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.

In vitro, cabotegravir inhibited the 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 drugs (e.g. methotrexate).

Cabotegravir has not been studied in patients 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 a patient on renal replacement therapy, cabotegravir should be used with caution.

Cabotegravir has not been studied in patients with severe hepatic impairment (ChildPugh score C. If administered in a patient with severe hepatic impairment, cabotegravir should be used with caution.

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 cabotegravir.

Rifabutin may decrease cabotegravir injection plasma concentration. Concomitant use should be avoided.

Rifabutin did not significantly change oral cabotegravir plasma concentration. No dose adjustment is required. Prior to initiation of oral cabotegravir therapy, the prescribing information for cabotegravir injection should be consulted regarding concomitant use with rifabutin.

Interaction – Geometric mean change (%):

Cabotegravir ↓
AUC ↓ 21%
C_max ↓ 17%
C_τ ↓ 8%

Patients with hepatitis B co-infection were excluded from studies with cabotegravir. It is not recommended to initiate cabotegravir in patients with hepatitis B co-infection. Physicians should refer to current treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus. Limited data is available in patients with hepatitis C co-infection. Monitoring of liver function is recommended in patients with hepatitis C co-infection.

There are a limited amount of data from the use of cabotegravir in pregnant women. The effect of cabotegravir on human 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. The relevance to human pregnancy is unknown.

Cabotegravir 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.

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 cabotegravir injection.

It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

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.

Patients should be informed that dizziness, fatigue and somnolence has been reported during treatment with cabotegravir injection. The clinical status of the patient and the adverse reaction profile of cabotegravir injection should be borne in mind when considering the patient’s ability to drive or operate machinery.

Summary of the safety profile

The most frequently reported adverse reactions (ARs) from monthly dosing studies were injection site reactions (up to 84%), headache (up to 12%) and pyrexia⁵ (10%).

The most frequently reported ARs from ATLAS-2M every 2 month dosing were injection site reactions (76%), headache (7%) and pyrexia⁵ (7%).

The SCARs SJS and TEN have been reported in association with cabotegravir treatment.

Tabulated list of adverse reactions

The ARs identified for cabotegravir or rilpivirine are listed in the following table by body 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).

Tabulated summary of adverse reactions¹:

¹ The frequency of the identified ARs are based on all reported occurrences of the events and are not limited to those considered at least possibly related by the investigator.
² Abdominal pain includes the following grouped MedDRA preferred term: abdominal pain, upper abdominal pain.
³ Rash includes the following grouped MedDRA preferred terms: rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic.
⁴ May rarely result in temporary gait disturbance.
⁵ Pyrexia includes the following grouped MedDRA preferred terms: feeling hot, body temperature increased. The majority of pyrexia events were reported within one week of injections.
^* Please refer to section 4.4.

The overall safety profile at Week 96 and Week 124 in the FLAIR study was consistent with that observed at Week 48, with no new safety findings identified. In the extension phase of the FLAIR study, initiating the cabotegravir and rilpivirine injection regimen with Direct to Injection did not identify any new safety concerns related to omitting the oral lead-in phase.

Description of selected adverse reactions

Local injection site reactions (ISRs)

Up to 1% of subjects discontinued treatment with cabotegravir plus rilpivirine because of ISRs. When dosing monthly, up to 84% of subjects reported injection site reactions; out of 30393 injections, 6815 ISRs were reported. When dosing every 2 months, 76% of patients reported injection site reactions; out of 8470 injections, 2507 ISRs were reported.

The severity of reactions was generally mild (Grade 1, 70%-75% of subjects) or moderate (Grade 2, 27%-36% of subjects). 3-4% of subjects experienced severe (Grade 3) ISRs. The median duration of overall ISR events was 3 days. The percentage of subjects reporting ISRs decreased over time.

Weight increased

At the Week 48 time point, subjects in studies FLAIR and ATLAS, who received cabotegravir plus rilpivirine gained a median of 1.5 kg in weight subjects continuing on their current antiretroviral therapy (CAR) gained a median of 1.0 kg (pooled analysis). In the individual studies FLAIR and ATLAS, the median weight gains in the cabotegravir plus rilpivirine arms were 1.3 kg and 1.8 kg respectively, compared to 1.5 kg and 0.3 kg in the CAR arms.

At the 48 week timepoint, in ATLAS-2M the median weight gain in both the monthly and 2-monthly cabotegravir plus rilpivirine dosing arms was 1.0 kg.

Changes in laboratory chemistries

Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with treatment with cabotegravir plus rilpivirine. These changes are not considered clinically relevant as they likely reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1).

Elevated transaminases (ALT/AST) were observed in subjects receiving cabotegravir plus rilpivirine during clinical studies. These elevations were primarily attributed to acute viral hepatitis. A few subjects on oral therapy had transaminase elevations attributed to suspected drug-related hepatotoxicity; these changes were reversible upon discontinuation of treatment.

Elevated lipases were observed during clinical trials with cabotegravir plus rilpivirine; Grade 3 and 4 lipase increases occurred at a higher incidence with cabotegravir plus rilpivirine compared with CAR. These elevations were generally asymptomatic and did not lead to cabotegravir plus rilpivirine discontinuation. One case of fatal pancreatitis with Grade 4 lipase and confounding factors (including history of pancreatitis) has been reported in study ATLAS-2M, for which causality to the injection regimen could not be ruled out.