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

HOS-288507 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most frequently reported adverse reactions in HPTN 083 were: Injection site reactions (82%), headache (17%) and diarrhoea (14%). The most frequently reported adverse reactions in HPTN 084 were: Injection site reactions (38%), headache (23%) and transaminase increased (19%). The SCARs SJS and TEN have been reported in association with cabotegravir administration (see section 4.4). Tabulated list of adverse reactions Adverse reactions for cabotegravir were identified from the Phase III clinical studies; HPTN 083 and HPTN 084; and post-marketing data. In HPTN 083, the median time on blinded study product was 65 weeks and 2 days (1 day to 156 weeks and 1 day), with a total exposure on cabotegravir of 3270 person years. In HPTN 084, the median time on blinded study product was 64 weeks and 1 day (1 day to 153 weeks and 1 day), with a total exposure on cabotegravir of 1920 person years. The adverse reactions considered at least possibly related to cabotegravir in adults and adolescents are listed in Table 4 by 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 4 Tabulated list of adverse reactions1 MedDRA System organ Frequency Adverse reactions class (SOC) category 9 Immune system disorders Uncommon Hypersensitivity* Psychiatric disorders Common Abnormal dreams Insomnia Depression Anxiety Uncommon Suicide attempt; Suicidal ideation (particularly in individuals with a pre-existing psychiatric illness) Nervous system disorders Very common Headache Common Dizziness Uncommon Somnolence Vasovagal reactions (in response to injections) Gastrointestinal disorders Very common Diarrhoea Common

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HOS-288513 · has-adverse-reaction-information · PDF-Seite 29

Summary of the safety profile The most frequently reported adverse reactions in HPTN 083 were: headache (17%) and diarrhoea (14%). The most frequently reported adverse reactions in HPTN 084 were: headache (23%) and transaminase increased (19%). The SCARs SJS and TEN have been reported in association with cabotegravir administration (see section 4.4). Tabulated list of adverse reactions Adverse reactions for cabotegravir were identified from the Phase III clinical studies; HPTN 083 and HPTN 084; and post-marketing data. In HPTN 083, the median time on blinded study product was 65 weeks and 2 days (1 day to 156 weeks and 1 day), with a total exposure on cabotegravir of 3231 person years. In HPTN 084, the median time on blinded study product was 64 weeks and 1 day (1 day to 153 weeks and 1 day), with a total exposure on cabotegravir of 2009 person years. 29 The adverse reactions identified for cabotegravir in adults and adolescents are listed in Table 3 by 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 list of adverse reactions MedDRA System organ Frequency Adverse reactions class (SOC) category Immune system disorders Uncommon Hypersensitivity* Psychiatric disorders Common Abnormal dreams Insomnia Depression Anxiety Uncommon Suicide attempt; Suicidal ideation (particularly in individuals with a pre-existing psychiatric illness) Nervous system disorders Very common Headache Common Dizziness Uncommon Somnolence Gastrointestinal disorders Very common Diarrhoea Common Nausea Abdominal pain1 Flatulence

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HOS-288509 · has-contraindication-information · PDF-Seite 25

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Individuals with an unknown or positive HIV-1 status (see sections 4.2 and 4.4). Concomitant use with rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or phenobarbital (see section 4.5).

HOS-288503 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Individuals with an unknown or positive HIV-1 status (see sections 4.2 and 4.4). Concomitant use with rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or phenobarbital (see section 4.5). 4

HOS-288508 · has-indication-information · PDF-Seite 23

Apretude is indicated in combination with safer sex practices for short term pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in high-risk adults and adolescents, weighing at least 35 kg (see section 4.2 and section 4.4). Apretude tablets may be used as: • oral lead-in to assess tolerability of Apretude prior to administration of long acting cabotegravir injection. • oral PrEP for individuals who will miss planned dosing with cabotegravir injection.

HOS-288502 · has-indication-information · PDF-Seite 2

Apretude is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in high-risk adults and adolescents, weighing at least 35 kg (see sections 4.2, 4.4 and 5.1).

HOS-288505 · has-interaction-information · PDF-Seite 6

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 3 below). In poor metabolisers of UGT1A1, representing a maximum clinical 6 UGT1A1 inhibition, the mean AUC, Cmax and Ctau of oral cabotegravir increased by up to 1.5-fold. No dosing adjustments for Apretude are recommended in the presence of UGT1A1 inhibitors. 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 medicinal products (e.g. methotrexate). Based on the in vitro and clinical drug interaction profile, cabotegravir is not expected to alter concentrations of other anti-retroviral medicinal products including protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors, and ibalizumab. No drug interaction studies have been performed with cabotegravir injection. The drug interaction data provided in Table 3 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 3 Drug interactions Medicinal products Interaction Recommendations concerning by therapeutic areas Geometric mean change (%) co-administration HIV-1 Antiviral medicinal products Non-nucleoside Cabotegravir  Etravirine did not significantly change Reverse Transcriptase AU

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HOS-288511 · has-interaction-information · PDF-Seite 27

Effect of other agents 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 (see section 5.2). No dosing adjustments for Apretude are recommended in the presence of UGT1A1 inhibitors. 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). Cabotegravir may increase the AUC of OAT1/3 substrates up to approximately 80% therefore caution is advised when co-dosing with narrow therapeutic index OAT1/3 substrate medicinal products (e.g. methotrexate). Based on the in vitro and clinical drug interaction profile, cabotegravir is not expected to alter concentrations of other anti-retroviral medicinal products 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 Interaction Recommendations concerning by therapeutic areas Geometric mean change (%) co-administration HIV-1 Antiviral medicinal products Non-nucleoside Cabotegravir  Etravirine did not significantly change Reverse Transcriptase AUC  1% cabotegra

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HOS-288506 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential Women of childbearing potential should be counselled about prolonged release characteristics of cabotegravir injection. If a woman plans a pregnancy, the benefits and the risks of starting/continuing PrEP with Apretude should be discussed (see section 4.4). Pregnancy There are limited data from the use of cabotegravir in pregnant women. The effect of cabotegravir on 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. Apretude injection is not recommended during pregnancy unless the expected benefit justifies the potential risk to the foetus. 8 Cabotegravir has been detected in systemic circulation for up to 12 months or longer after an injection, therefore, consideration should be given to the potential for foetal exposure during pregnancy (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 Apretude injection. It is recommended that women breast-feed only if the expected benefit justifies the potential risk to the infant. 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-288512 · has-pregnancy-information · PDF-Seite 28

Women of childbearing potential 28 If a woman plans a pregnancy, the benefits and the risks of starting/continuing PrEP with Apretude should be discussed. Pregnancy There are a limited amount of data from the use of cabotegravir in pregnant women. The effect of cabotegravir on 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. Apretude 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 breast-feed only if the expected benefit justifies the potential risk to the infant. 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-288504 · has-warning-information · PDF-Seite 5

Overall HIV-1 infection prevention strategy Apretude may not always be effective in preventing HIV-1 infection (see section 5.1). Cabotegravir concentrations associated with significant antiviral activity (> 4x Protein Adjusted-Inhibitory Concentration, PA-IC90, see section 5.2) are achieved and maintained within hours after initiation of oral lead-in and within 7 days from the first injection (without oral lead-in). The exact time from initiation of Apretude for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Apretude should be used for PrEP as part of an overall HIV-1 infection prevention strategy including the use of other HIV-1 prevention measures (e.g. knowledge of HIV-1 status, regular testing for other sexually transmitted infections, condom use). Apretude should only be used to reduce the risk of acquiring HIV-1 in individuals confirmed to be HIV negative (see section 4.3). Individuals should be re-confirmed to be HIV negative at each subsequent injection of Apretude. A combined antigen/antibody test as well as an HIV-RNA-based test should both be negative. Prescribers are advised to perform both tests, even if the result of the HIV-RNA-based test will become available after cabotegravir injection. If a combined testing strategy including both tests is not available, testing should follow local guidelines while taking Apretude. If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures to HIV-1 are suspected, HIV-1 status should be reconfirmed. Potential risk of resistance There is a potential risk of developing resistance to cabotegravir if an individual acquires HIV-1 either before or while taking Apretude, or following discontinuation of Apretude (see Long- acting properties of Apretude injection). To minimise this risk, it is essential to confirm HIV-1 negative status at each subsequent injection of Apretude. A combined antigen/antibody test as well as an HIV- RNA-based test should both be negative. Prescribers are advised to perform both tests, even if the result of the HIV-RNA-based test will become available after cabotegravir injection. If a combined testing strategy including both tests is not available, testing should follow local guidelines. Individuals who are diagnosed with HIV-1 should immediately begin anti-retroviral therapy (ART). Apretude alone does not constitute a complete regimen for the treatment of HIV-1 and HIV-1 resistance mutations have emerged in som

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HOS-288510 · has-warning-information · PDF-Seite 25

Overall HIV-1 infection prevention strategy Apretude may not always be effective in preventing HIV-1 infection (see section 5.1). Cabotegravir concentrations associated with significant antiviral activity (> 4x Protein Adjusted-Inhibitory Concentration, PA-IC90, see section 5.2) are achieved and maintained within hours after initiation of oral lead-in. The exact time from initiation of Apretude for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Apretude should be used for PrEP as part of an overall HIV-1 infection prevention strategy including the use of other HIV-1 prevention measures (e.g. knowledge of HIV1 status, regular testing for other sexually transmitted infections, condom use). Apretude should only be used to reduce the risk of acquiring HIV-1 in individuals confirmed to be HIV negative (see section 4.3). Individuals should be re-confirmed to be HIV-negative at frequent intervals. A combined antigen/antibody test as well as an HIV-RNA-based test should both be negative. Prescribers are advised to perform both tests, even if the result of the HIV-RNA-based test will become available after oral administration. If a combined testing strategy including both tests is not available, testing should follow local guidelines while taking Apretude. If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures to HIV-1 are suspected, HIV-1 status should be reconfirmed. Potential risk of resistance There is a potential risk of developing resistance to cabotegravir if an individual acquires HIV-1 either before, or while taking or following discontinuation of cabotegravir. To minimise this risk, it is essential to confirm HIV-1 negative status at frequent intervals. A combined antigen/antibody test as well as an HIV-RNA-based test should both be negative. Prescribers are advised to perform both tests, even if the result of the HIV-RNA-based test will become available after oral administration. If a combined testing strategy including both tests is not available, testing should follow local guidelines. Individuals who are diagnosed with HIV-1 should immediately begin anti-retroviral therapy (ART). Apretude alone does not constitute a complete regimen for the treatment of HIV-1 and HIV-1 resistance mutations have emerged in some individuals with undetected HIV-1 infection who were only taking Apretude. 25 Alternative forms of PrEP should

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