Applies to cabotegravir: oral tablet. Other dosage forms:

• intramuscular suspension extended release

Serious side effects of Cabotegravir

Along with its needed effects, cabotegravir may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking cabotegravir:

Less common

• Abnormal dreams
• dark urine
• difficulty in breathing or swallowing
• discouragement
• fast heartbeat
• feeling sad or empty
• irritability
• loss of appetite
• loss of interest or pleasure
• nausea or vomiting
• skin itching, rash, or redness
• stomach pain
• swelling of the face, throat, or tongue
• thoughts of hurting yourself
• trouble breathing
• trouble concentrating
• trouble sleeping
• unusual tiredness or weakness
• yellow eyes or skin

Other side effects of Cabotegravir

Some side effects of cabotegravir may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Body aches or pain
• chills
• cough
• diarrhea
• difficulty in breathing
• difficulty in moving
• dizziness
• ear congestion
• fever
• headache
• joint pain
• lack or loss of strength
• loss of voice
• muscle aches, cramps, pains, or stiffness
• runny or stuffy nose
• sleepiness or unusual drowsiness
• sneezing
• sore throat

For Healthcare Professionals

Applies to cabotegravir: intramuscular suspension extended release, oral tablet.

General

HIV-1 Treatment:

Side effects were reported after exposure to cabotegravir-rilpivirine long-acting injectable suspensions, as well as after exposure to cabotegravir tablets and rilpivirine tablets coadministered as oral lead-in therapy. Side effects included those attributable to both oral and injectable formulations of cabotegravir and rilpivirine administered as a combination regimen. The most common side effects reported during the oral lead-in period were headache, nausea, abnormal dreams, anxiety, insomnia, fatigue, diarrhea, dizziness, abdominal discomfort, abdominal distension, and asthenia. In 2 studies, 6 patients (1%) discontinued oral lead-in therapy due to side effects (including asthenia, myalgia, suicidal depression, headache); in another study, 4 patients (less than 1%) discontinued oral lead-in therapy due to side effects (including asthenia, skin lesion, fatigue, increased transaminases, depression).

The most common side effects reported from monthly and every-2-month dosing studies were injection site reactions, headache, and pyrexia (included feeling hot, body temperature increased).

The manufacturer product information for oral rilpivirine and cabotegravir-rilpivirine long-acting injectable suspensions should be consulted.

HIV-1 Preexposure Prophylaxis (PrEP):

The most common side effects reported with the oral tablets were headache, diarrhea, nausea, dizziness, upper respiratory tract infection, somnolence, fatigue, abnormal dreams, and abdominal pain; during the 2 trials, side effects leading to discontinuation of oral lead-in therapy included increased ALT, increased AST, suicide attempt, and dizziness in 1 trial (24 [1%] patients) and increased ALT and sleep disorders in the other trial (4 [less than 1%] patients). The most common side effects reported with the IM injection were injection site reactions, diarrhea, headache, pyrexia, fatigue, sleep disorders, nausea, dizziness, flatulence, abdominal pain, vomiting, myalgia, rash, decreased appetite, somnolence, back pain, and upper respiratory tract infection; the non-injection-site-associated side effect that led to discontinuation in 2 trials was increased ALT.^[Ref]

Dermatologic

Common (1% to 10%): Rash (included erythema, pruritus, generalized pruritus, purpura, rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, pruritic rash)

Frequency not reported: Skin lesion

Oral rilpivirine-containing regimens:

-Postmarketing reports: Severe skin and hypersensitivity reactions (including drug reaction with eosinophilia and systemic symptoms [DRESS])^[Ref]

Endocrine

In the pooled phase 3 trials of oral rilpivirine, the overall mean change from baseline in basal cortisol was -0.69 mcg/dL in the rilpivirine group compared with -0.02 mcg/dL in the control group. Abnormal responses to ACTH stimulation tests were also higher in the rilpivirine group; clinical significance of the higher rate of abnormal ACTH stimulation tests in the rilpivirine group has not been established.^[Ref]

Oral rilpivirine:

-Frequency not reported: Decreased basal cortisol, higher rate of abnormal responses to adrenocorticotropic hormone (ACTH) stimulation tests^[Ref]

Gastrointestinal

Common (1% to 10%): Increased lipase, nausea, vomiting, abdominal pain (included abdominal pain, upper abdominal pain), flatulence, diarrhea

Frequency not reported: Gastritis, dyspepsia, pancreatitis, abdominal discomfort, abdominal distension^[Ref]

In HIV-1 treatment studies, increased lipase (at least 3 times the upper limit of normal [3 x ULN]) was reported in 5% of patients.

During clinical studies for HIV-1 treatment, elevated lipases were observed with this drug plus rilpivirine; grade 3 and 4 lipase increases occurred at a higher incidence with this drug plus rilpivirine compared with current antiretroviral therapy. These elevations were generally asymptomatic and did not lead to discontinuation of therapy. A case of fatal pancreatitis with grade 4 lipase and confounding factors (including history of pancreatitis) was reported in 1 study; causality to the injection regimen could not be ruled out.

In HIV-1 PrEP trials, increased lipase (at least 3 x ULN) was reported in up to 3% of patients.^[Ref]

Hepatic

In HIV-1 treatment studies, increased AST (at least 5 x ULN), ALT (at least 5 x ULN), and bilirubin (at least 2.6 x ULN) were reported in 3%, 2%, and less than 1% of patients, respectively.

No cases of hepatotoxicity were reported in pivotal phase 3 trials for HIV-1 treatment; a few cases were reported with cabotegravir in phase 1 and 2 trials.

Small, nonprogressive increases in total bilirubin (without clinical jaundice) were observed with this drug plus rilpivirine; these changes were not considered clinically relevant as they likely reflected competition between this drug and unconjugated bilirubin for a common clearance pathway (UGT1A1).

During clinical studies for HIV-1 treatment, elevated transaminases (ALT/AST) were observed with this drug plus rilpivirine; these elevations were primarily attributed to acute viral hepatitis. A few patients on oral therapy had transaminase elevations attributed to suspected drug-related hepatotoxicity; these changes were reversible when therapy was stopped.

In HIV-1 PrEP trials, increased AST (at least 5 x ULN) and ALT (at least 5 x ULN) were reported in up to 3% and up to 2% of patients, respectively.^[Ref]

Common (1% to 10%): Increased AST, increased ALT

Uncommon (0.1% to 1%): Hepatotoxicity, increased transaminases, blood bilirubin increased^[Ref]

Hypersensitivity

Frequency not reported: Hypersensitivity reactions^[Ref]

Local

Very common (10% or more): Injection site reactions (up to 84%), injection site pain/tenderness, injection site pain and discomfort, injection site nodule, injection site induration, injection site swelling

Common (1% to 10%): Injection site erythema, injection site pruritus, injection site bruising, injection site warmth, injection site hematoma, injection site anesthesia, injection site abscess, injection site discoloration

Uncommon (0.1% to 1%): Injection site cellulitis, injection site hemorrhage^[Ref]

Injection site reactions (ISRs) were the most common side effects associated with the IM administration of this drug.

-HIV-1 Treatment: Up to 1% of patients discontinued this drug due to ISRs. When dosed monthly, up to 84% of patients reported ISRs; 6815 ISRs were reported out of 30,393 injections. When dosed every 2 months, 76% of patients reported ISRs; 2507 ISRs were reported out of 8470 injections. ISRs were generally of mild (grade 1: up to 75%) or moderate (grade 2: up to 36%) severity; while up to 4% of patients had severe (grade 3) ISRs, no patients had grade 4 reactions. The median duration of overall ISR events was 3 days. The percentage of patients reporting ISRs decreased over time.

-HIV-1 PrEP: In 1 trial, 8900 ISRs were reported out of 20,286 injections; of the 2117 patients who received at least 1 injection of this drug, 1740 (82%) patients had at least 1 ISR, of which 3% of patients discontinued this drug due to ISRs. Among those who used this drug and had at least 1 ISR, the maximum reaction severity was mild (grade 1), moderate (grade 2), and severe (grade 3) in 41%, 56%, and 3% of patients, respectively. The median duration of overall ISR events was 4 days; the proportion of patients reporting ISRs at each visit and the severity of the ISRs decreased over time.

-HIV-1 PrEP: In another trial, 1171 ISRs were reported out of 13,068 injections; of the 1519 patients who received at least 1 injection of this drug, 578 (38%) patients had at least 1 ISR and no patients discontinued this drug due to ISRs. Among those who used this drug and had at least 1 ISR, the maximum reaction severity was mild (grade 1), moderate (grade 2), and severe (grade 3) in 66%, 34%, and less than 1% of patients, respectively. The median duration of overall ISR events was 8 days; the proportion of patients reporting ISRs at each visit and the severity of the ISRs decreased over time.

In the 2 trials for HIV-1 PrEP, the following ISRs were reported in at least 1% of patients who had at least 1 ISR with this drug: pain/tenderness (up to 98%), swelling (up to 18%), nodules (up to 15%), induration (up to 15%), pruritus (up to 6%), erythema (up to 5%), bruising (up to 4%), warmth (up to 3%), abscess (up to 2%), anesthesia (1%), and discoloration (up to 1%).^[Ref]

Metabolic

Common (1% to 10%): Decreased appetite^[Ref]

Musculoskeletal

In HIV-1 treatment studies, increased CPK (at least 10 x ULN) was reported in 8% of patients.

Asymptomatic CPK elevations (mainly associated with exercise) have been reported with cabotegravir plus rilpivirine therapy.

In HIV-1 PrEP trials, increased CPK (at least 10 x ULN) was reported in up to 15% of patients.^[Ref]

Common (1% to 10%): Increased creatine phosphokinase (CPK), myalgia, musculoskeletal pain (included musculoskeletal pain, musculoskeletal discomfort, back pain, myalgia, pain in extremity), back pain

Frequency not reported: Asymptomatic CPK elevations^[Ref]

Nervous system

Very common (10% or more): Headache (up to 12%)

Common (1% to 10%): Dizziness, somnolence

Uncommon (0.1% to 1%): Vasovagal/presyncopal reactions (in response to injections)^[Ref]

Other

Very common (10% or more): Pyrexia (included pyrexia, feeling hot, chills, influenza-like illness, body temperature increased)

Common (1% to 10%): Fatigue (included fatigue, malaise), malaise, asthenia, increased weight

Frequency not reported: Increased total cholesterol, increased low-density lipoprotein (LDL) cholesterol, decreased LDL cholesterol, decreased high-density lipoprotein (HDL) cholesterol, increased triglycerides, increased total cholesterol/HDL cholesterol ratio^[Ref]

HIV-1 treatment: Most pyrexia events were reported within 1 week of injections.

HIV-1 treatment: At 48 weeks in 2 studies, patients who received this drug plus rilpivirine gained 1.5 kg (median) in weight, while patients who continued their current antiretroviral therapy gained 1 kg (median) in weight (pooled analysis). In the individual studies, the median weight gains in the arms with this drug plus rilpivirine were 1.3 and 1.8 kg, respectively, compared to 1.5 and 0.3 kg in the arms with current antiretroviral therapy. In another study, the median weight gain at 48 weeks was 1 kg in both the monthly and 2-monthly cabotegravir plus rilpivirine dosing arms.

HIV-1 PrEP: At 41 weeks and 97 weeks in 1 trial, patients who received this drug gained a median of 1.2 kg and 2.1 kg in weight from baseline, respectively; those who received emtricitabine-tenofovir gained a median of 0 kg and 1 kg in weight from baseline, respectively. At 41 weeks and 97 weeks in another trial, patients who received this drug gained a median of 2 kg and 4 kg in weight from baseline, respectively; those who received emtricitabine-tenofovir gained a median of 1 kg and 3 kg in weight from baseline, respectively.^[Ref]

Psychiatric

Common (1% to 10%): Sleep disorders (included insomnia, abnormal dreams, poor quality sleep, somnolence), depression, anxiety, abnormal dreams, insomnia

Frequency not reported: Anxiety (including irritability), depressive disorders (including depressed mood, depression, altered mood, mood swings, major depression, persistent depressive disorder, suicide ideation, suicide attempt), suicidal depression^[Ref]

Renal

Common (1% to 10%): Increased creatinine^[Ref]

In the HIV-1 PrEP trials, increased creatinine (greater than 1.8 x ULN or increased to at least 1.5 x baseline) was reported in up to 5% of patients.^[Ref]

Respiratory

Common (1% to 10%): Upper respiratory tract infection^[Ref]