Source: European Medicines Agency (EU) Revision Year: 2023 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 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.
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 HIVRNA-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 some individuals with undetected HIV-1 infection who were only taking Apretude.
Individuals should be counselled periodically to strictly adhere to the recommended oral lead-in and injection dosing schedule in order to reduce the risk of HIV-1 infection and the potential development of resistance.
Residual concentrations of cabotegravir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer), therefore, the prolonged release characteristics of Apretude injection should be taken into consideration when the medicinal product is discontinued and alternative not long-acting forms of PrEP are taken, as long as or at any time the risk of acquiring HIV is present in the months after discontinuation of Apretude (see section 5.2).
Healthcare professionals should discuss the benefit-risk of using Apretude with individuals of childbearing potential or during pregnancy (see section 4.6).
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, Long-acting properties of Apretude injection 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 leadin was used in clinical studies to help identify individuals who may be at risk of hepatotoxicity.
Clinical and laboratory monitoring are recommended and Apretude should be discontinued if hepatotoxicity is confirmed, and individuals managed as clinically indicated (see Long-acting properties of Apretude injection).
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 injection with medicinal products that may reduce its exposure (see section 4.5).
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 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 coadministered 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 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 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 is necessary when initiating injections following etravirine use. |
| 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. No dose adjustment of Apretude or rilpivirine is necessary when co-administered. |
| Anticonvulsants | ||
| Carbamazepine Oxcarbazepine Phenytoin Phenobarbital | Cabotegravir ↓ | Metabolic inducers may significantly decrease cabotegravir plasma concentration. Concomitant use is contraindicated (see section 4.3). |
| 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% | When rifabutin is started before or concomitantly with the first cabotegravir initiation injection the recommended cabotegravir dosing schedule is one 600 mg injection followed 2 weeks later by a second 600 mg initiation injection and monthly, thereafter, while on rifabutin. When rifabutin is started at the time of the second initiation injection or later, the recommended dosing schedule is 600 mg, monthly, while on rifabutin. After stopping rifabutin, the recommended cabotegravir dosing schedule is 600 mg every 2 months. |
| 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 coadministered with Apretude. |
Interaction studies have only been performed in adults.
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).
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.
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).
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.
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 injection. The clinical status of the individual and the adverse reaction profile of Apretude injection 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: 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%).
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 class (SOC) | Frequency category | Adverse reactions |
|---|---|---|
| Immune system disorders | Uncommon | Hypersensitivity6* |
| Psychiatric disorders | Common | Abnormal dreams Insomnia Depression Anxiety |
| Uncommon | Suicide attempt6; Suicidal ideation6 (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 | Nausea Abdominal pain2 Flatulence Vomiting | |
| Hepatobiliary Disorders | Uncommon | Hepatotoxicity |
| Skin and subcutaneous tissue disorders | Common | Rash3 |
| Uncommon | Urticaria6* Angioedema6* | |
| Musculoskeletal and connective tissue disorders | Common | Myalgia |
| General disorders and administrative site conditions | Very common | Pyrexia5 Injection site reactions4 (pain and tenderness, nodule, induration) |
| Common | Injection site reaction4 (swelling, bruising, erythema, warmth, pruritus, anaesthesia) Fatigue Malaise | |
| Uncommon | Injection site reactions4 (haematoma, discolouration, abscess) | |
| Investigations | Very common | Transaminase increased |
| Uncommon | Weight increased Blood bilirubin increased |
1 The frequency of the identified adverse reactions are based on all reported occurrences of the adverse reactions and are not limited to those considered at least possibly related by the investigator.
2 Abdominal pain includes the following grouped MedDRA preferred terms: upper abdominal pain and abdominal pain.
3 Rash includes the following grouped MedDRA preferred terms: rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic.
4 ISRs listed in the table have been seen in 2 participants or more.
5 Pyrexia includes the following grouped MedDRA preferred terms: pyrexia and feeling hot. The majority of pyrexia adverse reactions were reported within one week of injections.
6 This adverse reaction was identified through post-marketing reporting. The frequency category is based on individuals exposed to cabotegravir in randomised clinical studies.
* Please refer to section 4.4
In HPTN 083, 2% of participants discontinued cabotegravir because of ISRs. Out of 20286 injections, 8900 ISRs were reported. A total of 2117 participants received at least one injection. Of the 1740 (82%) participants who experienced at least one ISR, the maximum severity of ISRs reported was mild (Grade 1, 34% of participants), moderate (Grade 2, 46% of participants) or severe (Grade 3, 3% of participants). The median duration of overall ISR adverse reactions was 4 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs decreased over time.
In HPTN 084, no participants discontinued cabotegravir because of ISRs. Out of 13068 injections, 1171 ISRs were reported. A total of 1519 participants received at least one injection. Of the 578 (38%) participants who experienced at last one ISR, the maximum severity of ISRs reported was mild (Grade 1, 25% of participants), moderate (Grade 2, 13% of participants) or severe (Grade 3, <1% of participants). The median duration of overall ISR adverse reactions was 8 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs generally decreased over time.
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 in 64 HIV-uninfected, at-risk adolescents (below 18 years of age and 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 studies HPTN 083 and HPTN 084.
Based on data from the Week 16 analysis of the MOCHA study in 23 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=8) 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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