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Efavirenz  Audio icon

Brand Name: Sustiva
Other Names: EFV
Drug Class: Non-nucleoside Reverse Transcriptase Inhibitors
Approved Use: Treatment of HIV Infection
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efavirenz
efavirenz
Molecular Weight: 315.677

Several FDA-approved drug labels may be available for efavirenz. AIDSinfo provides the following drug label solely as an example of the labels available for efavirenz. Inclusion or absence of a drug label on the AIDSinfo site does not imply endorsement or lack thereof by AIDSinfo. Search Drugs@FDA to access more information on efavirenz, including additional drug labels and any generic equivalents.

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

Indications and Usage (1)    05/2013

Dosage and Administration
     Adults (2.1)    05/2013
     Pediatric Patients (2.2)    05/2013
     Capsule Sprinkle Method of Administration (2.3)    05/2013

Warnings and Precautions
     Coadministration with Related Products (5.3)    08/2012
     Rash (5.7)    05/2013
     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 in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg. (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 dosing is based on weight.  (2.2)

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, 6.2, 8.4)


See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 05/2013

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  in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg.

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)].  SUSTIVA capsules or tablets should be swallowed intact with liquid. For patients who cannot swallow capsules or tablets, the capsule sprinkle method of administration is recommended [see Dosage and Administration (2.3)].

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 6) 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 6) 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  months of age or older and weighing between 3.5 kg and 40 kg [see Clinical Pharmacology (12.3)]. The recommended dosage of SUSTIVA for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration [see Dosage and Administration (2.3)].

Table 1: SUSTIVA Dosing in Pediatric Patients
Patient Body Weight SUSTIVA Daily Dose Number of Capsulesa or Tabletsb
and Strength to Administer
a  Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.3)].
b  Tablets must not be crushed.
 3.5 kg to less than 5 kg 100 mg two 50 mg capsules
 5 kg to less than 7.5 kg 150 mg three 50 mg capsules
 7.5 kg to less than 15 kg 200 mg one 200 mg capsule
15 kg to less than 20 kg 250 mg one 200 mg + one 50 mg capsule
20 kg to less than 25 kg 300 mg one 200 mg + two 50 mg capsules
25 kg to less than 32.5 kg 350 mg one 200 mg + three 50 mg capsules
32.5 kg to less than 40 kg 400 mg two 200 mg capsules
at least 40 kg 600 mg one 600 mg tablet OR
three 200 mg capsules

2.3 Capsule Sprinkle Method of Administration

 For pediatric patients at least 3 months old and weighing at least 3.5 kg and adults who cannot swallow capsules or tablets, the capsule contents may be administered with a small amount (1 to 2 teaspoons) of food. Use of infant formula for mixing should only be considered for those young infants who cannot reliably consume solid foods. Patients and caregivers must be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. The capsule should be held horizontally over a small container and carefully twisted to open. For patients able to tolerate solid foods, the entire capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, in the small container. For young infants receiving the capsule sprinkle-infant formula mixture, the entire capsule contents should be gently mixed into 2 teaspoons (10 mL) of reconstituted room temperature infant formula in a medicine cup by carefully stirring with a small spoon, and then drawing up the mixture into a 10 mL oral dosing syringe for administration. After administration of the SUSTIVA-food or -formula mixture, an additional small amount (approximately 2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse any remaining SUSTIVA residue, and administered to the patient. The SUSTIVA-food or -formula mixture should be administered within 30 of mixing. No additional food should be consumed for 2 hours after administration of SUSTIVA.

 Further patient instructions on the capsule sprinkle method of administration are provided in the FDA-approved patient labeling (see Patient Information and Instructions for Use).

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 adult patients treated with 600 mg SUSTIVA experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups [see Adverse Reactions (6.1)]. 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 adult 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 adult clinical trials was 1.7% (17/1008).

 Rash was reported in 59 of 182 pediatric patients (32%) treated with SUSTIVA [see Adverse Reactions (6.2)]. Two pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 28 days (range 3-1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with SUSTIVA in pediatric patients should be considered.

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)].

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 adult and pediatric 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 greater than 2% among patients treated with SUSTIVA or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).

Rash

In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1008 adults treated with regimens containing SUSTIVA and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for SUSTIVA-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for SUSTIVA and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for SUSTIVA-treated patients and 0.3% for control groups [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 5.

Table 5: 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

Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received SUSTIVA in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash [see Warnings and Precautions (5.7)].

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 6 [for pharmacokinetics data see Clinical Pharmacology (12.3, Tables 8 and 9)]. The tables include potentially significant interactions, but are not all inclusive.

Table 6: 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

The safety, pharmacokinetic profile, and virologic and immunologic responses of SUSTIVA were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients 3 months to 21 years of age in three open-label clinical trials [see Adverse Reactions (6.2), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of a higher frequency of rash, including a higher frequency of Grade 3 or 4 rash, in pediatric patients compared to adults [see Warnings and Precautions (5.7) and Adverse Reactions (6.2)].

Use of SUSTIVA in patients younger than 3 months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral activity of SUSTIVA have not been evaluated in this age group and there is a risk of developing HIV resistance if SUSTIVA is underdosed. See Dosage and Administration (2.2) for dosing recommendations for pediatric patients.

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 chemical structure

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 Microbiology (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).

Bioavailability of capsule contents mixed with food vehicles: In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions.

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

Pediatric: The pharmacokinetic parameters for efavirenz at steady state in pediatric patients were predicted by a population pharmacokinetic model and are summarized in Table 7 by weight ranges that correspond to the recommended doses.

Table 7: Predicted Steady-State Pharmacokinetics of Recommended Doses of Efavirenz (Capsules/Capsule Sprinkles) in HIV-Infected Pediatric Patients
Body Weight Dose Mean AUC (0-24)
µM•h
Mean Cmax
µg/mL
Mean Cmin
µg/mL
3.5-5 kg 100 mg 220.52 5.81 2.43
5-7.5 kg 150 mg 262.62 7.07 2.71
7.5-10 kg 200 mg 284.28 7.75 2.87
10-15 kg 200 mg 238.14 6.54 2.32
15-20 kg 250 mg 233.98 6.47 2.3
20-25 kg 300 mg 257.56 7.04 2.55
25-32.5 kg 350 mg 262.37 7.12 2.68
32.5-40 kg 400 mg 259.79 6.96 2.69
>40 kg 600 mg 254.78 6.57 2.82

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 CYP2C9, CYP2C19, CYP3A, or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 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 is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.

Antiviral Activity in Cell Culture

The concentration of efavirenz 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. Efavirenz 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. Efavirenz demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the NNRTIs delavirdine and nevirapine, NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz 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 efavirenz (>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 reverse transcriptase.

Clinical studies

Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. One or more substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 in reverse transcriptase were observed in patients failing treatment with efavirenz in combination with indinavir, or with zidovudine plus lamivudine. The K103N substitution 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 efavirenz susceptibility in cell culture with a median 88-fold change in efavirenz 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 efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-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 efavirenz in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to efavirenz.

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

14.1 Adults

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.

14.2 Pediatric Patients

Study AI266922 is an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in antiretroviral-naive and -experienced pediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 years) were treated with SUSTIVA. At baseline, median plasma HIV-1 RNA was 5.88 log10 copies/mL, median CD4+ cell count was 1144 cells/mm3, and median CD4+ percentage was 25%. The median time on study therapy was 60 weeks; 27% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in CD4+ count at 48 weeks was 196 cells/mm3 and the median increase in CD4+ percentage was 6%.

Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in pediatric patients who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 9.6 years) were dosed with SUSTIVA. At baseline, median plasma HIV-1 RNA was 4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm3, and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm3 and the median increase in CD4+ percentage was 13%.

Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with nelfinavir and an NRTI in antiretroviral-naive and NRTI-experienced pediatric patients. One hundred two patients 3 months to 16 years of age (median 5.7 years) were treated with SUSTIVA. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median CD4+ cell count was 755 cells/mm3, and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 128 cells/mm3 and the median increase in CD4+ percentage was 5%.

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 and Instructions for Use).

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)]. Healthcare providers should assist parents or caregivers in determining the best SUSTIVA dosing schedule for infants and young children.

For adult and pediatric patients who cannot swallow capsules or tablets, patients or their caregivers should be advised to read and carefully follow the instructions for administering the capsule contents in a small amount of food or infant formula [see Dosage and Administration (2.3) and FDA-approved patient labeling (Patient Information and Instructions for Use)]. Patients should call their healthcare provider or pharmacist if they have any questions.

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)].

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

Rev May 2013

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 with other antiretroviral medicines to help treat infection with Human Immunodeficiency Virus type 1 (HIV-1) in adults and children 3 months or older and who weigh 7 pounds 12 ounces (3.5 kg) or more. HIV-1 is 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?

  • Take SUSTIVA exactly as your doctor tells you to. Do not stop taking SUSTIVA unless your doctor tells you to.
  • SUSTIVA must be used with other anti-HIV medicines.
  • You should take SUSTIVA on an empty stomach at bedtime. Some side effects may bother you less if you take SUSTIVA at bedtime.
  • SUSTIVA comes as tablets or capsules.
  • The usual dose of SUSTIVA for adults is 600 mg (one tablet or three 200 mg capsules) taken 1 time each day.
  • SUSTIVA tablets should not be broken.
  • Swallow SUSTIVA tablets or capsules whole with liquid.
  • If you have difficulty swallowing tablets or capsules, tell your doctor. If your doctor recommends opening the SUSTIVA capsule and mixing the contents with food or infant formula, see the detailed “Instructions for Use” at the end of this Patient Information leaflet for information about the right way to take a dose of SUSTIVA using the capsule sprinkle method.
  • Ask your doctor or pharmacist if you have any questions about how to take a dose of SUSTIVA using the capsule sprinkle method.
  • The dose of SUSTIVA for children may be lower than the dose for adults. Capsules containing lower amounts of SUSTIVA are available. Your child’s doctor will prescribe the right dose based on your child’s weight.
  • Taking SUSTIVA with food increases the amount of medicine in your body. This may cause side effects to happen more often.
  • Adults and children who take SUSTIVA using the capsule sprinkle method should not eat for 2 hours after taking a dose of SUSTIVA.
  • Babies should not be given infant formula for 2 hours after taking a dose of SUSTIVA using the capsule sprinkle method.
  • Talk with your doctor to help decide the best schedule for giving your baby SUSTIVA mixed with infant formula using the capsule sprinkle method.
  • 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 take 2 doses at one time. Just take your next dose at your regularly scheduled time. If you need help in planning the best times to take your medicine, ask your doctor or pharmacist.
  • 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 any of your current medicines. Your doses may need to be changed.
  • 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).

Who should not take SUSTIVA?

Do not take SUSTIVA if you are allergic to efavirenz or any of the ingredients in SUSTIVA. You can ask your doctor or pharmacist for a list of the ingredients in SUSTIVA.

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.

Do not take SUSTIVA with St. John’s wort (Hypericum perforatum), an herbal product sold as a dietary supplement, or products containing 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)

You should not take SUSTIVA with ATRIPLA (efavirenz, emtricitabine, tenofovir disoproxil fumarate) unless your doctor tells you to.

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 between 68°F to 77°F (20°C to 25°C).

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

Rev May 2013

Instructions for Use

SUSTIVA (sus-TEE-vah)

efavirenz
capsules

Preparing a dose of SUSTIVA using the capsule sprinkle method

Read this Instructions for Use before you prepare your first dose of SUSTIVA mixed with food or infant formula using the capsule sprinkle method, each time you get a refill, and as needed. There may be new information. This information does not take the place of talking to your doctor about your medical condition or treatment. Ask your doctor or pharmacist if you have any questions about how to mix or give a dose of SUSTIVA using the capsule sprinkle method.

Important Information:

  • For more information about SUSTIVA capsules, see the Patient Information leaflet.
  • The capsule sprinkle method for mixing the contents of SUSTIVA capsules with soft food or infant formula may be used for adults or children who cannot swallow capsules or tablets.
  • You should take SUSTIVA on an empty stomach at bedtime.
  • You should not eat for 2 hours after taking SUSTIVA mixed with food.
  • Babies who are old enough to swallow food should be given SUSTIVA using the capsule sprinkle method mixed with food instead of with infant formula.
  • Talk with your doctor to help decide the best schedule for giving your baby SUSTIVA mixed with infant formula using the capsule sprinkle method.

Preparing a dose of SUSTIVA mixed with food using the capsule sprinkle method.

Before you prepare a dose of SUSTIVA mixed with food using the capsule sprinkle method, gather the following supplies:

  • paper towels
  • small spoon
  • small clean container (such as a small cup or bowl)
  • soft food such as applesauce, grape jelly, or yogurt
Step 1. Choose a clean, flat work surface. Place a clean paper towel on the work surface. Then place the other supplies on the paper towel.
 
Step 2. Wash and dry your hands well.
 
Step 3. Place 1 to 2 teaspoons of soft food such as applesauce, grape jelly, or yogurt in the small container (see Figure A). The color and thickness of the food may change when mixed with the medicine. illustration aFigure A
 
Step 4. There are 2 parts of the SUSTIVA capsule. Look at the SUSTIVA capsule to see which part of the capsule overlaps the other part (see Figure B). illustration bFigure B
 
Step 5. Turn the SUSTIVA capsule so that you are holding it in a sideways (horizontal) position directly over the container of food. Hold each end of the SUSTIVA capsule between your thumbs and index (pointer) fingers (see Figure C). illustration cFigure C
 
Step 6. Use your thumb and index finger to pinch near the end of the overlapping part of the SUSTIVA capsule (see Figure D). illustration dFigure D
 
Then, carefully twist both ends of the SUSTIVA capsule in opposite directions to open it (see Figure E). Be careful not to spill the capsule contents or spread it in the air. illustration eFigure E
 
Step 7. Sprinkle the contents of the SUSTIVA capsule onto the food (see Figure F). Throw away the empty capsule shells. illustration fFigure F
 
If the total prescribed dose is more than 1 capsule, follow Steps 4 through 7 for each capsule. Do not add more food.
 
Steps 8 through 11 must be completed within 30 minutes of mixing the medicine.
 
Step 8. Use a spoon to gently mix the capsule contents and food together (see Figure G). illustration gFigure G
 
Step 9. Use the spoon to take the food and capsule contents mixture or feed it to your child. Swallow all of the mixture. If you are giving the mixture to your child, look in your child’s mouth to make sure that all of the mixture is swallowed.
 
Step 10. Add about 2 teaspoons more of the food to the empty container and gently stir to mix with any capsule contents that may still be in the container.
 
Step 11. Use the spoon to take the mixture or feed it to your child. Swallow all of the mixture. If you are giving the mixture to your child, look in your child’s mouth to make sure that all of the mixture is swallowed.
 
Step 12. Wash the container and spoon. Throw away the paper towel and clean the work surface.
 
Step 13. Wash your hands.
 
Preparing a dose of SUSTIVA mixed with infant formula using the capsule sprinkle method
 
Before you prepare a dose of SUSTIVA mixed with infant formula using the capsule sprinkle method, gather the following supplies:
  • paper towels
  • small spoon
  • 30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure H.
  • 10 mL oral dosing syringe (ask your pharmacist for this). See Figure H.
  • infant formula at room temperature. If you are using powdered formula, you should prepare the formula according to the formula directions before mixing with SUSTIVA capsule contents.


illustration hFigure H
 
Step 1. Choose a clean, flat work surface. Place a clean paper towel on the work surface. Place the supplies you will need on the paper towel.
 
Step 2. Wash and dry your hands well.
 
Step 3. Pour 10 mL of room temperature infant formula into the 30 mL medicine cup (see Figure I). illustration iFigure I
 
Step 4. There are 2 parts of the SUSTIVA capsule. Look at the SUSTIVA capsule to see which part of the capsule overlaps the other part (see Figure J). illustration jFigure J
 
Step 5. Turn the SUSTIVA capsule so that you are holding it in a sideways (horizontal) position directly over the medicine cup that contains the infant formula. Hold each end of the SUSTIVA capsule between your thumbs and index (pointer) fingers (see Figure K). illustration kFigure K
 
Step 6. Use your thumb and index finger to pinch near the end of the overlapping part of the SUSTIVA capsule (see Figure L). illustration lFigure L
 
Then, carefully twist both ends of the SUSTIVA capsule in opposite directions to open it (see Figure M). Be careful not to spill the capsule contents or spread it in the air. illustration mFigure M
 
Step 7. Sprinkle the contents of the SUSTIVA capsule onto the infant formula (see Figure N). Throw away the empty capsule shells. illustration nFigure N
 
If the total prescribed dose is more than 1 capsule, follow Steps 4 through 7 for each capsule. Do not add more infant formula.
 
Steps 8 through 11 must be completed within 30 minutes of mixing the medicine.
 
Step 8. Hold the medicine cup with one hand. With your other hand, use the small spoon to gently mix the capsule contents and the infant formula (see Figure O). illustration oFigure O
 
Step 9. Draw up the capsule contents and infant formula mixture into the 10 mL oral dosing syringe as follows:
  • Check that the plunger is completely pushed into barrel of the syringe (see Figure P).
illustration pFigure P
 
  • Place the tip of the syringe into the capsule contents and infant formula mixture in the medicine cup (see Figure Q).
illustration qFigure Q
 
  • Slowly pull back on the plunger and draw up all of the mixture (see Figure R).
illustration rFigure R
 
Step 10. Place the tip of the oral dosing syringe in your baby’s mouth along the inner cheek on either the right or left side (see Figure S). Slowly push on the plunger to give your baby all of the SUSTIVA capsule contents and infant formula mixture. illustration sFigure S
 
To make sure that your baby gets all of the medicine, do not give SUSTIVA capsule contents to your baby in a bottle.
 
Step 11. To make sure there is no capsule contents and formula mixture left in the medicine cup or syringe:
  • Repeat Step 3 above to add 10 mL more infant formula into the medicine cup.
  • Stir with a small spoon.
  • Then, repeat Steps 9 and 10 above.
Step 12. Remove the plunger from the oral dosing syringe. Wash the medicine cup, spoon, and oral dosing syringe. Allow the medicine cup, spoon, and oral dosing syringe to dry. Throw away the paper towel and clean the work surface.
 
Step 13. Wash your hands.

How should I store SUSTIVA capsules?

  • Store SUSTIVA capsules at room temperature between 68°F to 77°F (20°C to 25°C).

Keep SUSTIVA capsules and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Distributed by:

Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

SUSTIVA® (efavirenz) capsules made in India.

Issued: May 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
®

PRINCIPAL DISPLAY PANEL - 50 mg Label

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
®

PRINCIPAL DISPLAY PANEL - 200 mg Label

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
®

PRINCIPAL DISPLAY PANEL - 600 mg Label

SUSTIVA 
efavirenz capsule, gelatin coated
Product Information
Product Type Item Code (Source) 0056-0470
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
efavirenz (efavirenz) efavirenz 50 mg
Inactive Ingredients
Ingredient Name Strength
lactose monohydrate  
magnesium stearate  
sodium lauryl sulfate  
sodium starch glycolate type A potato  
gelatin  
titanium dioxide  
ferric oxide yellow  
silicon dioxide  
FD&C Blue No. 2  
Product Characteristics
Color white (white) , yellow (gold) Score no score
Shape CAPSULE (capsule) Size 14mm
Flavor Imprint Code SUSTIVA;50mg
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 0056-0470-30 30 CAPSULE, GELATIN COATED in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020972 09/17/1998

SUSTIVA 
efavirenz capsule, gelatin coated
Product Information
Product Type Item Code (Source) 0056-0474
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
efavirenz (efavirenz) efavirenz 200 mg
Inactive Ingredients
Ingredient Name Strength
lactose monohydrate  
magnesium stearate  
sodium lauryl sulfate  
sodium starch glycolate type A potato  
gelatin  
titanium dioxide  
ferric oxide yellow  
silicon dioxide  
FD&C Blue No. 2  
Product Characteristics
Color yellow (gold) Score no score
Shape CAPSULE (capsule) Size 22mm
Flavor Imprint Code SUSTIVA;200mg
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 0056-0474-92 90 CAPSULE, GELATIN COATED in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020972 09/17/1998

SUSTIVA 
efavirenz tablet, film coated
Product Information
Product Type Item Code (Source) 0056-0510
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
efavirenz (efavirenz) efavirenz 600 mg
Inactive Ingredients
Ingredient Name Strength
croscarmellose sodium  
hydroxypropyl cellulose  
lactose monohydrate  
magnesium stearate  
cellulose, microcrystalline  
sodium lauryl sulfate  
carnauba wax  
Product Characteristics
Color yellow (yellow) Score no score
Shape OVAL (capsule-shaped) Size 19mm
Flavor Imprint Code SUSTIVA;SUSTIVA
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 0056-0510-30 30 TABLET, FILM COATED in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021360 01/02/2002

Labeler - Bristol-Myers Squibb Pharma Company (830615030)

Revised: 05/2013 Bristol-Myers Squibb Pharma Company