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These highlights do not include all the information needed to use SUSTIVA safely and effectively. See full prescribing information for SUSTIVA.
SUSTIVA
® (efavirenz) capsules for oral use
SUSTIVA
® (efavirenz) tablets for oral use
Initial U.S. Approval: 1998
RECENT MAJOR CHANGES
|
Warnings and Precautions
Coadministration with Related Products (5.3) 08/2012
Rash (5.7) 06/2012
Immune Reconstitution Syndrome (5.11) 08/2012
|
INDICATIONS AND USAGE
|
SUSTIVA
is a non-nucleoside reverse transcriptase inhibitor indicated in combination
with other antiretroviral agents for the treatment of human immunodeficiency
virus type 1 infection. (1)
|
DOSAGE AND ADMINISTRATION
|
- SUSTIVA should be taken orally once daily on an empty stomach, preferably
at bedtime. (2)
- Recommended adult dose: 600 mg. (2.1)
- With voriconazole, increase voriconazole maintenance dose to 400
mg every 12 hours and decrease SUSTIVA dose to 300 mg once daily using the
capsule formulation. (2.1)
- With rifampin, increase SUSTIVA dose to 800 mg once daily for patients weighing 50 kg or more. (2.1)
Pediatric Patients at Least 3 Years and at Least 10 kg (2.2) |
kg |
lbs |
dose |
|
kg |
lbs |
dose |
10
- <15 |
22
- <33 |
200
mg |
|
25
- <32.5 |
55
- <71.5 |
350
mg |
15
- <20 |
33
- <44 |
250
mg |
|
32.5
- <40 |
71.5
- <88 |
400
mg |
20
- <25 |
44
- <55 |
300
mg |
|
at
least 40 |
at
least 88 |
600
mg |
|
DOSAGE FORMS AND STRENGTHS
|
- Capsules: 200 mg and 50 mg. (3)
- Tablets: 600 mg. (3)
|
CONTRAINDICATIONS
|
- SUSTIVA is contraindicated in patients with previously demonstrated
hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic
skin eruptions) to any of the components of this product. (4.1)
- For some drugs, competition for CYP3A by efavirenz could result
in inhibition of their metabolism and create the potential for serious and/or
life-threatening adverse reactions (eg, cardiac arrhythmias, prolonged sedation,
or respiratory depression). (4.2)
|
WARNINGS AND PRECAUTIONS
|
- Do not use as a single agent or add on as a sole
agent to a failing regimen. Consider potential for cross resistance when choosing
other agents. (5.2)
- Not recommended with ATRIPLA, which contains efavirenz, emtricitabine,
and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. (5.3)
- Serious psychiatric symptoms: Immediate medical
evaluation is recommended for serious psychiatric symptoms such as severe
depression or suicidal ideation. (5.4, 17.5)
- Nervous system symptoms (NSS): NSS are frequent,
usually begin 1-2 days after initiating therapy and resolve in 2-4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset
of psychiatric symptoms. (5.5, 6.1, 17.4)
- Pregnancy: Fetal harm can occur when administered
to a pregnant woman during the first trimester. Women should be apprised of
the potential harm to the fetus. (5.6, 17.7) Pregnancy registry is available. (8.1)
- Hepatotoxicity: Monitor liver function tests before
and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease. (5.8, 6.1, 8.6)
- Rash: Rash usually begins within 1-2 weeks after
initiating therapy and resolves within 4 weeks. Discontinue if severe rash
develops. (5.7, 6.1, 17.6)
- Convulsions: Use caution in patients with a history
of seizures. (5.9)
- Lipids: Total cholesterol and triglyceride elevations.
Monitor before therapy and periodically thereafter. (5.10)
- Immune reconstitution syndrome: May necessitate
further evaluation and treatment. (5.11)
- Redistribution/accumulation of body fat: Observed
in patients receiving antiretroviral therapy. (5.12, 17.8)
|
ADVERSE REACTIONS
|
Most
common adverse reactions (>5%, moderate-severe) are rash, dizziness, nausea,
headache, fatigue, insomnia, and vomiting. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
|
DRUG INTERACTIONS
|
Coadministration of efavirenz can alter the concentrations of
other drugs and other drugs may alter the concentrations of efavirenz. The
potential for drug-drug interactions must be considered before and during
therapy. (4.2, 7.1, 12.3)
|
USE IN SPECIFIC POPULATIONS
|
- Pregnancy: Women should avoid pregnancy during
SUSTIVA therapy and for 12 weeks after discontinuation. (5.6)
- Nursing mothers: Women infected with HIV should
be instructed not to breast-feed. (8.3)
- Hepatic impairment: SUSTIVA is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. (8.6)
- Pediatric patients: The incidence of rash was
higher than in adults. (5.7, 6.1, 6.2, 8.4)
|
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
Revised: 01/2013
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
SUSTIVA® (efavirenz) in combination
with other antiretroviral agents is indicated for the treatment of human immunodeficiency
virus type 1 (HIV-1) infection. This indication is based on two clinical trials
of at least one year duration that demonstrated prolonged suppression of HIV
RNA [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Adults
The recommended dosage of SUSTIVA
(efavirenz) is 600 mg orally, once daily, in combination with a protease inhibitor
and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is
recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime.
The increased efavirenz concentrations observed following administration of
SUSTIVA with food may lead to an increase in frequency of adverse reactions
[see Clinical Pharmacology (12.3)].
Dosing at bedtime may improve the tolerability of nervous system symptoms
[see Warnings and Precautions (5.5),
Adverse Reactions (6.1), and Patient
Counseling Information (17.4)].
Concomitant Antiretroviral Therapy
SUSTIVA must be given in combination
with other antiretroviral medications [see Indications and Usage (1), Warnings and Precautions (5.2),
Drug Interactions (7.1), and Clinical
Pharmacology (12.3)].
Dosage Adjustment
If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400
mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (one 200-mg and two 50-mg capsules or
six 50-mg capsules). SUSTIVA tablets should not be broken. See Drug Interactions (7.1, Table 7) and Clinical Pharmacology (12.3, Tables 8 and 9).
If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 7) and Clinical Pharmacology (12.3, Table 9)].
2.2 Pediatric Patients
It is recommended that SUSTIVA be
taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended
dose of SUSTIVA for pediatric patients 3 years of age or older and weighing
between 10 and 40 kg [see Use in Specific Populations (8.4)]. The recommended dosage of SUSTIVA for pediatric patients weighing
greater than 40 kg is 600 mg once daily.
Table 1: Pediatric Dose to be Administered Once Daily
Body Weight |
SUSTIVA Dose
(mg) |
kg |
lbs |
10 to less than
15 |
22 to less than
33 |
200 |
15 to less than 20 |
33 to less than 44 |
250 |
20 to less than 25 |
44 to less than 55 |
300 |
25 to less than 32.5 |
55 to less than 71.5 |
350 |
32.5 to less than 40 |
71.5 to less than 88 |
400 |
at least 40 |
at least 88 |
600 |
3 DOSAGE FORMS AND STRENGTHS
• Capsules
200-mg capsules are gold color, reverse printed with “SUSTIVA” on the body and imprinted “200 mg” on the cap.
50-mg capsules are
gold color and white, printed with “SUSTIVA” on the gold color cap and reverse
printed “50 mg” on the white body.
• Tablets
600-mg tablets are yellow,
capsular-shaped, film-coated tablets, with “SUSTIVA” printed on both sides.
4 CONTRAINDICATIONS
4.1 Hypersensitivity
SUSTIVA is contraindicated in patients
with previously demonstrated clinically significant hypersensitivity (eg,
Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to
any of the components of this product.
4.2 Contraindicated Drugs
For some drugs, competition for CYP3A
by efavirenz could result in inhibition of their metabolism and create the
potential for serious and/or life-threatening adverse reactions (eg, cardiac
arrhythmias, prolonged sedation, or respiratory depression). Drugs that are
contraindicated with SUSTIVA are listed in Table 2.
Table 2: Drugs That Are Contraindicated or Not Recommended for Use
With SUSTIVA
Drug
Class: Drug Name |
Clinical
Comment |
Antimigraine: ergot derivatives (dihydroergotamine,
ergonovine, ergotamine, methylergonovine) |
Potential for serious and/or life-threatening
reactions such as acute ergot toxicity characterized by peripheral vasospasm
and ischemia of the extremities and other tissues. |
Benzodiazepines: midazolam, triazolam |
Potential for serious and/or life-threatening
reactions such as prolonged or increased sedation or respiratory depression. |
Calcium channel blocker:
bepridil |
Potential for serious
and/or life-threatening reactions such as cardiac arrhythmias. |
GI motility agent: cisapride |
Potential for serious and/or life-threatening
reactions such as cardiac arrhythmias. |
Neuroleptic: pimozide |
Potential for serious and/or life-threatening
reactions such as cardiac arrhythmias. |
St. John’s wort (Hypericum
perforatum) |
May lead to loss
of virologic response and possible resistance to efavirenz or to the class
of non-nucleoside reverse transcriptase inhibitors (NNRTIs). |
5 WARNINGS AND PRECAUTIONS
5.1 Drug Interactions
Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz
may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6 [see Contraindications (4.2) and Drug Interactions (7.1)].
5.2 Resistance
SUSTIVA must not be used as a single
agent to treat HIV-1 infection or added on as a sole agent to a failing regimen.
Resistant virus emerges rapidly when efavirenz is administered as monotherapy.
The choice of new antiretroviral agents to be used in combination with efavirenz
should take into consideration the potential for viral cross-resistance.
5.3 Coadministration with Related Products
Coadministration of SUSTIVA with ATRIPLA
(efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg)
is not recommended unless needed for dose adjustment (eg, with rifampin), since efavirenz is one of its active ingredients.
5.4 Psychiatric Symptoms
Serious psychiatric adverse experiences
have been reported in patients treated with SUSTIVA. In controlled trials
of 1008 patients treated with regimens containing SUSTIVA for a mean of 2.1
years and 635 patients treated with control regimens for a mean of 1.5 years,
the frequency (regardless of causality) of specific serious psychiatric events
among patients who received SUSTIVA or control regimens, respectively, were
severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide
attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%,
0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar
to those noted above were combined and evaluated as a group in a multifactorial
analysis of data from Study 006, treatment with efavirenz was associated with
an increase in the occurrence of these selected psychiatric symptoms. Other
factors associated with an increase in the occurrence of these psychiatric
symptoms were history of injection drug use, psychiatric history, and receipt
of psychiatric medication at study entry; similar associations were observed
in both the SUSTIVA and control treatment groups. In Study 006, onset of new
serious psychiatric symptoms occurred throughout the study for both SUSTIVA-treated
and control-treated patients. One percent of SUSTIVA-treated patients discontinued
or interrupted treatment because of one or more of these selected psychiatric
symptoms. There have also been occasional postmarketing reports of death by
suicide, delusions, and psychosis-like behavior, although a causal relationship
to the use of SUSTIVA cannot be determined from these reports. Patients with
serious psychiatric adverse experiences should seek immediate medical evaluation
to assess the possibility that the symptoms may be related to the use of SUSTIVA,
and if so, to determine whether the risks of continued therapy outweigh the
benefits. See Adverse Reactions (6.1).
5.5 Nervous System Symptoms
Fifty-three percent (531/1008) of
patients receiving SUSTIVA in controlled trials reported central nervous system
symptoms (any grade, regardless of causality) compared to 25% (156/635) of
patients receiving control regimens [see Adverse Reactions (6.1, Table 4)]. These symptoms included, but
were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%),
impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%),
and hallucinations (1.2%). These symptoms were severe in 2.0% of patients,
and 2.1% of patients discontinued therapy as a result. These symptoms usually
begin during the first or second day of therapy and generally resolve after
the first 2-4 weeks of therapy. After 4 weeks of therapy, the prevalence of
nervous system symptoms of at least moderate severity ranged from 5% to 9%
in patients treated with regimens containing SUSTIVA and from 3% to 5% in
patients treated with a control regimen. Patients should be informed that
these common symptoms were likely to improve with continued therapy and were
not predictive of subsequent onset of the less frequent psychiatric symptoms
[see Warnings and Precautions (5.4)].
Dosing at bedtime may improve the tolerability of these nervous system symptoms
[see Dosage and Administration (2)].
Analysis of long-term data from Study 006 (median follow-up 180
weeks, 102 weeks, and 76 weeks for patients treated with SUSTIVA + zidovudine
+ lamivudine, SUSTIVA + indinavir, and indinavir + zidovudine + lamivudine,
respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset
nervous system symptoms among SUSTIVA-treated patients were generally similar
to those in the indinavir-containing control arm.
Patients
receiving SUSTIVA should be alerted to the potential for additive central
nervous system effects when SUSTIVA is used concomitantly with alcohol or
psychoactive drugs.
Patients who experience central
nervous system symptoms such as dizziness, impaired concentration, and/or
drowsiness should avoid potentially hazardous tasks such as driving or operating
machinery.
5.6 Reproductive Risk Potential
Pregnancy Category D.
Efavirenz may cause fetal harm when administered during the first trimester to a pregnant
woman. Pregnancy should be avoided in women receiving SUSTIVA. Barrier contraception must always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of SUSTIVA is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of SUSTIVA. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to
the fetus.
There are no adequate and well-controlled studies in pregnant women. SUSTIVA should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. [See Use in Specific Populations (8.1).]
5.7 Rash
In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg SUSTIVA experienced new-onset skin
rash compared with 17% (111/635) of patients treated in control groups [see Adverse Reactions (6.1, Table 5)]. Rash associated with blistering, moist desquamation, or ulceration occurred
in 0.9% (9/1008) of patients treated with SUSTIVA. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in patients treated
with SUSTIVA in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first
2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz,
rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1008). SUSTIVA can be reinitiated
in patients interrupting therapy because of rash. SUSTIVA should be discontinued in patients developing severe rash associated with blistering, desquamation,
mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (eg, Stevens-Johnson syndrome), alternative therapy should be considered [see also Contraindications (4.1)].
Rash was reported in 26 of 57 pediatric patients (46%) treated with SUSTIVA capsules [see Adverse Reactions (6.1, 6.2)]. One pediatric patient experienced Grade 3 rash (confluent rash with fever), and two patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 8 days. Prophylaxis with appropriate antihistamines before initiating therapy with SUSTIVA in pediatric patients should be considered.
5.8 Hepatotoxicity
Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity [see Adverse Reactions (6.1) and Use in Specific Populations (8.6)]. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors [see Adverse Reactions (6.3)]. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with SUSTIVA needs to be weighed against the unknown risks of significant liver toxicity.
5.9 Convulsions
Convulsions have been observed in
patients receiving efavirenz, generally in the presence of known medical history
of seizures [see Nonclinical Toxicology (13.2)].
Caution must be taken in any patient with a history of seizures. Patients
who are receiving concomitant anticonvulsant medications primarily metabolized
by the liver, such as phenytoin and phenobarbital, may require periodic monitoring
of plasma levels [see Drug Interactions (7.1)].
5.10 Lipid Elevations
Treatment with SUSTIVA has resulted
in increases in the concentration of total cholesterol and triglycerides [see Adverse
Reactions (6.1)]. Cholesterol and
triglyceride testing should be performed before initiating SUSTIVA therapy
and at periodic intervals during therapy.
5.11 Immune Reconstitution Syndrome
Immune reconstitution syndrome has
been reported in patients treated with combination antiretroviral therapy,
including SUSTIVA. During the initial phase of combination antiretroviral
treatment, patients whose immune system responds may develop an inflammatory
response to indolent or residual opportunistic infections [such as Mycobacterium
avium infection, cytomegalovirus, Pneumocystis jiroveci
pneumonia (PCP), or tuberculosis], which may necessitate further evaluation
and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.12 Fat Redistribution
Redistribution/accumulation of body
fat including central obesity, dorsocervical fat enlargement (buffalo hump),
peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance”
have been observed in patients receiving antiretroviral therapy. The mechanism
and long-term consequences of these events are currently unknown. A causal
relationship has not been established.
6 ADVERSE REACTIONS
The most significant adverse reactions
observed in patients treated with SUSTIVA are:
- psychiatric symptoms [see Warnings and Precautions (5.4)],
- nervous system symptoms [see Warnings and Precautions (5.5)],
- rash [see Warnings and Precautions (5.7)].
The most common (>5% in either efavirenz treatment group)
adverse reactions of at least moderate severity among patients in Study 006
treated with SUSTIVA in combination with zidovudine/lamivudine or indinavir
were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.
6.1 Clinical Trials Experience in Adults
Because clinical studies are conducted
under widely varying conditions, the adverse reaction rates reported cannot
be directly compared to rates in other clinical studies and may not reflect
the rates observed in clinical practice.
Selected
clinical adverse reactions of moderate or severe intensity observed in ≥2%
of SUSTIVA-treated patients in two controlled clinical trials are presented
in Table 3.
Table 3: Selected Treatment-Emergenta Adverse
Reactions of Moderate or Severe Intensity Reported in ≥2% of SUSTIVA-Treated
Patients in Studies 006 and ACTG 364
|
Study 006 LAM-,
NNRTI-, and Protease Inhibitor-Naive Patients |
Study ACTG 364 NRTI-experienced,
NNRTI-, and Protease Inhibitor-Naive Patients |
Adverse Reactions |
SUSTIVAb + ZDV/LAM (n=412) |
SUSTIVAb + Indinavir (n=415) |
Indinavir + ZDV/LAM (n=401) |
SUSTIVAb + Nelfinavir + NRTIs (n=64) |
SUSTIVAb + NRTIs (n=65) |
Nelfinavir + NRTIs (n=66) |
180 weeksc |
102 weeksc |
76 weeksc |
71.1 weeksc |
70.9 weeksc |
62.7 weeksc |
a Includes adverse events at least
possibly related to study drug or of unknown relationship for Study 006. Includes
all adverse events regardless of relationship to study drug for Study ACTG
364. |
b SUSTIVA provided as 600 mg once
daily. |
c Median duration of treatment. |
d Includes erythema multiforme,
rash, rash erythematous, rash follicular, rash maculopapular, rash petechial,
rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema,
redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and
pruritus for ACTG 364. |
— = Not Specified. |
ZDV = zidovudine, LAM = lamivudine. |
Body as a Whole |
Fatigue |
8% |
5% |
9% |
0 |
2% |
3% |
Pain |
1% |
2% |
8% |
13% |
6% |
17% |
Central and Peripheral Nervous System |
Dizziness |
9% |
9% |
2% |
2% |
6% |
6% |
Headache |
8% |
5% |
3% |
5% |
2% |
3% |
Insomnia |
7% |
7% |
2% |
0 |
0 |
2% |
Concentration impaired |
5% |
3% |
<1% |
0 |
0 |
0 |
Abnormal dreams |
3% |
1% |
0 |
— |
— |
— |
Somnolence |
2% |
2% |
<1% |
0 |
0 |
0 |
Anorexia |
1% |
<1% |
<1% |
0 |
2% |
2% |
Gastrointestinal |
Nausea |
10% |
6% |
24% |
3% |
2% |
2% |
Vomiting |
6% |
3% |
14% |
— |
— |
— |
Diarrhea |
3% |
5% |
6% |
14% |
3% |
9% |
Dyspepsia |
4% |
4% |
6% |
0 |
0 |
2% |
Abdominal pain |
2% |
2% |
5% |
3% |
3% |
3% |
Psychiatric |
Anxiety |
2% |
4% |
<1% |
— |
— |
— |
Depression |
5% |
4% |
<1% |
3% |
0 |
5% |
Nervousness |
2% |
2% |
0 |
2% |
0 |
2% |
Skin & Appendages |
Rashd |
11% |
16% |
5% |
9% |
5% |
9% |
Pruritus |
<1% |
1% |
1% |
9% |
5% |
9% |
Pancreatitis has been reported, although a causal
relationship with efavirenz has not been established. Asymptomatic increases
in serum amylase levels were observed in a significantly higher number of
patients treated with efavirenz 600 mg than in control patients (see Laboratory Abnormalities).
Nervous System Symptoms
For 1008 patients treated with regimens
containing SUSTIVA and 635 patients treated with a control regimen in controlled
trials, Table 4 lists the frequency of symptoms of different degrees of severity
and gives the discontinuation rates for one or more of the following nervous
system symptoms: dizziness, insomnia, impaired concentration, somnolence,
abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations,
stupor, abnormal thinking, and depersonalization [see Warnings and
Precautions (5.5)]. The frequencies
of specific central and peripheral nervous system symptoms are provided in Table 3.
Table 4: Percent of Patients with One or More Selected Nervous System
Symptomsa,b
Percent of Patients
with: |
SUSTIVA
600 mg Once Daily (n=1008) |
Control
Groups (n=635) |
% |
% |
a Includes events
reported regardless of causality. |
b Data from Study
006 and three Phase 2/3 studies. |
c “Mild” = Symptoms
which do not interfere with patient’s daily activities. |
d “Moderate” = Symptoms
which may interfere with daily activities. |
e “Severe” = Events
which interrupt patient’s usual daily activities. |
Symptoms of any severity |
52.7 |
24.6 |
Mild symptomsc |
33.3 |
15.6 |
Moderate symptomsd |
17.4 |
7.7 |
Severe symptomse |
2.0 |
1.3 |
Treatment discontinuation as
a result of symptoms |
2.1 |
1.1 |
Psychiatric Symptoms
Serious psychiatric adverse experiences
have been reported in patients treated with SUSTIVA. In controlled trials,
psychiatric symptoms observed at a frequency of >2% among patients treated
with SUSTIVA or control regimens, respectively, were depression (19%, 16%),
anxiety (13%, 9%), and nervousness (7%, 2%).
Rash
For 1008 adult and 57 pediatric
patients treated with regimens containing SUSTIVA and 635 patients treated
with a control regimen in controlled trials, the frequency of rash by NCI
grade and the discontinuation rates as a result of rash in clinical studies
are provided in Table 5 [see Warnings and Precautions (5.7)].
Table 5: Percent of Patients with Treatment-Emergent Rasha,b
Percent of Patients with: |
Description of Rash Gradec |
SUSTIVA
600 mg Once Daily Adults (n=1008) |
SUSTIVA Pediatric
Patients (n=57) |
Control
Groups Adults (n=635) |
% |
% |
% |
a Includes events
reported regardless of causality. |
b Data from Study
006 and three Phase 2/3 studies. |
c NCI Grading System. |
Rash of any grade |
— |
26.3 |
45.6 |
17.5 |
Grade 1 rash |
Erythema, pruritus |
10.7 |
8.8 |
9.8 |
Grade 2 rash |
Diffuse maculopapular rash, dry desquamation |
14.7 |
31.6 |
7.4 |
Grade 3 rash |
Vesiculation, moist desquamation,
ulceration |
0.8 |
1.8 |
0.3 |
Grade 4 rash |
Erythema multiforme, Stevens-Johnson
syndrome, toxic epidermal necrolysis, necrosis requiring surgery, exfoliative
dermatitis |
0.1 |
3.5 |
0.0 |
Treatment discontinuation
as a result of rash |
— |
1.7 |
8.8 |
0.3 |
As seen in Table 5, rash is more common in pediatric
patients and more often of higher grade (ie, more severe) [see Warnings
and Precautions (5.7)].
Experience with SUSTIVA in patients who discontinued other antiretroviral
agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine
because of rash have been treated with SUSTIVA. Nine of these patients developed
mild-to-moderate rash while receiving therapy with SUSTIVA, and two of these
patients discontinued because of rash.
Laboratory Abnormalities
Selected Grade 3-4 laboratory abnormalities
reported in ≥2% of SUSTIVA-treated patients in two clinical trials are presented
in Table 6.
Table 6: Selected Grade 3-4 Laboratory Abnormalities Reported in ≥2% of SUSTIVA-Treated Patients in Studies 006 and ACTG 364
|
Study 006 LAM-,
NNRTI-, and Protease Inhibitor-Naive Patients |
Study ACTG 364 NRTI-experienced,
NNRTI-, and Protease Inhibitor-Naive Patients |
Variable |
Limit |
SUSTIVAa + ZDV/LAM (n=412) |
SUSTIVAa + Indinavir (n=415) |
Indinavir + ZDV/LAM (n=401) |
SUSTIVAa + Nelfinavir + NRTIs (n=64) |
SUSTIVAa + NRTIs (n=65) |
Nelfinavir + NRTIs (n=66) |
180 weeksb |
102 weeksb |
76 weeksb |
71.1 weeksb |
70.9 weeksb |
62.7 weeksb |
a SUSTIVA provided
as 600 mg once daily. |
b Median duration
of treatment. |
c Isolated elevations
of GGT in patients receiving SUSTIVA may reflect enzyme induction not associated
with liver toxicity. |
d Nonfasting. |
ZDV = zidovudine, LAM = lamivudine,
ULN = Upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase. |
Chemistry |
ALT |
>5 x ULN |
5% |
8% |
5% |
2% |
6% |
3% |
AST |
>5 x ULN |
5% |
6% |
5% |
6% |
8% |
8% |
GGTc |
>5 x ULN |
8% |
7% |
3% |
5% |
0 |
5% |
Amylase |
>2 x ULN |
4% |
4% |
1% |
0 |
6% |
2% |
Glucose |
>250 mg/dL |
3% |
3% |
3% |
5% |
2% |
3% |
Triglyceridesd |
≥751 mg/dL |
9% |
6% |
6% |
11% |
8% |
17% |
Hematology |
Neutrophils |
<750/mm3 |
10% |
3% |
5% |
2% |
3% |
2% |
Patients Coinfected with Hepatitis B or C
Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with SUSTIVA-containing regimens (median duration
of therapy, 68 weeks) and 84 treated with a control regimen (median duration,
56 weeks) were seropositive at screening for hepatitis B (surface antigen
positive) and/or C (hepatitis C antibody positive). Among these coinfected
patients, elevations in AST to greater than five times ULN developed in 13%
of patients in the SUSTIVA arms and 7% of those in the control arm, and elevations
in ALT to greater than five times ULN developed in 20% of patients in the
SUSTIVA arms and 7% of patients in the control arm. Among coinfected patients,
3% of those treated with SUSTIVA-containing regimens and 2% in the control
arm discontinued from the study because of liver or biliary system disorders
[see Warnings and Precautions (5.8)].
Lipids
Increases from baseline in total
cholesterol of 10-20% have been observed in some uninfected volunteers receiving
SUSTIVA. In patients treated with SUSTIVA + zidovudine + lamivudine, increases
from baseline in nonfasting total cholesterol and HDL of approximately 20%
and 25%, respectively, were observed. In patients treated with SUSTIVA + indinavir,
increases from baseline in nonfasting cholesterol and HDL of approximately
40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients
treated with SUSTIVA + zidovudine + lamivudine; 54% and 20%, respectively,
of patients treated with SUSTIVA + indinavir; and 28% and 4%, respectively,
of patients treated with indinavir + zidovudine + lamivudine. The effects
of SUSTIVA on triglycerides and LDL in this study were not well characterized
since samples were taken from nonfasting patients. The clinical significance
of these findings is unknown [see Warnings and Precautions (5.10)].
6.2 Clinical Trial Experience in Pediatric Patients
Clinical adverse experiences observed
in ≥10% of 57 pediatric patients aged 3 to 16 years who received SUSTIVA capsules,
nelfinavir, and one or more NRTIs in Study ACTG 382 [see Use In Specific
Populations (8.4)] were rash (46%),
diarrhea/loose stools (39%), fever (21%), cough (16%), dizziness/lightheaded/fainting
(16%), ache/pain/discomfort (14%), nausea/vomiting (12%), and headache (11%).
The incidence of nervous system symptoms was 18% (10/57). One patient experienced
Grade 3 rash, two patients had Grade 4 rash, and five patients (9%) discontinued
because of rash [see Warnings and Precautions (5.7) and Adverse
Reactions (6.1, Table 5)].
6.3 Postmarketing Experience
The following adverse reactions have
been identified during postapproval use of SUSTIVA. Because these reactions
are reported voluntarily from a population of unknown size, it is not always
possible to reliably estimate their frequency or establish a causal relationship
to drug exposure.
Body as a Whole: allergic
reactions, asthenia, redistribution/accumulation of body fat [see Warnings
and Precautions (5.12)]
Central and Peripheral Nervous System: abnormal
coordination, ataxia, cerebellar coordination and balance disturbances, convulsions,
hypoesthesia, paresthesia, neuropathy, tremor, vertigo
Endocrine: gynecomastia
Gastrointestinal: constipation, malabsorption
Cardiovascular: flushing, palpitations
Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis. A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.
Metabolic and
Nutritional: hypercholesterolemia, hypertriglyceridemia
Musculoskeletal: arthralgia, myalgia, myopathy
Psychiatric: aggressive reactions, agitation,
delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide
Respiratory: dyspnea
Skin
and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson
syndrome
Special Senses: abnormal
vision, tinnitus
7 DRUG INTERACTIONS
7.1 Drug-Drug Interactions
Efavirenz has been shown in
vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6
may have decreased plasma concentrations when coadministered with SUSTIVA. In
vitro studies have demonstrated that efavirenz inhibits CYP2C9, 2C19,
and 3A4 isozymes in the range of observed efavirenz plasma concentrations.
Coadministration of efavirenz with drugs primarily metabolized by these isozymes
may result in altered plasma concentrations of the coadministered drug. Therefore,
appropriate dose adjustments may be necessary for these drugs.
Drugs that induce CYP3A activity (eg, phenobarbital, rifampin,
rifabutin) would be expected to increase the clearance of efavirenz resulting
in lowered plasma concentrations. Drug interactions with SUSTIVA are summarized
in Tables 2 and 7 [for
pharmacokinetics data see Clinical Pharmacology (12.3,
Tables 8 and 9)].
The tables include potentially significant interactions, but are not all inclusive.
Table 7: Established and Other Potentially Significant Drug
Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug
Interaction Studies or Predicted Interaction
Concomitant
Drug Class: Drug Name |
Effect |
Clinical
Comment |
* The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. |
This table is not all-inclusive. |
HIV antiviral agents |
Protease inhibitor: Fosamprenavir calcium |
↓ amprenavir |
Fosamprenavir
(unboosted): Appropriate doses of the combinations with respect to safety
and efficacy have not been established. Fosamprenavir/ritonavir:
An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA
is administered with fosamprenavir/ritonavir once daily. No change in the
ritonavir dose is required when SUSTIVA is administered with fosamprenavir
plus ritonavir twice daily. |
Protease inhibitor: Atazanavir sulfate |
↓ atazanavir* |
Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended. |
Protease inhibitor: Indinavir |
↓ indinavir* |
The optimal dose
of indinavir, when given in combination with SUSTIVA, is not known. Increasing
the indinavir dose to 1000 mg every 8 hours does not compensate for the increased
indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg
every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC
and Cmin were decreased on average by 33-46% and 39-57%,
respectively, compared to when indinavir (800 mg every 8 hours) was given
alone. |
Protease inhibitor: Lopinavir/ritonavir |
↓ lopinavir* |
Lopinavir/ritonavir
tablets should not be administered once daily in combination with SUSTIVA.
In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used
twice daily in combination with SUSTIVA with no dose adjustment. A dose increase
of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be
considered when used in combination with SUSTIVA in treatment-experienced
patients where decreased susceptibility to lopinavir is clinically suspected
(by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir
oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended
when used in combination with SUSTIVA. |
Protease inhibitor: Ritonavir |
↑ ritonavir* ↑ efavirenz* |
When ritonavir
500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination
was associated with a higher frequency of adverse clinical experiences (eg,
dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver
enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used
in combination with ritonavir. |
Protease inhibitor: Saquinavir |
↓ saquinavir* |
Should not be used as sole protease inhibitor in combination with SUSTIVA. |
NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI
|
Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs. |
CCR5 co-receptor antagonist: Maraviroc |
↓ maraviroc* |
Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz. |
Integrase strand transfer inhibitor: Raltegravir |
↓ raltegravir* |
SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
|
Hepatitis C antiviral agents |
Protease inhibitor: Boceprevir |
↓ boceprevir* |
Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.
|
Protease inhibitor: Telaprevir |
↓ telaprevir* ↓ efavirenz* |
Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.
|
Other agents |
Anticoagulant: Warfarin |
↑ or ↓ warfarin |
Plasma concentrations
and effects potentially increased or decreased by SUSTIVA. |
Anticonvulsants: Carbamazepine |
↓ carbamazepine* ↓ efavirenz* |
There are insufficient
data to make a dose recommendation for efavirenz. Alternative anticonvulsant
treatment should be used. |
Phenytoin Phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for
reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring
of anticonvulsant plasma levels should be conducted. |
Antidepressants: Bupropion |
↓ bupropion* |
The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
Sertraline |
↓ sertraline* |
Increases in sertraline
dosage should be guided by clinical response. |
Antifungals: Voriconazole |
↓ voriconazole* ↑ efavirenz* |
SUSTIVA and voriconazole
must not be coadministered at standard doses. Efavirenz significantly decreases
voriconazole plasma concentrations, and coadministration may decrease the
therapeutic effectiveness of voriconazole. Also, voriconazole significantly
increases efavirenz plasma concentrations, which may increase the risk of
SUSTIVA-associated side effects. When voriconazole is coadministered with
SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every
12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the
capsule formulation. SUSTIVA tablets should not be broken. [See Dosage
and Administration (2.1) and Clinical
Pharmacology (12.3, Tables 8 and 9).] |
Itraconazole |
↓ itraconazole* ↓ hydroxyitraconazole* |
Since no dose recommendation
for itraconazole can be made, alternative antifungal treatment should be considered. |
Ketoconazole |
↓ ketoconazole |
Drug interaction
studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has
the potential to decrease plasma concentrations of ketoconazole. |
Posaconazole |
↓ posaconazole* |
Avoid concomitant use unless the benefit outweighs the risks.
|
Anti-infective: Clarithromycin |
↓ clarithromycin* ↑ 14-OH
metabolite* |
Plasma concentrations
decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers,
46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment
of SUSTIVA is recommended when given with clarithromycin. Alternatives to
clarithromycin, such as azithromycin, should be considered (see Other Drugs, following table). Other
macrolide antibiotics, such as erythromycin, have not been studied in combination
with SUSTIVA. |
Antimycobacterials: Rifabutin |
↓ rifabutin* |
Increase daily dose of rifabutin
by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is
given 2 or 3 times a week. |
Rifampin |
↓ efavirenz* |
If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended. |
Calcium channel blockers: Diltiazem |
↓ diltiazem* ↓ desacetyl diltiazem* ↓ N-monodesmethyl diltiazem* |
Diltiazem dose adjustments should
be guided by clinical response (refer to the full prescribing information
for diltiazem). No dose adjustment of efavirenz is necessary when administered
with diltiazem. |
Others (eg, felodipine,
nicardipine, nifedipine, verapamil) |
↓ calcium
channel blocker |
No data are available
on the potential interactions of efavirenz with other calcium channel blockers
that are substrates of CYP3A. The potential exists for reduction in plasma
concentrations of the calcium channel blocker. Dose adjustments should be
guided by clinical response (refer to the full prescribing information
for the calcium channel blocker). |
HMG-CoA reductase
inhibitors: Atorvastatin Pravastatin Simvastatin |
↓ atorvastatin* ↓ pravastatin* ↓ simvastatin* |
Plasma concentrations
of atorvastatin, pravastatin, and simvastatin decreased. Consult the full
prescribing information for the HMG-CoA reductase inhibitor for guidance on
individualizing the dose. |
Hormonal contraceptives: Oral Ethinyl
estradiol/ Norgestimate |
↓ active metabolites of norgestimate* |
A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
|
Implant Etonogestrel |
↓ etonogestrel |
A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immunosuppressant
|
Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
|
Narcotic analgesic: Methadone |
↓ methadone* |
Coadministration
in HIV-infected individuals with a history of injection drug use resulted
in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone
dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients
should be monitored for signs of withdrawal and their methadone dose increased
as required to alleviate withdrawal symptoms. |
Other Drugs
Based on the results of drug interaction
studies [see Clinical Pharmacology (12.3,
Tables 8 and 9)],
no dosage adjustment is recommended when SUSTIVA (efavirenz) is given with
the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine,
famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, tenofovir
disoproxil fumarate, and zidovudine.
Specific
drug interaction studies have not been performed with SUSTIVA and NRTIs other
than lamivudine and zidovudine. Clinically significant interactions would
not be expected since the NRTIs are metabolized via a different route than
efavirenz and would be unlikely to compete for the same metabolic enzymes
and elimination pathways.
7.2 Cannabinoid Test Interaction
Efavirenz does not bind to cannabinoid
receptors. False-positive urine cannabinoid test results have been observed
in non-HIV-infected volunteers receiving SUSTIVA when the Microgenics CEDIA
DAU Multi-Level THC assay was used for screening. Negative results were obtained
when more specific confirmatory testing was performed with gas chromatography/mass
spectrometry.
Of the three assays analyzed (Microgenics
CEDIA DAU Multi-Level THC assay, Cannabinoid Enzyme Immunoassay [Diagnostic
Reagents, Inc], and AxSYM Cannabinoid Assay), only the Microgenics CEDIA DAU
Multi-Level THC assay showed false-positive results. The other two assays
provided true-negative results. The effects of SUSTIVA on cannabinoid screening
tests other than these three are unknown. The manufacturers of cannabinoid
assays should be contacted for additional information regarding the use of
their assays with patients receiving efavirenz.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D: See Warnings and Precautions (5.6).
Antiretroviral Pregnancy Registry: To monitor fetal
outcomes of pregnant women exposed to SUSTIVA, an Antiretroviral Pregnancy
Registry has been established. Physicians are encouraged to register patients
by calling 1-800-258-4263.
As of July 2010, the
Antiretroviral Pregnancy Registry has received prospective reports of 792
pregnancies exposed to efavirenz-containing regimens, nearly all of which
were first-trimester exposures (718 pregnancies). Birth defects occurred in
17 of 604 live births (first-trimester exposure) and 2 of 69 live births (second/third-trimester
exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. There have been six retrospective reports of findings consistent
with neural tube defects, including meningomyelocele. All mothers were exposed
to efavirenz-containing regimens in the first trimester. Although a causal
relationship of these events to the use of SUSTIVA has not been established,
similar defects have been observed in preclinical studies of efavirenz.
Animal Data
Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microophthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.
8.3 Nursing Mothers
The Centers for Disease Control
and Prevention recommend that HIV-infected mothers not breast-feed their
infants to avoid risking postnatal transmission of HIV. Although it is not
known if efavirenz is secreted in human milk, efavirenz is secreted into the
milk of lactating rats. Because of the potential for HIV transmission and
the potential for serious adverse effects in nursing infants, mothers should
be instructed not to breast-feed if they are receiving SUSTIVA.
8.4 Pediatric Use
ACTG 382 is an ongoing, open-label
study in 57 NRTI-experienced pediatric patients to characterize the safety,
pharmacokinetics, and antiviral activity of SUSTIVA in combination with nelfinavir
(20-30 mg/kg three times daily) and NRTIs. Mean age was 8 years (range 3-16).
SUSTIVA has not been studied in pediatric patients below 3 years of age or
who weigh less than 13 kg. At 48 weeks, the type and frequency of adverse
experiences was generally similar to that of adult patients with the exception
of a higher incidence of rash, which was reported in 46% (26/57) of pediatric
patients compared to 26% of adults, and a higher frequency of Grade 3 or 4
rash reported in 5% (3/57) of pediatric patients compared to 0.9% of adults
[see Warnings and Precautions (5.7) and Adverse
Reactions (6.1, Table 5; 6.2)].
The starting dose of SUSTIVA was
600 mg once daily adjusted to body size, based on weight, targeting AUC levels
in the range of 190-380 µM•h [see Dosage and Administration (2.2)]. The pharmacokinetics of efavirenz
in pediatric patients were similar to the pharmacokinetics in adults who received
600-mg daily doses of SUSTIVA. In 48 pediatric patients receiving the equivalent
of a 600-mg dose of SUSTIVA, steady-state Cmax was
14.2 ± 5.8 µM (mean ± SD), steady-state Cmin was 5.6 ± 4.1 µM, and AUC was 218 ± 104 µM•h.
8.5 Geriatric Use
Clinical studies of SUSTIVA did
not include sufficient numbers of subjects aged 65 years and over to determine
whether they respond differently from younger subjects. In general, dose selection
for an elderly patient should be cautious, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease
or other therapy.
8.6 Hepatic Impairment
SUSTIVA is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering SUSTIVA to these patients [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)].
10 OVERDOSAGE
Some patients accidentally taking
600 mg twice daily have reported increased nervous system symptoms. One patient
experienced involuntary muscle contractions.
Treatment
of overdose with SUSTIVA should consist of general supportive measures, including
monitoring of vital signs and observation of the patient’s clinical status.
Administration of activated charcoal may be used to aid removal of unabsorbed
drug. There is no specific antidote for overdose with SUSTIVA. Since efavirenz
is highly protein bound, dialysis is unlikely to significantly remove the
drug from blood.
11 DESCRIPTION
SUSTIVA® (efavirenz)
is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI).
Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
Its empirical formula is C14H9ClF3NO2 and
its structural formula is:
Efavirenz is a white to slightly pink crystalline powder
with a molecular mass of 315.68. It is practically insoluble in water (<10
microgram/mL).
Capsules: SUSTIVA is
available as capsules for oral administration containing either 50 mg or 200 mg of efavirenz and the following inactive ingredients: lactose monohydrate,
magnesium stearate, sodium lauryl sulfate, and sodium starch glycolate. The
capsule shell contains the following inactive ingredients and dyes: gelatin,
sodium lauryl sulfate, titanium dioxide, and/or yellow iron oxide. The capsule
shells may also contain silicon dioxide. The capsules are printed with ink
containing carmine 40 blue, FD&C Blue No. 2, and titanium dioxide.
Tablets: SUSTIVA
is available as film-coated tablets for oral administration containing 600
mg of efavirenz and the following inactive ingredients: croscarmellose sodium,
hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline
cellulose, and sodium lauryl sulfate. The film coating contains Opadry Yellow
and Opadry Clear. The tablets are polished with carnauba wax and printed with
purple ink, Opacode WB.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Efavirenz is an antiviral drug
[see Clinical Pharmacology (12.4)].
12.3 Pharmacokinetics
Absorption
Peak efavirenz plasma concentrations
of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100
mg to 1600 mg administered to uninfected volunteers. Dose-related increases
in Cmax and AUC were seen for doses up to 1600 mg;
the increases were less than proportional suggesting diminished absorption
at higher doses.
In HIV-1-infected patients at
steady state, mean Cmax, mean Cmin,
and mean AUC were dose proportional following 200-mg, 400-mg, and 600-mg daily
doses. Time-to-peak plasma concentrations were approximately 3-5 hours and
steady-state plasma concentrations were reached in 6-10 days. In 35 patients
receiving SUSTIVA 600 mg once daily, steady-state Cmax was
12.9 ± 3.7 μM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•h.
Effect of Food on Oral Absorption:
Capsules: Administration
of a single 600-mg dose of efavirenz capsules with a high-fat/high-caloric
meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric
meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean
increase of 22% and 17% in efavirenz AUC∞ and a mean
increase of 39% and 51% in efavirenz Cmax, respectively,
relative to the exposures achieved when given under fasted conditions. See Dosage
and Administration (2) and Patient
Counseling Information (17.3).
Tablets: Administration of a single 600-mg efavirenz
tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600
kcal from fat) was associated with a 28% increase in mean AUC∞ of
efavirenz and a 79% increase in mean Cmax of efavirenz
relative to the exposures achieved under fasted conditions. See Dosage
and Administration (2) and Patient
Counseling Information (17.3).
Distribution
Efavirenz is highly bound (approximately
99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected
patients (n=9) who received SUSTIVA 200 to 600 mg once daily for at least
one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean
0.69%) of the corresponding plasma concentration. This proportion is approximately
3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.
Metabolism
Studies in humans and in vitro studies
using human liver microsomes have demonstrated that efavirenz is principally
metabolized by the cytochrome P450 system to hydroxylated metabolites with
subsequent glucuronidation of these hydroxylated metabolites. These metabolites
are essentially inactive against HIV-1. The in vitro studies
suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz
metabolism.
Efavirenz has been shown to induce
CYP enzymes, resulting in the induction of its own metabolism. Multiple doses
of 200-400 mg per day for 10 days resulted in a lower than predicted extent
of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours
(single dose half-life 52-76 hours).
Elimination
Efavirenz has a terminal half-life
of 52-76 hours after single doses and 40-55 hours after multiple doses. A
one-month mass balance/excretion study was conducted using 400 mg per day
with a 14C-labeled dose administered on Day 8.
Approximately 14-34% of the radiolabel was recovered in the urine and 16-61%
was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled
drug was in the form of metabolites. Efavirenz accounted for the majority
of the total radioactivity measured in feces.
Special Populations
Gender and race: The
pharmacokinetics of efavirenz in patients appear to be similar between men
and women and among the racial groups studied.
Renal
impairment: The pharmacokinetics of efavirenz have not been studied
in patients with renal insufficiency; however, less than 1% of efavirenz is
excreted unchanged in the urine, so the impact of renal impairment on efavirenz
elimination should be minimal.
Hepatic impairment: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics.
Drug Interaction Studies
Efavirenz has been shown in
vivo to cause hepatic enzyme induction, thus increasing the biotransformation
of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have
shown that efavirenz inhibited CYP isozymes 2C9, 2C19, and 3A4 with Ki values
(8.5-17 μM) in the range of observed efavirenz plasma concentrations. In in
vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6
and CYP1A2 (Ki values 82-160 μM) only at concentrations
well above those achieved clinically. The inhibitory effect on CYP3A is expected
to be similar between 200-mg, 400-mg, and 600-mg doses of efavirenz. Coadministration
of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A isozymes
may result in altered plasma concentrations of the coadministered drug. Drugs
which induce CYP3A activity would be expected to increase the clearance of
efavirenz resulting in lowered plasma concentrations.
Drug
interaction studies were performed with efavirenz and other drugs likely to
be coadministered or drugs commonly used as probes for pharmacokinetic interaction.
The effects of coadministration of efavirenz on the Cmax,
AUC, and Cmin are summarized in Table 8 (effect of
efavirenz on other drugs) and Table 9 (effect of other drugs on efavirenz).
For information regarding clinical recommendations see Contraindications (4.2) and Drug Interactions (7.1).
Table 8: Effect of Efavirenz on Coadministered Drug Plasma Cmax,
AUC, and Cmin
Coadministered
Drug |
Dose |
Efavirenz
Dose |
Number of Subjects |
Coadministered
Drug (mean % change) |
Cmax (90%
CI) |
AUC (90%
CI) |
Cmin (90%
CI) |
↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. |
a Compared with atazanavir 400
mg qd alone. |
b Comparator dose of indinavir
was 800 mg q8h x 10 days. |
c Parallel-group design; n for
efavirenz + lopinavir/ritonavir, n for lopinavir/ritonavir alone. |
d Values are for lopinavir;
the pharmacokinetics of ritonavir in this study were unaffected by concurrent
efavirenz. |
e 95% CI. |
f Soft Gelatin Capsule. |
g Tenofovir disoproxil fumarate. |
h 90% CI not available. |
i Relative to steady-state administration
of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). |
j Not available because
of insufficient data. |
NA = not available. |
Atazanavir |
400 mg qd with a
light meal d 1‑20 |
600 mg qd with a
light meal d 7‑20 |
27 |
↓ 59% (49-67%) |
↓ 74% (68-78%) |
↓ 93% (90-95%) |
|
400 mg qd d 1‑6, then 300 mg qd d 7‑20 with ritonavir 100 mg qd and a light meal |
600 mg qd 2 h after atazanavir and
ritonavir d 7‑20 |
13 |
↑ 14%a (↓ 17-↑ 58%) |
↑ 39%a (2-88%) |
↑ 48%a (24-76%) |
|
300 mg qd/ritonavir 100 mg qd d 1‑10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11‑24 (pm) (simultaneous with efavirenz) |
600 mg qd with a light snack d 11‑24 (pm) |
14 |
↑ 17% (8-27%) |
↔ |
↓ 42%
(31-51%) |
Indinavir |
1000 mg q8h x 10 days |
600 mg qd x 10 days |
20 |
|
|
After morning dose |
↔b |
↓ 33%b (26-39%) |
↓ 39%b (24-51%) |
|
After afternoon dose |
↔b |
↓ 37%b (26-46%) |
↓ 52%b (47-57%) |
|
After evening dose |
↓ 29%b (11-43%) |
↓ 46%b (37-54%) |
↓ 57%b (50-63%) |
Lopinavir/ ritonavir |
400/100 mg capsule q12h
x 9 days |
600 mg qd x 9 days |
11,7c |
↔d |
↓ 19%d (↓ 36-↑ 3%) |
↓ 39%d (3-62%) |
|
600/150 mg tablet q12h
x 10 days with efavirenz compared to 400/100 mg q12h
alone |
600 mg qd x 9 days |
23 |
↑ 36%d (28-44%) |
↑ 36%d (28-44%) |
↑ 32%d (21-44%) |
Nelfinavir |
750 mg q8h x 7 days |
600 mg qd x 7 days |
10 |
↑ 21% (10-33%) |
↑ 20% (8-34%) |
↔ |
Metabolite AG-1402 |
|
↓ 40% (30-48%) |
↓ 37% (25-48%) |
↓ 43% (21-59%) |
Ritonavir |
500 mg q12h x 8 days |
600 mg qd x 10 days |
11 |
|
|
After AM dose |
↑ 24% (12-38%) |
↑ 18% (6-33%) |
↑ 42% (9-86%)e |
|
After PM dose |
↔ |
↔ |
↑ 24% (3-50%)e |
Saquinavir SGCf |
1200 mg q8h x 10 days |
600 mg qd x 10 days |
12 |
↓ 50% (28-66%) |
↓ 62% (45-74%) |
↓ 56% (16-77%)e |
Lamivudine |
150 mg q12h x 14 days |
600 mg qd x 14 days |
9 |
↔ |
↔ |
↑ 265% (37-873%) |
Tenofovirg |
300 mg qd |
600 mg qd x 14 days |
29 |
↔ |
↔ |
↔ |
Zidovudine |
300 mg q12h x 14 days |
600 mg qd x 14 days |
9 |
↔ |
↔ |
↑ 225% (43-640%) |
Maraviroc |
100 mg bid |
600 mg qd |
12 |
↓ 51% (37-62%) |
↓ 45% (38-51%) |
↓ 45% (28-57%) |
Raltegravir |
400 mg single dose |
600 mg qd |
9 |
↓ 36% (2-59%) |
↓ 36% (20-48%) |
↓ 21% (↓ 51-↑ 28%) |
Boceprevir |
800 mg tid x 6 days |
600 mg qd x 16 days |
NA |
↓ 8% (↓ 22-↑ 8%) |
↓ 19% (11-25%) |
↓ 44% (26-58%) |
Telaprevir |
750 mg q8h x 10 days |
600 mg qd x 20 days |
21 |
↓ 9% (↓ 18-↑ 2%) |
↓ 26% (16-35%) |
↓ 47% (35-56%) |
Azithromycin |
600 mg single dose |
400 mg qd x 7 days |
14 |
↑ 22% (4-42%) |
↔ |
NA |
Clarithromycin |
500 mg q12h x 7 days |
400 mg qd x 7 days |
11 |
↓ 26% (15-35%) |
↓ 39% (30-46%) |
↓ 53% (42-63%) |
14-OH metabolite |
|
↑ 49% (32-69%) |
↑ 34% (18-53%) |
↑ 26% (9-45%) |
Fluconazole |
200 mg x 7 days |
400 mg qd x 7 days |
10 |
↔ |
↔ |
↔ |
Itraconazole |
200 mg q12h x 28 days |
600 mg qd x 14 days |
18 |
↓ 37% (20-51%) |
↓ 39% (21-53%) |
↓ 44% (27-58%) |
Hydroxy-itraconazole |
|
↓ 35% (12-52%) |
↓ 37% (14-55%) |
↓ 43% (18-60%) |
Posaconazole |
400 mg (oral suspension) bid x 10 and 20 days |
400 mg qd x 10 and 20 days |
11 |
↓ 45% (34-53%) |
↓ 50% (40-57%) |
NA |
Rifabutin |
300 mg qd x 14 days |
600 mg qd x 14 days |
9 |
↓ 32% (15-46%) |
↓ 38% (28-47%) |
↓ 45% (31-56%) |
Voriconazole |
400 mg po q12h x 1 day, then 200
mg po q12h x 8 days |
400 mg qd x 9 days |
NA |
↓ 61%h |
↓ 77%h |
NA |
|
300 mg po q12h days 2‑7 |
300 mg qd x 7 days |
NA |
↓ 36%i (21-49%) |
↓ 55%i (45-62%) |
NA |
|
400 mg po q12h days 2‑7 |
300 mg qd x 7 days |
NA |
↑ 23%i (↓ 1-↑ 53%) |
↓ 7%i (↓ 23-↑ 13%) |
NA |
Atorvastatin |
10 mg qd x 4 days |
600 mg qd x 15 days |
14 |
↓ 14% (1-26%) |
↓ 43% (34-50%) |
↓ 69% (49-81%) |
Total active (including metabolites) |
|
↓ 15% (2-26%) |
↓ 32% (21-41%) |
↓ 48% (23-64%) |
Pravastatin |
40 mg qd x 4 days |
600 mg qd x 15 days |
13 |
↓ 32% (↓ 59-↑ 12%) |
↓ 44% (26-57%) |
↓ 19% (0-35%) |
Simvastatin |
40 mg qd x 4 days |
600 mg qd x 15 days |
14 |
↓ 72% (63-79%) |
↓ 68% (62-73%) |
↓ 45% (20-62%) |
Total active (including metabolites) |
|
↓ 68% (55-78%) |
↓ 60% (52-68%) |
NAj |
Carbamazepine |
200 mg qd x 3 days,
200 mg bid x 3 days, then 400 mg qd x 29 days |
600 mg qd x 14 days |
12 |
↓ 20% (15-24%) |
↓ 27% (20-33%) |
↓ 35% (24-44%) |
Epoxide metabolite |
|
↔ |
↔ |
↓ 13% (↓ 30-↑ 7%) |
Cetirizine |
10 mg single dose |
600 mg qd x 10 days |
11 |
↓ 24% (18-30%) |
↔ |
NA |
Diltiazem |
240 mg x 21 days |
600 mg qd x 14 days |
13 |
↓ 60% (50-68%) |
↓ 69% (55-79%) |
↓ 63% (44-75%) |
Desacetyl diltiazem |
|
↓ 64% (57-69%) |
↓ 75% (59-84%) |
↓ 62% (44-75%) |
N- monodesmethyl diltiazem |
|
↓ 28% (7-44%) |
↓ 37% (17-52%) |
↓ 37% (17-52%) |
Ethinyl estradiol/
Norgestimate |
0.035 mg/ 0.25 mg x 14 days |
600 mg qd x 14 days |
|
|
|
|
Ethinyl estradiol |
|
21 |
↔ |
↔ |
↔ |
Norelgestromin |
|
21 |
↓ 46% (39-52%) |
↓ 64% (62-67%) |
↓ 82% (79-85%) |
Levonorgestrel |
|
6 |
↓ 80% (77-83%) |
↓ 83% (79-87%) |
↓ 86% (80-90%) |
Lorazepam |
2 mg single dose |
600 mg qd x 10 days |
12 |
↑ 16% (2-32%) |
↔ |
NA |
Methadone |
Stable maintenance
35- 100 mg daily |
600 mg qd x 14-21 days |
11 |
↓ 45% (25-59%) |
↓ 52% (33-66%) |
NA |
Bupropion |
150 mg single dose (sustained-release) |
600 mg qd x 14 days |
13 |
↓ 34% (21-47%) |
↓ 55% (48-62%) |
NA |
Hydroxy- bupropion |
|
↑ 50% (20-80%) |
↔ |
NA |
Paroxetine |
20 mg qd x 14 days |
600 mg qd x 14 days |
16 |
↔ |
↔ |
↔ |
Sertraline |
50 mg qd x 14 days |
600 mg qd x 14 days |
13 |
↓ 29% (15-40%) |
↓ 39% (27-50%) |
↓ 46% (31-58%) |
Table 9: Effect of Coadministered Drug on Efavirenz Plasma Cmax,
AUC, and Cmin
|
Efavirenz (mean % change) |
Coadministered Drug |
Dose |
Efavirenz Dose |
Number of Subjects |
Cmax (90% CI) |
AUC (90% CI) |
Cmin (90% CI) |
↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. |
a Parallel-group design; n for
efavirenz + lopinavir/ritonavir, n for efavirenz alone. |
b 95% CI. |
c Soft Gelatin Capsule. |
d Tenofovir disoproxil fumarate. |
e 90% CI not available. |
f Relative to steady-state administration
of efavirenz (600 mg once daily for 9 days). |
NA = not available. |
Indinavir |
800 mg q8h x 14 days |
200 mg qd x 14 days |
11 |
↔ |
↔ |
↔ |
Lopinavir/ ritonavir |
400/100 mg q12h x
9 days |
600 mg qd x 9 days |
11,12a |
↔ |
↓ 16% (↓ 38-↑ 15%) |
↓ 16% (↓ 42-↑ 20%) |
Nelfinavir |
750 mg q8h x 7 days |
600 mg qd x 7 days |
10 |
↓ 12% (↓ 32-↑ 13%)b |
↓ 12% (↓ 35-↑ 18%)b |
↓ 21% (↓ 53-↑ 33%) |
Ritonavir |
500 mg q12h x 8 days |
600 mg qd x 10 days |
9 |
↑ 14% (4-26%) |
↑ 21% (10-34%) |
↑ 25% (7-46%)b |
Saquinavir SGCc |
1200 mg q8h x 10 days |
600 mg qd x 10 days |
13 |
↓ 13% (5-20%) |
↓ 12% (4-19%) |
↓ 14% (2-24%)b |
Tenofovird |
300 mg qd |
600 mg qd x 14 days |
30 |
↔ |
↔ |
↔ |
Boceprevir |
800 mg tid x 6 days |
600 mg qd x 16 days |
NA |
↑ 11% (2-20%) |
↑ 20% (15-26%) |
NA |
Telaprevir |
750 mg q8h x 10 days |
600 mg qd x 20 days |
21 |
↓ 16% (7-24%) |
↓ 7% (2-13%) |
↓ 2% (↓ 6-↑ 2%) |
Telaprevir, coadministered with tenofovir disoproxil fumarate (TDF) |
1125 mg q8h x 7 days |
600 mg efavirenz/300 mg TDF qd x 7 days |
15 |
↓ 24% (15-32%) |
↓ 18% (10-26%) |
↓ 10% (↓ 19-↑ 1%) |
1500 mg q12h x 7 days |
600 mg efavirenz/300 mg TDF qd x 7 days |
16 |
↓ 20% (14-26%) |
↓ 15% (9-21%) |
↓ 11% (4-18%) |
Azithromycin |
600 mg single dose |
400 mg qd x 7 days |
14 |
↔ |
↔ |
↔ |
Clarithromycin |
500 mg q12h x 7 days |
400 mg qd x 7 days |
12 |
↑ 11% (3-19%) |
↔ |
↔ |
Fluconazole |
200 mg x 7 days |
400 mg qd x 7 days |
10 |
↔ |
↑ 16% (6-26%) |
↑ 22% (5-41%) |
Itraconazole |
200 mg q12h x 14 days |
600 mg qd x 28 days |
16 |
↔ |
↔ |
↔ |
Rifabutin |
300 mg qd x 14 days |
600 mg qd x 14 days |
11 |
↔ |
↔ |
↓ 12% (↓ 24-↑ 1%) |
Rifampin |
600 mg x 7 days |
600 mg qd x 7 days |
12 |
↓ 20% (11-28%) |
↓ 26% (15-36%) |
↓ 32% (15-46%) |
Voriconazole |
400 mg po q12h x
1 day, then 200 mg po q12h x 8 days |
400 mg qd x 9 days |
NA |
↑ 38%e |
↑ 44%e |
NA |
|
300 mg po q12h days
2-7 |
300 mg qd x 7 days |
NA |
↓ 14%f (7-21%) |
↔f |
NA |
|
400 mg po q12h days
2-7 |
300 mg qd x 7 days |
NA |
↔f |
↑ 17%f (6-29%) |
NA |
Atorvastatin |
10 mg qd x 4 days |
600 mg qd x 15 days |
14 |
↔ |
↔ |
↔ |
Pravastatin |
40 mg qd x 4 days |
600 mg qd x 15 days |
11 |
↔ |
↔ |
↔ |
Simvastatin |
40 mg qd x 4 days |
600 mg qd x 15 days |
14 |
↓ 12% (↓ 28-↑ 8%) |
↔ |
↓ 12% (↓ 25-↑ 3%) |
Aluminum hydroxide
400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg |
30 mL single dose |
400 mg single dose |
17 |
↔ |
↔ |
NA |
Carbamazepine |
200 mg qd x 3 days,
200 mg bid x 3 days, then 400 mg qd x 15 days |
600 mg qd x 35 days |
14 |
↓ 21% (15-26%) |
↓ 36% (32-40%) |
↓ 47% (41-53%) |
Cetirizine |
10 mg single dose |
600 mg qd x 10 days |
11 |
↔ |
↔ |
↔ |
Diltiazem |
240 mg x 14 days |
600 mg qd x 28 days |
12 |
↑ 16% (6-26%) |
↑ 11% (5-18%) |
↑ 13% (1-26%) |
Famotidine |
40 mg single dose |
400 mg single dose |
17 |
↔ |
↔ |
NA |
Paroxetine |
20 mg qd x 14 days |
600 mg qd x 14 days |
12 |
↔ |
↔ |
↔ |
Sertraline |
50 mg qd x
14 days |
600 mg qd x 14 days |
13 |
↑ 11% (6-16%) |
↔ |
↔ |
12.4 Microbiology
Mechanism of Action
Efavirenz (EFV) is an NNRTI of HIV-1.
EFV activity is mediated predominantly by noncompetitive inhibition of HIV-1
reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by EFV.
Antiviral Activity in Cell Culture
The concentration of EFV inhibiting
replication of wild-type laboratory adapted strains and clinical isolates
in cell culture by 90-95% (EC90-95) ranged from 1.7
to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells
(PBMCs), and macrophage/monocyte cultures. EFV demonstrated antiviral activity
against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F,
G, J, N), but had reduced antiviral activity against group O viruses. EFV
demonstrated additive antiviral activity without cytotoxicity against HIV-1
in cell culture when combined with the NNRTIs delavirdine (DLV) and nevirapine
(NVP), NRTIs (abacavir, didanosine, emtricitabine, lamivudine [LAM], stavudine,
tenofovir, zalcitabine, zidovudine [ZDV]), PIs (amprenavir, indinavir [IDV],
lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide.
EFV demonstrated additive to antagonistic antiviral activity in cell culture
with atazanavir. EFV was not antagonistic with adefovir, used for the treatment
of hepatitis B virus infection, or ribavirin, used in combination with interferon
for the treatment of hepatitis C virus infection.
Resistance
In cell culture
In cell culture, HIV-1 isolates with
reduced susceptibility to EFV (>380-fold increase in EC90 value)
emerged rapidly in the presence of drug. Genotypic characterization of these
viruses identified single amino acid substitutions L100I or V179D, double
substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in
RT.
Clinical studies
Clinical isolates with reduced susceptibility
in cell culture to EFV have been obtained. One or more RT substitutions at
amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 were
observed in patients failing treatment with EFV in combination with IDV, or
with ZDV plus LAM. The mutation K103N was the most frequently observed. Long-term
resistance surveillance (average 52 weeks, range 4-106 weeks) analyzed 28
matching baseline and virologic failure isolates. Sixty-one percent (17/28)
of these failure isolates had decreased EFV susceptibility in cell culture
with a median 88-fold change in EFV susceptibility (EC50 value)
from reference. The most frequent NNRTI substitution to develop in these patient
isolates was K103N (54%). Other NNRTI substitutions that developed included
L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and
M230I/L (11%).
Cross-Resistance
Cross-resistance among NNRTIs has been
observed. Clinical isolates previously characterized as EFV-resistant were
also phenotypically resistant in cell culture to DLV and NVP compared to baseline.
DLV- and/or NVP-resistant clinical viral isolates with NNRTI resistance-associated
substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X,
P225H, F227L, or M230L) showed reduced susceptibility to EFV in cell culture.
Greater than 90% of NRTI-resistant clinical isolates tested in cell culture
retained susceptibility to EFV.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0,
25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose.
Mutagenesis
Efavirenz tested negative in a battery of in
vitro and in vivo genotoxicity assays. These included bacterial
mutation assays in S. typhimurium and E. coli,
mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay.
Impairment of Fertility
Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately ≤0.15 times that in humans at the recommended clinical dose.
13.2 Animal Toxicology
Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values
4- to 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.9)].
14 CLINICAL STUDIES
Study 006, a randomized, open-label trial, compared SUSTIVA (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or SUSTIVA (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years [range 18-81], 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm3 and the median baseline HIV-1 RNA level was 4.8 log10 copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 10. Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) versions of the AMPLICOR HIV-1 MONITOR assay. During the study, version 1.5 of the assay was introduced in Europe to enhance detection of non-clade B virus.
Table 10: Outcomes of Randomized Treatment Through 48 and 168 Weeks,
Study 006
|
SUSTIVA
+ ZDV + LAM (n=422) |
SUSTIVA
+ IDV (n=429) |
IDV
+ ZDV + LAM (n=415) |
Outcome |
Week 48 |
Week 168 |
Week 48 |
Week 168 |
Week 48 |
Week 168 |
a Patients achieved
and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 or Week
168. |
b Includes patients
who rebounded, patients who were on study at Week 48 and failed to achieve
confirmed HIV-1 RNA <400 copies/mL at time of discontinuation, and patients
who discontinued due to lack of efficacy. |
c Includes consent
withdrawn, lost to follow-up, noncompliance, never treated, missing data,
protocol violation, death, and other reasons. Patients with HIV-1 RNA levels <400 copies/mL who chose not to continue in the voluntary extension phases
of the study were censored at date of last dose of study medication. |
Respondera |
69% |
48% |
57% |
40% |
50% |
29% |
Virologic failureb |
6% |
12% |
15% |
20% |
13% |
19% |
Discontinued for adverse events |
7% |
8% |
6% |
8% |
16% |
20% |
Discontinued for other reasonsc |
17% |
31% |
22% |
32% |
21% |
32% |
CD4+ cell count (cells/mm3) |
Observed subjects (n) |
(279) |
(205) |
(256) |
(158) |
(228) |
(129) |
Mean change
from baseline |
190 |
329 |
191 |
319 |
180 |
329 |
For patients treated with SUSTIVA + zidovudine + lamivudine,
SUSTIVA + indinavir, or indinavir + zidovudine + lamivudine, the percentage
of responders with HIV-1 RNA <50 copies/mL was 65%, 50%, and 45%, respectively,
through 48 weeks, and 43%, 31%, and 23%, respectively, through 168 weeks.
A Kaplan-Meier analysis of time to loss of virologic response (HIV RNA <400
copies/mL) suggests that both the trends of virologic response and differences
in response continue through 4 years.
ACTG
364 is a randomized, double-blind, placebo-controlled, 48-week study
in NRTI-experienced patients who had completed two prior ACTG studies. One-hundred
ninety-six patients (mean age 41 years [range 18-76], 74% Caucasian, 88% male)
received NRTIs in combination with SUSTIVA (efavirenz) (600 mg once daily),
or nelfinavir (NFV, 750 mg three times daily), or SUSTIVA (600 mg once daily)
+ nelfinavir in a randomized, double-blinded manner. The mean baseline CD4+
cell count was 389 cells/mm3 and mean baseline
HIV-1 RNA level was 8130 copies/mL. Upon entry into the study, all patients
were assigned a new open-label NRTI regimen, which was dependent on their
previous NRTI treatment experience. There was no significant difference in
the mean CD4+ cell count among treatment groups; the overall mean increase
was approximately 100 cells at 48 weeks among patients who continued on study
regimens. Treatment outcomes are shown in Table 11. Plasma HIV RNA levels
were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit
of quantification of 500 copies/mL.
Table 11: Outcomes of Randomized Treatment Through 48 Weeks, Study
ACTG 364*
Outcome |
SUSTIVA +
NFV + NRTIs (n=65) |
SUSTIVA + NRTIs (n=65) |
NFV + NRTIs (n=66) |
* For some patients, Week 56 data
were used to confirm the status at Week 48. |
a Subjects achieved
virologic response (two consecutive viral loads <500 copies/mL) and maintained
it through Week 48. |
b Includes viral rebound
and failure to achieve confirmed <500 copies/mL by Week 48. |
c See Adverse
Reactions (6.1) for a safety profile
of these regimens. |
d Includes loss to
follow-up, consent withdrawn, noncompliance. |
HIV-1 RNA <500 copies/mLa |
71% |
63% |
41% |
HIV-1 RNA ≥500 copies/mLb |
17% |
34% |
54% |
CDC Category C Event |
2% |
0% |
0% |
Discontinuations
for adverse eventsc |
3% |
3% |
5% |
Discontinuations
for other reasonsd |
8% |
0% |
0% |
A Kaplan-Meier analysis of time to treatment failure
through 72 weeks demonstrates a longer duration of virologic suppression (HIV
RNA <500 copies/mL) in the SUSTIVA-containing treatment arms.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 Capsules
SUSTIVA® (efavirenz)
capsules are available as follows:
Capsules
200 mg are gold color, reverse printed with “SUSTIVA” on the body and imprinted “200 mg” on the cap.
Bottles
of 90 NDC 0056-0474-92
Capsules 50
mg are gold color and white, printed with “SUSTIVA” on the gold color
cap and reverse printed “50 mg” on the white body.
Bottles of 30 NDC 0056-0470-30
16.2 Tablets
SUSTIVA® (efavirenz) tablets are available
as follows:
Tablets 600 mg are
yellow, capsular-shaped, film-coated tablets, with “SUSTIVA” printed on both
sides.
Bottles of 30 NDC 0056-0510-30
16.3 Storage
SUSTIVA capsules and SUSTIVA tablets
should be stored at 25° C (77° F); excursions permitted to 15°–30° C (59°–86°
F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information).
17.1 Drug Interactions
A statement to patients and healthcare
providers is included on the product’s bottle labels:
ALERT: Find
out about medicines that should NOT be taken with SUSTIVA.
SUSTIVA may interact with some drugs; therefore, patients should
be advised to report to their doctor the use of any other prescription, nonprescription
medication, or herbal products, particularly St. John’s wort.
17.2 General Information for Patients
Patients should be informed that SUSTIVA is not a cure for HIV-1 infection and patients may continue to experience
illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician while taking SUSTIVA.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breast-feed. It is not known if SUSTIVA can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk.
17.3 Dosing Instructions
Patients should be advised to take SUSTIVA
every day as prescribed. SUSTIVA must always be used in combination with other
antiretroviral drugs. Patients should be advised to take SUSTIVA on an empty
stomach, preferably at bedtime. Taking SUSTIVA with food increases efavirenz
concentrations and may increase the frequency of adverse reactions. Dosing
at bedtime may improve the tolerability of nervous system symptoms [see Dosage
and Administration (2) and Adverse
Reactions (6.1)].
17.4 Nervous System Symptoms
Patients should be informed that central
nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration,
drowsiness, and abnormal dreams are commonly reported during the first weeks
of therapy with SUSTIVA [see Warnings and Precautions (5.5)].
Dosing at bedtime may improve the tolerability of these symptoms, which are
likely to improve with continued therapy. Patients should be alerted to the
potential for additive effects when SUSTIVA is used concomitantly with alcohol
or psychoactive drugs. Patients should be instructed that if they experience
NSS they should avoid potentially hazardous tasks such as driving or operating
machinery.
17.5 Psychiatric Symptoms
Patients should be informed that serious
psychiatric symptoms including severe depression, suicide attempts, aggressive
behavior, delusions, paranoia, and psychosis-like symptoms have been reported
in patients receiving SUSTIVA [see Warnings and Precautions (5.4)]. If they experience severe
psychiatric adverse experiences they should seek immediate medical evaluation.
Patients should be advised to inform their physician of any history of mental
illness or substance abuse.
17.6 Rash
Patients should be informed that a
common side effect is rash [see Warnings and Precautions (5.7)]. Rashes usually go away without any change in treatment. However,
since rash may be serious, patients should be advised to contact their physician
promptly if rash occurs.
17.7 Reproductive Risk Potential
Women receiving SUSTIVA should be
instructed to avoid pregnancy [see Warnings and Precautions (5.6)]. A reliable form of barrier
contraception must always be used in combination with other methods of contraception,
including oral or other hormonal contraception. Because of the long half-life
of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation
of SUSTIVA is recommended. Women should be advised to notify their physician
if they become pregnant or plan to become pregnant while taking SUSTIVA. If
this drug is used during the first trimester of pregnancy, or if the patient
becomes pregnant while taking this drug, she should be apprised of the potential
harm to the fetus.
17.8 Fat Redistribution
Patients should be informed that redistribution
or accumulation of body fat may occur in patients receiving antiretroviral
therapy and that the cause and long-term health effects of these conditions
are not known [see Warnings and Precautions (5.12)].
Patient Information
SUSTIVA® (sus-TEE-vah)
[efavirenz (eh-FAH-vih-rehnz)]
capsules and tablets
ALERT:
Find out about medicines that should NOT be taken with SUSTIVA.
Please also read the section “MEDICINES YOU SHOULD NOT
TAKE WITH SUSTIVA.”
Read this information
before you start taking SUSTIVA. Read it again each time you refill your prescription,
in case there is any new information. This leaflet provides a summary about
SUSTIVA and does not include everything there is to know about your medicine.
This information is not meant to take the place of talking with your doctor.
What is SUSTIVA?
SUSTIVA
is a medicine used in combination with other medicines to help treat infection
with Human Immunodeficiency Virus type 1 (HIV-1), the virus that causes AIDS
(acquired immune deficiency syndrome). SUSTIVA is a type of anti-HIV drug
called a “non-nucleoside reverse transcriptase inhibitor” (NNRTI). NNRTIs
are not used in the treatment of Human Immunodeficiency Virus type 2 (HIV-2)
infection.
SUSTIVA works by lowering the amount
of HIV-1 in the blood (viral load). SUSTIVA must be taken with other anti-HIV
medicines. When taken with other anti-HIV medicines, SUSTIVA has been shown
to reduce viral load and increase the number of CD4+ cells, a type of immune
cell in blood. SUSTIVA may not have these effects in every patient.
SUSTIVA does not cure HIV or AIDS and you may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. You should remain under the care of a doctor when using SUSTIVA.
Avoid doing things that can spread HIV-1 infection.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
What are the possible side effects of SUSTIVA?
Serious psychiatric problems. A small number of
patients experience severe depression, strange thoughts, or angry behavior
while taking SUSTIVA. Some patients have thoughts of suicide and a few have
actually committed suicide. These problems tend to occur more often in patients
who have had mental illness. Contact your doctor right away if you think you
are having these psychiatric symptoms, so your doctor can decide if you should
continue to take SUSTIVA (efavirenz).
Common
side effects. Many patients have dizziness, trouble sleeping, drowsiness,
trouble concentrating, and/or unusual dreams during treatment with SUSTIVA.
These side effects may be reduced if you take SUSTIVA at bedtime on an empty
stomach. They also tend to go away after you have taken the medicine for a
few weeks. If you have these common side effects, such as dizziness, it does
not mean that you will also have serious psychiatric problems, such as severe
depression, strange thoughts, or angry behavior. Tell your doctor right away
if any of these side effects continue or if they bother you. It is possible
that these symptoms may be more severe if SUSTIVA is used with alcohol or
mood altering (street) drugs.
If you are dizzy,
have trouble concentrating, or are drowsy, avoid activities that may be dangerous,
such as driving or operating machinery.
Rash is
common. Rashes usually go away without any change in treatment. In a small
number of patients, rash may be serious. If you develop a rash, call your
doctor right away. Rash may be a serious problem in some children. Tell
your child’s doctor right away if you notice rash or any other side effects
while your child is taking SUSTIVA.
Other common
side effects include tiredness, upset stomach, vomiting, and diarrhea. Some
patients taking SUSTIVA have experienced increased levels of lipids (cholesterol
and triglycerides) in the blood.
Changes in
body fat. Changes in body fat develop in some patients taking anti-HIV
medicine. These changes may include an increased amount of fat in the upper
back and neck (“buffalo hump”), in the breasts, and around the trunk. Loss
of fat from the legs, arms, and face may also happen. The cause and long-term
health effects of these fat changes are not known.
Liver problems. Some patients taking SUSTIVA have experienced serious liver problems including liver failure resulting in transplantation or death. Most of these serious side effects occurred in patients with a chronic liver disease such as hepatitis infection, but there have also been a few reports in patients without any existing liver disease.
Tell
your doctor or healthcare provider if you notice any side effects while taking
SUSTIVA.
Contact your doctor before stopping SUSTIVA
because of side effects or for any other reason.
This
is not a complete list of side effects possible with SUSTIVA. Ask your doctor
or pharmacist for a more complete list of side effects of SUSTIVA and all
the medicines you will take.
How should I
take SUSTIVA?
General Information
- You should take SUSTIVA on an empty stomach, preferably at bedtime.
- Swallow SUSTIVA with water.
- Taking SUSTIVA with food increases the amount of medicine in your
body, which may increase the frequency of side effects.
- Taking SUSTIVA at bedtime may make some side effects less bothersome.
- SUSTIVA must be taken in combination with other anti-HIV medicines.
If you take only SUSTIVA, the medicine may stop working.
- Do not miss a dose of SUSTIVA. If you forget to take SUSTIVA, take
the missed dose right away, unless it is almost time for your next dose. Do
not double the next dose. Carry on with your regular dosing schedule. If you
need help in planning the best times to take your medicine, ask your doctor
or pharmacist.
- Take the exact amount of SUSTIVA your doctor prescribes. Never change
the dose on your own. Do not stop this medicine unless your doctor tells you
to stop.
- If you believe you took more than the prescribed amount of SUSTIVA,
contact your local Poison Control Center or emergency room right away.
- Tell your doctor if you start any new medicine or change how you
take old ones. Your doses may need adjustment.
- When your SUSTIVA supply starts to run low, get more from your doctor
or pharmacy. This is very important because the amount of virus in your blood
may increase if the medicine is stopped for even a short time. The virus may
develop resistance to SUSTIVA and become harder to treat.
- Your doctor may want to do blood tests to check for certain side
effects while you take SUSTIVA (efavirenz).
Capsules
- The dose of SUSTIVA capsules for adults is 600 mg (three 200-mg
capsules, taken together) once a day by mouth. The dose of SUSTIVA for children
may be lower (see “Can children take SUSTIVA?”).
Tablets
- The dose of SUSTIVA tablets for adults is 600 mg (one tablet) once
a day by mouth.
Can children take SUSTIVA?
Yes, children who are able to swallow capsules can take SUSTIVA.
Rash may be a serious problem in some children. Tell your child’s doctor right
away if you notice rash or any other side effects while your child is taking
SUSTIVA. The dose of SUSTIVA for children may be lower than the dose for adults.
Capsules containing lower doses of SUSTIVA are available. Your child’s doctor
will determine the right dose based on your child’s weight.
Who should not take SUSTIVA?
Do
not take SUSTIVA if you are allergic to the active ingredient, efavirenz,
or to any of the inactive ingredients. Your doctor and pharmacist have a list
of the inactive ingredients.
What should I
avoid while taking SUSTIVA?
- Women should not become pregnant while taking SUSTIVA and
for 12 weeks after stopping it. Serious birth defects have been seen
in the offspring of animals and women treated with SUSTIVA during pregnancy.
It is not known whether SUSTIVA caused these defects. Tell your doctor
right away if you are pregnant. Also talk with your doctor if you want
to become pregnant.
- Women should not rely only on hormone-based birth control, such
as pills, injections, or implants, because SUSTIVA may make these contraceptives
ineffective. Women must use a reliable form of barrier contraception, such
as a condom or diaphragm, even if they also use other methods of birth control.
SUSTIVA may remain in your blood for a time after therapy is stopped. Therefore,
you should continue to use contraceptive measures for 12 weeks after you stop
taking SUSTIVA.
- Do not breast-feed if you are taking SUSTIVA. It is not known if SUSTIVA can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in the breast milk. Talk with your doctor if you are breast-feeding. You may need to stop breast-feeding or use a different medicine.
- Taking SUSTIVA with alcohol or other medicines causing similar side effects as SUSTIVA, such as drowsiness, may increase those side effects.
- Do not take any other medicines without checking with your doctor. These medicines include prescription and nonprescription medicines and herbal
products, especially St. John’s wort (Hypericum perforatum).
Before using SUSTIVA, tell your doctor if you
- have problems with your liver or have hepatitis. Your
doctor may want to do tests to check your liver while you take SUSTIVA or may switch you to another medicine.
- have ever had mental illness or are using drugs or alcohol.
- have ever had seizures or are taking medicine for seizures [for
example, Dilantin (phenytoin), Tegretol (carbamazepine), or phenobarbital].
Your doctor may want to switch you to another medicine or check drug levels
in your blood from time to time.
What important information should I know about
taking other medicines with SUSTIVA?
SUSTIVA
may change the effect of other medicines, including ones for HIV, and cause
serious side effects. Your doctor may change your other medicines or
change their doses. Other medicines, including herbal products, may affect
SUSTIVA. For this reason, it is very important to:
- let all your doctors and pharmacists know that you take SUSTIVA.
- tell your doctors and pharmacists about all medicines you take.
This includes those you buy over-the-counter and herbal or natural remedies.
Bring all your prescription and nonprescription medicines
as well as any herbal remedies that you are taking when you see a doctor,
or make a list of their names, how much you take, and how often you take them.
This will give your doctor a complete picture of the medicines you use. Then
he or she can decide the best approach for your situation.
Taking
SUSTIVA with St. John’s wort (Hypericum perforatum), an herbal
product sold as a dietary supplement, or products containing St. John’s wort
is not recommended. Talk with your doctor if you are taking or are planning
to take St. John’s wort. Taking St. John’s wort may decrease SUSTIVA levels
and lead to increased viral load and possible resistance to SUSTIVA or cross-resistance
to other anti-HIV drugs.
MEDICINES YOU SHOULD
NOT TAKE WITH SUSTIVA
The following medicines
may cause serious and life-threatening side effects when taken with SUSTIVA.
You should not take any of these medicines while taking SUSTIVA:
- Vascor (bepridil)
- Propulsid (cisapride)
- Versed (midazolam)
- Orap (pimozide)
- Halcion (triazolam)
- Ergot medications (for example, Wigraine and Cafergot)
The following medicine should not be taken with SUSTIVA
since it contains efavirenz, the active ingredient in SUSTIVA:
- ATRIPLA (efavirenz, emtricitabine, tenofovir disoproxil fumarate)
The following medicines may need to be replaced
with another medicine when taken with SUSTIVA:
- Fortovase, Invirase (saquinavir)
- Biaxin (clarithromycin)
- Carbatrol, Tegretol (carbamazepine)
- Noxafil (posaconazole)
- Sporanox (itraconazole)
- REYATAZ (atazanavir sulfate), if this is not the first time you are receiving treatment for your HIV infection
- Victrelis (boceprevir)
The following medicines may require a change in
the dose of either SUSTIVA or the other medicine:
- Calcium channel blockers such as Cardizem or Tiazac (diltiazem),
Covera HS or Isoptin SR (verapamil), and others.
- The cholesterol-lowering medicines Lipitor (atorvastatin), PRAVACHOL
(pravastatin sodium), and Zocor (simvastatin).
- Crixivan (indinavir)
- Kaletra (lopinavir/ritonavir)
- Methadone
- Mycobutin (rifabutin)
- REYATAZ (atazanavir sulfate). If you are taking SUSTIVA and REYATAZ,
you should also be taking Norvir (ritonavir).
- Rifadin (rifampin) or the rifampin-containing medicines Rifamate
and Rifater.
- Selzentry (maraviroc)
- Vfend (voriconazole) and SUSTIVA must not be taken together at standard
doses. Some doses of voriconazole can be taken at the same time as a lower
dose of SUSTIVA, but you must check with your doctor first.
- Zoloft (sertraline)
- Wellbutrin, Wellbutrin SR, Wellbutrin XL, or Zyban (bupropion)
- The immunosuppressant medicines cyclosporine (Gengraf, Neoral, Sandimmune, and others), Prograf (tacrolimus), or Rapamune (sirolimus).
These are not all the medicines that may cause
problems if you take SUSTIVA. Be sure to tell your doctor about all medicines
that you take.
General advice about
SUSTIVA:
Medicines are sometimes prescribed
for conditions that are not mentioned in patient information leaflets. Do
not use SUSTIVA for a condition for which it was not prescribed. Do not give
SUSTIVA to other people, even if they have the same symptoms you have. It
may harm them.
Keep SUSTIVA at room temperature
(77° F) in the bottle given to you by your pharmacist. The temperature can
range from 59° to 86° F.
Keep SUSTIVA out
of the reach of children.
This leaflet summarizes
the most important information about SUSTIVA. If you would like more information,
talk with your doctor. You can ask your pharmacist or doctor for the full
prescribing information about SUSTIVA, or you can visit the SUSTIVA website
at www.sustiva.com or call 1-800-321-1335.
__________________
SUSTIVA is a registered
trademark of Bristol-Myers Squibb Pharma Company, ATRIPLA is a trademark of
Bristol-Myers Squibb & Gilead Sciences, LLC, PRAVACHOL is a registered
trademark of ER Squibb & Sons, LLC, and REYATAZ is a registered trademark
of Bristol-Myers Squibb Company. Other brands listed are the trademarks of
their respective owners.
Distributed by:
Bristol-Myers
Squibb Company
Princeton, NJ 08543 USA
SUSTIVA® (efavirenz) capsules made in India.
© Bristol-Myers Squibb Company 2013
1262274A9
510230013IN10
Rev January 2013
---------------------------------------------
REPRESENTATIVE PACKAGING
See HOW SUPPLIED section for a complete list of available packages of SUSTIVA.
NDC 0056-0470-30 30 Capsules
SUSTIVA® Rx only
(efavirenz) capsules
50 mg
Each capsule contains 50 mg of efavirenz.
DOSAGE: For dosage and full prescribing
information, read accompanying package
insert.
Note to pharmacist: Do not cover
ALERT box with pharmacy label.
ALERT: Find out about medicines that
should NOT be taken with SUSTIVA®
NDC 0056-0474-92 90 Capsules
SUSTIVA® Rx only
(efavirenz) capsules
200 mg
Each capsule contains 200 mg of efavirenz.
DOSAGE: For dosage and full prescribing information,
read accompanying package insert.
Note to pharmacist: Do not cover ALERT box with
pharmacy label.
ALERT: Find out about medicines that
should NOT be taken with SUSTIVA®
NDC 0056-0510-30 30 Tablets
SUSTIVA® Rx only
(efavirenz) tablets
600 mg
Each tablet contains 600 mg of efavirenz.
DOSAGE: For dosage and full prescribing
information, read accompanying package
insert.
Note to pharmacist: Do not cover
ALERT box with pharmacy label.
ALERT: Find out about medicines that
should NOT be taken with SUSTIVA®
SUSTIVA
efavirenz capsule, gelatin coated
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SUSTIVA
efavirenz capsule, gelatin coated
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SUSTIVA
efavirenz tablet, film coated
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Revised: 01/2013 Bristol-Myers Squibb Pharma Company