Applies to cabotegravir / rilpivirine: intramuscular suspension extended release.

Serious side effects

Along with its needed effects, cabotegravir/rilpivirine 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 or nurse immediately if any of the following side effects occur while taking cabotegravir / rilpivirine:

Less common

• Bone or muscle pain
• changes in behavior
• dark urine
• discouragement
• feeling sad or empty
• headache
• irritability
• loss of appetite
• loss of interest or pleasure
• nausea or vomiting
• sleepiness or unusual drowsiness
• stomach pain
• thoughts of killing oneself
• trouble concentrating
• trouble sleeping
• unusual tiredness or weakness
• yellow eyes or skin

Rare

• Anxiety
• back pain
• chest pain or tightness
• cough
• diarrhea
• dizziness, lightheadedness, fainting
• feeling of warmth
• hives, itching skin, rash
• light-colored stools
• noisy breathing
• numbness of the mouth
• redness of the face, neck, arms and occasionally, upper chest
• redness of the skin
• stomach cramps
• sweating
• trouble breathing
• upper right stomach pain

Incidence not known

• Black, tarry stools
• chills
• cloudy or blood urine
• fever
• high blood pressure
• painful or difficult urination
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swelling of the face, feet, or lower legs
• swollen glands
• unusual bleeding or bruising

Other side effects

Some side effects of cabotegravir / rilpivirine 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:

More common

• Bleeding, blistering, burning, coldness, discoloration of skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• small lumps under the skin

Less common

• Bloated
• collection of blood under skin
• deep, dark purple bruise
• difficulty in moving
• excess air or gas in the stomach or intestines
• full feeling
• general feeling of discomfort or illness
• increased weight
• joint pain
• lack or loss of strength
• muscle aches, cramps, pains, or stiffness
• passing gas

For Healthcare Professionals

Applies to cabotegravir / rilpivirine: intramuscular suspension extended release.

General

Side effects were reported after exposure to cabotegravir-rilpivirine extended-release 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 with this drug were injection site pain, nasopharyngitis, upper respiratory tract infection, headache, diarrhea, injection site nodule, and injection site induration.

The manufacturer product information for oral rilpivirine should be consulted for other side effects associated with oral rilpivirine.^[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: Hyperhidrosis

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, diarrhea, gastroenteritis, hemorrhoids, vomiting, abdominal pain (included abdominal pain, upper abdominal pain), flatulence

Frequency not reported: Gastritis, dyspepsia^[Ref]

In 2 studies with the monthly dosing regimen, increased lipase (at least 3 times the upper limit of normal [3 x ULN]) was reported in 5% of patients. In another study, increased lipase (at least 3 x ULN) was reported in 2% and 3% of patients on the monthly and every-2-month dosing regimens, respectively.

During clinical studies for HIV-1 treatment, elevated lipases were observed with cabotegravir plus rilpivirine; grade 3 and 4 lipase increases occurred at a higher incidence with cabotegravir plus rilpivirine compared with current antiretroviral therapy. These elevations were generally asymptomatic and did not lead to discontinuation of therapy.^[Ref]

Hepatic

In 2 studies with the monthly dosing regimen, increased AST (at least 5 x ULN), ALT (at least 5 x ULN), and total bilirubin (at least 2.6 x ULN) were reported in 2%, 2%, and less than 1% of patients, respectively. In another study, increased AST (at least 5 x ULN), ALT (at least 5 x ULN), and total bilirubin (at least 2.6 x ULN) were reported in less than 1%, 1%, and less than 1% of patients on the monthly dosing regimen, respectively, and less than 1% each of patients on the every-2-month dosing regimen.

No cases of hepatotoxicity were reported in pivotal phase 3 trials; 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 cabotegravir plus rilpivirine; these changes were not considered clinically relevant as they likely reflected competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1).^[Ref]

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

Uncommon (0.1% to 1%): Hepatotoxicity, transaminase elevations

Frequency not reported: Increased bilirubin, hepatitis A, acute hepatitis B^[Ref]

Hypersensitivity

Frequency not reported: Hypersensitivity reactions, drug hypersensitivity^[Ref]

Local

Very common (10% or more): Injection site reactions (up to 84%), localized pain/discomfort (up to 79%), injection site pain (up to 77%), injection site nodules (up to 14%), injection site induration (up to 12%)

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

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

Injection site reactions (ISRs) were the most common side effect associated with the IM administration of this drug; in a pooled analysis of 2 studies, 83% of patients reported any ISR with the monthly dosing regimen, with 1% of patients who discontinued this drug due to ISRs. After 14,682 injection, 3663 ISRs were reported. ISRs included pain/discomfort (79%), nodules (14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising/discoloration (3%), warmth (2%), and hematoma (2%); anesthesia, abscess, cellulitis, and hemorrhage at the injection site were each reported in less than 1% of patients. 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 ISRs was 3 days.

In another study, 75% of patients reported any ISR in both the monthly and every-2-month dosing regimens, with less than 1% of patients who discontinued this drug due to ISRs. When dosed monthly, after 15,711 injections, 3152 ISRs were reported; when dosed every 2 months, after 8470 injections, 2507 ISRs were reported. ISRs included pain/discomfort (71% and 73%), nodules (17% and 10%), induration (7% and 8%), swelling (5% and 6%), erythema (3% and 2%), pruritus (5% and 5%), bruising/discoloration (2% and 2%), warmth (2% and 1%), and hematoma (3% and less than 1%) with the monthly and every-2-month regimens, respectively; anesthesia, abscess, cellulitis, and hemorrhage at the injection site were each reported in less than 1% of patients (both dosing regimens). ISRs were generally of mild (grade 1: up to 70% and up to 71%) or moderate (grade 2: up to 28% and up to 27%) severity with monthly and every-2-month dosing regimens, respectively; while up to 4% of patients in the monthly group and up to 3% of patients in the every-2-month group had severe (grade 3) ISRs, no patients had grade 4 reactions. The median duration of overall ISRs was 3 days for both dosing regimens. The severity and duration of ISRs (including pain/discomfort) were similar for both dosing regimens and in patients without prior exposure to this drug.^[Ref]

Metabolic

Common (1% to 10%): Vitamin D deficiency

Musculoskeletal

In 2 studies with the monthly dosing regimen, increased CPK (at least 10 x ULN) was reported in 8% of patients. In another study, increased CPK (at least 10 x ULN) was reported in 4% and 3% of patients on the monthly and every-2-month dosing regimens, respectively.

Asymptomatic CPK elevations (mainly associated with exercise) have been reported.^[Ref]

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

Frequency not reported: Asymptomatic CPK elevations^[Ref]

Nervous system

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

Common (1% to 10%): Dizziness

Uncommon (0.1% to 1%): Somnolence, vasovagal reactions (after/in response to injections)

Frequency not reported: Presyncopal reactions after injection, sciatica, presyncope^[Ref]

Other

Most reports of pyrexia occurred within 1 week of injections.

At 48 weeks in 2 studies, patients who received this drug monthly 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 were 1.3 and 1.8 kg, respectively, compared to 1.5 and 0.3 kg, respectively, 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 every-2-month dosing arms.^[Ref]

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

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

Frequency not reported: Post-injection reactions^[Ref]

Psychiatric

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

Frequency not reported: Anxiety (including irritability), depressive disorders (including depressed mood, depression, major depression, altered mood, mood swings, dysphoria, negative thoughts, suicidal ideation/attempt)^[Ref]

Renal

Oral rilpivirine-containing regimens:

-Postmarketing reports: Nephrotic syndrome^[Ref]

Respiratory

Very common (10% or more): Nasopharyngitis (up to 18%), upper respiratory tract infection (up to 12%)

Common (1% to 10%): Influenza, viral respiratory tract infection, pharyngitis, cough