Vocabria

HOS-099011 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The most frequently reported adverse reactions (ARs) were injection site reactions, headache, and pyrexia5. The SCARs SJS and TEN have been reported in association with cabotegravir treatment (see section 4.4). Tabulated list of adverse reactions The ARs identified for cabotegravir or rilpivirine are listed in Table 7 by body system organ class and 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). Table 7 Tabulated summary of adverse reactions1 MedDRA System Organ Frequency ARs for Vocabria + rilpivirine regimen Class (SOC) Category Immune system disorders Uncommon Hypersensitivity* Psychiatric disorders Common Depression Anxiety Abnormal dreams Insomnia Uncommon Suicide attempt; Suicidal ideation (particularly in patients with a pre-existing history of psychiatric illness) Nervous system disorders Very common Headache Common Dizziness Uncommon Somnolence 11  Vasovagal reactions (in response to injections) Gastrointestinal disorders Common Nausea Vomiting Abdominal pain2 Flatulence Diarrhoea Hepatobiliary Disorders Uncommon Hepatotoxicity Skin and subcutaneous tissue Common Rash3 disorders Uncommon Urticaria* Angioedema* Very rare

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HOS-099017 · has-adverse-reaction-information · PDF-Seite 34

Summary of the safety profile The most frequently reported adverse reactions (ARs) were headache and pyrexia4. The SCARs SJS and TEN have been reported in association with cabotegravir treatment (see section 4.4). Tabulated list of adverse reactions The ARs identified for cabotegravir and rilpivirine are listed in Table 3 by body system organ class and 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). Table 3 Tabulated summary of adverse reactions1 MedDRA System Organ Frequency ARs for Vocabria + rilpivirine regimen Class (SOC) Category Immune system disorders Uncommon Hypersensitivity* Psychiatric disorders Common Depression Anxiety Abnormal dreams Insomnia Uncommon Suicide attempt; Suicidal ideation (particularly in patients with a pre-existing history of psychiatric illness) Nervous system disorders Very common Headache Common Dizziness 34  Uncommon Somnolence Gastrointestinal disorders Common Nausea Vomiting Abdominal pain2 Flatulence Diarrhoea Hepatobiliary Disorders Uncommon Hepatotoxicity Skin and subcutaneous tissue Common Rash3 disorders Uncommon Urticaria* Angioedema* Very rare Stevens-Johnson syndrome*, toxic epidermal necrolysis* Musculoskeletal and Common

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HOS-099013 · has-contraindication-information · PDF-Seite 30

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant use with rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or phenobarbital (see section 4.5).

HOS-099007 · has-contraindication-information · PDF-Seite 7

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant use with rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or phenobarbital (see section 4.5).

HOS-099006 · has-indication-information · PDF-Seite 2

Vocabria injection is indicated, in combination with rilpivirine injection, for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and adolescents (at least 12 years of age and weighing at least 35 kg), who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the non-nucleoside reverse transcriptase inhibitor (NNRTI) and integrase inhibitor (INI) class (see sections 4.2, 4.4 and 5.1).

HOS-099012 · has-indication-information · PDF-Seite 28

Vocabria tablets are indicated in combination with rilpivirine tablets for the short-term treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and adolescents (at least 12 years of age and weighing at least 35 kg) who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the non-nucleoside reverse transcriptase inhibitor (NNRTI) and integrase inhibitor (INI) class (see sections 4.2, 4.4 and 5.1) for: • Oral lead-in to assess tolerability of Vocabria and rilpivirine prior to administration of long acting cabotegravir injection plus long acting rilpivirine injection. • Oral therapy for adults and adolescents who will miss planned dosing with cabotegravir injection plus rilpivirine injection.

HOS-099015 · has-interaction-information · PDF-Seite 32

Vocabria tablets, in combination with rilpivirine tablets, are indicated for the treatment of HIV-1, therefore, the prescribing information for rilpivirine tablets should be consulted for associated interactions. Effect of other medicinal products on the pharmacokinetics of cabotegravir Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1 and to a lesser extent by UGT1A9. Medicinal products which are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations leading to lack of efficacy (see section 4.3 and table 2 below). In poor metabolizers of UGT1A1, representing a maximum clinical UGT1A1 inhibition, the mean AUC, Cmax and Ctau of oral cabotegravir increased by up to 1.5-fold. The impact of an UGT1A1 inhibitor may be slightly more pronounced, however, considering the safety margins of cabotegravir, this increase is not expected to be clinically relevant. No dosing adjustments for Vocabria are, therefore, recommended in the presence of UGT1A1 inhibitors (e.g. atazanavir, erlotinib, sorafenib). Cabotegravir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), however, because of its high permeability, no alteration in absorption is expected when co- administered with either P-gp or BCRP inhibitors. Effect of cabotegravir on the pharmacokinetics of other medicinal products In vivo, cabotegravir did not have an effect on midazolam, a cytochrome P450 (CYP) 3A4 probe. In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4. In vitro, cabotegravir inhibited the organic anion transporters (OAT) 1 (IC50=0.81 µM) and OAT3 (IC50=0.41 µM). Therefore, caution is advised when co-dosing with narrow therapeutic index OAT1/3 substrate drugs (e.g. methotrexate). Based on the in vitro and clinical drug interaction profile, cabotegravir is not expected to alter concentrations of other anti-retroviral medications including protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors and ibalizumab. The drug interaction data provided in Table 2 is obtained from studies with oral cabotegravir (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “Cτ”). Table 2 Drug Interactions Medicinal products Int

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HOS-099009 · has-interaction-information · PDF-Seite 9

Vocabria injection, in combination with rilpivirine injection, is indicated for the treatment of HIV-1, therefore, the prescribing information for rilpivirine injection should be consulted for associated interactions. Effect of other medicinal products on the pharmacokinetics of cabotegravir Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1 and to a lesser extent by UGT1A9. Medicinal products which are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations leading to lack of efficacy (see section 4.3 and table 6 below). In poor metabolizers of UGT1A1, representing a maximum clinical UGT1A1 inhibition, the mean AUC, Cmax and Ctau of oral cabotegravir increased by up to 1.5-fold. The impact of an UGT1A1 inhibitor may be slightly more pronounced, however, considering the safety margins of cabotegravir, this increase is not expected to be clinically relevant. No dosing adjustments for Vocabria are, therefore, recommended in the presence of UGT1A1 inhibitors (e.g. atazanavir, erlotinib, sorafenib). Cabotegravir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), however, because of its high permeability, no alteration in absorption is expected when co- administered with either P-gp or BCRP inhibitors. Effect of cabotegravir on the pharmacokinetics of other medicinal products In vivo, cabotegravir did not have an effect on midazolam, a cytochrome P450 (CYP) 3A4 probe. In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4. In vitro cabotegravir inhibited organic anion transporters (OAT) 1 (IC50=0.81 µM) and OAT3 (IC50=0.41 µM). Therefore, caution is advised when co-dosing with narrow therapeutic index OAT1/3 substrate drugs (e.g. methotrexate). Vocabria and rilpivirine injections are intended for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medicinal products for the treatment of HIV. The following information regarding drug-drug interactions with other antiretroviral medicinal products is provided in the event that Vocabria and rilpivirine injections are stopped and initiation of an alternative antiviral therapy is necessary (see section 4.4). Based on the in vitro and clinical drug interaction profile, cabotegravir is not expected to alter concentrations of other anti- retroviral medications including protease inhibitors, nucleoside reverse transcriptas

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HOS-099010 · has-pregnancy-information · PDF-Seite 10

Pregnancy There are a limited amount of data from the use of cabotegravir in pregnant women. The effect of Vocabria on human pregnancy is unknown. Cabotegravir was not teratogenic when studied in pregnant rats and rabbits but, exposures higher than the therapeutic dose showed reproductive toxicity in animals (see section 5.3). The relevance to human pregnancy is unknown. Vocabria injection is not recommended during pregnancy unless the expected benefit justifies the potential risk to the foetus. 10 Cabotegravir has been detected in systemic circulation for up to 12 months or longer after an injection (see section 4.4). Breast-feeding It is expected that cabotegravir will be secreted into human milk based on animal data, although this has not been confirmed in humans. Cabotegravir may be present in human milk for up to 12 months or longer after the last cabotegravir injection. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility There are no data on the effects of cabotegravir on human male or female fertility. Animal studies indicate no effects of cabotegravir on male or female fertility (see section 5.3).

HOS-099016 · has-pregnancy-information · PDF-Seite 33

Pregnancy There are a limited amount of data from the use of cabotegravir in pregnant women. The effect of Vocabria on human pregnancy is unknown. Cabotegravir was not teratogenic when studied in pregnant rats and rabbits but, exposures higher than the therapeutic dose showed reproductive toxicity in animals (see section 5.3). The relevance to human pregnancy is unknown. 33 Vocabria tablets are not recommended during pregnancy unless the expected benefit justifies the potential risk to the foetus. Breast-feeding It is expected that cabotegravir will be secreted into human milk based on animal data, although this has not been confirmed in humans. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility There are no data on the effects of cabotegravir on human male or female fertility. Animal studies indicate no effects of cabotegravir on male or female fertility (see section 5.3).

HOS-099008 · has-warning-information · PDF-Seite 7

Risk of resistance following treatment discontinuation To minimise the risk of developing viral resistance it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the final injection of Vocabria when dosed monthly and no later than two months after the final injection of Vocabria when dosed every 2 months. If virologic failure is suspected, an alternative regimen should be adopted as soon as possible. Long acting properties of Vocabria injection Residual concentrations of cabotegravir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer), therefore, physicians should take the prolonged release characteristics of Vocabria injection into consideration when the medicinal product is discontinued (see sections 4.5, 4.6, 4.7 and 4.9). Baseline factors associated with virological failure Before starting the regimen, it should be taken into account that multivariable analyses indicate that a combination of at least 2 of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI 30 kg/m2. Available data suggest that virologic failure occurs more often when these patients are treated according to the every 2 month dosing regimen as compared to the monthly dosing regimen. In patients with an incomplete or uncertain treatment history without pre-treatment resistance analyses, caution is warranted in the presence of either BMI 30 kg/m2 or HIV-1 A6/A1 subtype (see section 5.1). Severe cutaneous adverse reactions (SCARs) The severe cutaneous adverse reactions, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported very rarely in association with cabotegravir treatment. At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, cabotegravir should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or TEN with the use of cabotegravir, treatment with cabotegravir must not be restarted in this patient at any time. Hypersensitivity reactions 7 Hypersensitivity reactions have been reported in association with integrase

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HOS-099014 · has-warning-information · PDF-Seite 30

Baseline factors associated with virological failure Before starting the regimen, it should be taken into account that multivariable analyses indicate that a combination of at least 2 of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI 30 kg/m2. Available data suggest that virologic failure occurs more often when these patients are treated according to the every 2 month dosing regimen as compared to the monthly dosing regimen. In patients with an incomplete or uncertain treatment history without pre-treatment resistance analyses, caution is warranted in the presence of either BMI 30 kg/m2 or HIV-1 A6/A1 subtype (see section 5.1). Severe cutaneous adverse reactions (SCARs) The severe cutaneous adverse reactions, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported very rarely in association with cabotegravir treatment. At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, cabotegravir should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or TEN with the use of cabotegravir, treatment with cabotegravir must not be restarted in this patient at any time. Hypersensitivity reactions Hypersensitivity reactions have been reported in association with integrase inhibitors including cabotegravir. These reactions were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. Vocabria and other suspected medicinal products should be discontinued immediately, should signs or symptoms of hypersensitivity develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia or angioedema). Clinical 30 status, including liver aminotransferases should be monitored and appropriate therapy initiated. (See sections 4.2, 4.8 and 5.1). Hepatoxicity Hepatotoxicity has been reported in a limited number of patients receiving Vocabria with or without known pre-existing hepatic disease (see section 4.8). Administration of cabot

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