HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CABENUVA safely
and effectively. See full prescribing information for
CABENUVA.
CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use
Initial U.S. Approval:
2021
---------------------------
INDICATIONS AND USAGE----------------------------
CABENUVA, a 2-drug
co-packaged product of cabotegravir,
a human immunodeficiency virus
type-1 (HIV-1) integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor
(NNRTI), is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace
the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history
of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. (1)
-----------------------DOSAGE AND ADMINISTRATION -----------------------
•
Prior to initiating treatment with CABENUVA, oral lead-in dosing
should be used for approximately 1 month to assess
the tolerability of cabotegravir and rilpivirine. (2.2)
•
For intramuscular
(IM) gluteal injection only. (2.3, 2.5)
•
Recommended Dosing Schedule: Initiate injections of CABENUVA (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of oral lead-in and continue
with injections of CABENUVA (400 mg of cabotegravir and 600 mg of rilpivirine) every month thereafter. (2.3)
---------------------
DOSAGE FORMS AND STRENGTHS----------------------
Cabotegravir extended-release injectable suspension and rilpivirine extended- release injectable suspension, co-packaged
as follows: (3)
CABENUVA 400-mg/600-mg Kit:
•
single-dose vial of 400 mg/2 mL (200 mg/mL) cabotegravir
• 
single-dose vial of 600 mg/2 mL (300 mg/mL) rilpivirine CABENUVA 600-mg/900-mg Kit:
•
single-dose vial of 600 mg/3 mL (200 mg/mL) cabotegravir
•
single-dose vial of 900 mg/3 mL (300 mg/mL) rilpivirine
------------------------------ CONTRAINDICATIONS ------------------------------
•
Previous hypersensitivity reaction to cabotegravir or rilpivirine. (4)
•
Coadministration with drugs where significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur, which may result in loss of virologic response.
(4)
-----------------------
WARNINGS AND PRECAUTIONS------------------------
•
Hypersensitivity reactions have been reported
with rilpivirine-containing regimens and in association
with other integrase inhibitors. Discontinue
CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop.
(5.1)
•
Serious post-injection reactions with rilpivirine were reported.
Monitor and treat as clinically indicated. (5.2)
•
Hepatotoxicity has been reported in patients
receiving cabotegravir or rilpivirine. Monitoring of liver chemistries is recommended. Discontinue
CABENUVA if hepatotoxicity is suspected. (5.3)
•
Depressive disorders
have been reported with CABENUVA. Immediate medical
evaluation is recommended for depressive symptoms. (5.4)
•
Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients up to 12 months or longer.
It is essential to initiate
an alternative, fully suppressive antiretroviral regimen no later
than 1 month after the final injection
doses of CABENUVA. If virologic failure is suspected, prescribe an alternative regimen as soon as possible. (5.6)
------------------------------
ADVERSE REACTIONS ------------------------------
The
most common adverse
reactions (Grades 1 to 4) observed in ≥2% of subjects receiving CABENUVA
were injection site reactions, pyrexia, fatigue,
headache, musculoskeletal pain,
nausea, sleep disorders, dizziness, and rash. (6.1)
To report
SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------
DRUG INTERACTIONS-------------------------------
•
Refer to the full prescribing information for important
drug interactions with CABENUVA. (4, 5.5, 7)
•
Because CABENUVA
is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection
is not recommended.
(7.1)
•
Drugs that induce uridine
diphosphate glucuronosyltransferase (UGT)1A1 or cytochrome P450 (CYP)3A4 may decrease the plasma
concentrations of the components of CABENUVA. (4, 7.3, 7.4)
•
CABENUVA should be used with caution
in combination with drugs with a known risk of Torsade
de Pointes. (7.3)
-----------------------
USE IN SPECIFIC POPULATIONS -----------------------
•
Pregnancy: After oral use of rilpivirine, exposures were generally lower during pregnancy compared with the postpartum period.
(8.1)
•
Lactation: Breastfeeding is not recommended due to the potential
for HIV-1 transmission. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 1/2021
FULL PRESCRIBING INFORMATION
1 INDICATIONS
AND USAGE
CABENUVA is indicated as a complete regimen for the treatment
of human immunodeficiency virus
type 1 (HIV-1) infection in
adults to replace the current antiretroviral regimen in
those who are virologically suppressed (HIV-1 RNA less than
50 copies per mL)
on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or
rilpivirine [see Clinical Studies (14.1)].
2
DOSAGE AND ADMINISTRATION
2.1 Adherence to CABENUVA
CABENUVA must
be administered
by a healthcare professional.
Prior to starting CABENUVA, healthcare professionals should carefully select patients
who agree to the required monthly
injection dosing schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain
viral suppression and reduce the
risk of viral rebound and potential development of resistance with missed doses [see Warnings and Precautions (5.6)].
2.2
Oral Lead-in Dosing
to Assess Tolerability of CABENUVA
Oral lead-in should be used for approximately
1 month (at least 28 days) prior
to the initiation of CABENUVA to assess the tolerability of cabotegravir and rilpivirine. The
recommended oral lead-in
daily dose is one 30-mg tablet of VOCABRIA (cabotegravir) and one 25-mg tablet of EDURANT (rilpivirine). See
Table 1 for recommended oral lead-in and intramuscular
injection dosing schedule for CABENUVA [Dosage and Administration (2.3)].
2.3
Intramuscular Injection Dosing
with CABENUVA
Initiation Injections
(CABENUVA 600-mg/900-mg Kit)
Initiate injections on the last day of oral lead-in. CABENUVA contains cabotegravir and rilpivirine extended-release injectable suspensions. The
recommended initial injection doses of
CABENUVA in adults are a
single 600-mg (3-mL) gluteal
intramuscular injection
of cabotegravir and
a single 900-mg (3-mL) gluteal
intramuscular injection of rilpivirine. Administer
cabotegravir and rilpivirine at separate gluteal injection sites (on
opposite sides or 2 cm apart)
during the same visit [see Dosage and Administration (2.5)]. Continuation
injections should be initiated a month after the initiation injections.
Continuation Injections (CABENUVA
400-mg/600-mg Kit)
After the initiation
injections, the recommended monthly
continuation injection doses of CABENUVA
in adults are a single 400-mg (2-mL) gluteal intramuscular
injection of cabotegravir
and a single 600-mg (2-mL)
gluteal intramuscular injection
of rilpivirine at each visit. Administer
cabotegravir and rilpivirine at separate gluteal injection
sites (on opposite sides or 2
cm apart) during the same
visit [see Dosage and
2
Administration (2.5)]. Patients may
be given CABENUVA up to 7 days before or
after the date the
patient is scheduled to receive
monthly injections.
Table 1. Recommended Oral Lead-In and
Intramuscular Injection Dosing Schedule in Adults
|
Drug
|
Oral Lead-In
(at
Least 28 Days)
|
Intramuscular (Gluteal) Initiation Injections
(One-Time Dosing)
|
Intramuscular (Gluteal) Continuation Injections
(Once-Monthly Dosing)
|
|
Month 1
|
At
Month 2 (On the Last Day of
Oral Lead-In Dosing)
|
Month
3 Onwards
|
|
Cabotegravir
|
30 mg once daily with a meal
|
600 mg (3 mL)
|
400 mg (2 mL)
|
|
Rilpivirine
|
25 mg once daily with a meal
|
900 mg (3 mL)
|
600 mg (2 mL)
|
2.4 Missed Injections
Adherence to the monthly
injection dosing schedule is strongly recommended. Patients who miss a scheduled injection visit should be clinically reassessed
to ensure resumption of therapy remains
appropriate. Refer to Table 2 for
dosing recommendations
after missed injections.
Planned
Missed Injections (Oral Dosing to Replace Up to
2 Consecutive Monthly Injections)
If a patient plans to miss a scheduled injection visit
by more than 7 days, take daily
oral therapy to replace up to 2
consecutive monthly injection visits.
The recommended oral daily dose is one
30-mg tablet of VOCABRIA (cabotegravir) and one 25-mg tablet of EDURANT
(rilpivirine). The first dose of oral therapy should be taken approximately 1 month
after the last injection dose
of CABENUVA and continued until the
day injection dosing is restarted.
Refer to Table 2 for injection
dosing recommendations.
Unplanned
Missed Injections
If monthly injections are missed or delayed by more than 7 days and oral therapy has not been taken in the interim, clinically
reassess the patient to determine if
resumption of injection dosing remains appropriate [see
Warnings and Precautions (5.6)]. If injection
dosing will be continued, see Table 2 for
dosing recommendations.
Table 2.
Injection Dosing Recommendations after Missed Injectionsa
|
Time Since Last Injection
|
Recommendation
|
|
Less than or equal to 2
months
|
Resume with 400-mg (2-mL) cabotegravir and 600-mg
(2-mL) rilpivirine intramuscular monthly
injections as soon as possible.
|
|
Greater than 2 months
|
Re-initiate
the patient with 600-mg (3-mL) cabotegravir and 900-mg
(3-mL) rilpivirine intramuscular
injections then continue to
follow the 400-mg
|
3
(2-mL) cabotegravir and
600-mg (2-mL) rilpivirine intramuscular monthly injection dosing schedule.
a Refer to oral dosing recommendations if a patient plans to miss
a scheduled injection visit.
2.5
Administration Instructions
Refer
to the Instructions for Use for complete administration instructions with illustrations.
A complete dose requires 2 injections: one injection of cabotegravir and one
injection of rilpivirine[see Dosage and Administration (2.3)].
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 2 cm apart) during the same visit.
The ventrogluteal site is recommended. 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: greater
than
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. 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 which 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. If 2 hours are exceeded, the medication,
syringes, and needles must
be discarded [see How
Supplied/Storage and Handling
(16)].
3
DOSAGE FORMS AND STRENGTHS
CABENUVA contains a single-dose vial of
cabotegravir as a white
to light pink, free-flowing extended-
release injectable suspension and a single-dose vial of rilpivirine as a white to off-white extended- release injectable
suspension, co-packaged as follows:
CABENUVA
400-mg/600-mg Kit
• Injection: 400 mg/2 mL
(200 mg/mL) of cabotegravir suspension in single-dose vial
4
• Injection: 600 mg/2 mL
(300 mg/mL) of rilpivirine suspension in single-dose
vial
CABENUVA
600-mg/900-mg Kit
• Injection: 600 mg/3 mL
(200 mg/mL) of cabotegravir suspension in single-dose vial
• Injection: 900 mg/3 mL (300 mg/mL) of rilpivirine suspension in single-dose
vial
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 (UDP)-glucuronosyl transferase
(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.
Remain vigilant and discontinue CABENUVA
if a hypersensitivity reaction is suspected [see Adverse Reactions (6.1)].
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
(2.2), Contraindications (4)].
5
5.2
Post-Injection Reactions
In clinical trials, serious
post-injection reactions were
reported within minutes after the injection of rilpivirine, including
dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events were reported in less than 1%
of subjects and began to resolve within a few minutes
after the injection. These events may have been associated
with inadvertent (partial)
intravenous administration [see Adverse Reactions (6.1)].
Carefully follow the Instructions
for Use when preparing and administering
CABENUVA to avoid accidental intravenous administration [see Dosage and Administration (2.5)]. 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 the recommended oral
dosage) in healthy adults resulted in mean steady-state
Cmax values 4.4-fold
and 11.6-fold higher than Cmax values associated with the
recommended 600-mg dose of
rilpivirine extended-release injectable
suspension and prolonged the QTc interval [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)].
6
See Table 5 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 (7.2)].
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 injection dosing schedule because non-adherence
to monthly injections or
missed doses could lead to loss of virologic response
and development of resistance [see Dosage and Administration (2.1), Adverse
Reactions (6.1), Drug Interactions (7.2)].
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 injection
doses of CABENUVA. 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:
•
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.
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 [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: 54
weeks) and data from VOCABRIA
(cabotegravir) tablets and EDURANT
(rilpivirine) tablets administered in combination
as oral lead-in therapy
(median
time exposure: 5.3 weeks). 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 for
other adverse reactions associated
with oral rilpivirine.
7
The most common adverse reactions regardless
of severity reported in greater than
or equal to 2% of adult subjects
in the pooled analyses from FLAIR
and ATLAS are presented
in Table 3. Selected laboratory abnormalities are included in Table 4.
Overall, 4% of subjects
in the group receiving CABENUVA and 2% of subjects in the control group
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 less than 1%).
|
Adverse Reactions
|
Cabotegravir plus Rilpivirine
(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
|
|
Rash g
|
2%
|
<1%
|
0
|
0
|
|
|
Table 3. Adverse Reactionsa
(Grades 1 to 4) Reported in at Least 2% of Subjects with HIV-1 Infection in FLAIR
and ATLAS Trials (Week 48 Pooled Analyses)
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.
Injection-Associated
Adverse Reactions
Local Injection Site Reactions (ISRs):The most frequent
adverse reactions associated
with the intramuscular administration of CABENUVA were ISRs. After 14,682 injections, 3,663 ISRs
were reported. One percent (1%)
of subjects discontinued
treatment with CABENUVA
because of ISRs. Most ISRs
were mild (Grade 1, 75%) or moderate (Grade
2, 36%). Four percent (4%) of subjects
experienced
8
severe (Grade 3) ISRs, and no subjects experienced Grade 4 ISRs. The most commonly reported ISR was localized
pain/discomfort (79%) regardless
of severity or relatedness. Other manifestations of
ISRs reported in more than 1%
of subjects over the duration of the analysis period included
nodules (14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%), warmth (2%),
and hematoma (2%). Abscess and cellulitis at the injection
site were each reported in less than
1% of subjects. The median
duration of ISR events was 3 days.
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.
No cases were serious or led to withdrawal and the occurrences of pyrexia may represent a response to administration of CABENUVA via intramuscular injection.
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 less than 1% of
subjects after injection
with rilpivirine or cabotegravir.
Less Common Adverse Reactions
The following select adverse reactions (regardless
of severity) occurred in less than 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 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.
9
Laboratory Abnormalities
Selected laboratory abnormalities with a worsening grade from baseline and representing the
worst- grade toxicity are presented in Table 4.
|
Laboratory Parameter
|
Cabotegravir
plus Rilpivirine
(n = 591)
|
Current Antiretroviral Regimen
(n = 591)
|
|
ALT (≥5.0 x ULN)
|
2%
|
<1%
|
|
AST (≥5.0 x ULN)
|
2%
|
<1%
|
|
Total bilirubin
(≥2.6 x ULN)
|
<1%
|
<1%
|
|
Creatine phosphokinase (≥10.0 x ULN)
|
8%
|
4%
|
|
Lipase (≥3.0 x ULN)
|
5%
|
3%
|
|
|
Table
4. Selected Laboratory Abnormalities (Grades 3 to 4; Week 48 Pooled
Analyses) in FLAIR and ATLAS
Trials
ULN = Upper
limit of normal.
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) micrograms/dL in the
group receiving
EDURANT compared with -0.02 (-0.48,
0.44) micrograms/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.
6.2 Postmarketing Experience
The following adverse reactions
have been identified during postmarketing
experience in patients
receiving an oral rilpivirine-containing regimen.
Because these reactions are reported voluntarily from a
population of uncertain size, it
is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Renal and Genitourinary
Disorders Nephrotic syndrome.
Skin and Subcutaneous Tissue Disorders
Severe skin and hypersensitivity reactions,
including DRESS[see Warnings and Precautions (5.1)].
10
7
DRUG INTERACTIONS
7.1 Concomitant Use with
Other Antiretroviral Medicines
Because CABENUVA
is a complete regimen, coadministration
with other antiretroviral medications for the treatment of HIV-1 infection is not
recommended [see Indications and Usage (1)].
7.2
Use of Other Antiretroviral Drugs after
Discontinuation of CABENUVA
Residual concentrations of
cabotegravir and rilpivirine may
remain in the systemic circulation of patients for prolonged periods
(up to 12 months or longer). These residual concentrations are not
expected to affect the exposures of antiretroviral drugs
that are initiated after discontinuation of CABENUVA[see
Warnings and Precautions (5.6), Drug Interactions (7.4), Clinical Pharmacology (12.3)].
7.3
Potential for Other Drugs to Affect CABENUVA
Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively.
Cabotegravir
Cabotegravir is primarily
metabolized by UGT1A1 with some
contribution from UGT1A9.
Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease cabotegravir
plasma
concentrations and may result in
loss of virologic response;
therefore, coadministration of
CABENUVA
with these drugs is contraindicated [see Contraindications
(4)].
Rilpivirine
Rilpivirine is primarily metabolized by CYP3A. Coadministration
of CABENUVA and drugs that induce CYP3A may
result in decreased plasma concentrations of rilpivirine and loss of virologic response
and possible resistance to rilpivirine or
to the class of NNRTIs[see Contraindications (4), Drug
Interactions (7.4)].Coadministration of CABENUVA
and drugs that inhibit CYP3A
may result in increased plasma concentrations of rilpivirine[see Drug Interactions (7.4), Clinical
Pharmacology (12.3)].
QT-Prolonging Drugs:At mean steady-state Cmax
values 4.4-fold and
11.6-fold higher than those with the recommended 600-mg dose of rilpivirine extended-release
injectable suspension, rilpivirine
may prolong the QTc
interval[see Clinical Pharmacology (12.2)]. CABENUVA should be used with caution in combination with drugs with
a known risk of Torsade de Pointes[see
Warnings and Precautions (5.5), Drug
Interactions (7.4)].
7.4
Established and Other
Potentially Significant Drug Interactions
Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively.
11
Information regarding potential drug interactions with cabotegravir
and rilpivirine is provided in Table
5. These recommendations are based on
either drug interaction
trials following oral administration of cabotegravir or rilpivirine or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response[see
Contraindications (4), Warnings and Precautions (5.5),
Clinical Pharmacology (12.3)].Table 5 includes potentially significant
interactions but is not all inclusive.
Table 5. Drug Interactions with
CABENUVA
|
Concomitant Drug
Class: Drug Name
|
Effect on Concentration
|
Clinical
Comment
|
|
Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital
Phenytoin
|
¯Cabotegravir
¯Rilpivirine
|
Coadministration is contraindicated with CABENUVA due
to potential for loss of
virologic response and development of
resistance[see Contraindications (4)].
|
|
Antimycobacterials:
Rifampina Rifapentine
|
¯Cabotegravir
¯Rilpivirine
|
|
Antimycobacterial:
Rifabutina
|
¯Cabotegravir
«Rifabutin
¯Rilpivirine
|
|
Glucocorticoid (systemic):
Dexamethasone
(more
than a single-dose treatment)
|
¯Rilpivirine
|
|
Herbal Product:
St John’s wort (Hypericum
perforatum)
|
¯Rilpivirine
|
|
Macrolide or ketolide
antibiotics: Azithromycin Clarithromycin Erythromycin
|
«Cabotegravir
Rilpivirine
|
Macrolides are expected to increase concentrations
of rilpivirine and are associated with a risk of Torsade de Pointes[Warnings and Precautions (5.5)].Where
possible, consider alternatives, such as azithromycin,
which increases rilpivirine
concentrations less
than
other macrolides.
|
|
Narcotic analgesic:
Methadonea
|
«Cabotegravir
¯Methadone
«Rilpivirine
|
No dose adjustment of methadone
is required when starting coadministration of methadone with CABENUVA.
However,
clinical monitoring is
|
12
|
|
|
recommended as methadone maintenance therapy may need to be adjusted in some patients.
|
= Increase, ¯ = Decrease, « =
No change.
aSee Clinical Pharmacology (12.3) for magnitude of interaction.
7.5
Drugs without Clinically
Significant Interactions
Cabotegravir
Based on drug interaction
study results, the following
drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation
of cabotegravir (antiretrovirals
and non-antiretrovirals) without a dose adjustment: etravirine, midazolam,
oral contraceptives containing
levonorgestrel and ethinyl
estradiol, and rilpivirine [see
Clinical Pharmacology (12.3)].
Rilpivirine
Based on drug interaction
study results, the following
drugs can be coadministered with rilpivirine (non- antiretrovirals and cabotegravir)
or given after discontinuation of rilpivirine (antiretrovirals and non-
antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone,
dolutegravir, ethinyl
estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir,
sildenafil, tenofovir alafenamide,
and tenofovir disoproxil fumarate [see Clinical Pharmacology
(12.3)]. Rilpivirine did not have a clinically
significant effect on the pharmacokinetics of digoxin or metformin.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy
Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in women
exposed to CABENUVA during pregnancy. Healthcare
providers are encouraged to register patients by calling the Antiretroviral Pregnancy
Registry (APR) at 1-800-258-4263.
Risk Summary
There are insufficient human
data on the use of CABENUVA
during pregnancy to adequately
assess a drug-associated risk
of birth defects and miscarriage. While there are insufficient human data to assess the
risk of neural tube defects (NTDs)
with exposure to CABENUVA during pregnancy, NTDs were
associated with dolutegravir, another integrase inhibitor. Discuss the benefit-risk of using CABENUVA with individuals of
childbearing potential or during pregnancy.
Cabotegravir and rilpivirine are detected in systemic circulation for
up to 12 months or longer after
discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy[see
Warnings and Precautions (5.6),
Drug Interactions (7.2)].
Cabotegravir use in pregnant women has not been evaluated. Available data
from the APR show no difference
in the overall risk of birth
defects for rilpivirine compared with the background rate for major
13
birth defects of 2.7% in a U.S. reference population
of the Metropolitan Atlanta Congenital
Defects Program (MACDP) (see Data).
The rate of miscarriage is not
reported in the APR. The
background risk for major birth defects and miscarriage for the indicated population is
unknown. The background rate for
major birth defects in a
U.S. reference population
of the Metropolitan Atlanta Congenital
Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in
clinically recognized pregnancies in the
U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth
defects in the general population.
The MACDP evaluates women and infants from a limited geographic area and does not include
outcomes for births that occurred at less
than 20 weeks’ gestation.
In animal reproduction studies with oral
cabotegravir, a delay
in the onset of parturition
and increased stillbirths and neonatal
deaths were observed in a rat pre- and postnatal
development study at greater than 28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in
rats or rabbits (greater
than 28 times or similar to the exposure at the RHD,
respectively) given during organogenesis (see Data).
No adverse developmental outcomes were observed when rilpivirine
was administered orally at
exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD (see Data).
Clinical Considerations
Lower exposures with oral rilpivirine were observed during pregnancy. Viral load should be monitored
closely if the patient remains on
CABENUVA during pregnancy. Cabotegravir and
rilpivirine are
detected in systemic circulation for up to 12 months
or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to
the potential for fetal exposure during pregnancy [see Warnings
and Precautions (5.6)].
Data
Human Data: Cabotegravir:Data from an
observational study in Botswana showed that dolutegravir,
another integrase inhibitor, was associated with increased risk of NTDs when administered at the time of conception and in early pregnancy.
Data from clinical trials are insufficient to address this
risk with cabotegravir.
Rilpivirine:Based on prospective
reports to the APR of over 390
exposures to oral rilpivirine-containing regimens
during the first trimester of
pregnancy and over 170 during second/third trimester of pregnancy, the prevalence
of birth defects in live births was
1.3% (95% CI: 0.4% to 3.0%) and
1.1% (95% CI: 0.1% to 4.0%) following first
and second/third trimester exposures, respectively,
compared with the background birth defect rate of 2.7% in the
U.S. reference population of the MACDP. In a clinical trial, total oral rilpivirine
exposures were generally
lower during pregnancy compared with the
postpartum period. Refer
to the prescribing information for EDURANT for
additional information on rilpivirine.
Animal Data: Cabotegravir:Cabotegravir was administered
orally to pregnant rats at
0, 0.5, 5, or 1,000 mg/kg/day
from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to
14
17. There were no effects
on fetal viability when fetuses
were delivered by caesarean,
although a minor decrease in fetal body weight was observed at
1,000 mg/kg/day (greater than
28 times the exposure in humans
at the RHD). No drug-related fetal toxicities
were observed at 5 mg/kg/day (approximately 13
times the exposure in humans at
the RHD) and no drug-related fetal
malformations were observed at any dose.
Cabotegravir was administered
orally to pregnant rabbits
at 0,
30, 500, or 2,000 mg/kg/day
from Gestation Days 7 to 19. No drug-related fetal
toxicities were observed at 2,000
mg/kg/day (approximately 0.7
times
the exposure in humans at the
RHD).
In a rat pre- and postnatal development
study, cabotegravir was
administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from
Gestation Day 6 to Lactation
Day 21. A delay in the onset
of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000
mg/kg/day (greater than 28
times the exposure in humans at the RHD); there were no alterations
to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers
were nursed from birth by
control mothers. There was no effect on neonatal survival of control
pups nursed from birth by cabotegravir-treated mothers.
A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or
neonatal mortality in rats. Studies
in pregnant rats showed that cabotegravir
crosses the placenta and can be detected in fetal tissue.
Rilpivirine:Rilpivirine was
administered orally to pregnant rats
(40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through
organogenesis (on Gestation
Days 6 through 17, and 6 through 19, respectively). No significant
toxicological effects were
observed in embryo-fetal toxicity
studies performed with rilpivirine
in rats and rabbits at exposures
15 (rats) and 70 (rabbits) times the exposure
in humans at the RHD. In a pre- and postnatal development
study, rilpivirine was administered orally
up to 400 mg/kg/day through
lactation. No adverse effects were
noted in the offspring
at maternal exposures up to 63 times the exposure in humans at the
RHD.
8.2
L
actation
Risk Summary
The Centers for Disease Control
and Prevention recommends that HIV-1−infected mothers in the United States not breastfeed their
infants to avoid risking postnatal transmission of HIV-1 infection.
It is not known if the components of CABENUVA are
present in human breast milk, affect
human milk production, or have effects on the breastfed
infant. When administered to lactating rats,
cabotegravir and rilpivirine were present in milk (see Data). If cabotegravir and/or rilpivirine
are present in human milk, residual exposures may remain for
12 months or longer after the last injections
have been administered [see Warnings and
Precautions (5.6)].
Because of the potential for
(1) HIV-1 transmission
(in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants),
(3) adverse reactions in a breastfed infant similar
to those seen in adults, and (4) detectable cabotegravir and rilpivirine concentrations
in systemic circulation for up
to 12
15
months or longer after discontinuing injections
of CABENUVA, instruct mothers not to breastfeed if they are receiving CABENUVA.
Data
Animal Data: Cabotegravir:Animal lactation studies with cabotegravir
have not been conducted. However,
cabotegravir was detected in the plasma of nursing pups on Lactation Day
10 in the rat pre- and postnatal development study.
Rilpivirine:Animal lactation studies with rilpivirine have not been conducted. However,
rilpivirine was detected in the plasma of nursing
pups on Lactation Day 7 in the rat
pre- and postnatal development study.
8.4
Pediatric Use
The safety and efficacy of CABENUVA have
not been evaluated in pediatric
patients.
8.5
Geriatric Use
Clinical trials of
CABENUVA did not
include sufficient numbers of
subjects aged 65 and older to determine
whether they respond differently
from younger subjects. In general, caution should be exercised in administration
of CABENUVA in elderly patients
reflecting greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy [see Clinical
Pharmacology (12.3)].
8.6
Renal Impairment
Based on studies with oral
cabotegravir and population
pharmacokinetic analyses of oral
rilpivirine, no dosage adjustment
of CABENUVA is necessary for patients with
mild
(creatinine clearance greater
than or equal to 60 to less than 90 mL/min) or moderate renal impairment (creatinine clearance greater than or equal
to 30 to less than 60 mL/min). In patients with severe renal
impairment (creatinine clearance 15 to less
than 30 mL/min) or end-stage
renal disease (creatinine clearance
less than 15 mL/min),
increased monitoring for adverse
effects
is recommended [see Clinical Pharmacology
(12.3)]. In
patients with end-stage renal
disease not on dialysis, effects on the pharmacokinetics of cabotegravir or rilpivirine are unknown. As cabotegravir and
rilpivirine are greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine.
8.7
Hepatic Impairment
Based on separate studies
with oral cabotegravir and oral rilpivirine, no dosage adjustment of CABENUVA
is necessary for patients with mild
or moderate hepatic impairment
(Child-Pugh A or B). The effect
of severe hepatic impairment (Child-Pugh
C) on the pharmacokinetics of cabotegravir or rilpivirine is unknown [see Clinical Pharmacology (12.3)].
10
OVERDOSAGE
There is no known specific treatment
for overdose with cabotegravir or rilpivirine. If overdose occurs, monitor the patient
and apply standard supportive treatment
as required, including monitoring of vital
16
signs and ECG (QT interval) as well
as observation of the clinical status of the
patient. As both cabotegravir and
rilpivirine are highly bound to plasma proteins, it is unlikely
that either would be significantly removed by
dialysis. Consider the prolonged exposure to cabotegravir
and rilpivirine (components of CABENUVA) following
an injection when assessing treatment needs and recovery [see Warnings and Precautions (5.6)].
11
DESCRIPTION
CABENUVA contains cabotegravir extended-release injectable
suspension, an HIV INSTI, co-packaged with rilpivirine
extended-release injectable
suspension, an HIV NNRTI.
Cabotegravir: The chemical name
for cabotegravir is (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-
hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8- carboxamide.The empirical formula is C19H17F2N3O5 and the molecular weight is 405.35 g/mol. It has the
following structural formula:
Cabotegravir extended-release injectable suspension is a white to light pink free-flowing suspension for intramuscular
injection. Each sterile single-dose vial contains 2 mL or 3 mL
of the following: cabotegravir 200
mg/mL and
the following inactive ingredients:
mannitol (35 mg/mL), polyethylene
glycol (PEG) 3350 (20 mg/mL), polysorbate 20 (20 mg/mL), and Water
for Injection.
Rilpivirine: The chemical name for rilpivirine
is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile. Its molecular formula is C22H18N6 and its molecular weight is 366.42.
Rilpivirine has the following structural formula:
Rilpivirine extended-release
injectable suspension is a white
to off-white suspension for intramuscular injection. Each sterile single-dose vial contains 2 mL or
3 mL
of the following: rilpivirine 300 mg/mL and the following
inactive ingredients: citric acid monohydrate
(1 mg/mL), poloxamer
338 (50 mg/mL), Water for Injection, glucose monohydrate
to ensure isotonicity, sodium dihydrogen phosphate monohydrate, and sodium hydroxide to adjust
pH.
The vial stoppers are not made
with natural rubber latex.
17
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
CABENUVA contains 2 long-acting HIV-1
antiretroviral drugs, cabotegravir
and rilpivirine[see Microbiology (12.4)].
12.2
Pharmacodynamics
Cardiac
Electrophysiology
At a dose of cabotegravir 150 mg
orally every 12 hours (10 times the recommended total daily oral
lead- in dosage for CABENUVA), the QT interval is not prolonged to any clinically
relevant extent.
Administration of 3 doses of
cabotegravir 150 mg orally every 12
hours resulted in a geometric mean Cmax approximately 2.8-fold and 5.4-fold above the geometric mean steady-state
Cmax associated with the recommended
30-mg
dose of oral cabotegravir and
the recommended 400-mg monthly dose of cabotegravir extended-release injectable suspension,
respectively.
At the recommended
dose of rilpivirine 25 mg orally once daily, the QT interval is
not prolonged to any clinically relevant extent. The rilpivirine 25-mg
once-daily mean steady-state Cmax was 247 ng/mL,
which is 1.7-fold higher than the mean
steady-state Cmax observed with
the recommended 600-mg monthly dose
of rilpivirine
extended-release injectable
suspension.
When rilpivirine 75-mg and 300-mg once-daily oral
doses (3 and 12 times the recommended
oral lead-in dosage) were studied in
healthy adults, the maximum
mean time-matched (95% upper confidence bound) differences in QTcF interval were
10.7 (15.3) and 23.3 (28.4) msec, respectively, after baseline and placebo adjustment. Steady-state administration of rilpivirine
75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 4.4-fold and 11.6-fold, respectively,
higher than the mean steady-state Cmax observed with the recommended 600-mg monthly
dose of rilpivirine extended-release injectable suspension. The corresponding Cmax ratios are 2.6 and 6.7 when compared with the recommended oral
rilpivirine dosage [see Warnings and Precautions (5.5)].
12.3
Pharmacokinetics
Absorption, Distribution, Metabolism, and Excretion
The pharmacokinetic properties of the components
of CABENUVA are provided in Table 6. The multiple-dose
pharmacokinetic parameters
are provided in Table 7. For the
pharmacokinetic properties of oral
cabotegravir and oral rilpivirine, refer to the full prescribing
information for VOCABRIA and EDURANT, respectively.
Table 6. Pharmacokinetic Properties of the Components of CABENUVA
|
|
Cabotegravir
|
Rilpivirine
|
|
Absorptiona
|
|
Tmax (days), median
|
7
|
3 to 4
|
|
Distribution
|
18
|
% Bound to human plasma proteins
|
>99.8
|
99.7
|
|
Blood-to-plasma ratio
|
0.52
|
0.7
|
|
CSF-to-plasma concentration ratio (median
[range])b
|
0.003
(0.002 to 0.004)
|
0.01
(BLQ to 0.02)
|
|
Elimination
|
|
t1/2 (weeks) meanc
|
5.6 to 11.5
|
13 to 28
|
|
Metabolism
|
|
Metabolic pathways
|
UGT1A1
UGT1A9 (minor)
|
CYP3A
|
|
Excretion
|
|
Major route of elimination
|
Metabolism
|
Metabolism
|
|
% of dose excreted as total 14C (unchanged drug) in urined
|
27 (0)
|
6 (<1)
|
|
% of dose
excreted as total 14C (unchanged drug) in fecesd
|
59 (47)
|
85 (26)
|
a When taken orally with a high-fat meal
versus fasted, the AUC(0-inf) (geometric mean
ratio [90% CI] of cabotegravir and rilpivirine are 1.14 [1.02,
1.28] and 1.72 [1.36, 2.16]), respectively.
b The
clinical relevance of CSF-to-plasma concentration ratios is unknown.
Concentrations were
measured at
steady-state one week after
administration of cabotegravir and
rilpivirine extended-release injectable
suspensions given monthly
or every 2 months.
c Elimination
half-life driven by slow absorption rate from the
injection site.
d Dosing in mass balance studies: single-dose oral administration of [14C] cabotegravir; single-dose oral administration of [14C] rilpivirine.
BLQ = Below limit of quantification.
|
Drug
|
Dosing Phase
|
Dosage Regimen
|
Geometric Mean (5th, 95th Percentile)a
|
|
AUC(0-tau)b (mcg•h/mL)
|
Cmax (mcg/mL)
|
Ctau (mcg/mL)
|
|
Cabotegravir
|
Oral Lead-Inc
|
30 mg once daily
|
145
(93.5, 224)
|
8.0
(5.3, 11.9)
|
4.6
(2.8, 7.5)
|
|
Initial
|
600 mg IM
|
1,591
|
8.0
|
1.5
|
|
Injectiond
|
initial
dose
|
(714, 3,245)
|
(5.3, 11.9)
|
(0.65, 2.9)
|
|
Monthly
|
400 mg IM
|
2,415
|
4.2
|
2.8
|
|
Injectione
|
monthly
|
(1,494, 3,645)
|
(2.5, 6.5)
|
(1.7, 4.6)
|
|
|
Table 7. Pharmacokinetic Parameters following Once-Daily Oral Cabotegravir and Rilpivirine and following Initiation and Monthly Continuation Intramuscular Injections of the Components of
CABENUVA
19
|
Drug
|
Dosing Phase
|
Dosage Regimen
|
Geometric Mean (5th, 95th Percentile)a
|
|
AUC(0-tau)b (ng•h/mL)
|
Cmax (ng/mL)
|
Ctau (ng/mL)
|
|
Rilpivirine
|
Oral Lead-Inb,f
|
25 mg once daily
|
2,083
(1,125, 3,748)
|
116
(48.6, 244)
|
78.9
(32.2, 180)
|
|
Initial
|
900 mg IM
|
41,069
|
139
|
37.2
|
|
Injectiond
|
initial dose
|
(20,062,
76,855)
|
(87.6, 219)
|
(19.4, 69.2)
|
|
Monthly
|
600 mg IM
|
65,603
|
116
|
82.2
|
|
Injectione
|
monthly
|
(37,239, 113,092)
|
(66.8, 199)
|
(47.5, 140)
|
a Pharmacokinetic parameter values based on individual post-hoc estimates
from separate cabotegravir and
rilpivirine population pharmacokinetic models (pooled FLAIR
and ATLAS, n = 581),
except for oral rilpivirine (see
footnote e).
b tau
is dosing interval: 24 hours for oral cabotegravir and rilpivirine; 1 month
for cabotegravir and
rilpivirine extended-release injectable suspensions.
c Oral lead-in
pharmacokinetic parameter values represent
steady-state.
d Initial injection
AUC(0-tau) and Cmax values primarily reflect
values following oral dosing because the
initial injection was administered
on the same day as the last oral dose;
however, the Ctau value at
Week
4 reflects the initial injection.
e Monthly
injection pharmacokinetic parameter values
represent Week 48 data.
f Oral rilpivirine: AUC(0-tau) based on population pharmacokinetic estimates
of rilpivirine 25 mg
once daily from pooled Phase 3 trials with EDURANT (rilpivirine); Ctau
based on observed data from FLAIR and ATLAS; Cmax based on observed
data for rilpivirine 25 mg once daily from a pharmacokinetic substudy
in pooled Phase 3 trials
with EDURANT.
IM = Intramuscular. Specific
Populations
No clinically
significant differences in the pharmacokinetics of cabotegravir or rilpivirine were
observed based on age, sex, race/ethnicity, body
mass index, or UGT1A1 polymorphisms.
The effect of hepatitis B
and C virus co-infection on the
pharmacokinetics of cabotegravir is unknown. No clinically relevant differences
in the pharmacokinetics of oral rilpivirine
have been observed with hepatitis B and/or C virus co-infection.
The pharmacokinetics of cabotegravir (oral or
injectable) and of injectable
rilpivirine have not been studied in pediatric patients and data are limited in subjects aged
65 years or older [see Use in Specific Populations (8.4,
8.5)].
Patients with Renal
Impairment:With oral cabotegravir, no
clinically significant differences in the pharmacokinetics
of cabotegravir are expected in patients with
mild, moderate, or severe
renal impairment. Cabotegravir
has not been studied in patients with
end-stage renal disease not on dialysis.
20
As cabotegravir is greater than 99% protein bound,
dialysis is not expected to alter exposures of cabotegravir[see Use in Specific Populations
(8.6)].
Population pharmacokinetic analyses indicated
that mild renal impairment
had no clinically relevant effect
on the exposure of oral rilpivirine.
There is limited or no information
regarding the pharmacokinetics
of rilpivirine in patients with moderate or severe
renal impairment, or end-stage
renal disease not on dialysis. As rilpivirine
is greater than 99% protein bound, dialysis is not
expected to alter exposures of rilpivirine [see Use in Specific
Populations (8.6)].
Patients with
Hepatic Impairment:No clinically significant differences in the pharmacokinetics of
cabotegravir are expected in mild to moderate (Child-Pugh A or B)
hepatic impairment. The effect
of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir has not been
studied[see
Use in Specific Populations (8.7)].
No clinically significant differences in the pharmacokinetics of rilpivirine were
observed in mild to moderate (Child-Pugh A or B) hepatic impairment.
The effect of severe hepatic
impairment (Child-Pugh
C) has not been studied[see Use in Specific Populations (8.7)]. Drug
Interaction Studies
Cabotegravir is not a clinically relevant inhibitor of the
following enzymes and transporters: CYP1A2, 2A6, 2B6, 2C8,
2C9, 2C19, 2D6, and 3A4; UGT1A1, 1A3,
1A4, 1A6, 1A9, 2B4, 2B7, 2B15, and 2B17;
P-glycoprotein (P-gp);
breast cancer resistance protein (BCRP); bile salt export pump (BSEP); organic cation transporter (OCT)1,
OCT2;
organic anion transporter polypeptide
(OATP)1B1, OATP1B3;
multidrug and toxin extrusion transporter (MATE) 1, MATE 2-K;
multidrug resistance protein (MRP)2 or MRP4.
In vitro, cabotegravir inhibited
renal OAT1 (IC50 = 0.81 microM) and OAT3
(IC50 = 0.41 microM).
Based
on physiologically based pharmacokinetic (PBPK) modeling, cabotegravir may
increase the AUC of OAT1/3 substrates up to approximately 80%.
In vitro, cabotegravir did not
induce CYP1A2, CYP2B6, or CYP3A4.
Simulations using PBPK modeling show that no clinically significant
interaction is expected during coadministration
of cabotegravir with drugs that inhibit UGT1A1.
In vitro, cabotegravir was not a substrate of OATP1B1,
OATP1B3, or OCT1.
Cabotegravir is a substrate of P-gp
and BCRP in vitro; however,
because of its high permeability, no alteration
in cabotegravir absorption is expected with coadministration
of P-gp
or BCRP inhibitors.
Rilpivirine is
not likely to have a clinically
relevant effect on the exposure of drugs metabolized by CYP
enzymes.
Drug interaction studies were not conducted with injectable cabotegravir or
injectable rilpivirine.
Drug interaction studies with oral cabotegravir or oral rilpivirine
are summarized in Tables
8, 9, 10, and 11.
21
Table 8. Effect of Coadministered Drugs
on the Pharmacokinetics of Cabotegravir
|
Coadministered
Drug(s)
and Dose(s)
|
Dose of Cabotegravir
|
n
|
Geometric Mean Ratio (90% CI) of Cabotegravir Pharmacokinetic
Parameters with/without Coadministered Drugs
No Effect = 1.00
|
|
Cmax
|
AUC
|
Ct or C24
|
|
Etravirine
|
30 mg
|
12
|
1.04
|
1.01
|
1.00
|
|
200 mg twice
daily
|
once daily
|
(0.99, 1.09)
|
(0.96, 1.06)
|
(0.94, 1.06)
|
|
Rifabutin
|
30 mg
|
12
|
0.83
|
0.77
|
0.74
|
|
300 mg once
daily
|
once daily
|
(0.76, 0.90)
|
(0.74, 0.83)
|
(0.70, 0.78)
|
|
Rifampin
|
30-mg
|
15
|
0.94
|
0.41
|
0.50
|
|
600 mg once
daily
|
single dose
|
(0.87, 1.02)
|
(0.36, 0.46)
|
(0.44, 0.57)
|
|
Rilpivirine
|
30 mg
|
11
|
1.05
|
1.12
|
1.14
|
|
25 mg once daily
|
once daily
|
(0.96, 1.15)
|
(1.05, 1.19)
|
(1.04, 1.24)
|
CI = Confidence Interval; n =
Maximum number of subjects with data; NA = Not available.
T
able 9. Effect of Coadministered Drugs on the Pharmacokinetics of Rilpivirine
|
Coadministered
Drug(s)
and Dose(s)
|
Dose of
Rilpivirine
|
n
|
Geometric Mean Ratio (90% CI) of Rilpivirine Pharmacokinetic Parameters with/without Coadministered Drugs
No Effect = 1.00
|
|
Cmax
|
AUC
|
Cmin
|
|
Acetaminophen
|
150 mg
|
16
|
1.09
|
1.16
|
1.26
|
|
500-mg single dose
|
once dailya
|
(1.01 to 1.18)
|
(1.10 to 1.22)
|
(1.16 to 1.38)
|
|
Atorvastatin
|
150 mg
|
16
|
0.91
|
0.90
|
0.90
|
|
40 mg once daily
|
once dailya
|
(0.79 to 1.06)
|
(0.81 to 0.99)
|
(0.84 to 0.96)
|
|
Chlorzoxazone
|
150 mg
|
16
|
1.17
|
1.25
|
1.18
|
|
500-mg single
dose taken
|
once dailya
|
(1.08 to 1.27)
|
(1.16 to 1.35)
|
(1.09 to 1.28)
|
|
2 hours after rilpivirine
|
|
Darunavir/ritonavir
|
150 mg
|
14
|
1.79
|
2.30
|
2.78
|
|
800/100 mg once daily
|
once dailya
|
(1.56 to 2.06)
|
(1.98 to 2.67)
|
(2.39 to 3.24)
|
|
Didanosine
|
150 mg
|
21
|
1.00
|
1.00
|
1.00
|
|
400 mg once daily
|
once dailya
|
(0.90 to 1.10)
|
(0.95 to 1.06)
|
(0.92 to 1.09)
|
|
delayed release capsules
|
|
taken 2 hours
before
|
|
rilpivirine
|
|
Ethinylestradiol/ Norethindrone
0.035 mg once daily/
1 mg once daily
|
25 mg once
daily
|
15
|
«b
|
«b
|
«b
|
22
|
Ketoconazole
400 mg once daily
|
150 mg once dailyb
|
15
|
1.30
(1.13 to 1.48)
|
1.49
(1.31 to 1.70)
|
1.76
(1.57 to 1.97)
|
|
Lopinavir/ritonavir 400/100 mg twice daily
(soft gel capsule)
|
150 mg once dailya
|
15
|
0.96
(0.88 to 1.05)
|
0.99
(0.89 to 1.10)
|
0.89
(0.73 to 1.08)
|
|
Methadone
60 to 100 mg once daily,
individualized dose
|
25 mg once
daily
|
12
|
«b
|
«b
|
«b
|
|
Raltegravir
|
25 mg
|
23
|
1.12
|
1.12
|
1.03
|
|
400 mg twice daily
|
once
daily
|
(1.04 to 1.20)
|
(1.05 to 1.19)
|
(0.96 to 1.12)
|
|
Rifabutin
|
25 mg
|
18
|
0.69
|
0.58
|
0.52
|
|
300 mg once daily
|
once
daily
|
(0.62 to 0.76)
|
(0.52 to 0.65)
|
(0.46 to 0.59)
|
|
Rifabutin
|
50 mg
|
18
|
1.43
|
1.16
|
0.93
|
|
300 mg once daily
|
once daily
|
(1.30 to 1.56)
|
(1.06 to 1.26)
|
(0.85 to 1.01)
|
|
(reference arm for comparison was 25 mg-once- daily rilpivirine administered
alone)
|
|
Rifampin
|
150 mg
|
16
|
0.31
|
0.20
|
0.11
|
|
600 mg once daily
|
once dailya
|
(0.27 to 0.36)
|
(0.18 to 0.23)
|
(0.10 to 0.13)
|
|
Sildenafil
|
75 mg
|
16
|
0.92
|
0.98
|
1.04
|
|
50-mg single dose
|
once dailya
|
(0.85 to 0.99)
|
(0.92 to 1.05)
|
(0.98 to 1.09)
|
|
Tenofovir disoproxil
|
150 mg
|
16
|
0.96
|
1.01
|
0.99
|
|
fumarate
|
once dailya
|
(0.81 to 1.13)
|
(0.87 to 1.18)
|
(0.83 to 1.16)
|
|
300 mg once daily
|
CI = Confidence Interval; n =
Maximum number of subjects with data; NA = Not
available; « = No change.
a This
interaction study has been
performed with a dose higher than
the recommended dose for
rilpivirine
(25 mg once daily) assessing the maximal effect on the coadministered drug.
b Comparison based on historic controls.
23
Table 10. Effect of Cabotegravir on the Pharmacokinetics of Coadministered Drugs
|
Coadministered
Drug(s)
and Dose(s)
|
Dose of
Cabotegravir
|
n
|
Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters
of Coadministered Drug with/without Cabotegravir
No Effect = 1.00
|
|
Cmax
|
AUC
|
Ct or C24
|
|
Ethinyl estradiol
|
30 mg
|
19
|
0.92
|
1.02
|
1.00
|
|
0.03 mg once daily
|
once daily
|
(0.83, 1.03)
|
(0.97, 1.08)
|
(0.92, 1.10)
|
|
Levonorgestrel
|
30 mg
|
19
|
1.05
|
1.12
|
1.07
|
|
0.15 mg once daily
|
once daily
|
(0.96, 1.15)
|
(1.07, 1.18)
|
(1.01, 1.15)
|
|
Midazolam
|
30 mg
|
12
|
1.09
|
1.10
|
NA
|
|
3 mg
|
once daily
|
(0.94, 1.26)
|
(0.95, 1.26)
|
|
Rilpivirine
|
30 mg
|
11
|
0.96
|
0.99
|
0.92
|
|
25 mg once daily
|
once daily
|
(0.85, 1.09)
|
(0.89, 1.09)
|
(0.79, 1.07)
|
CI = Confidence Interval; n =
Maximum number of subjects with data; NA = Not
available.
Table 11. Effect of Rilpivirine on the Pharmacokinetics of
Coadministered Drugs
|
Coadministered
Drug(s)
and Dose(s)
|
Dose of
Rilpivirine
|
n
|
Geometric Mean Ratio (90% CI) of Coadministered Drug Pharmacokinetic Parameters with/without EDURANT
No Effect = 1.00
|
|
Cmax
|
AUC
|
Cmin
|
|
Acetaminophen
500-mg single dose
|
150 mg once dailya
|
16
|
0.97
(0.86 to 1.10)
|
0.91
(0.86 to 0.97)
|
NA
|
|
Atorvastatin
|
150 mg
|
16
|
1.35
|
1.04
|
0.85
|
|
40 mg once daily
|
once dailya
|
(1.08 to 1.68)
|
(0.97 to 1.12)
|
(0.69 to 1.03)
|
|
2-hydroxy-atorvastatin
|
1.58
|
1.39
|
1.32
|
|
|
(1.33 to 1.87)
|
(1.29 to 1.50)
|
(1.10 to 1.58)
|
|
4-hydroxy-atorvastatin
|
1.28
|
1.23
|
NA
|
|
(1.15 to 1.43)
|
(1.13 to 1.33)
|
|
Chlorzoxazone
|
150 mg
|
16
|
0.98
|
1.03
|
NA
|
|
500-mg single
dose taken
|
once dailya
|
(0.85 to 1.13)
|
(0.95 to 1.13)
|
|
2 hours after rilpivirine
|
|
Darunavir/ritonavir
|
150 mg
|
15
|
0.90
|
0.89
|
0.89
|
|
800/100 mg once daily
|
once dailya
|
(0.81 to 1.00)
|
(0.81 to 0.99)
|
(0.68 to 1.16)
|
24
|
Didanosine
400 mg once daily delayed release capsules taken 2 hours
before
rilpivirine
|
150 mg
once dailya
|
13
|
0.96
(0.80 to 1.14)
|
1.12
(0.99 to 1.27)
|
NA
|
|
Digoxin
0.5-mg single dose
|
25 mg once daily
|
22
|
1.06
(0.97 to 1.17)
|
0.98
(0.93 to 1.04)c
|
NA
|
|
Ethinylestradiol
|
25 mg
|
17
|
1.17
|
1.14
|
1.09
|
|
0.035 mg once daily
|
once daily
|
(1.06 to 1.30)
|
(1.10 to 1.19)
|
(1.03 to 1.16)
|
|
Norethindrone
|
0.94
|
0.89
|
0.99
|
|
1 mg once daily
|
(0.83 to 1.06)
|
(0.84 to 0.94)
|
(0.90 to 1.08)
|
|
Ketoconazole
|
150 mg
|
14
|
0.85
|
0.76
|
0.34
|
|
400 mg once daily
|
once dailya
|
(0.80 to 0.90)
|
(0.70 to 0.82)
|
(0.25 to 0.46)
|
|
Lopinavir/ritonavir
|
150 mg
|
15
|
0.96
|
0.99
|
0.89
|
|
400/100 mg twice
daily
|
once dailya
|
(0.88 to 1.05)
|
(0.89 to 1.10)
|
(0.73 to 1.08)
|
|
(soft gel capsule)
|
|
Methadone
|
25 mg
|
13
|
0.86
|
0.84
|
0.78
|
|
60 to 100 mg
once daily,
|
once daily
|
|
individualized dose
|
|
R(-) methadone
|
|
|
(0.78 to 0.95)
|
(0.74 to 0.95)
|
(0.67 to 0.91)
|
|
S(+) methadone
|
0.87
|
0.84
|
0.79
|
|
(0.78 to 0.97)
|
(0.74 to 0.96)
|
(0.67 to 0.92)
|
|
Metformin
850-mg single dose
|
25 mg once daily
|
20
|
1.02
(0.95 to -1.10)
|
0.97
(0.90 to 1.06)b
|
NA
|
|
Raltegravir
|
25 mg
|
23
|
1.10
|
1.09
|
1.27
|
|
400 mg twice daily
|
once
daily
|
(0.77 to 1.58)
|
(0.81 to 1.47)
|
(1.01 to 1.60)
|
|
Rifampin
|
150 mg
|
16
|
1.02
|
0.99
|
NA
|
|
600 mg once daily
|
once dailya
|
(0.93 to 1.12)
|
(0.92 to 1.07)
|
|
|
25-desacetylrifampin
|
1.00
|
0.91
|
NA
|
|
(0.87 to 1.15)
|
(0.77 to 1.07)
|
|
Sildenafil
|
75 mg
|
16
|
0.93
|
0.97
|
NA
|
|
50-mg single
dose
|
once dailya
|
(0.80 to 1.08)
|
(0.87 to 1.08)
|
|
|
N-desmethyl-sildenafil
|
0.90
|
0.92
|
NA
|
|
(0.80 to 1.02)
|
(0.85 to 0.99)c
|
|
Tenofovir disoproxil
|
150 mg
|
16
|
1.19
|
1.23
|
1.24
|
|
fumarate
|
once dailya
|
(1.06 to 1.34)
|
(1.16 to 1.31)
|
(1.10 to 1.38)
|
|
300 mg once daily
|
CI = Confidence Interval; n =
Maximum number of subjects with data; NA = Not
available.
25
a This interaction study has been performed with a dose higher than the
recommended dose for rilpivirine
(25 mg once daily) assessing the maximal effect on the coadministered drug.
b n = (maximum number
of subjects with data) for AUC(0-∞) = 15.
c AUC(0-last).
12.4
Microbiology
Mechanism of Action
Cabotegravir inhibits HIV
integrase by binding to the integrase
active site and blocking the
strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. The mean
50% inhibitory concentration (IC50) value of
cabotegravir in a strand transfer assay using purified recombinant
HIV-1 integrase was 3.0 nM.
Rilpivirine is a diarylpyrimidine NNRTI of HIV-1
and inhibits HIV-1 replication by non-competitive inhibition of
HIV-1 reverse transcriptase
(RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and γ.
Antiviral
Activity in Cell Culture
Cabotegravir exhibited antiviral activity against laboratory strains of HIV-1 (subtype
B, n = 4) with mean 50 percent effective concentration (EC50) values of 0.22 nM to 1.7 nM in peripheral blood mononuclear cells
(PBMCs) and 293 cells. Cabotegravir demonstrated antiviral activity in PBMCs against a panel
of 24 HIV-1 clinical isolates (3
in each of group M subtypes
A, B, C, D, E, F, and G
and 3 in group O) with a median EC50 value of 0.19
nM (range: 0.02 nM to 1.06 nM, n = 24). The median
EC50 value against
subtype B clinical isolates was 0.05
nM (range: 0.02 to 0.50 nM, n = 3). Against clinical HIV-2
isolates, the median EC50 value was 0.12 nM (range: 0.10 nM to 0.14 nM, n = 4).
Rilpivirine exhibited activity against laboratory strains
of wild-type HIV-1 in
an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine
demonstrated antiviral activity against
a broad panel of HIV-1
group M (subtypes A,
B, C, D, F, G, and H) primary isolates with EC50 values ranging from 0.07 nM
to 1.01 nM (0.03 to 0.37 ng/mL) and was less active against
group O primary isolates with EC50 values ranging from
2.88 to 8.45 nM (1.06 to 3.10 ng/mL).
In cell culture, cabotegravir was not antagonistic in
combination with the NNRTI rilpivirine, or the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine
(FTC), lamivudine (3TC), or tenofovir
disoproxil fumarate (TDF).
The antiviral activity
of rilpivirine was not antagonistic
when combined with the NNRTIs efavirenz, etravirine,
or nevirapine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine,
stavudine, tenofovir, or zidovudine; the protease inhibitors amprenavir, atazanavir, darunavir, indinavir, lopinavir,
nelfinavir, ritonavir, saquinavir, or tipranavir; the fusion
inhibitor enfuvirtide; the CCR5 co-receptor
antagonist maraviroc, or the
INSTI raltegravir.
26
Resistance
Cell Culture:Cabotegravir-resistant viruses were selected during passage of
HIV-1 strain IIIB in MT-2
cells in the presence of
cabotegravir. Amino acid
substitutions in integrase which
emerged and conferred decreased susceptibility to cabotegravir included
Q146L (fold change: 1.3 to 4.6), S153Y (fold
change:
2.8 to 8.4), and I162M
(fold change: 2.8). The integrase substitution
T124A also emerged alone (fold
change: 1.1 to 7.4 in cabotegravir susceptibility), in
combination with S153Y (fold
change: 3.6 to 6.6 in cabotegravir susceptibility),
or I162M (2.8-fold change in cabotegravir susceptibility). Cell culture passage of
virus harboring integrase substitutions
Q148H, Q148K, or Q148R
selected for additional substitutions (C56S, V72I,
L74M, V75A, T122N, E138K,
G140S, G149A, and M154I), with substituted viruses having
reduced susceptibility to cabotegravir
of 2.0-fold to 410-fold change. The combinations of E138K+Q148K and V72I+E138K+Q148K conferred the greatest
reductions of 53-fold
to 260-fold change and 410-fold
change, respectively.
Rilpivirine-resistant strains were selected in cell culture starting from wild-type
HIV-1 of different origins
and subtypes as well as NNRTI-resistant HIV-1.
The frequently observed amino acid substitutions
that emerged and conferred decreased
phenotypic susceptibility to rilpivirine
included L100I; K101E; V106I and A;
V108I; E138K and G, Q, R; V179F and
I; Y181C and I; V189I; G190E; H221Y;
F227C; and M230I and L.
Clinical Trials:In the pooled Phase
3 FLAIR and ATLAS
trials, there were 7 confirmed virologic
failures (2 consecutive HIV-1 RNA
greater than or equal to 200
copies/mL) on cabotegravir plus rilpivirine (7/591,
1.2%) and 7 confirmed virologic failures on current antiretroviral regimen (7/591, 1.2%). Of the 7 virologic failures in the
cabotegravir plus rilpivirine arm, 6 had post-baseline resistance
data. All 6 had treatment-emergent NNRTI resistance-associated substitutions
K101E, V108I, E138A, E138K,
or H221H/L in reverse transcriptase,
and 5 of them showed reduced
phenotypic susceptibility to rilpivirine
(range: 2.4-fold to 7.1-fold).
Additionally, 4 of the 6 (67%) cabotegravir plus rilpivirine virologic
failures with post-baseline resistance data had treatment-emergent INSTI resistance-associated substitutions and reduced
phenotypic susceptibility to cabotegravir (Q148R
[n = 2; 5-fold and 9-fold decreased susceptibility
to cabotegravir], G140R [n = 1; 7-fold decreased susceptibility to cabotegravir], or N155H [n = 1; 3-fold decreased
susceptibility to cabotegravir]).
In comparison, 2 of the 7 (29%) virologic failures in the current antiretroviral regimen arm who
had post-baseline resistance data had treatment-emergent resistance
substitutions and phenotypic resistance
to their antiretroviral drugs;
both had treatment-emergent NRTI
substitutions, M184V or I, which conferred resistance to emtricitabine or lamivudine
in their regimen and one of them also had the treatment-emergent NNRTI resistance substitution G190S, conferring resistance to efavirenz in their regimen.
In other Phase
2 and 3 clinical trials (207966,
LATTE and LATTE-2), virologic failures on cabotegravir plus rilpivirine also showed emergent
genotypic and phenotypic cabotegravir
and rilpivirine resistance (with emergent INSTI resistance-associated
substitutions Q148R,
N155H, E138K+Q148R,
27
E138K+G140A+Q148R, G140S+Q148R, Q148R+N155H, and NNRTI
resistance-associated substitutions K101E, K101E+E138A or K, K101E+M230L, K103N+K238T, K103N+E138G+K238T,
E138K or Q, and Y188L).
Association of Subtype
A1 and Baseline L74I Substitution in Integrase with Cabotegravir plus Rilpivirine Virologic
Failure
Five of the 7 cabotegravir
plus rilpivirine virologic failures
in FLAIR and ATLAS
had HIV-1 subtype A1 and the integrase
substitution L74I detected at baseline
and failure timepoints. Subjects
with subtype A1 infection whose virus did not have L74I at
baseline did not experience virologic failure (Table 12). In addition, there was no detectable
phenotypic resistance to cabotegravir conferred by the presence
of L74I at baseline.
The other 2 virologic failures had subtype AG and did
not have the integrase substitution L74I at baseline or at failure. Six of the virologic failures with subtype A1 and AG were from Russia
where the prevalence of subtypes A,
A1, and AG are high. Subtypes A, A1,
and AG are uncommon in the United States.
The presence of the integrase substitution L74I in other
subtypes, such as subtype B commonly seen in the
United States, was not associated
with virologic failure (Table 12).
In contrast to the Phase 3 trials where all virologic failures
were subtype A1 or AG, subtypes of the cabotegravir plus rilpivirine virologic failures in Phase
2 clinical trials included A1, A,
B, and C.
Table 12. Rate of Virologic
Failure in FLAIR Trial: Baseline Analysis
(Subtypes A1 and B, and Presence of Integrase Substitution L74I)
|
Patient
Characteristics
|
Cabotegravir plus Rilpivirinea
|
Current Antiretroviral Regimenb
|
|
Subtype A1
|
3/8 (38%)
|
1/4 (25%)
|
|
+L74I
|
3/5 (60%)
|
1/3 (33%)
|
|
-L74I
|
0/3
|
0/1
|
|
Subtype B
|
0/174
|
2/174 (1%)
|
|
+L74I
|
0/12
|
0/11
|
|
-L74I
|
0/153
|
2/150 (1%)
|
|
Missing data
|
0/9
|
0/13
|
|
Russia
|
4/54 (7%)
|
1/39 (3%)
|
|
+L74I
|
3/35 (9%)
|
1/29 (3%)
|
|
-L74I
|
1/12 (8%)
|
0/7
|
|
Missing data
|
0/7
|
0/3
|
a There were 4 virologic failures
in the cabotegravir arm.
One virologic failure in the
cabotegravir arm had subtype AG.
b There
were 3 virologic failures in the current antiretroviral regimen arm. Two
virologic failures in the
current
antiretroviral regimen arm had
subtype B.
28
Cross-Resistance
Cabotegravir:Cross-resistance has
been observed among INSTIs.
Cabotegravir had reduced susceptibility
(greater than
5-fold change) to recombinant
HIV-1 strain NL432 viruses
harboring the following integrase
amino acid substitutions: G118R, Q148K, Q148R, T66K+L74M, E92Q+N155H, E138A+Q148R, E138K+Q148K/R, G140C+Q148R,
G140S+Q148H/K/R, Y143H+N155H, and
Q148R+N155H (range: 5.1-fold
to 81-fold). The
substitutions E138K+Q148K
and Q148R+N155H conferred the greatest
reductions in susceptibility of 81-fold and 61-fold, respectively.
Cabotegravir was active against viruses harboring the NNRTI
substitutions K103N or Y188L, or the NRTI substitutions M184V,
D67N/K70R/T215Y, or
V75I/F77L/F116Y/Q151M.
Rilpivirine:Cross-resistance has been observed among
NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52-, 15-, and 12-times
fold change to rilpivirine,
respectively. The K103N substitution
did
not show reduced susceptibility
to rilpivirine by itself. Combinations of 2 or 3 NNRTI resistance-associated substitutions
gave 3.7-fold to 554-fold
change to rilpivirine in 38% and 66% of substitutions, respectively. Considering
all available cell
culture and clinical data,
any of the following amino
acid substitutions, when
present at baseline, are likely
to decrease the antiviral
activity of rilpivirine:
K101E and P; E138A, G, K, R, and Q;
V179L; Y181C, I, and V; Y188L; H221Y; F227C;
M230I and L, and the combination of L100I/K103N.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis,
Mutagenesis, Impairment of Fertility
Carcinogenesis
Two-year carcinogenicity studies in mice and rats were conducted with cabotegravir. In mice, no drug- related increases
in tumor incidence were observed at cabotegravir exposures
(AUC) up to approximately 8
times (males) and 7 times (females)
higher than those in humans at the
RHD. In rats, no drug-related increases in tumor incidence were observed at cabotegravir
exposures up to approximately
26 times higher than those in humans
at the RHD.
Two-year carcinogenicity studies in mice and rats were conducted with rilpivirine.
In mice, rilpivirine was positive for hepatocellular
neoplasms in both males and females. The observed hepatocellular
findings in mice may
be rodent-specific. At the lowest
tested dose in the mouse carcinogenicity study, the systemic exposure to rilpivirine was 21 times that observed in humans at the RHD. In rats, no drug- related neoplasms
were observed at exposures 3 times those observed in humans at the RHD.
Mutagenesis
Cabotegravir and rilpivirine
were not genotoxic in the bacterial reverse
mutation assay, mouse lymphoma
assay, or in the in vivo rodent micronucleus
assay.
29
Impairment
of Fertility
In rats, no effects on
fertility were observed at
cabotegravir exposures (AUC)
greater than 20 times (male)
and 28 times (female) the exposure
in humans at the RHD. Similarly,
no effects on fertility were observed in rats at rilpivirine exposures
(AUC) greater than 36
times (male) and 40 times (female) the exposure in humans at the
RHD.
14
CLINICAL STUDIES
14.1 Clinical
Trials
in Adults
The efficacy of CABENUVA has
been evaluated in two Phase 3
randomized, multicenter, active-
controlled, parallel-arm,
open-label, non-inferiority trials:
• Trial 201584 (FLAIR, [NCT02938520]), (n = 629): HIV-1–infected, antiretroviral treatment
(ART)- naive subjects received a dolutegravir INSTI-containing
regimen for 20 weeks (either dolutegravir/abacavir/lamivudine
or dolutegravir plus 2
other NRTIs if subjects were HLA-B*5701 positive). Subjects who
were virologically suppressed (HIV-1
RNA
less than 50 copies/mL, n = 566) were then randomized (1:1) to
receive either a cabotegravir plus
rilpivirine regimen or remain
on the current antiretroviral
regimen. Subjects randomized
to receive cabotegravir plus
rilpivirine initiated treatment
with daily oral lead-in
dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one 25-mg
EDURANT (rilpivirine) tablet
for at least 4 weeks followed by monthly
injections with CABENUVA for an additional 44 weeks.
• Trial 201585 (ATLAS,
[NCT02951052]), (n = 616): HIV-1–infected, ART-experienced, virologically-suppressed (for at least 6
months; median prior treatment
duration was 4.3 years) subjects (HIV-1
RNA
less than 50 copies/mL)
were randomized and received
either a cabotegravir plus
rilpivirine regimen or remained
on their current antiretroviral regimen.
Subjects randomized to receive cabotegravir plus
rilpivirine initiated treatment
with daily oral lead-in
dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one
25-mg EDURANT (rilpivirine) tablet
for at least 4 weeks followed by monthly injections with CABENUVA for
an additional 44 weeks.
The primary analysis was conducted after all subjects completed
their Week 48 visit or discontinued
the trial prematurely.
At baseline, in FLAIR and
ATLAS, respectively, the median
age was 34 years and 40 years, 22% and 32% were female, 24% and 31% were nonwhite. In
both studies, 7% had CD4+
cell count less than 350 cells/mm3; these characteristics were similar between treatment arms. In ATLAS, subjects received an NNRTI (50%), integrase inhibitor
(33%), or protease inhibitor
(17%) as their baseline third-agent class
prior to randomization; this was similar between treatment arms. Subjects
with hepatitis B co-infection were excluded from the trial.
The primary endpoint of FLAIR
and ATLAS was the proportion of subjects with
plasma HIV-1 RNA greater than or
equal to 50 copies/mL at
Week 48.
30
The primary endpoint and other
Week 48 outcomes, including outcomes by key baseline factors, for FLAIR
and ATLAS are shown
in Tables 13 and 14.
Table 13. Virologic Outcomes of Randomized Treatment in FLAIR and ATLAS Trials at Week 48
|
Virologic Outcomes
|
FLAIR
|
ATLAS
|
|
CAB plus RPV
(n = 283)
|
CAR (n = 283)
|
CAB plus RPV
(n = 308)
|
CAR (n = 308)
|
|
HIV-1 RNA
≥50 copies/mLa
|
2%
|
2%
|
2%
|
1%
|
|
Treatment Difference
|
-0.4%
(95%
CI: -2.8%, 2.1%)
|
0.7%
(95%
CI: -1.2%, 2.5%)
|
|
HIV-1
RNA <50 copies/mL
|
94%
|
93%
|
93%
|
95%
|
|
No
virologic data at Week 48 window
|
4%
|
4%
|
6%
|
4%
|
|
Discontinued
due to adverse event or
|
3%
|
<1%
|
4%
|
2%
|
|
death
|
|
|
|
|
|
Discontinued for other reasons
|
1%
|
4%
|
2%
|
2%
|
|
Missing
data during window but on
|
0
|
0
|
0
|
0
|
|
study
|
a Includes subjects who
discontinued for lack of efficacy
and discontinued while not suppressed. n = Number of subjects in each treatment group, CI = Confidence interval, CAB = Cabotegravir, RPV = Rilpivirine, CAR = Current antiretroviral regimen.
Adjusted for study and
randomization stratification factors, treatment difference of HIV-1 RNA greater
than or equal to 50 copies/mL
for the pooled data was 0.2% with 95%
CI (-1.4%, 1.7%).
|
Baseline
Factors
|
FLAIR
|
ATLAS
|
|
CAB plus RPV
(N = 283)
n/N (%)
|
CAR (N = 283)
n/N (%)
|
CAB plus RPV
(N = 308)
n/N (%)
|
CAR (N = 308)
n/N (%)
|
|
Baseline CD4+ (cells/mm3)
|
0/19
|
1/27 (4%)
|
0/23
|
1/27 (4%)
|
|
<350
|
|
³350
to <500
|
3/64 (5%)
|
0/60
|
2/56 (4%)
|
0/60
|
|
³500
|
3/200 (2%)
|
6/196 (3%)
|
3/299 (1%)
|
2/224 (<1%)
|
|
Gender
|
3/220 (1%)
|
6/219 (3%)
|
3/209 (1%)
|
3/204 (1%)
|
|
Male
|
|
Female
|
3/63 (5%)
|
1/64 (2%)
|
2/99 (2%)
|
0/104
|
|
Race
|
6/216 (3%)
|
5/201 (2%)
|
3/214 (1%)
|
2/207 (<1%)
|
|
White
|
|
African American/African Heritage
|
0/47
|
2/56 (4%)
|
2/62 (3%)
|
1/77 (1%)
|
|
Asian/Other
|
0/20
|
0/24
|
0/32
|
0/24
|
|
|
Table
14. Proportion of Subjects in FLAIR
and ATLAS Trials with Plasma HIV-1 RNA Greater
than or Equal to 50 copies/mL at Week 48 for Key Baseline
Factors
31
|
BMI
<30 kg/m2
³30 kg/m2
|
3/243 (1%)
3/40 (8%)
|
7/246 (3%)
0/37
|
3/248 (1%)
2/60 (3%)
|
1/242 (<1%)
2/66 (3%)
|
|
Age (years)
<50
³50
|
5/250 (2%)
1/33 (3%)
|
6/254 (2%)
1/29 (3%)
|
4/242 (2%)
1/66 (2%)
|
2/212 (<1%)
1/96 (1%)
|
|
Baseline antiviral therapy at
|
0
|
0
|
1/51 (2%)
|
0/54
|
|
randomization
|
|
Protease inhibitor-containing
regimen
|
|
Integrase inhibitor-containing regimen
|
6/283 (2%)
|
7/283 (2%)
|
0/102
|
2/99 (2%)
|
|
Non-nucleoside reverse transcriptase
|
0
|
0
|
4/155 (3%)
|
1/155 (<1%)
|
|
inhibitor-containing regimen
|
CAB = Cabotegravir, RPV = Rilpivirine, CAR = Current
antiretroviral
regimen.
Subjects in both the FLAIR and ATLAS trials were
virologically suppressed prior to Day 1 or at study entry, respectively, and no
clinically relevant change from
baseline in CD4+ cell counts
was observed.
16
HOW SUPPLIED/STORAGE AND
HANDLING
How Supplied
CABENUVA
is supplied in 2 dosing kits. Each kit contains one vial of cabotegravir extended-release injectable
suspension and one vial of rilpivirine
extended-release injectable
suspension, co-packaged as follows:
CABENUVA 400-mg/600-mg
Kit (NDC 49702-253-15) containing:
• One single-dose vial
of cabotegravir extended-release injectable suspension
containing 400 mg/2 mL (200 mg/mL)
of cabotegravir.
• One single-dose vial
of rilpivirine extended-release injectable suspension containing
600 mg/2 mL
(300 mg/mL) of rilpivirine
CABENUVA 600-mg/900-mg
Kit (NDC 49702-240-15) containing:
• One single-dose vial
of cabotegravir extended-release injectable suspension
containing 600 mg/3 mL (200 mg/mL)
of cabotegravir.
• One single-dose vial
of rilpivirine extended-release injectable suspension containing
900 mg/3 mL (300 mg/mL)
of rilpivirine.
Each dosing kit also contains
2 syringes, 2 syringe labels, 2 vial
adapters, and 2 needles for intramuscular
injection (23-gauge, 1½ inch). The vial stoppers are not made with natural rubber
latex.
Storage
and Handling
Store CABENUVA in the
refrigerator at 2°C to 8°C (36°F
to 46°F) in the original carton
until ready to use. Do not freeze. Do not mix
with any other product or diluent.
32
Prior to administration, vials
should be brought to room temperature (not to
exceed 25°C [77°F]). Vials may remain in
the carton at room temperature for
up to 6 hours. If not used within 6 hours, they must be
discarded.
Once the suspensions have been drawn into the respective
syringes, the injections should
be administered as soon as possible, but may remain in
the syringe for up to 2 hours. If 2 hours
are exceeded, the medication, syringes, and needles must be
discarded [see Dosage and Administration (2.5)].
17
PATIENT COUNSELING
INFORMATION
Advise the patient
to read the FDA-approved patient labeling (Patient Information).
Hypersensitivity Reactions
Advise patients to immediately
contact their healthcare
provider if they develop a
rash. Instruct patients to immediately stop taking CABENUVA and seek
medical attention if they develop
a rash associated with any of the
following symptoms, as it may
be a sign of a more serious reaction
such as DRESS or severe hypersensitivity: fever; generally ill
feeling; extreme tiredness;
muscle or joint aches; blisters; oral blisters or lesions; eye inflammation; facial swelling; swelling
of the eyes, lips, tongue, or mouth;
difficulty breathing; and/or signs and symptoms
of liver problems (e.g.,
yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale-colored stools or bowel movements;
nausea; vomiting; loss of appetite; or pain, aching, or sensitivity
on the right side below the ribs).
Advise patients that if hypersensitivity occurs, they
will be closely monitored, laboratory
tests will be ordered,
and appropriate therapy will be initiated [see Warnings and Precautions (5.1)].
Adverse
Reactions Following Injections
Advise patients that injection site reactions have been
reported in the majority of patients receiving CABENUVA. These
local reactions typically consist
of one or more of the following: pain,
erythema, tenderness, pruritus, and local swelling. Systemic reactions have
also been reported, such as
fever, musculoskeletal pain, and
sciatica pain [see
Adverse Reactions (6.1)]. Serious post-injection reactions were reported within minutes after the injection of
rilpivirine, including dyspnea, agitation, abdominal cramping,
flushing, sweating, oral numbness, and changes in blood pressure. These events began to resolve within a few minutes after
the injection. Advise patients that they will
be observed briefly (approximately 10 minutes) after the injection.
If they experience a post-injection reaction,
they will be monitored, and
appropriate treatment administered [see
Warnings and Precautions (5.2)].
Hepatotoxicity
Inform patients that hepatotoxicity has been reported with cabotegravir and
rilpivirine, components of CABENUVA[see
Warnings and Precautions (5.3), Adverse Reactions (6.1)]. Inform patients
that monitoring for liver
transaminases is recommended.
33
Depressive Disorders
Inform patients that
depressive disorders (including
depressed mood, depression, major
depression, mood altered, mood
swings, unusual mood, feeling
tense, negative thoughts, suicidal ideation
or attempt) have been reported with
at least one of the components of CABENUVA. Advise patients to seek immediate medical evaluation if
they experience depressive symptoms [see Warnings and Precautions (5.4),
Adverse Reactions (6.1)].
Drug
Interactions
CABENUVA may interact with other drugs;
therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products,
including St. John’s wort. CABENUVA is an extended-release injectable
which may be systemically present for 12 months or longer. These residual concentrations are
not expected to affect the exposures of antiretroviral drugs that are initiated after discontinuation
of CABENUVA [see Contraindications (4), Drug Interactions (7)].
Adherence
to CABENUVA
Counsel patients about the importance
of continued medication adherence
and scheduled visits to help maintain viral suppression and to reduce
risk of loss of virologic response and development of resistance[see Dosage and Administration (2.1),
Warnings and Precautions (5.6)].
Missed Dose
Inform patients that CABENUVA
can remain in the body for
up to 12 months or longer after receiving their last injection.
Advise patients that
they should contact their healthcare provider if they miss
or plan to miss a scheduled monthly injection
visit and that oral therapy may
be used to replace up to 2 consecutive monthly
injections. Advise patients that
if they stop treatment with CABENUVA, they will need to take other medicines to treat
their HIV-1 infection [see Dosage and Administration
(2.1, 2.5), Warnings and Precautions (5.6)].
Pregnancy Registry
Inform patients that there is an antiretroviral
pregnancy registry to monitor fetal outcomes in those exposed to CABENUVA during
pregnancy. Patients who are of
reproductive potential should be
informed of the long duration of
exposure of CABENUVA and
that there is very limited clinical experience in human pregnancy [see Warnings and
Precautions (5.6),
Use in Specific Populations (8.1)].
Lactation
Instruct mothers with HIV-1 infection not to
breastfeed because HIV-1 can be passed to the
baby in the breast milk[see Use in Specific Populations
(8.2)].
CABENUVA and VOCABRIA are
trademarks owned by or licensed to the
ViiV Healthcare group of
companies.
34
The other brand listed is a trademark owned by or licensed to its
respective owner and is not a trademark
owned by or licensed to the
ViiV Healthcare group of companies.
The maker of this brand is not affiliated
with and does not endorse the ViiV
Healthcare group of companies
or its products.
Manufactured for:
ViiV Healthcare
Research Triangle Park,
NC 27709
by: GlaxoSmithKline
Research Triangle Park,
NC 27709
©2021 ViiV Healthcare
group of companies or its licensor. CBN:1PI
35
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
|
PATIENT
INFORMATION
CABENUVA (kab' en ue vah) (cabotegravir
extended-release injectable suspension;
rilpivirine
extended-release injectable suspension) co-packaged for intramuscular use
|
|
What is CABENUVA?
CABENUVA is
a prescription medicine used without other Human Immunodeficiency Virus-1
(HIV-1) medicines to treat HIV-1 infection in adults to replace their current HIV-1 medicines when
their healthcare provider determines that they meet certain requirements.
HIV-1
is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).
CABENUVA contains 2 different medicines:
• cabotegravir
• rilpivirine
It is not known if CABENUVA is
safe and effective in
children.
|
|
Do not receive CABENUVA
if you:
• have ever had
an allergic reaction to
cabotegravir or rilpivirine.
• are taking any of the following medicines:
o carbamazepine o rifampin
o oxcarbazepine o rifapentine
o phenobarbital o dexamethasone
(more than a single-dose treatment
o phenytoin o St John’s wort (Hypericum perforatum)
o rifabutin
|
|
Before you receive CABENUVA, tell your healthcare provider about all your medical conditions, including if you:
• have ever had
a skin rash or an allergic reaction to medicines that contain
cabotegravir or rilpivirine.
• have or have had
liver problems, including
hepatitis B or C infection.
• have ever had
mental health problems.
• are pregnant or plan to become pregnant. It is not known if CABENUVA will harm your unborn baby.
CABENUVA can remain in your body for up to 12
months or longer after the
last injection.
Pregnancy Registry. There is a pregnancy registry for
women who take CABENUVA during pregnancy. The purpose of this
registry is to collect information about the
health of you and your baby. Talk
to your healthcare
provider about how you can take part in this registry.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you take CABENUVA.
o You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
o It is
not known if CABENUVA can pass to your
baby in your breast milk.
Talk with your healthcare provider about the best way to feed your baby during treatment with CABENUVA.
Tell your healthcare provider about all the medicines you
take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Some medicines
interact with CABENUVA. Keep
a list of your medicines and show it to your
healthcare provider and
pharmacist when you get a new medicine. You can ask your healthcare
provider or pharmacist for a list of medicines that interact with CABENUVA.
|
1
|
Do not start taking a new medicine without
telling your healthcare provider. Your healthcare provider can tell you if it is safe to take CABENUVA with other medicines.
|
|
How will I receive CABENUVA?
• Your healthcare provider will inject CABENUVA into the muscle of each side of your buttocks.
• You will receive CABENUVA as 2 injections (cabotegravir and
rilpivirine), one time every month.
• Before receiving your first injection doses
of CABENUVA, your healthcare provider
will have you take 1 VOCABRIA (cabotegravir) tablet and 1 EDURANT (rilpivirine) tablet one time a day for one month (at least 28 days). This will allow your healthcare provider to assess how well you tolerate these medicines.
• CABENUVA is a long-acting medicine and
may stay in your system for 12 months or longer
after your last injection.
• Stay under
the care of a healthcare provider during treatment with CABENUVA. It is important that you
attend your planned appointments
to receive your injection doses of CABENUVA.
• If you
miss or plan to miss a scheduled monthly injection of CABENUVA by more than 7 days, call your healthcare provider
right away to discuss your treatment options.
• If you
stop treatment with CABENUVA you will need to take
other medicines to treat your HIV-1 infection
and reduce the risk of developing viral resistance. Call your healthcare provider right away to discuss your
treatment options.
|
|
What
are the possible side
effects of CABENUVA?
CABENUVA may cause serious side effects including:
• Allergic reactions. Call your healthcare provider right away if you develop a rash with CABENUVA. Stop receiving CABENUVA and
get medical help right away if you develop a rash with
any of the following signs or symptoms:
o fever o blisters or
sores in mouth
o generally ill feeling o blisters
o tiredness o redness or swelling of the eyes
o muscle or joint aches o swelling of the mouth, face, lips, or tongue
o trouble breathing
• Post-injection
reactions. Post-injection reaction symptoms
have happened within
minutes in some people after
receiving their rilpivirine injection. Most symptoms resolved within a few minutes
after the injection. Symptoms of post-injection reactions may include:
o trouble breathing o feeling anxious
o stomach cramps o feeling warm
o sweating o feeling lightheaded or feeling like you are going to pass out (faint)
o numbness of your mouth o blood pressure changes
• Liver problems. People with a history of hepatitis
B or C virus or people who have certain liver function test changes may have an increased risk of developing new or worsening changes in
certain liver tests during treatment with CABENUVA. Liver
problems have also happened
in people without history of liver problems
or other risk factors.
Your healthcare provider may do blood tests to check your liver function.
Call your healthcare provider right away if you
develop any of
the following
signs or symptoms
of liver problems:
|
2
|
o your skin or
the white part of your eyes o loss of appetite
turns yellow (jaundice) o pain or tenderness on the right side of your
o dark or “tea-colored” urine stomach area
o light-colored stools (bowel movements) o itching
o nausea or vomiting
• Depression or mood changes. Call your healthcare provider or
get emergency medical help right away if you have
any of the following symptoms:
o feeling sad or hopeless
o feeling anxious or restless
o have thoughts of hurting yourself (suicide) or have tried to hurt yourself
The most common
side effects of CABENUVA include:
• Pain, tenderness, hardened mass
or lump, muscle or bone pain swelling, redness, itching, bruising, and warmth
at nausea
the injection site sleep problems
• fever dizziness
• tiredness rash
• headache
These are not all the
possible side effects of CABENUVA. Call your doctor for medical advice about side
effects. You may report
side effects to FDA at 1-800-FDA-1088.
|
|
General information about
the safe and effective
use of CABENUVA.
Medicines are sometimes prescribed for purposes other than
those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for
information about CABENUVA that is written for health professionals.
|
|
What
are the ingredients in CABENUVA?
Cabotegravir extended-release injectable suspension: Active
ingredient: cabotegravir
Inactive ingredients: mannitol, polyethylene
glycol (PEG) 3350, polysorbate 20, and Water
for Injection.
Rilpivirine extended-release injectable suspension:
Active ingredient: rilpivirine
Inactive ingredients: citric acid monohydrate, poloxamer
338, Water for Injection, glucose monohydrate
to ensure isotonicity, sodium dihydrogen phosphate monohydrate, and sodium hydroxide to adjust pH.
|
|
Manufactured for: by:
GlaxoSmithKline
Research Triangle Park, NC 27709
ViiV Healthcare
Research Triangle Park, NC 27709
CABENUVA and VOCABRIA are trademarks owned by or licensed to the ViiV Healthcare group of companies.
The other brand listed is a trademark owned by or licensed to its respective owner and is not a trademark owned by or licensed to the ViiV Healthcare group of companies. The maker of this brand is not affiliated with and does not endorse the ViiV Healthcare group of companies or its products.
©2021 ViiV Healthcare group of companies or its licensor. CBN:1PIL
For more information, go to www.cabenuva.com or call 1-877-844-8872.
|
This Patient Information has
been approved by the U.S. Food and Drug Administration. Issued:
01/2021
3
|
|
|
Overview:
A complete dose of CABENUVA requires two injections: 400 mg (2 mL) of cabotegravir and 600 mg (2 mL) of rilpivirine.
Cabotegravir and rilpivirine are suspensions that do not need further dilution or reconstitution. The preparation steps for both medicines are the same.
Cabotegravir and rilpivirine are for gluteal intramuscular use only. Each injection must be administered to separate gluteal intramuscular sites (on opposite sides or at least 2 cm apart). The administration order is not important.
Note: The ventrogluteal site is recommended.
|
|
|
Storage information
|
|
• Store in refrigerator at 2°C to 8°C (36°F to 46°F)
Do not freeze.
|
|
Prior to administration:
|
|
· Before preparing the injections, the vials may sit in the carton at room temperature (maximum temperature of 25°C [77°F]) for up to 6 hours. If not used within 6 hours, the medication must be discarded.
· Once the medicines have been drawn into the syringe, the medication can remain in the syringes for
up to 2 hours before injecting. If 2 hours are exceeded, the medication, syringes, and needles must be discarded.
· It is recommended to label the syringe with the time that the medication has been drawn into the
syringe if the medication is not administered immediately.
|
1
|
|
|
Your pack contains:
|
|
· 1 vial of Cabotegravir
· 1 vial of Rilpivirine
· 2 vial adaptors
· 2 syringes
· 2 syringe labels
· 2 injection needles (23 gauge, 1½ inch)
Consider the patient’s build and use medical judgment to select an appropriate injection needle length.
|
|
You will also need:
|
|
· Non-sterile gloves
· 4 alcohol wipes
· 4 gauze pads
· A suitable sharps container
|
|
Preparation:
|
|
1. Inspect both vials.
|
|
Figure A
|
· Check that the expiration date has not passed. See Figure A.
· Inspect the vials immediately. If you can see
foreign matter, do not use the product.
Note: The Cabotegravir vial has a brown tint to the glass.
Do not use if the expiration date has passed.
|
2
|
2. Wait 15 minutes.
|
|
Figure B
|
· Wait at least 15 minutes before you are ready to give the injection to allow the medication to come to room temperature. See Figure B.
|
|
3. Shake the vial vigorously.
|
|
10
secs
Figure C
|
· Hold the vial firmly, and vigorously shake for a full 10 seconds. See Figure C.
· Invert the vial and confirm the suspension is
uniform.
· If the suspension is not uniform, shake the vial again.
· It is also normal to see small air bubbles.
|
|
4. Remove the vial cap.
|
|
Figure D
|
· Remove the cap from the vial. See Figure D.
· Wipe the rubber stopper with an alcohol wipe.
Do not allow anything to touch the rubber stopper after wiping it.
|
|
5. Peel open the vial adaptor.
|
|
Figure E
|
· Peel off the paper backing from the vial adaptor packaging. See Figure E.
Note: Keep the adaptor in place in its packaging for the next step.
|
3
|
6. Attach the vial adaptor.
|
|
Figure F
|
· Press the vial adaptor straight down onto the vial using the packaging, as shown.
The vial adaptor should snap securely into place.
· When you are ready, lift off the vial adaptor packaging as shown.
See Figure F.
|
|
7. Prepare the syringe.
|
|
Figure G
|
· Remove the syringe from its packaging.
· Draw 1 mL of air into the syringe. This will make it easier to draw up the medicine later. See Figure G.
|
|
8. Attach the syringe.
|
|
Figure H
|
· Hold the vial adaptor and vial firmly, as shown.
· Screw the syringe firmly onto the vial adaptor.
· Press the plunger all the way down to push the air into the vial.
See Figure H.
|
|
9. Slowly draw up the dose.
|
|
Figure I
|
· Invert the syringe and vial and slowly withdraw as much of the medicine as possible into the syringe. There may be more medicine than the dose amount. See Figure I.
|
4
|
10. Unscrew the syringe.
|
|
Figure J
|
· Unscrew the syringe from the vial adaptor, holding the vial adaptor as shown.
See Figure J.
Note: Keep the syringe upright to avoid leakage. Check that the suspension looks uniform and milky white.
|
|
11. Attach the needle and affix syringe label.
|
|
Figure K
|
· Peel open the needle packaging part way to expose the needle base.
· Keeping the syringe upright, firmly twist the syringe
onto the needle.
· Remove the needle packaging from the needle.
· Write the name of the medicine on the syringe label. Affix the label to the syringe making sure the gradations remain visible.
See Figure K.
|
|
Injection:
|
|
12. Prepare the injection site.
|
|
Figure L
|
Injections must be administered to the gluteal sites.
See Figure L.
Select from the following areas for the injection:
• Ventrogluteal, as shown (recommended)
• Dorsogluteal (upper outer quadrant)
Note: For gluteal intramuscular use only.
Do not inject intravenously.
|
|
13. Remove the cap.
|
|
Figure M
|
· Fold the needle guard away from the needle. See Figure M.
· Pull off the injection needle cap.
|
5
|
14. Remove extra liquid from the syringe.
|
|
2 mL
Figure N
|
· Hold the syringe with the needle pointing up. Press the plunger to the 2-mL dosing mark to remove extra liquid and any air bubbles. See Figure N.
Note: Clean the injection site with an alcohol wipe. Allow the skin to air dry before continuing.
|
|
15. Stretch the skin.
|
|
1 inch
(2.5 cm)
Figure O
|
Use the z-track injection technique to minimize medicine leakage from the injection site.
· Firmly drag the skin covering the injection site, displacing it by about an inch (2.5 cm). See Figure O.
· Keep it held in this position for the injection.
|
|
16. Insert the needle.
|
|
Figure P
|
· Insert the needle to its full depth, or deep enough to reach the muscle. See Figure P.
|
|
17. Inject the dose of medicine.
|
|
Figure Q
|
· Still holding the skin stretched – slowly press the plunger all the way down. See Figure Q.
· Ensure the syringe is empty.
· Withdraw the needle and release the stretched skin immediately.
|
6
|
18. Assess the injection site.
|
|
Figure R
|
· Apply pressure to the injection site using a gauze pad. See Figure R.
· A small bandage may be used if bleeding occurs.
Do not massage the area.
|
|
19. Make the needle safe.
|
|
click
Figure S
|
· Fold the needle guard over the needle.
· Gently apply pressure using a hard surface to lock the needle guard in place.
· The needle guard will make a click when it locks.
See Figure S.
|
|
After injection:
|
|
20. Dispose safely.
|
|
SHARPS DISPOSAL CONTAINER
Figure T
|
· Dispose of used needles, syringes, vials, and vial adaptors according to local health and safety laws. See Figure T.
|
|
Repeat for 2nd medicine.
|
|
Repeat all steps for 2nd medicine
|
· If you have not yet injected both medicines, use the same steps for preparation and injection of the other medicine.
· The second medicine must be injected into a
separate gluteal intramuscular site (on opposite sides or at least 2 cm apart).
|
7
Questions and Answers
1. How long can the medicine be left out of the refrigerator?
It is best to inject the medicine as soon as it reaches room temperature. However, the vials may sit in the carton at room temperature (maximum temperature of 25°C [77°F]) for up to 6 hours. If not used within 6 hours, the medication must be discarded.
2. How long can the medicine be left in the syringe?
It is best to inject the (room temperature)
medicine as soon as possible after drawing it up. However, the medication can remain in the syringe
for up to 2 hours before injecting.
If 2 hours are exceeded,
the medication,
syringes, and needles must be discarded.
3. Why do I need to inject air into the vial?
Injecting 1 mL of air into the vial makes it easier to draw up the medicine into the syringe. Without the air, some liquid may flow back into the vial unintentionally, leaving less medicine than intended in the syringe.
4. Does the order in which I give the medicines
matter?
No, the order is unimportant.
5. Is it safe to warm the vials up to room temperature more quickly?
It is best to let the vials come to room temperature naturally. However, you can use the warmth of your hands to speed up the warm-up time, but make sure the vials do not get above 25°C (77°F).
Do not use any other heating methods. Manufactured for:
by: GlaxoSmithKline
Research Triangle Park, NC 27709
ViiV Healthcare
Research Triangle Park, NC 27709
Trademark is owned by or licensed to the ViiV Healthcare group of companies.
©2021 ViiV Healthcare group of companies or its licensor. CBN:1IFU2
This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 01/2021
8
|
|
|
Overview:
A complete dose of CABENUVA requires two injections: 600 mg (3 mL) of cabotegravir and 900 mg (3 mL) of rilpivirine.
Cabotegravir and rilpivirine are suspensions that do not need further dilution or reconstitution. The preparation steps for both medicines are the same.
Cabotegravir and rilpivirine are for gluteal intramuscular use only. Each injection must be administered to separate gluteal intramuscular sites (on opposite sides or at least 2 cm apart). The administration order is not important.
Note: The ventrogluteal site is recommended.
|
|
|
Storage information
|
|
• Store in refrigerator at 2°C to 8°C (36°F to 46°F).
Do not freeze.
|
|
Prior to administration:
|
|
· Before preparing the injections, the vials may sit in the carton at room temperature (maximum temperature of 25°C [77°F]) for up to 6 hours. If not used within 6 hours, the medication must be discarded.
· Once the medicines have been drawn into the syringe, the medication can remain in the syringes for
up to 2 hours before injecting. If 2 hours are exceeded, the medication, syringes, and needles must be discarded.
· It is recommended to label the syringe with the time that the medication has been drawn into the
syringe if the medication is not administered immediately.
|
1
|
3 ml
|
|
Your pack contains:
|
|
· 1 vial of Cabotegravir
· 1 vial of Rilpivirine
· 2 vial adaptors
· 2 syringes
· 2 syringe labels
· 2 injection needles (23 gauge, 1½ inch)
Consider the patient’s build and use medical judgment to select an appropriate injection needle length.
|
|
You will also need:
|
|
· Non-sterile gloves
· 4 alcohol wipes
· 4 gauze pads
· A suitable sharps container
|
|
Preparation:
|
|
1. Inspect both vials.
|
|
Figure A
|
· Check that the expiration date has not passed.
See Figure A.
· Inspect the vials immediately. If you can see foreign matter, do not use the product.
Note: The Cabotegravir vial has a brown tint to the glass.
Do not use if the expiration date has passed.
|
2
|
2. Wait 15 minutes
|
|
Figure B
|
· Wait at least 15 minutes before you are ready to give the injection to allow the medication to come to room temperature. See Figure B.
|
|
3. Shake the vial vigorously.
|
|
10
secs
Figure C
|
· Hold the vial firmly, and vigorously shake for a full 10 seconds. See Figure C.
· Invert the vial and confirm the suspension is
uniform.
· If the suspension is not uniform, shake the vial again.
· It is also normal to see small air bubbles.
|
|
4. Remove the vial cap.
|
|
Figure D
|
· Remove the cap from the vial. See Figure D.
· Wipe the rubber stopper with an alcohol wipe.
Do not allow anything to touch the rubber stopper after wiping it.
|
|
5. Peel open the vial adaptor.
|
|
Figure E
|
· Peel off the paper backing from the vial adaptor packaging. See Figure E.
Note: Keep the adaptor in place in its packaging for the next step.
|
3
|
6. Attach the vial adaptor.
|
|
Figure F
|
· Press the vial adaptor straight down onto the vial using the packaging, as shown.
The vial adaptor should snap securely into place.
· When you are ready, lift off the vial adaptor packaging as shown.
See Figure F.
|
|
7. Prepare the syringe.
|
|
Figure G
|
· Remove the syringe from its packaging.
· Draw 1 mL of air into the syringe. This will make it easier to draw up the medicine later. See Figure G.
|
|
8. Attach the syringe.
|
|
Figure H
|
· Hold the vial adaptor and vial firmly, as shown.
· Screw the syringe firmly onto the vial adaptor.
· Press the plunger all the way down to push the air into the vial.
See Figure H.
|
|
9. Slowly draw up the dose.
|
|
Figure I
|
· Invert the syringe and vial and slowly withdraw as much of the medicine as possible into the
syringe. There may be more medicine than the dose amount. See Figure I.
|
4
|
10. Unscrew the syringe.
|
|
Figure J
|
· Unscrew the syringe from the vial adaptor, holding the vial adaptor as shown. See Figure J.
Note: Keep the syringe upright to avoid leakage. Check that the suspension looks uniform and milky white.
|
|
11. Attach the needle and affix syringe label.
|
|
Figure K
|
· Peel open the needle packaging part way to expose the needle base.
· Keeping the syringe upright, firmly twist the
syringe onto the needle.
· Remove the needle packaging from the needle.
· Write the name of the medicine on the syringe label. Affix the label to the syringe making sure the gradations remain visible.
See Figure K.
|
|
Injection:
|
|
12. Prepare the injection site.
|
|
Figure L
|
Injections must be administered to the gluteal sites.
See Figure L.
Select from the following areas for the injection:
• Ventrogluteal, as shown (recommended)
• Dorsogluteal (upper outer quadrant)
Note: For gluteal intramuscular use only.
Do not inject intravenously.
|
|
13. Remove the cap.
|
|
Figure M
|
· Fold the needle guard away from the needle. See Figure M.
· Pull off the injection needle cap.
|
5
|
14. Remove extra liquid from the syringe.
|
|
3 mL
Figure N
|
· Hold the syringe with the needle pointing up.
Press the plunger to the 3-mL dosing mark to remove extra liquid and any air bubbles. See Figure N.
Note: Clean the injection site with an alcohol wipe. Allow the skin to air dry before continuing.
|
|
15. Stretch the skin.
|
|
1 inch
(2.5 cm)
Figure O
|
Use the z-track injection technique to minimize medicine leakage from the injection site.
· Firmly drag the skin covering the injection site, displacing it by about an inch (2.5 cm). See Figure O.
· Keep it held in this position for the injection.
|
|
16. Insert the needle.
|
|
Figure P
|
· Insert the needle to its full depth, or deep enough to reach the muscle. See Figure P.
|
|
17. Inject the dose of medicine.
|
|
Figure Q
|
· Still holding the skin stretched – slowly press the plunger all the way down. See Figure Q.
· Ensure the syringe is empty.
· Withdraw the needle and release the stretched skin immediately.
|
6
|
18. Assess the injection site.
|
|
Figure R
|
· Apply pressure to the injection site using a gauze pad. See Figure R.
· A small bandage may be used if bleeding occurs.
Do not massage the area.
|
|
19. Make the needle safe.
|
|
click
Figure S
|
· Fold the needle guard over the needle.
· Gently apply pressure using a hard surface to lock the needle guard in place.
· The needle guard will make a click when it locks.
See Figure S.
|
|
After injection:
|
|
20. Dispose safely.
|
|
SHARPS DISPOSAL CONTAINER
Figure T
|
· Dispose of used needles, syringes, vials and vial adaptors according to local health and safety laws. See Figure T.
|
|
Repeat for 2nd medicine.
|
|
Repeat all steps for 2nd medicine
|
· If you have not yet injected both medicines, use the same steps for preparation and injection of the other medicine.
· The second medicine must be injected into a
separate gluteal intramuscular site (on opposite sides or at least 2 cm apart).
|
7
Questions and Answers
1. How long can the medicine be left out of the refrigerator?
It is best to inject the medicine as soon as it reaches room temperature. However, the vials may sit in the carton at room temperature (maximum temperature of 25°C [77°F]) for up to 6 hours.
If not used within 6 hours, the medication must be discarded.
2. How long can the medicine be left in the syringe?
It is best to inject the (room temperature) medicine as soon as possible after drawing it up. However, the medication can remain in the syringe for up to 2 hours before injecting.
If 2 hours are exceeded, the medication, syringes, and needles must be discarded.
3. Why do I need to inject air into the vial?
Injecting 1 mL of air into the vial makes it easier to draw up the medicine into the syringe. Without the air, some liquid may flow back into the vial unintentionally, leaving less medicine than intended in the syringe.
4. Does the order in which I give the medicines matter?
No, the order is unimportant.
5. Is it safe to warm the vials up to room temperature
more quickly?
It is best to let the vials come to room temperature naturally. However, you can use the warmth of your hands to speed up the warm-up time, but make sure the vials do not get above 25°C (77°F).
Do not use any other heating methods.
Manufactured for:
ViiV Healthcare
Research Triangle Park, NC 27709
by: GlaxoSmithKline
Research Triangle Park, NC 27709
Trademark is owned by or licensed to the ViiV Healthcare group of companies.
©2021 ViiV Healthcare group
of companies or its licensor. CBN:1IFU3
This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 01/2021
8
