Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands
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).
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.
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.
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.
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 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, cabotegravir 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 cabotegravir, treatment with cabotegravir must not be restarted in this patient at any time.
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).
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.
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.
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).
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’.
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.
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 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% Cτ ↔ 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% Cτ ↑ 14% Rilpivirine ↔ AUC ↓1% Cmax ↓ 4% Cτ ↓ 8% | Rilpivirine did not significantly change cabotegravir plasma concentration or vice versa. |
| Anticonvulsants | ||
| Carbamazepine Oxcarbazepine Phenytoin Phenobarbital | 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% Cτ ↓ 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% Cτ ↔ 0% LNG ↔ AUC ↑ 12% Cmax ↑ 5% Cτ ↑ 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. |
Interaction studies have only been performed in adults.
If a woman plans a pregnancy, the benefits and the risks of starting/continuing PrEP with Apretude should be discussed.
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.
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.
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).
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.
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).
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* |
| 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 Vomiting | |
| Hepatobiliary Disorders | Uncommon | Hepatotoxicity |
| Skin and subcutaneous tissue disorders | Common | Rash2 |
| Uncommon | Urticaria* Angioedema* | |
| Very rare | Stevens-Johnson syndrome*, toxic epidermal necrolysis* | |
| 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 |
1 Abdominal pain includes the following grouped MedDRA preferred terms: upper abdominal pain and abdominal pain.
2 Rash includes the following grouped MedDRA preferred terms: rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic.
3 Pyrexia includes the following grouped MedDRA preferred terms: pyrexia and feeling hot.
* Please refer to section 4.4.
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.
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.
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 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 the national reporting system listed in Appendix V.
Not applicable.
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