Celsentri · 4.1 Therapeutic indications · 1

HOS-094838 · has-adverse-reaction-information · PDF-Seite 40

Summary of the safety profile Adults Assessment of treatment related adverse reactions is based on pooled data from two Phase 2b/3 studies in treatment-experienced adult patients (MOTIVATE 1 and MOTIVATE 2) and one study in treatment-naïve adult patients (MERIT) infected with CCR5-tropic HIV-1 (see sections 4.4 and 5.1). The most frequently reported adverse reactions occurring in the Phase 2b/3 studies were nausea, diarrhoea, fatigue and headache. These adverse reactions were common (≥ 1/100 to < 1/10). 40 Tabulated list of adverse reactions The adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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) , or not known (cannot be estimated from the available data). The adverse reactions and laboratory abnormalities presented below are not exposure adjusted. Table 3: Adverse reactions observed in clinical trials or post-marketing System Organ Class Adverse reaction Frequency Infections and infestations Pneumonia, oesophageal candidiasis uncommon Neoplasm benign, malignant and Bile duct cancer, diffuse large B-cell rare unspecified (including cysts and lymphoma, Hodgkin’s disease, polyps) metastases to bone, metastases to liver, metastases to peritoneum, nasopharyngeal cancer, oesophageal carcinoma Blood and lymphatic system Anaemia common disorders Pancytopenia, granulocytopenia rare Metabolism and nutrition disorders Anorexia common Psychiatric disorders Depression, insomnia common Nervous system disorders Seizures and seizure disorders uncommon Cardiac disorders Angina pectoris rare Vascular disorders Postural hypotension (see section 4.4) uncommon Gastrointestinal disorders Abdominal pain, flatulence, nausea common Hepatobiliary

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HOS-094832 · has-adverse-reaction-information · PDF-Seite 14

Summary of the safety profile Adults Assessment of treatment related adverse reactions is based on pooled data from two Phase 2b/3 studies in treatment-experienced adult patients (MOTIVATE 1 and MOTIVATE 2) and one study in treatment-naïve adult patients (MERIT) infected with CCR5-tropic HIV-1 (see sections 4.4 and 5.1). The most frequently reported adverse reactions occurring in the Phase 2b/3 studies were nausea, diarrhoea, fatigue and headache. These adverse reactions were common (≥ 1/100 to < 1/10). Tabulated list of adverse reactions 14 The adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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 <1/1,000) , not known (cannot be estimated from the available data). The adverse reactions and laboratory abnormalities presented below are not exposure adjusted. Table 3: Adverse reactions observed in clinical trials or post-marketing System Organ Class Adverse reaction Frequency Infections and infestations Pneumonia, oesophageal candidiasis uncommon Neoplasm benign, malignant and Bile duct cancer, diffuse large B-cell rare unspecified (including cysts and lymphoma, Hodgkin’s disease, polyps) metastases to bone, metastases to liver, metastases to peritoneum, nasopharyngeal cancer, oesophageal carcinoma Blood and lymphatic system Anaemia common disorders Pancytopenia, granulocytopenia rare Metabolism and nutrition disorders Anorexia common Psychiatric disorders Depression, insomnia common Nervous system disorders Seizures and seizure disorders uncommon Cardiac disorders Angina pectoris rare Vascular disorders Postural hypotension (see section 4.4) uncommon Gastrointestinal disorders Abdominal pain, flatulence, nausea common Hepatobiliary dis

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HOS-094828 · has-contraindication-information · PDF-Seite 4

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

HOS-094834 · has-contraindication-information · PDF-Seite 31

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

HOS-094827 · has-indication-information · PDF-Seite 2

CELSENTRI film-coated tablets, in combination with other antiretroviral medicinal products, is indicated for treatment-experienced adults, adolescents and children weighing at least 30 kg infected with only CCR5-tropic HIV-1 detectable (see sections 4.2 and 5.1).

HOS-094833 · has-indication-information · PDF-Seite 29

CELSENTRI, in combination with other antiretroviral medicinal products, is indicated for treatment-experienced adults, adolescents and children of 2 years of age, and older and weighing at least 10 kg infected with only CCR5-tropic HIV-1 detectable (see sections 4.2 and 5.1).

HOS-094836 · has-interaction-information · PDF-Seite 33

Maraviroc is a metabolised by cytochrome P450 CYP3A4 and CYP3A5. Co-administration of maraviroc with medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its therapeutic effects. Co-administration of maraviroc with medicinal products that inhibit CYP3A4 may increase maraviroc plasma concentrations. Dose adjustment of maraviroc is recommended when maraviroc is co-administered with potent CYP3A4 inhibitors and/or inducers. Further details for concomitantly administered medicinal products are provided below (see Table 2). Maraviroc is a substrate for the transporters P-glycoprotein and OATP1B1, but the effect of these transporters on the exposure to maraviroc is not known. Based on the in vitro and clinical data, the potential for maraviroc to affect the pharmacokinetics of co-administered medicinal products is low. In vitro studies have shown that maraviroc does not inhibit OATP1B1, MRP2 or any of the major P450 enzymes at clinically relevant concentrations 33 (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, or urinary 6β-hydroxycortisol/cortisol ratio, suggesting no inhibition or induction of CYP3A4 in vivo. At higher exposure of maraviroc a potential inhibition of CYP2D6 cannot be excluded. Renal clearance accounts for approximately 23% of total clearance of maraviroc when maraviroc is administered without CYP3A4 inhibitors. In vitro studies have shown that maraviroc does not inhibit any of the major renal uptake transporters at clinically relevant concentrations (OAT1, OAT3, OCT2, OCTN1, and OCTN2). Additionally, co-administration of maraviroc with tenofovir (substrate for renal elimination) and cotrimoxazole (contains trimethoprim, a renal cation transport inhibitor), showed no effect on the pharmacokinetics of maraviroc. In addition, co-administration of maraviroc with lamivudine/zidovudine showed no effect of maraviroc on lamivudine (primarily renally cleared) or zidovudine (non-P450 metabolism and renal clearance) pharmacokinetics. Maraviroc inhibits P-glycoprotein in vitro (IC50 is 183 μM). However, maraviroc does not significantly affect the pharmacokinetics of digoxin in vivo. It may not be excluded that maraviroc can increase the exposure to the P-glycoprotein substrate dabigatran etexilate.

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HOS-094830 · has-interaction-information · PDF-Seite 7

Maraviroc is metabolised by cytochrome P450 CYP3A4 and CYP3A5. Co-administration of maraviroc with medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its therapeutic effects. Co-administration of maraviroc with medicinal products that inhibit CYP3A4 may increase maraviroc plasma concentrations. Dose adjustment of maraviroc is recommended when maraviroc is co-administered with potent CYP3A4 inhibitors and/or inducers. Further details for concomitantly administered medicinal products are provided below (see Table 2). Maraviroc is a substrate for the transporters P-glycoprotein and OATP1B1, but the effect of these transporters on the exposure to maraviroc is not known. Based on the in vitro and clinical data, the potential for maraviroc to affect the pharmacokinetics of co-administered medicinal products is low. In vitro studies have shown that maraviroc does not inhibit OATP1B1, MRP2 or any of the major P450 enzymes at clinically relevant concentrations (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, or urinary 6β-hydroxycortisol/cortisol ratio, suggesting no inhibition or induction of CYP3A4 in vivo. At higher exposure of maraviroc a potential inhibition of CYP2D6 cannot be excluded. Renal clearance accounts for approximately 23% of total clearance of maraviroc when maraviroc is administered without CYP3A4 inhibitors. In vitro studies have shown that maraviroc does not inhibit any of the major renal uptake transporters at clinically relevant concentrations (OAT1, OAT3, OCT2, OCTN1, and OCTN2). Additionally, co-administration of maraviroc with tenofovir (substrate for renal elimination) and cotrimoxazole (contains trimethoprim, a renal cation transport inhibitor), showed no effect on the pharmacokinetics of maraviroc. In addition, co-administration of maraviroc with lamivudine/zidovudine showed no effect of maraviroc on lamivudine (primarily renally cleared) or zidovudine (non-P450 metabolism and renal clearance) pharmacokinetics. Maraviroc inhibits P-glycoprotein in vitro (IC50 is 183 μM). However, maraviroc does not significantly affect the pharmacokinetics of digoxin in vivo. It may not be excluded that maraviroc can increase the exposure to the P-glycoprotein substrate dabigatran etexilate. 7 Table 2: Intera

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HOS-094837 · has-pregnancy-information · PDF-Seite 40

Pregnancy There are limited data from the use of maraviroc in pregnant women. The effect of maraviroc on human pregnancy is unknown. Studies in animals showed reproductive toxicity at high exposures. Primary pharmacological activity (CCR5 receptor affinity) was limited in the species studied (see section 5.3). Maraviroc should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus. Breast-feeding It is unknown whether maraviroc is excreted in human milk. Available toxicological data in animals has shown extensive excretion of maraviroc in milk. Primary pharmacological activity (CCR5 receptor affinity) was limited in the species studied (see section 5.3). A risk to the newborn/infants cannot be excluded. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility There is no data on the effects of maraviroc on human fertility. In rats, there were no adverse effects on male or female fertility (see section 5.3).

HOS-094831 · has-pregnancy-information · PDF-Seite 14

Pregnancy There are limited data from the use of maraviroc in pregnant women. The effect of maraviroc on human pregnancy is unknown. Studies in animals showed reproductive toxicity at high exposures. Primary pharmacological activity (CCR5 receptor affinity) was limited in the species studied (see section 5.3). Maraviroc should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus. Breast-feeding It is unknown whether maraviroc is excreted in human milk. Available toxicological data in animals has shown extensive excretion of maraviroc in milk. Primary pharmacological activity (CCR5 receptor affinity) was limited in the species studied (see section 5.3). A risk to the newborn/infants cannot be excluded. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility There is no data on the effects of maraviroc on human fertility. In rats, there were no adverse effects on male or female fertility (see section 5.3).

HOS-094835 · has-warning-information · PDF-Seite 31

Hepatic disease The safety and efficacy of maraviroc have not been specifically studied in patients with significant underlying liver disorders. Cases of hepatotoxicity and hepatic failure with allergic features have been reported in association with maraviroc. In addition, an increase in hepatic adverse reactions with maraviroc was observed during studies of treatment-experienced subjects with HIV infection, although there was no overall increase in ACTG Grade 3/4 liver function test abnormalities (see section 4.8). Hepatobiliary disorders reported in treatment-naïve patients were uncommon and balanced between treatment groups (see section 4.8). Patients with pre-existing liver dysfunction, including chronic active hepatitis, can have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. Discontinuation of maraviroc should be strongly considered in any patient with signs or symptoms of acute hepatitis, in particular if drug-related hypersensitivity is suspected or with increased liver transaminases combined with rash or other systemic symptoms of potential hypersensitivity (e.g. pruritic rash, eosinophilia or elevated IgE). There are limited data in patients with hepatitis B and/or C virus co-infection (see section 5.1). Caution should be exercised when treating these patients. In case of concomitant antiviral therapy for hepatitis B and/or C, please refer to the relevant product information for these medicinal products. There is limited experience in patients with reduced hepatic function, therefore maraviroc should be used with caution in this population (see sections 4.2 and 5.2). 31 Severe skin and hypersensitivity reactions Hypersensitivity reactions including severe and potentially life-threatening events have been reported in patients taking maraviroc, in most cases concomitantly with other medicinal products associated with these reactions. These reactions included rash, fever, and sometimes organ dysfunction and hepatic failure. Discontinue maraviroc and other suspect agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop. Clinical status and relevant blood chemistry should be monitored and appropriate symptomatic therapy initiated. Cardiovascular safety Limited data exist with the use of maraviroc in patients with severe cardiovascular disease, theref

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HOS-094829 · has-warning-information · PDF-Seite 4

Hepatic disease The safety and efficacy of maraviroc have not been specifically studied in patients with significant underlying liver disorders. 4 Cases of hepatotoxicity and hepatic failure with allergic features have been reported in association with maraviroc. In addition, an increase in hepatic adverse reactions with maraviroc was observed during studies of treatment-experienced subjects with HIV infection, although there was no overall increase in ACTG Grade 3/4 liver function test abnormalities (see section 4.8). Hepatobiliary disorders reported in treatment-naïve patients were uncommon and balanced between treatment groups (see section 4.8). Patients with pre-existing liver dysfunction, including chronic active hepatitis, can have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. Discontinuation of maraviroc should be strongly considered in any patient with signs or symptoms of acute hepatitis, in particular if drug-related hypersensitivity is suspected or with increased liver transaminases combined with rash or other systemic symptoms of potential hypersensitivity (e.g. pruritic rash, eosinophilia or elevated IgE). There are limited data in patients with hepatitis B and/or C virus co-infection (see section 5.1). Caution should be exercised when treating these patients. In case of concomitant antiviral therapy for hepatitis B and/or C, please refer to the relevant product information for these medicinal products. There is limited experience in patients with reduced hepatic function, therefore maraviroc should be used with caution in this population (see sections 4.2 and 5.2). Severe skin and hypersensitivity reactions Hypersensitivity reactions including severe and potentially life-threatening events have been reported in patients taking maraviroc, in most cases concomitantly with other medicinal products associated with these reactions. These reactions included rash, fever, and sometimes organ dysfunction and hepatic failure. Discontinue maraviroc and other suspect agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop. Clinical status and relevant blood chemistry should be monitored and appropriate symptomatic therapy initiated. Cardiovascular safety Limited data exist with the use of maraviroc in patients with severe cardiovascular disease, theref

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