Cabotegravir

Chemical formula: C₁₉H₁₇F₂N₃O₅  Molecular mass: 405.358 g/mol  PubChem compound: 54713659

Interactions

Cabotegravir interacts in the following cases:

UGT1A1 strong inducers, UGT1A9 strong inducers

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.

OAT1/3 substrates

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).

End-stage renal disease

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.

Severe hepatic impairment

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.

Antacids

Polyvalent cation containing antacids are recommended to be taken at least 2 hours before and 4 hours after taking cabotegravir tablets.

Rifabutin

Concomitant use of cabotegravir injection with rifabutin is not recommended.

Geometric mean change (%):

Cabotegravir ↓
AUC ↓ 21%
Cmax ↓ 17%
Cτ ↓ 8%

Recommendations concerning co-administration:

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

HBV/HCV co-infection

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.

Pregnancy

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 tablets are not recommended during pregnancy unless the expected benefit justifies the potential risk to the foetus.

Cabotegravir 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.

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

Carcinogenesis and mutagenesis

Cabotegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay. Cabotegravir was not carcinogenic in long term studies in the mouse and rat.

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.

Effects on ability to drive and use machines

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.

Adverse reactions


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 pyrexia4 (10%). The most frequently reported ARs from ATLAS-2M every 2 month dosing were injection site reactions (76%), headache (7%) and pyrexia4 (7%).

Tabulated list of adverse reactions

The ARs identified for cabotegravir or rilpivirine are listed in Table 6 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:

MedDRA System Organ
Class (SOC)
Frequency
Category
ARs for Vocabria + rilpivirine regimen
Immune system disorders UncommonType I hypersensitivity
Psychiatric disorders Common Depression
Anxiety
Abnormal dreams
Insomnia
UncommonSuicide attempt; Suicidal ideation
(particularly in patients with a pre-existing
history of psychiatric illness)
Nervous system disordersVery common Headache
Common Dizziness
Uncommon Somnolence
Vasovagal reactions (in response to
injections)
Gastrointestinal disorders CommonNausea
Vomiting
Abdominal pain2
Flatulence
Diarrhoea
Hepatobiliary Disorders Uncommon Hepatotoxicity
Skin and subcutaneous tissue
disorders
Common Rash3
Uncommon Urticaria*
Angioedema
Musculoskeletal and
connective tissue disorders
CommonMyalgia
General disorders and
administrative site conditions
Very common Injection site reactions (pain and discomfort,
nodule, induration)
Pyrexia4
Common Injection site reactions (swelling, erythema,
pruritus, bruising, warmth, haematoma)
Fatigue
Asthenia
Malaise
Uncommon Injection site reactions(cellulitis, abscess,
anaesthesia, haemorrhage, discolouration)
InvestigationsCommon Weight increased
Uncommon Transaminase increased
Blood bilirubin increased

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 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.

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.

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