Cabenuva: Package Insert and Label Information (Page 2 of 7)

2.9 Administration Instructions for Injections

Refer to the Instructions for Use for complete administration instructions with illustrations.

A complete dose requires 2 injections: 1 injection of cabotegravir and 1 injection of rilpivirine [see Dosage and Administration (2.4, 2.5)].

Cabotegravir and rilpivirine are suspensions for gluteal intramuscular injection that do not need further dilution or reconstitution.

Administer each injection at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit. The ventrogluteal site is recommended. A dorsogluteal approach (upper outer quadrant) is acceptable, if preferred by the healthcare professional. Do not administer by any other route or anatomical site. Consider the body mass index (BMI) of the patient to ensure that the needle length is sufficient to reach the gluteus muscle. Longer needle lengths (not included in the dosing kit) may be required for patients with higher BMI (example: >30 kg/m²) to ensure that injections are administered intramuscularly as opposed to subcutaneously. The administration order of cabotegravir and rilpivirine injections is not important.

Before preparing the injections, remove CABENUVA from the refrigerator and wait at least 15 minutes to allow the medicines to come to room temperature. The vials may remain in the carton at room temperature for up to 6 hours; do not put back into the refrigerator. If not used within 6 hours, the medication must be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The cabotegravir vial has a brown tint to the glass that may limit visual inspection. Discard CABENUVA if either medicine exhibits particulate matter or discoloration.

Shake each vial of CABENUVA vigorously so that the suspensions look uniform before injecting. Small air bubbles are expected and acceptable.

Once the suspensions have been drawn into the respective syringes, the injections should be administered as soon as possible, but may remain in the syringes for up to 2 hours. The filled syringes should not be placed in the refrigerator. If the medicine remains in the syringes for more than 2 hours, the filled syringes and needles must be discarded [see How Supplied/Storage and Handling (16)].

3 DOSAGE FORMS AND STRENGTHS

Injection:

•

Kit of single-dose vials of 400 mg/2 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 600 mg/2 mL (300 mg/mL) of rilpivirine extended-release injectable suspension. (3)

•

Kit of single-dose vials of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 900 mg/3 mL (300 mg/mL) of rilpivirine extended-release injectable suspension. (3)

4 CONTRAINDICATIONS

CABENUVA is contraindicated in patients:

•

with previous hypersensitivity reaction to cabotegravir or rilpivirine [see Warnings and Precautions (5.1)].

•

receiving the following coadministered drugs for which significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur due to uridine diphosphate glucuronosyltransferase (UGT)1A1 and/or cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response [see Drug Interactions (7), Clinical Pharmacology (12.3)]:

o

Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin

o

Antimycobacterials: Rifabutin, rifampin, rifapentine

o

Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment)

o

Herbal product: St John’s wort (Hypericum perforatum)

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Hypersensitivity reactions have been reported during postmarketing experience with rilpivirine-containing regimens [see Adverse Reactions (6.2)]. Reactions include cases of drug reaction with eosinophilia and systemic symptoms (DRESS). While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA [see Adverse Reactions (6.1)]. Administration of cabotegravir and rilpivirine oral lead-in dosing was used in clinical studies to help identify patients who may be at risk of a hypersensitivity reaction [see Dosage and Administration (2.3), Contraindications (4)]. Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected [see Contraindications (4), Adverse Reactions (6)].

Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. For information regarding the long-acting properties of CABENUVA, [see Warnings and Precautions (5.6)]. Administer oral lead-in dosing prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction [see Dosage and Administration (2.3), Contraindications (4)].

5.2 Post-Injection Reactions

In clinical trials, serious post-injection reactions were reported within minutes after the injection of rilpivirine. These events included symptoms such as dyspnea, bronchospasm, agitation, abdominal cramping, rash/urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, and pain (e.g., back and chest). These events were reported in <1% of subjects and began to resolve within minutes after the injection, with some patients receiving supportive care. These events may have been associated with accidental intravenous administration during the intramuscular injection procedure [see Adverse Reactions (6.1)].

Carefully follow the Instructions for Use when preparing and administering CABENUVA. The suspensions should be injected slowly via intramuscular injection, and care should be taken to avoid accidental intravenous administration [see Dosage and Administration (2.9)]. Observe patients briefly (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated.

5.3 Hepatotoxicity

Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors [see Adverse Reactions (6.1)].

Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations.

Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected. For information regarding the long-acting properties of CABENUVA, [see Warnings and Precautions (5.6)].

5.4 Depressive Disorders

Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with CABENUVA or the individual drug products [see Adverse Reactions (6.1)]. Promptly evaluate patients with depressive symptoms to assess whether the symptoms are related to CABENUVA and to determine whether the risks of continued therapy outweigh the benefits.

5.5 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance [see Contraindications (4), Drug Interactions (7.4)].

Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times, respectively, the recommended oral dosage) in healthy adults prolonged the QTc interval with mean steady-state C_max values 4.4- and 11.6-fold, respectively, higher than C_max values associated with the recommended 600-mg monthly dose of rilpivirine extended-release injectable suspension and 4.1- and 10.7-fold, respectively, higher than C_max values associated with the recommended 900-mg every-2-month dose of rilpivirine extended‑release injectable suspension [see Clinical Pharmacology (12.2)]. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes [see Drug Interactions (7.3, 7.4)].

See Table 8 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with, and after discontinuation of, CABENUVA; review concomitant medications during therapy with CABENUVA [see Drug Interactions (7.4)].

5.6 Long-Acting Properties and Potential Associated Risks with CABENUVA

Residual concentrations of both cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). It is important to carefully select patients who agree to the required monthly or every-2-month injection dosing schedule because non-adherence to monthly or every-2-month injections or missed doses could lead to loss of virologic response and development of resistance [see Dosage and Administration (2.2), Adverse Reactions (6.1), Drug Interactions (7.4)].

To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injections of CABENUVA when dosed monthly and no later than 2 months after the final injections of CABENUVA when dosed every 2 months. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible.

6 ADVERSE REACTIONS

The following adverse reactions are described below and in other sections of the labeling:

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Hypersensitivity reactions [see Warnings and Precautions (5.1)]

•

Post-injection reactions [see Warnings and Precautions (5.2)]

•

Hepatotoxicity [see Warnings and Precautions (5.3)]

•

Depressive disorders [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect rates observed in practice.

Clinical Trials Experience in Adults

The safety assessment of CABENUVA is based on the analysis of pooled 48-week data from 1,182 virologically suppressed subjects with HIV-1 infection in 2 international, multicenter, open-label pivotal trials, FLAIR and ATLAS, and 1,045 virologically suppressed subjects from the ATLAS-2M trial [see Clinical Studies (14.1)]. Additional safety information from other ongoing or earlier clinical trials in the cabotegravir and rilpivirine program have been considered in assessing the overall safety profile of CABENUVA.

Adverse reactions were reported following exposure to CABENUVA extended-release injectable suspensions (median time exposure at the time of analysis: 54 weeks in FLAIR and ATLAS, and 64 weeks in ATLAS-2M) and data from VOCABRIA (cabotegravir) tablets and EDURANT (rilpivirine) tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks in FLAIR and ATLAS, and 5.6 weeks in ATLAS-2M). Adverse reactions included those attributable to both the oral and injectable formulations of cabotegravir and rilpivirine administered as a combination regimen. Refer to the prescribing information for EDURANT (rilpivirine) for other adverse reactions associated with oral rilpivirine.

The most common adverse reactions regardless of severity reported in ≥2% of adult subjects from FLAIR and ATLAS at Week 48 are presented in Table 5. Selected laboratory abnormalities are included in Table 7. At Week 96, the overall safety profile for FLAIR was consistent with that observed at Week 48, with no new safety findings identified.

In the extension phase of the FLAIR study at Week 124, the overall safety profile was consistent with that observed at Week 48 and when injection therapy with CABENUVA was initiated directly without the oral lead-in phase.

Overall, 4% of subjects in the group receiving CABENUVA and 2% of subjects in the control group in FLAIR and ATLAS discontinued due to adverse events. Non-injection-site-related adverse events leading to discontinuation and occurring in more than 1 subject were headache, diarrhea, hepatitis A, and acute hepatitis B (all with an incidence <1%). In ATLAS-2M, 2% of subjects in both treatment groups discontinued due to adverse events. Non-injection-site–related adverse events leading to discontinuation and occurring in more than 1 subject in ATLAS-2M were fatigue, pyrexia, headache, presyncope, acute hepatitis B, hyperhidrosis, and abnormal dreams that occurred with an incidence of ≤1% in either treatment group.

Table 5. Adverse Reactions^a (Grades 1 to 4) Reported in at Least 2% of Subjects with HIV-1 Infection in FLAIR and ATLAS Trials (Week 48 Pooled Analyses)

Adverse Reactions	Cabotegravir plus Rilpivirine Once Monthly (n = 591)		Current Antiretroviral Regimen (n = 591)
	All Grades	At Least Grade 2	All Grades	At Least Grade 2
Injection site reactionsb	83%	37%	0	0
Pyrexiac	8%	2%	0	0
Fatigued	5%	1%	<1%	<1%
Headache	4%	<1%	<1%	<1%
Musculoskeletal paine	3%	1%	<1%	0
Nausea	3%	<1%	1%	<1%
Sleep disordersf	2%	<1%	<1%	0
Dizziness	2%	<1%	<1%	0
Rashg	2%	<1%	0	0

^a Adverse reactions defined as “treatment-related” as assessed by the investigator.
^b See Injection-Associated Adverse Reactions for additional information.
^c Pyrexia: includes pyrexia, feeling hot, chills, influenza-like illness, body temperature increased.
^d Fatigue: includes fatigue, malaise, asthenia.
^e Musculoskeletal pain: includes musculoskeletal pain, musculoskeletal discomfort, back pain, myalgia, pain in extremity.
^f Sleep disorders: includes insomnia, poor quality sleep, somnolence.^g Rash: includes erythema, pruritus, pruritus generalized, purpura, rash, rash- erythematous, generalized, macular.

In ATLAS-2M, the type and frequency of adverse reactions reported in subjects receiving CABENUVA once monthly or CABENUVA once every 2 months for 48 weeks were similar. Differences between treatment arms were reported for the types of injection-associated adverse reactions (see Injection-Associated Adverse Reactions for additional information).

Injection-Associated Adverse Reactions: Local Injection Site Reactions (ISRs): In the 3 Phase 3 studies, FLAIR, ATLAS, and ATLAS‑2M, the most frequent adverse reactions associated with the intramuscular administration of CABENUVA were ISRs.

In the pooled analysis of FLAIR and ATLAS, 83% of subjects reported any injection site reaction with the monthly dosing regimen, with 1% of subjects who discontinued treatment with CABENUVA because of ISRs. After 14,682 injections, 3,663 ISRs were reported. The severity of ISRs was generally mild (Grade 1: 75% of subjects) or moderate (Grade 2: 36% of subjects). Four percent (4%) of subjects experienced severe (Grade 3) ISRs, and no subject experienced Grade 4 ISRs. The median duration of overall ISR events was 3 days. The most commonly reported ISR in FLAIR and ATLAS was pain/discomfort, with 79% reported in the group receiving CABENUVA.

In ATLAS-2M, 75% of subjects reported any injection site reaction in both the monthly and every‑2‑month dosing regimens, with <1% of subjects who discontinued treatment with CABENUVA because of ISRs. When dosing monthly, after 15,711 injections, 3,152 ISRs were reported. When dosing every 2 months, after 8,470 injections, 2,507 ISRs were reported. The severity of ISRs was generally mild (Grade 1: 70% and 71% of subjects) or moderate (Grade 2: 28% and 27% of subjects) in monthly and every‑2‑month dosing regimens, respectively. Four percent (4%) of subjects in the monthly group and 3% of subjects in the every‑2‑month group experienced severe (Grade 3) ISRs, and no subject experienced Grade 4 ISRs. The median duration of overall ISR events was 3 days for both dosing regimens. The most commonly reported ISR in ATLAS‑2M was pain/discomfort, with 71% and 73% reported in the monthly and every‑2‑month dosing regimens, respectively. The severity and duration of ISRs, including pain/discomfort, were similar for both dosing regimens and in subjects without prior exposure to CABENUVA.

The most commonly reported ISR (Grades 1 to 3) in at least 1% of adult subjects in the pooled analyses from FLAIR and ATLAS, and from ATLAS‑2M, are presented in Table 6. The side‑by‑side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trials.

Table 6. Injection Site Reactions (Grades 1 to 3) Reported in at Least 1% of Subjects in FLAIR and ATLAS (Pooled Analysis) and ATLAS-2M Trials (Week 48 Analysis)

Injection Site Reactions	FLAIR and ATLAS	ATLAS-2M
	Cabotegravir plus Rilpivirine Once Monthly (n = 591)	Cabotegravir plus Rilpivirine Once Every 2 Months (n = 522)	Cabotegravir plus Rilpivirine Once Monthly (n = 523)
Any injection site reaction	83%	75%	75%
Pain/discomfort	79%	73%	71%
Nodules	14%	10%	17%
Induration	12%	8%	7%
Swelling	8%	6%	5%
Erythema	4%	2%	3%
Pruritus	4%	5%	5%
Bruising/discoloration	3%	2%	2%
Warmth	2%	1%	2%
Hematoma	2%	<1%	3%

Anesthesia, abscess, cellulitis, and hemorrhage at the injection site were each reported in <1% of subjects.

Other Injection-Associated Adverse Reactions: In the ATLAS and FLAIR clinical trials, an increased incidence of pyrexia (8%) was reported by subjects receiving cabotegravir plus rilpivirine injections compared with no events among subjects receiving current antiretroviral regimen. In ATLAS and FLAIR, no cases were serious or led to withdrawal and the occurrences of pyrexia may represent a response to administration of CABENUVA via intramuscular injection. In ATLAS-2M, 1 subject in each arm reported pyrexia that led to withdrawal.

In ATLAS and FLAIR, reports of musculoskeletal pain (3%) and less frequently, sciatica, were also more common in subjects receiving cabotegravir plus rilpivirine compared with the current antiretroviral regimen and some events had a temporal association with injection.

Vasovagal or pre-syncopal reactions were reported in <1% of subjects after injection with rilpivirine or cabotegravir.

Less Common Adverse Reactions: The following select adverse reactions (regardless of severity) occurred in <2% of subjects receiving cabotegravir plus rilpivirine.

Gastrointestinal Disorders: Abdominal pain (including upper abdominal pain), gastritis, dyspepsia, vomiting, diarrhea, and flatulence.

Hepatobiliary Disorders: Hepatotoxicity.

Investigations: Weight increase (see below).

Psychiatric Disorders: Anxiety (including anxiety and irritability), depression, abnormal dreams.

Skin and Hypersensitivity Reactions: Hypersensitivity reactions.

Weight Increase: At Week 48, subjects in FLAIR and ATLAS who received cabotegravir plus rilpivirine had a median weight gain of 1.5 kg; those in the current antiretroviral regimen group had a median weight gain of 1.0 kg (pooled analysis). In the FLAIR trial, the median weight gain in subjects receiving cabotegravir plus rilpivirine or a dolutegravir-containing regimen was 1.3 kg and 1.5 kg, respectively, compared with 1.8 kg and 0.3 kg, respectively, in the ATLAS trial in subjects receiving either cabotegravir plus rilpivirine or a protease inhibitor-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or integrase strand transfer inhibitor (INSTI)-containing regimen, respectively. At Week 48, subjects in ATLAS-2M who received cabotegravir plus rilpivirine in both the monthly and every-2-month treatment arms had a median weight gain of 1.0 kg.

Laboratory Abnormalities: Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 7. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trials.

Table 7. Selected Laboratory Abnormalities (Grades 3 to 4, Week 48) in FLAIR and ATLAS (Pooled Analyses) and ATLAS-2M Trials

ALT = Alanine aminotransferase, ULN = Upper limit of normal, AST = Aspartate transaminase.
Laboratory Parameter	FLAIR and ATLAS		ATLAS-2M
	Cabotegravir plus Rilpivirine Once Monthly (n = 591)	Current Antiretroviral Regimen (n = 591)	Cabotegravir plus Rilpivirine Once Every 2 Months (n = 522)	Cabotegravir plus Rilpivirine Once Monthly (n = 523)
ALT (≥5.0 x ULN)	2%	<1%	<1%	<1%
AST (≥5.0 x ULN)	2%	<1%	<1%	1%
Total bilirubin (≥2.6 x ULN)	<1%	<1%	<1%	<1%
Creatine phosphokinase (≥10.0 x ULN)	8%	4%	3%	4%
Lipase (≥3.0 x ULN)	5%	3%	3%	2%

Changes in Total Bilirubin: Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed 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) [see Clinical Pharmacology (12.3)].

Serum Cortisol: In pooled Phase 3 trials of EDURANT (rilpivirine), the overall mean change from baseline in basal cortisol was -0.69 (-1.12, 0.27) mcg/dL in the group receiving EDURANT compared with -0.02 (-0.48, 0.44) mcg/dL in the control group. Abnormal responses to ACTH stimulation tests were also higher in the group receiving EDURANT. The clinical significance of the higher abnormal rate of ACTH stimulation tests in the group receiving EDURANT is not known. Refer to the prescribing information for EDURANT for additional information.

Clinical Trial Experience in Adolescents

Based on data from the Week 16 analysis of the MOCHA study in 23 adolescents (aged 12 to younger than 18 years and weighing ≥35 kg) receiving background antiretroviral therapy, the safety profile in adolescents with the addition of either oral cabotegravir followed by injectable cabotegravir (n = 8) or oral rilpivirine (n = 15) followed by injectable rilpivirine (n = 13) was consistent with the safety profile established with cabotegravir plus rilpivirine in adults. Adverse reactions were reported in 61% of adolescent subjects receiving either cabotegravir or rilpivirine. The majority of these subjects (86%) had a Grade 1 or Grade 2 adverse reaction. The adverse reactions reported by more than one subject (regardless of severity) were injection site pain (n = 13) and insomnia (n = 2). Two subjects had Grade 3 adverse reactions of hypersensitivity (n = 1) and insomnia (n = 1). The Grade 3 adverse reaction of drug hypersensitivity led to discontinuation of rilpivirine during oral lead-in. Sixty-two percent of subjects who received at least 1 injection of cabotegravir or rilpivirine reported at least 1 ISR. All ISRs were Grade 1 or Grade 2.