Apretude 30 mg Tablets or 600 mg/3ml Injection

Film-coated tablets: APRETUDE tablets are indicated for short term pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in at-risk individuals 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 cabotegravir prior to administration of APRETUDE injection
• oral PrEP in individuals who will miss planned dosing with APRETUDE injection.

Suspension for injection: APRETUDE injection is indicated for PrEP to reduce the risk of sexually acquired HIV-1 infection in at-risk individuals weighing at least 35 kg (see section 4.2 and section 4.4).

Posology: Individuals must have had a documented negative HIV-1 test, in accordance with applicable guidelines, prior to initiating APRETUDE. Prior to starting APRETUDE, individuals should be carefully selected to agree to the required dosing schedule and counselled about the importance of adherence to scheduled dosing visits to help reduce the risk of acquiring HIV-1 infection.

Film-coated tablets: APRETUDE may be taken with or without food. Suspension for injection: Refer to the Instructions for Use for detailed step by step injection procedure (see section 6.6). APRETUDE injection should be administered by a healthcare professional. When administering APRETUDE injection, the body mass index (BMI) of the individual should be taken into consideration to ensure that the needle length is sufficient to reach the gluteus muscle.

Adults, adolescents weighing at least 35 kg: Following discussion with the individual, the medical practitioner may proceed directly to APRETUDE injection, (see Table 2 for dosing recommendations). Alternatively, APRETUDE tablets may be used as an oral lead-in prior to the initiation of APRETUDE injection to assess tolerability to cabotegravir (see Table 1).

Oral lead-in (film-coated tablets): When used for oral lead-in, APRETUDE 30 mg tablets are recommended for approximately one month (at least 28 days), prior to the initiation of APRETUDE 600mg/3 mL injection to assess tolerability to cabotegravir.

Suspension for injection: The recommended initial APRETUDE injection dose is a single 3 mL (600 mg) intramuscular injection. If oral lead-in has been used, the first injection should be planned for the last day of oral lead-in or within 3 days thereafter. One month later, a second 3 mL (600 mg) intramuscular injection should be administered. Individuals may be given the second 3 mL (600 mg) initiation injection up to 7 days before or after the scheduled dosing date. Continuation injections: After the second initiation injection, the recommended APRETUDE continuation injection dose is a single 3 mL (600 mg) intramuscular injection administered every 2 months. Individuals may be given injections up to 7 days before or after the scheduled dosing date.

APRETUDE is contraindicated in patients:

• with known hypersensitivity to cabotegravir (CAB) or to any of the excipients in the tablets or the injection formulation, listed in section 6.1
• receiving rifampicin, rifapentine, phenytoin, phenobarbitone, carbamazepine and oxcarbazepine (see section 4.5)
• with a positive HIV-1 status.

Overall HIV-1 infection prevention strategy: APRETUDE is not always effective in preventing HIV-1 acquisition. The time to onset of protection after commencing APRETUDE is unknown. APRETUDE should be used for pre-exposure prophylaxis 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 frequent intervals (e.g., in line with local guidelines, but at no more than 3-month intervals) while taking APRETUDE for pre-exposure prophylaxis. 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 CAB if an individual acquires HIV-1 either before or during administration of APRETUDE or following discontinuation of APRETUDE (see Long-acting properties of APRETUDE injection). To minimise this, it is essential to clinically reassess individuals for risk of HIV acquisition and to frequently test to confirm HIV-negative status. Individuals who are suspected or confirmed with HIV-1 should immediately begin antiretroviral therapy (ART).

Alternative forms of PrEP should be considered following discontinuation of APRETUDE for those individuals at continuing risk of HIV acquisition and initiated within 2 months of the final APRETUDE injection.

Long acting properties of APRETUDE injection: Residual concentrations of APRETUDE injection may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer), therefore, medical practitioners should take the prolonged release characteristics of APRETUDE into consideration when the medicinal product is discontinued (see section 4.5, section 4.6 and section 4.9).

Importance of adherence: Individuals should be counselled periodically to strictly adhere to the recommended dosing schedule in order to reduce the risk of HIV-1 acquisition and the potential development of resistance.

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 APRETUDE administration. 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, APRETUDE should be withdrawn immediately and an alternative form of PrEP considered (as appropriate). If the patient has developed a serious reaction such as SJS or TEN with the use of APRETUDE, 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. These reactions were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. Discontinue APRETUDE and other suspected medicines 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 status, including liver aminotransferases should be monitored and appropriate therapy initiated. Administration of oral lead-in is recommended to help identify patients who may be at risk of a hypersensitivity reaction (see section 4.2, section 4.3, Long-acting properties of APRETUDE injection below, see section 4.8).

Hepatotoxicity: Hepatotoxicity has been reported in a limited number of patients receiving APRETUDE with or without known pre-existing hepatic disease (see section 4.8). Monitoring of liver chemistries is recommended and treatment with APRETUDE should be discontinued if hepatotoxicity is suspected (see Long - acting properties of APRETUDE injection).

Caution should be given to prescribing APRETUDE with medicines that may reduce its exposure (see section 4.5). APRETUDE tablets contain lactose and sodium: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take APRETUDE tablets. APRETUDE tablets contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially u2018sodium-freeu2019. APRETUDE suspension for injections contain mannitol: mannitol may have a mild laxative effect.

Effect of CAB on the pharmacokinetics of other medicines: In vivo, CAB did not have an effect on midazolam, a CYP3A4 probe. CAB is not a clinically relevant inhibitor of the following enzymes and transporters: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B15, and UGT2B17, P-gp, breast cancer resistance protein (BCRP), Bile salt export pump (BSEP), organic cation transporter (OCT)1, OCT2, OATP1B1, OATP1B3, multidrug and toxin extrusion transporter (MATE) 1, MATE 2-K, multidrug resistance protein (MRP) 2 or MRP4. CAB inhibited the organic anion transporters (OAT)1 (IC50 = 0,81 u03bcM) and OAT3 (IC50 = 0,41 u03bcM) in vitro, however, based on physiologically based pharmacokinetic (PBPK) modelling no interaction with OAT substrates is expected at clinically relevant concentrations. In vitro, CAB did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of interaction studies, CAB is not expected to affect the pharmacokinetics of medicines that are substrates of these enzymes or transporters.

Effect of other medicines on the pharmacokinetics of CAB: CAB is primarily metabolised by UGT1A1 with some contribution from UGT1A9. Medicines which are strong inducers of UGT1A1 or UGT1A9 are expected to decrease CAB plasma concentrations leading to lack of efficacy (see section 4.3). Simulations using PBPK show that no clinically significant interaction is expected following co-administration of APRETUDE with medicines that inhibit UGT enzymes. In vitro, CAB was not a substrate of OATP1B1, OATP1B3, OATP2B1 or OCT1. CAB is a substrate of P-gp and BCRP, however, because of its high permeability, no alteration in absorption is expected when co-administered with either P-gp or BCRP inhibitors. No interaction studies have been performed with APRETUDE injection. The interaction data provided in Table 4 is obtained from studies with oral APRETUDE.

Pregnancy: Safety in pregnancy has not been established. There are no studies of CAB in pregnant women. The effect on human pregnancy is unknown. CAB was not teratogenic when studied in pregnant rats and rabbits but caused a delay in delivery that was associated with reduced survival and viability of rat offspring at exposures higher than for therapeutic doses (see section 5.3). The relevance to human pregnancy is unknown. CAB 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).

Breastfeeding: Safety in lactation has not been established. It is expected that CAB will be secreted into human milk based on animal data, although this has not been confirmed in humans. CAB may be present in human milk for up to 12 months or longer after the last APRETUDE injection.

Fertility: Animal studies indicate no effects of CAB on male or female fertility (see section 5.3).

APRETUDE may cause dizziness. Patients experiencing dizziness should avoid driving and operation of machinery.

Clinical trial data: Adverse reactions for APRETUDE were identified from the Phase III clinical studies, HPTN 083 and HPTN 084. 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 APRETUDE of 3 270 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 APRETUDE of 1 920 person years. Adverse events (AEs) listed include those attributable to the oral or injectable formulations of APRETUDE. When frequencies differed between HPTN 083 and 084, the highest frequency category is quoted. The most frequently reported AEs in HPTN 083 were: Injection site reactions (82 %), headache (17 %) and diarrhoea (14 %). The most frequently reported AEs in HPTN 084 were: Injection site reactions (38 %), headache (23 %) and transaminase increased (19 %). The AEs identified in these studies are listed below by MedDRA system organ class and by frequency. Frequencies are defined as: very common (u2265 1/10), common (u2265 1/100 and < 1/10), uncommon (u2265 1/1000 and < 1/100), rare (u2265 1/10 000 and < 1/1000) and very rare (< 1/10 000), including isolated reports.

Table 5: Adverse Events

There is no specific treatment for overdose with APRETUDE. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Further management should be as clinically indicated or as recommended by the national poisons centre, where available. CAB is known to be highly protein bound in plasma; therefore, dialysis is unlikely to be helpful in removal of drug from the body. Management of overdose with APRETUDE injection should take into consideration the prolonged exposure to medicine following an injection (see section 4.4).