products (e.g. phenytoin and rifampicin). These interactions are noted in the medicinal product interaction tables below. Medicinal products that are affected by the use of ritonavir Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal products are listed in the tables below. This list is not

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HOS-083290 · has-pregnancy-information · PDF-Seite 24

Pregnancy A large amount (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of these, 2800 live births were exposed during the first trimester. These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic enhancer for other PIs. These data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems. Animal data have shown reproductive toxicity (see section 5.3). Norvir can be used during pregnancy if clinically needed. Ritonavir adversely interacts with oral contraceptives (OCs). Therefore, an alternative, effective and safe method of contraception should be used during treatment. Breast-feeding Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, women living with HIV should not breast-feed their infants if they are receiving Norvir. Fertility No human data on the effect of ritonavir on fertility are available. Animal studies do not indicate harmful effects of ritonavir on fertility (see section 5.3).

HOS-083296 · has-pregnancy-information · PDF-Seite 57

Pregnancy A large amount (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of these, 2800 live births were exposed during the first trimester. These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic enhancer for other PIs. These data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems. Animal data have shown reproductive toxicity (see section 5.3). Norvir can be used during pregnancy if clinically needed. Ritonavir adversely interacts with oral contraceptives (OCs). Therefore, an alternative, effective and safe method of contraception should be used during treatment. Breast-feeding Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, women living with HIV should not breast-feed their infants if they are receiving Norvir. Fertility No human data on the effect of ritonavir on fertility are available. Animal studies do not indicate harmful effects of ritonavir on fertility (see section 5.3).

HOS-083288 · has-warning-information · PDF-Seite 5

General Ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors. Full details on the warnings and precautions relevant to that particular protease inhibitor should be considered, therefore the SmPC for the particular protease inhibitor must be consulted. Ritonavir is not a cure for HIV-1 infection or AIDS. Patients receiving ritonavir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of 5 HIV-1 infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases. Patients with coexisting conditions Patients with chronic diarrhoea or malabsorption Extra monitoring is recommended when diarrhoea occurs. The relatively high frequency of diarrhoea during treatment with ritonavir may compromise the absorption and efficacy (due to decreased compliance) of ritonavir or other concurrent medicinal products. Serious persistent vomiting and/or diarrhoea associated with ritonavir use might also compromise renal function. It is advisable to monitor renal function in patients with renal function impairment. Haemophilia There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than a half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding. Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate. Pancreatitis Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such

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HOS-083294 · has-warning-information · PDF-Seite 37

General Ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors. Full details on the warnings and precautions relevant to that particular protease inhibitor should be considered, therefore the SmPC for the particular protease inhibitor must be consulted. Ritonavir is not a cure for HIV-1 infection or AIDS. Patients receiving Ritonavir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases. 37 Patients with co-existing conditions Patients with chronic diarrhoea or malabsorption Extra monitoring is recommended when diarrhoea occurs. The relatively high frequency of diarrhoea during treatment with ritonavir may compromise the absorption and efficacy (due to decreased compliance) of ritonavir or other concurrent medicinal products. Serious persistent vomiting and/or diarrhoea associated with ritonavir use might also compromise renal function. It is advisable to monitor renal function in patients with renal function impairment. Haemophilia There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than a half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate. Pancreatitis Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (suc

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