4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Apretude should be prescribed by a healthcare professional experienced in the management of HIV PrEP.

Individuals must be tested for HIV-1 prior to initiating cabotegravir (see section 4.3). 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.

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.

The healthcare provider and individual may decide to use cabotegravir tablets as an oral lead-in prior to the initiation of Apretude injection to assess tolerability (see Table 1) or may proceed directly to Apretude injections (see Apretude injection SmPC).

Posology

Oral lead-in

When used for oral lead-in, cabotegravir tablets should be taken for approximately one month (at least 28 days) to assess tolerability to cabotegravir (see section 4.4). One Apretude 30 mg tablet should be taken, once daily with or without food.

Table 1 Recommended dosing schedule

Oral lead-in

Medicinal product

During month 1

Apretude

30 mg once daily

Oral dosing for missed injections of cabotegravir.

If a delay of more than 7 days from a scheduled injection visit cannot be avoided, Apretude 30 mg tablets may be used once daily to replace one scheduled injection visit. The first dose of oral cabotegravir (or an alternative oral PrEP therapy) should be taken two months (+/- 7 days) after the last injection of cabotegravir. For oral PrEP durations greater than two months, an alternative PrEP regimen to oral cabotegravir is recommended.

Injection dosing should be resumed on the day oral cabotegravir dosing completes or within 3 days, thereafter (see Apretude injection SmPC).

Missed doses

If the individual misses a dose of Apretude tablets, the individual should take the missed dose as soon as possible, providing the next dose is not due within 12 hours. If the next dose is due within 12 hours, the individual should not take the missed dose and simply resume the usual dosing schedule.

Vomiting

If an individual vomits within 4 hours of taking Apretude tablets, another Apretude tablet should be taken. If an individual vomits more than 4 hours after taking Apretude tablets, the individual does not need to take another tablet until the next regularly scheduled dose.

Special populations

Elderly

No dose adjustment is required in elderly individuals. There are limited data available on the use of cabotegravir in individuals aged 65 years and over (see section 5.2).

Hepatic impairment

No dose adjustment is required in individuals with mild or moderate hepatic impairment (Child-Pugh score A or B). Cabotegravir has not been studied in individuals with severe hepatic impairment (Child-Pugh score C [see section 5.2]).

If administered in an individual with severe hepatic impairment, cabotegravir should be used with caution.

Renal impairment

No dose adjustment is required in individuals with mild (creatinine clearance ≥60 to <90 mL/min), moderate (creatinine clearance ≥30 to <60 mL/min) or severe renal impairment (creatinine clearance ≥15 to <30 mL/min and not on dialysis [see section 5.2]). Cabotegravir has not been studied in individuals with end-stage renal disease on renal replacement therapy. As cabotegravir is greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir. If administered in an individual on renal replacement therapy, cabotegravir should be used with caution.

Paediatric population

The safety and efficacy of cabotegravir in children and adolescents weighing less than 35 kg have not been established. No data are available.

Method of administration

Oral use.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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.

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

Importance of adherence

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

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. Apretude 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 status, including liver aminotransferases should be monitored and appropriate therapy initiated (see sections 4.2 and 4.8).

Hepatoxicity

Hepatotoxicity has been reported in a limited number of individuals receiving cabotegravir with or without known pre-existing hepatic disease (see section 4.8). Administration of cabotegravir oral lead-in was used in clinical studies to help identify individuals who may be at risk of hepatotoxicity.

Clinical and laboratory monitoring are recommended and Apretude tablets should be discontinued if hepatotoxicity is confirmed, and individuals managed as clinically indicated.

Adolescents

Suicidal ideation and suicide attempt have been reported with cabotegravir, particularly in those with pre-existing psychiatric illness (see section 4.8). Although clinical studies did not show an increased incidence of psychiatric illness in adolescents compared to adult subjects, given the vulnerability of the adolescent population, adolescents should be counselled before prescribing, and periodically while receiving Apretude, and managed as clinically indicated.

Interactions with medicinal products

Caution should be given to prescribing Apretude tablets with medicinal products that may reduce its exposure (see section 4.5).

Polyvalent cation containing antacids are recommended to be taken at least 2 hours before and 4 hours after taking Apretude tablets (see section 4.5).

Excipients

Individuals with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 “C”).

Table 2 Drug interactions

Medicinal products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co‑administration

HIV-1 Antiviral medicinal products

Non-nucleoside Reverse Transcriptase Inhibitor:Etravirine

Cabotegravir ↔

AUC ↑ 1%

Cmax ↑ 4%

C ↔ 0%

Etravirine did not significantly change cabotegravir plasma concentration. No dose adjustment of Apretude tablets is necessary.

Non-nucleoside Reverse Transcriptase Inhibitor:Rilpivirine

Cabotegravir ↔AUC ↑ 12%Cmax ↑ 5%C ↑ 14%

Rilpivirine ↔AUC ↓1%Cmax ↓ 4%C ↓ 8%

Rilpivirine did not significantly change cabotegravir plasma concentration or vice versa. No dose adjustment of Apretude or rilpivirine is necessary when co-administered.

Anticonvulsants

CarbamazepineOxcarbazepinePhenytoinPhenobarbital

Cabotegravir ↓

Metabolic inducers may significantly decrease cabotegravir plasma concentrations, concomitant use is contraindicated (see section 4.3).

Antacids

Antacids (e.g. magnesium, aluminium, or calcium)

Cabotegravir ↓

Co-administration of antacid supplements has the potential to decrease oral cabotegravir absorption and has not been studied.

Antacid products containing polyvalent cations are recommended to be administered at least 2 hours before or 4 hours after oral Apretude (see section 4.4).

Antimycobacterials

Rifampicin

Cabotegravir ↓

AUC ↓ 59%

Cmax ↓ 6%

Rifampicin significantly decreased cabotegravir plasma concentration which is likely to result in loss of therapeutic effect. Dosing recommendations for co-administration of Apretude with rifampicin have not been established and co-administration of Apretude with rifampicin is contraindicated (see section 4.3).

Rifapentine

Cabotegravir ↓

Rifapentine may significantly decrease cabotegravir plasma concentrations, concomitant use is contraindicated (see section 4.3).

Rifabutin

Cabotegravir ↓

AUC ↓ 21%

Cmax ↓ 17%

C ↓ 26%

Rifabutin did not significantly change cabotegravir plasma concentration. No dose adjustment is required.

Oral Contraceptives

Ethinyl estradiol (EE) and Levonorgestrel (LNG)

EE ↔

AUC ↑ 2%

Cmax ↓ 8%

C ↔ 0%

LNG ↔

AUC ↑ 12%

Cmax ↑ 5%

C ↑ 7%

Cabotegravir did not significantly change ethinyl estradiol and levonorgestrel plasma concentrations to a clinically relevant extent. No dose adjustment of oral contraceptives is necessary when co-administered with Apretude tablets.

Paediatric population

Interaction studies have only been performed in adults

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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).

4.7. Effects on ability to drive and use machines

Individuals should be informed that dizziness, somnolence and fatigue have been reported during treatment with Apretude tablets. The clinical status of the individual and the adverse reaction profile of Apretude tablets should be borne in mind when considering the individual's ability to drive or operate machinery.

4.8. Undesirable effects

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%).

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.

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 class (SOC)

Frequency category

Adverse reactions

Immune system disorders

Uncommon

Hypersensitivity*4

Psychiatric disorders

Common

Abnormal dreams

Insomnia

Depression

Anxiety

Uncommon

Suicide attempt4; Suicidal ideation4 (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

Vomiting

Hepatobiliary Disorders

Uncommon

Hepatotoxicity

Skin and subcutaneous tissue disorders

Common

Rash2

Uncommon

Urticaria*4

Angioedema*4

Very rare

Stevens-Johnson syndrome*4, toxic epidermal necrolysis*4

Musculoskeletal and connective tissue disorders

Common

Myalgia

General disorders and administrative site conditions

Very common

Pyrexia3

Common

Fatigue

Malaise

Investigations

Very common

Transaminase increased

Uncommon

Weight increased

Blood bilirubin increased

1Abdominal pain includes the following grouped MedDRA preferred terms: upper abdominal pain and abdominal pain.

2Rash includes the following grouped MedDRA preferred terms: rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic.

3Pyrexia includes the following grouped MedDRA preferred terms: pyrexia and feeling hot.

4This adverse reaction was identified through post-marketing reporting. The frequency category is based on individuals exposed to cabotegravir in clinical studies.

*Please refer to section 4.4 'Hypersensitivity reactions'.

Description of selected adverse reactions

Weight increased

At the week 41 and week 97 timepoints in HPTN 083, participants who received cabotegravir gained a median of 1.2 kg (Interquartile Range [IQR] -1.0, 3.5; n=1623) and 2.1 kg (IQR; -0.9, 5.9 n=601) in weight from baseline, respectively; those in the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) group gained a median of 0.0 kg (IQR -2.1, 2.4, n=1611) and 1.0 kg (IQR; -1.9, 4.0 n=598) in weight from baseline, respectively.

At the Week 41 and Week 97 timepoints in HPTN 084, participants who received cabotegravir gained a median of 2.0 kg (IQR 0.0, 5.0; n=1151) and 4.0 kg (IQR; 0.0, 8.0, n=216) in weight from baseline, respectively; those in the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) group gained a median of 1.0 kg (IQR -1.0, 4.0, n=1131) and 3.0 kg (IQR; -1.0, 6.0 n=218) in weight from baseline, respectively.

Changes in laboratory chemistries

In both HPTN 083 and HPTN 084, a similar proportion of participants in the cabotegravir and TDF/FTC groups were observed to have elevated hepatic transaminases (ALT/AST) levels and maximum post baseline increases were mostly Grades 1 and 2. In HPTN 083, the number of participants in the cabotegravir vs TDF/FTC groups who experienced maximum post baseline Grade 3 or 4 ALT levels were 40 (2%) vs 44 (2%) and Grade 3 or 4 AST levels were; 68 (3%) vs 79 (3%), respectively. In HPTN 084, the number of participants in the cabotegravir vs TDF/FTC groups who experienced maximum post baseline Grade 3 or 4 ALT levels were 12 (< 1%) vs 18 (1%) and Grade 3 and 4 AST levels were; 15 (< 1%) vs 14 (< 1%), respectively.

A few participants in both the cabotegravir and TDF/FTC groups had adverse reactions of AST or ALT increased which resulted in discontinuation of study product. In HPTN 083, the number of participants in the cabotegravir vs TDF/FTC groups who discontinued due to ALT increased were: 29 (1%) vs 31 (1%) and due to AST increased were 7 (< 1%) vs 8 (< 1%), respectively. In HPTN 084, the number of participants in the cabotegravir vs TDF/FTC groups who discontinued due to ALT increased were 12 (< 1%) vs 15 (< 1%) and there were no discontinuations due to AST increased.

Adolescents

Based on data from two open-label multicenter clinical trials (HPTN 083-01 and HPTN 084-01) in 64 HIV-uninfected, at-risk adolescents (weighing ≥ 35 kg at enrolment) receiving cabotegravir, no new safety issues were identified in adolescents compared with the safety profile established in adults receiving cabotegravir for HIV-1 PrEP in HPTN 083 and HPTN 084.

Based on data from the Week 16 analysis of the MOCHA study in HIV-infected adolescents (aged at least 12 years and weighing ≥ 35 kg) receiving background combination anti-retroviral therapy, no new safety concerns were identified in adolescents with the addition of oral cabotegravir followed by injectable cabotegravir (n=29) when compared with the safety profile established with cabotegravir in adults (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no specific treatment for Apretude overdose. If overdose occurs, the individual should be treated supportively with appropriate monitoring as necessary.

Cabotegravir is known to be highly protein bound in plasma; therefore, dialysis is unlikely to be helpful in removal of medicinal product from the body.