NDC 54868-4668 Sustiva

NDC Product Code 54868-4668

NDC CODE: 54868-4668

Proprietary Name: Sustiva What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This drug is used with other HIV medications to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better. This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life. Efavirenz belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Efavirenz is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, do all of the following: (1) continue to take all HIV medications exactly as prescribed by your doctor, (2) always use an effective barrier method (latex or polyurethane condoms/dental dams) during all sexual activity, and (3) do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.

Product Characteristics

Color(s):
YELLOW (C48330 - YELLOW)
Shape: OVAL (C48345)
Size(s):
19 MM
Imprint(s):
SUSTIVA;SUSTIVA
Score: 1

NDC Code Structure

  • 54868 - Physicians Total Care, Inc.

NDC 54868-4668-0

Package Description: 30 TABLET, FILM COATED in 1 BOTTLE

This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Sustiva with NDC 54868-4668 is a product labeled by Physicians Total Care, Inc.. The generic name of Sustiva is . The product's dosage form is and is administered via form.

Labeler Name: Physicians Total Care, Inc.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • HYDROXYPROPYL CELLULOSE (UNII: RFW2ET671P)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • CARNAUBA WAX (UNII: R12CBM0EIZ)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Physicians Total Care, Inc.
Labeler Code: 54868
Start Marketing Date: 10-11-2012 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2017 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: I - INACTIVATED, the listing data was inactivated by the FDA. What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Efavirenz

Efavirenz is pronounced as (e fa veer' ens)

Why is efavirenz medication prescribed?
Efavirenz is used along with other medications to treat human immunodeficiency virus (HIV) infection. Efavirenz is in a class of medications called non-nucleoside reverse...
[Read More]

* Please review the disclaimer below.

Sustiva Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

SUSTIVA® (efavirenz) in combination
with other antiretroviral agents is indicated for the treatment of human immunodeficiency
virus type 1 (HIV-1) infection. This indication is based on two clinical trials
of at least one year duration that demonstrated prolonged suppression of HIV
RNA [see Clinical Studies (14)].

2.1 Adults

The recommended dosage of SUSTIVA
(efavirenz) is 600 mg orally, once daily, in combination with a protease inhibitor
and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is
recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime.
The increased efavirenz concentrations observed following administration of
SUSTIVA with food may lead to an increase in frequency of adverse reactions
[see Clinical Pharmacology (12.3)].
Dosing at bedtime may improve the tolerability of nervous system symptoms
[see Warnings and Precautions (5.5),
Adverse Reactions (6.1), and Patient
Counseling Information (17.4)].

Concomitant Antiretroviral Therapy

SUSTIVA must be given in combination
with other antiretroviral medications [see Indications and Usage (1), Warnings and Precautions (5.2),
Drug Interactions (7.1), and Clinical
Pharmacology (12.3)].

Dosage Adjustment

If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400
mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (one 200-mg and two 50-mg capsules or
six 50-mg capsules). SUSTIVA tablets should not be broken. See Drug Interactions (7.1, Table 7) and Clinical Pharmacology (12.3, Tables 8 and 9).If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 7) and Clinical Pharmacology (12.3, Table 9)].

2.2 Pediatric Patients

It is recommended that SUSTIVA be
taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended
dose of SUSTIVA for pediatric patients 3 years of age or older and weighing
between 10 and 40 kg [see Use in Specific Populations (8.4)]. The recommended dosage of SUSTIVA for pediatric patients weighing
greater than 40 kg is 600 mg once daily.Table 1: Pediatric Dose to be Administered Once DailyBody WeightSUSTIVA Dose
(mg)kglbs10 to less than
1522 to less than
3320015 to less than 2033 to less than 4425020 to less than 2544 to less than 5530025 to less than 32.555 to less than 71.535032.5 to less than 4071.5 to less than 88400at least 40at least 88600

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.

4.1 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 SUSTIVADrug
Class: Drug NameClinical
CommentAntimigraine: 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, triazolamPotential for serious and/or life-threatening
reactions such as prolonged or increased sedation or respiratory depression.Calcium channel blocker:
bepridilPotential for serious
and/or life-threatening reactions such as cardiac arrhythmias.GI motility agent: cisapridePotential for serious and/or life-threatening
reactions such as cardiac arrhythmias.Neuroleptic: pimozidePotential 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).

5.1 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.

Coadministration of SUSTIVA with ATRIPLA
(efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg)
is not recommended unless needed for dose adjustment (eg, with rifampin), since efavirenz is one of its active ingredients.

5.4 Psychiatric Symptoms

Serious psychiatric adverse experiences
have been reported in patients treated with SUSTIVA. In controlled trials
of 1008 patients treated with regimens containing SUSTIVA for a mean of 2.1
years and 635 patients treated with control regimens for a mean of 1.5 years,
the frequency (regardless of causality) of specific serious psychiatric events
among patients who received SUSTIVA or control regimens, respectively, were
severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide
attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%,
0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar
to those noted above were combined and evaluated as a group in a multifactorial
analysis of data from Study 006, treatment with efavirenz was associated with
an increase in the occurrence of these selected psychiatric symptoms. Other
factors associated with an increase in the occurrence of these psychiatric
symptoms were history of injection drug use, psychiatric history, and receipt
of psychiatric medication at study entry; similar associations were observed
in both the SUSTIVA and control treatment groups. In Study 006, onset of new
serious psychiatric symptoms occurred throughout the study for both SUSTIVA-treated
and control-treated patients. One percent of SUSTIVA-treated patients discontinued
or interrupted treatment because of one or more of these selected psychiatric
symptoms. There have also been occasional postmarketing reports of death by
suicide, delusions, and psychosis-like behavior, although a causal relationship
to the use of SUSTIVA cannot be determined from these reports. Patients with
serious psychiatric adverse experiences should seek immediate medical evaluation
to assess the possibility that the symptoms may be related to the use of SUSTIVA,
and if so, to determine whether the risks of continued therapy outweigh the
benefits. See Adverse Reactions (6.1).

5.5 Nervous System Symptoms

Fifty-three percent (531/1008) of
patients receiving SUSTIVA in controlled trials reported central nervous system
symptoms (any grade, regardless of causality) compared to 25% (156/635) of
patients receiving control regimens [see Adverse Reactions (6.1, Table 4)]. These symptoms included, but
were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%),
impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%),
and hallucinations (1.2%). These symptoms were severe in 2.0% of patients,
and 2.1% of patients discontinued therapy as a result. These symptoms usually
begin during the first or second day of therapy and generally resolve after
the first 2-4 weeks of therapy. After 4 weeks of therapy, the prevalence of
nervous system symptoms of at least moderate severity ranged from 5% to 9%
in patients treated with regimens containing SUSTIVA and from 3% to 5% in
patients treated with a control regimen. Patients should be informed that
these common symptoms were likely to improve with continued therapy and were
not predictive of subsequent onset of the less frequent psychiatric symptoms
[see Warnings and Precautions (5.4)].
Dosing at bedtime may improve the tolerability of these nervous system symptoms
[see Dosage and Administration (2)].Analysis of long-term data from Study 006 (median follow-up 180
weeks, 102 weeks, and 76 weeks for patients treated with SUSTIVA + zidovudine
+ lamivudine, SUSTIVA + indinavir, and indinavir + zidovudine + lamivudine,
respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset
nervous system symptoms among SUSTIVA-treated patients were generally similar
to those in the indinavir-containing control arm.Patients
receiving SUSTIVA should be alerted to the potential for additive central
nervous system effects when SUSTIVA is used concomitantly with alcohol or
psychoactive drugs.Patients who experience central
nervous system symptoms such as dizziness, impaired concentration, and/or
drowsiness should avoid potentially hazardous tasks such as driving or operating
machinery.

5.6 Reproductive Risk Potential

Pregnancy Category D.
Efavirenz may cause fetal harm when administered during the first trimester to a pregnant
woman. Pregnancy should be avoided in women receiving SUSTIVA. Barrier contraception must always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of SUSTIVA is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of SUSTIVA. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to
the fetus.There are no adequate and well-controlled studies in pregnant women. SUSTIVA should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. [See Use in Specific Populations (8.1).]

5.7 Rash

In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg SUSTIVA experienced new-onset skin
rash compared with 17% (111/635) of patients treated in control groups [see Adverse Reactions (6.1, Table 5)]. Rash associated with blistering, moist desquamation, or ulceration occurred
in 0.9% (9/1008) of patients treated with SUSTIVA. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in patients treated
with SUSTIVA in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first
2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz,
rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1008). SUSTIVA can be reinitiated
in patients interrupting therapy because of rash. SUSTIVA should be discontinued in patients developing severe rash associated with blistering, desquamation,
mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (eg, Stevens-Johnson syndrome), alternative therapy should be considered [see also Contraindications (4.1)].Rash was reported in 26 of 57 pediatric patients (46%) treated with SUSTIVA capsules [see Adverse Reactions (6.1, 6.2)]. One pediatric patient experienced Grade 3 rash (confluent rash with fever), and two patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 8 days. Prophylaxis with appropriate antihistamines before initiating therapy with SUSTIVA in pediatric patients should be considered.

5.8 Hepatotoxicity

Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity [see Adverse Reactions (6.1) and Use in Specific Populations (8.6)]. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors [see Adverse Reactions (6.3)]. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with SUSTIVA needs to be weighed against the unknown risks of significant liver toxicity.

5.9 Convulsions

Convulsions have been observed in
patients receiving efavirenz, generally in the presence of known medical history
of seizures [see Nonclinical Toxicology (13.2)].
Caution must be taken in any patient with a history of seizures. Patients
who are receiving concomitant anticonvulsant medications primarily metabolized
by the liver, such as phenytoin and phenobarbital, may require periodic monitoring
of plasma levels [see Drug Interactions (7.1)].

5.10 Lipid Elevations

Treatment with SUSTIVA has resulted
in increases in the concentration of total cholesterol and triglycerides [see Adverse
Reactions (6.1)]. Cholesterol and
triglyceride testing should be performed before initiating SUSTIVA therapy
and at periodic intervals during therapy.

5.11 Immune Reconstitution Syndrome

Immune reconstitution syndrome has
been reported in patients treated with combination antiretroviral therapy,
including SUSTIVA. During the initial phase of combination antiretroviral
treatment, patients whose immune system responds may develop an inflammatory
response to indolent or residual opportunistic infections [such as Mycobacterium
avium infection, cytomegalovirus, Pneumocystis jiroveci
pneumonia (PCP), or tuberculosis], which may necessitate further evaluation
and treatment.Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.12 Fat Redistribution

Redistribution/accumulation of body
fat including central obesity, dorsocervical fat enlargement (buffalo hump),
peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance”
have been observed in patients receiving antiretroviral therapy. The mechanism
and long-term consequences of these events are currently unknown. A causal
relationship has not been established.

6 Adverse Reactions

  • The most significant adverse reactions
  • Observed in patients treated with SUSTIVA are:psychiatric symptoms [see Warnings and Precautions (5.4)],nervous system symptoms [see Warnings and Precautions (5.5)],rash [see Warnings and Precautions (5.7)].The most common (>5% in either efavirenz treatment group)
  • Adverse reactions of at least moderate severity among patients in Study 006
  • Treated with SUSTIVA in combination with zidovudine/lamivudine or indinavir
  • Were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.

6.1 Clinical Trials Experience In Adults

Because clinical studies are conducted
under widely varying conditions, the adverse reaction rates reported cannot
be directly compared to rates in other clinical studies and may not reflect
the rates observed in clinical practice.Selected
clinical adverse reactions of moderate or severe intensity observed in ≥2%
of SUSTIVA-treated patients in two controlled clinical trials are presented
in Table 3.Table 3: Selected Treatment-Emergenta Adverse
Reactions of Moderate or Severe Intensity Reported in ≥2% of SUSTIVA-Treated
Patients in Studies 006 and ACTG 364Study 006 LAM-,
NNRTI-, and Protease Inhibitor-Naive PatientsStudy ACTG 364 NRTI-experienced,
NNRTI-, and Protease Inhibitor-Naive PatientsAdverse ReactionsSUSTIVAb+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 weeksc102 weeksc76 weeksc71.1 weeksc70.9 weeksc62.7 weeksca 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   Fatigue8%5%9%02%3%   Pain1%2%8%13%6%17%Central and Peripheral Nervous System   Dizziness9%9%2%2%6%6%   Headache8%5%3%5%2%3%   Insomnia7%7%2%002%   Concentration impaired5%3%<1%000   Abnormal dreams3%1%0———   Somnolence2%2%<1%000   Anorexia1%<1%<1%02%2%Gastrointestinal  Nausea10%6%24%3%2%2%  Vomiting6%3%14%———  Diarrhea3%5%6%14%3%9%  Dyspepsia4%4%6%002%  Abdominal pain2%2%5%3%3%3%Psychiatric  Anxiety2%4%<1%———  Depression5%4%<1%3%05%  Nervousness2%2%02%02%Skin & Appendages  Rashd11%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,bPercent 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 severity52.724.6Mild symptomsc33.315.6Moderate symptomsd17.47.7Severe symptomse2.01.3Treatment discontinuation as
a result of symptoms2.11.1

Psychiatric Symptoms

Serious psychiatric adverse experiences
have been reported in patients treated with SUSTIVA. In controlled trials,
psychiatric symptoms observed at a frequency of >2% among patients treated
with SUSTIVA or control regimens, respectively, were depression (19%, 16%),
anxiety (13%, 9%), and nervousness (7%, 2%).

Rash

For 1008 adult and 57 pediatric
patients treated with regimens containing SUSTIVA and 635 patients treated
with a control regimen in controlled trials, the frequency of rash by NCI
grade and the discontinuation rates as a result of rash in clinical studies
are provided in Table 5 [see Warnings and Precautions (5.7)].Table 5: Percent of Patients with Treatment-Emergent Rasha,bPercent of Patients with:Description of Rash GradecSUSTIVA
600 mg Once Daily Adults(n=1008)SUSTIVAPediatric
Patients(n=57)Control
GroupsAdults(n=635)%%%a  Includes events
reported regardless of causality.b  Data from Study
006 and three Phase 2/3 studies.c  NCI Grading System.Rash of any grade—26.345.617.5Grade 1 rashErythema, pruritus10.78.89.8Grade 2 rashDiffuse maculopapular rash, dry desquamation14.731.67.4Grade 3 rashVesiculation, moist desquamation,
ulceration0.81.80.3Grade 4 rashErythema multiforme, Stevens-Johnson
syndrome, toxic epidermal necrolysis, necrosis requiring surgery, exfoliative
dermatitis0.13.50.0Treatment discontinuation
as a result of rash—1.78.80.3As seen in Table 5, rash is more common in pediatric
patients and more often of higher grade (ie, more severe) [see Warnings
and Precautions (5.7)].Experience with SUSTIVA in patients who discontinued other antiretroviral
agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine
because of rash have been treated with SUSTIVA. Nine of these patients developed
mild-to-moderate rash while receiving therapy with SUSTIVA, and two of these
patients discontinued because of rash.

Laboratory Abnormalities

Selected Grade 3-4 laboratory abnormalities
reported in ≥2% of SUSTIVA-treated patients in two clinical trials are presented
in Table 6.Table 6: Selected Grade 3-4 Laboratory Abnormalities Reported in ≥2% of SUSTIVA-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-,
NNRTI-, and ProteaseInhibitor-Naive PatientsStudy ACTG 364 NRTI-experienced,
NNRTI-, and ProteaseInhibitor-Naive PatientsVariableLimitSUSTIVAa+ 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 weeksb102 weeksb76 weeksb71.1 weeksb70.9 weeksb62.7 weeksba  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 ULN5%8%5%2%6%3%   AST>5 x ULN5%6%5%6%8%8%   GGTc>5 x ULN8%7%3%5%05%   Amylase>2 x ULN4%4%1%06%2%   Glucose>250 mg/dL3%3%3%5%2%3%   Triglyceridesd≥751 mg/dL9%6%6%11%8%17%Hematology   Neutrophils<750/mm310%3%5%2%3%2%

Patients Coinfected With Hepatitis B Or C

Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with SUSTIVA-containing regimens (median duration
of therapy, 68 weeks) and 84 treated with a control regimen (median duration,
56 weeks) were seropositive at screening for hepatitis B (surface antigen
positive) and/or C (hepatitis C antibody positive). Among these coinfected
patients, elevations in AST to greater than five times ULN developed in 13%
of patients in the SUSTIVA arms and 7% of those in the control arm, and elevations
in ALT to greater than five times ULN developed in 20% of patients in the
SUSTIVA arms and 7% of patients in the control arm. Among coinfected patients,
3% of those treated with SUSTIVA-containing regimens and 2% in the control
arm discontinued from the study because of liver or biliary system disorders
[see Warnings and Precautions (5.8)].

Lipids

Increases from baseline in total
cholesterol of 10-20% have been observed in some uninfected volunteers receiving
SUSTIVA. In patients treated with SUSTIVA + zidovudine + lamivudine, increases
from baseline in nonfasting total cholesterol and HDL of approximately 20%
and 25%, respectively, were observed. In patients treated with SUSTIVA + indinavir,
increases from baseline in nonfasting cholesterol and HDL of approximately
40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients
treated with SUSTIVA + zidovudine + lamivudine; 54% and 20%, respectively,
of patients treated with SUSTIVA + indinavir; and 28% and 4%, respectively,
of patients treated with indinavir + zidovudine + lamivudine. The effects
of SUSTIVA on triglycerides and LDL in this study were not well characterized
since samples were taken from nonfasting patients. The clinical significance
of these findings is unknown [see Warnings and Precautions (5.10)].

6.2 Clinical Trial Experience In Pediatric Patients

Clinical adverse experiences observed
in ≥10% of 57 pediatric patients aged 3 to 16 years who received SUSTIVA capsules,
nelfinavir, and one or more NRTIs in Study ACTG 382 [see Use In Specific
Populations (8.4)] were rash (46%),
diarrhea/loose stools (39%), fever (21%), cough (16%), dizziness/lightheaded/fainting
(16%), ache/pain/discomfort (14%), nausea/vomiting (12%), and headache (11%).
The incidence of nervous system symptoms was 18% (10/57). One patient experienced
Grade 3 rash, two patients had Grade 4 rash, and five patients (9%) discontinued
because of rash [see Warnings and Precautions (5.7) and Adverse
Reactions (6.1, Table 5)].

6.3 Postmarketing Experience

The following adverse reactions have
been identified during postapproval use of SUSTIVA. Because these reactions
are reported voluntarily from a population of unknown size, it is not always
possible to reliably estimate their frequency or establish a causal relationship
to drug exposure. Body as a Whole: allergic
reactions, asthenia, redistribution/accumulation of body fat [see Warnings
and Precautions (5.12)]Central and Peripheral Nervous System: abnormal
coordination, ataxia, cerebellar coordination and balance disturbances, convulsions,
hypoesthesia, paresthesia, neuropathy, tremor, vertigoEndocrine: gynecomastiaGastrointestinal: constipation, malabsorption Cardiovascular: flushing, palpitationsLiver 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, hypertriglyceridemiaMusculoskeletal: arthralgia, myalgia, myopathy Psychiatric: aggressive reactions, agitation,
delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicideRespiratory: dyspnea Skin
and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson
syndromeSpecial Senses: abnormal
vision, tinnitus

7.1 Drug-Drug Interactions

Efavirenz has been shown in
vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6
may have decreased plasma concentrations when coadministered with SUSTIVA. In
vitro studies have demonstrated that efavirenz inhibits CYP2C9, 2C19,
and 3A4 isozymes in the range of observed efavirenz plasma concentrations.
Coadministration of efavirenz with drugs primarily metabolized by these isozymes
may result in altered plasma concentrations of the coadministered drug. Therefore,
appropriate dose adjustments may be necessary for these drugs.Drugs that induce CYP3A activity (eg, phenobarbital, rifampin,
rifabutin) would be expected to increase the clearance of efavirenz resulting
in lowered plasma concentrations. Drug interactions with SUSTIVA are summarized
in Tables 2 and 7 [for
pharmacokinetics data see Clinical Pharmacology (12.3,
Tables 8 and 9)].
The tables include potentially significant interactions, but are not all inclusive.Table 7: Established and Other Potentially Significant Drug
Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug
Interaction Studies or Predicted InteractionConcomitant
Drug Class: Drug NameEffectClinical
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 agentsProtease inhibitor: Fosamprenavir calcium↓ amprenavirFosamprenavir
(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 ↓ efavirenzand/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 agentsProtease 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 agentsAnticoagulant: Warfarin↑ or ↓ warfarinPlasma 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↓ efavirenzPotential 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↓ ketoconazoleDrug 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 blockerNo 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 metabolitesof 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↓ etonogestrelA 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.

8.1 Pregnancy

Pregnancy Category D: See Warnings and Precautions (5.6).Antiretroviral Pregnancy Registry: To monitor fetal
outcomes of pregnant women exposed to SUSTIVA, an Antiretroviral Pregnancy
Registry has been established. Physicians are encouraged to register patients
by calling 1-800-258-4263.As of July 2010, the
Antiretroviral Pregnancy Registry has received prospective reports of 792
pregnancies exposed to efavirenz-containing regimens, nearly all of which
were first-trimester exposures (718 pregnancies). Birth defects occurred in
17 of 604 live births (first-trimester exposure) and 2 of 69 live births (second/third-trimester
exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. There have been six retrospective reports of findings consistent
with neural tube defects, including meningomyelocele. All mothers were exposed
to efavirenz-containing regimens in the first trimester. Although a causal
relationship of these events to the use of SUSTIVA has not been established,
similar defects have been observed in preclinical studies of efavirenz.

Animal Data

Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microophthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.

8.3 Nursing Mothers

The Centers for Disease Control
and Prevention recommend that HIV-infected mothers not breast-feed their
infants to avoid risking postnatal transmission of HIV. Although it is not
known if efavirenz is secreted in human milk, efavirenz is secreted into the
milk of lactating rats. Because of the potential for HIV transmission and
the potential for serious adverse effects in nursing infants, mothers should
be instructed not to breast-feed if they are receiving SUSTIVA.

8.4 Pediatric Use

ACTG 382 is an ongoing, open-label
study in 57 NRTI-experienced pediatric patients to characterize the safety,
pharmacokinetics, and antiviral activity of SUSTIVA in combination with nelfinavir
(20-30 mg/kg three times daily) and NRTIs. Mean age was 8 years (range 3-16).
SUSTIVA has not been studied in pediatric patients below 3 years of age or
who weigh less than 13 kg. At 48 weeks, the type and frequency of adverse
experiences was generally similar to that of adult patients with the exception
of a higher incidence of rash, which was reported in 46% (26/57) of pediatric
patients compared to 26% of adults, and a higher frequency of Grade 3 or 4
rash reported in 5% (3/57) of pediatric patients compared to 0.9% of adults
[see Warnings and Precautions (5.7) and Adverse
Reactions (6.1, Table 5; 6.2)].The starting dose of SUSTIVA was
600 mg once daily adjusted to body size, based on weight, targeting AUC levels
in the range of 190-380 µM•h [see Dosage and Administration (2.2)]. The pharmacokinetics of efavirenz
in pediatric patients were similar to the pharmacokinetics in adults who received
600-mg daily doses of SUSTIVA. In 48 pediatric patients receiving the equivalent
of a 600-mg dose of SUSTIVA, steady-state Cmax was
14.2 ± 5.8 µM (mean ± SD), steady-state Cmin was 5.6 ± 4.1 µM, and AUC was 218 ± 104 µM•h.

8.5 Geriatric Use

Clinical studies of SUSTIVA did
not include sufficient numbers of subjects aged 65 years and over to determine
whether they respond differently from younger subjects. In general, dose selection
for an elderly patient should be cautious, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease
or other therapy.

8.6 Hepatic Impairment

SUSTIVA is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering SUSTIVA to these patients [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)].

10 Overdosage

Some patients accidentally taking
600 mg twice daily have reported increased nervous system symptoms. One patient
experienced involuntary muscle contractions.Treatment
of overdose with SUSTIVA should consist of general supportive measures, including
monitoring of vital signs and observation of the patient’s clinical status.
Administration of activated charcoal may be used to aid removal of unabsorbed
drug. There is no specific antidote for overdose with SUSTIVA. Since efavirenz
is highly protein bound, dialysis is unlikely to significantly remove the
drug from blood.

11 Description

SUSTIVA® (efavirenz)
is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI).
Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
Its empirical formula is C14H9ClF3NO2 and
its structural formula is:Efavirenz is a white to slightly pink crystalline powder
with a molecular mass of 315.68. It is practically insoluble in water (<10
microgram/mL).Capsules: SUSTIVA is
available as capsules for oral administration containing either 50 mg or 200 mg of efavirenz and the following inactive ingredients: lactose monohydrate,
magnesium stearate, sodium lauryl sulfate, and sodium starch glycolate. The
capsule shell contains the following inactive ingredients and dyes: gelatin,
sodium lauryl sulfate, titanium dioxide, and/or yellow iron oxide. The capsule
shells may also contain silicon dioxide. The capsules are printed with ink
containing carmine 40 blue, FD&C Blue No. 2, and titanium dioxide.Tablets: SUSTIVA
is available as film-coated tablets for oral administration containing 600
mg of efavirenz and the following inactive ingredients: croscarmellose sodium,
hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline
cellulose, and sodium lauryl sulfate. The film coating contains Opadry Yellow
and Opadry Clear. The tablets are polished with carnauba wax and printed with
purple ink, Opacode WB.

12.1 Mechanism Of Action

Efavirenz is an antiviral drug
[see Clinical Pharmacology (12.4)].

Absorption

Peak efavirenz plasma concentrations
of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100
mg to 1600 mg administered to uninfected volunteers. Dose-related increases
in Cmax and AUC were seen for doses up to 1600 mg;
the increases were less than proportional suggesting diminished absorption
at higher doses. In HIV-1-infected patients at
steady state, mean Cmax, mean Cmin,
and mean AUC were dose proportional following 200-mg, 400-mg, and 600-mg daily
doses. Time-to-peak plasma concentrations were approximately 3-5 hours and
steady-state plasma concentrations were reached in 6-10 days. In 35 patients
receiving SUSTIVA 600 mg once daily, steady-state Cmax was
12.9 ± 3.7 μM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•h.

Effect Of Food On Oral Absorption:

Capsules: Administration
of a single 600-mg dose of efavirenz capsules with a high-fat/high-caloric
meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric
meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean
increase of 22% and 17% in efavirenz AUC∞ and a mean
increase of 39% and 51% in efavirenz Cmax, respectively,
relative to the exposures achieved when given under fasted conditions. See Dosage
and Administration (2) and Patient
Counseling Information (17.3).Tablets: Administration of a single 600-mg efavirenz
tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600
kcal from fat) was associated with a 28% increase in mean AUC∞ of
efavirenz and a 79% increase in mean Cmax of efavirenz
relative to the exposures achieved under fasted conditions. See Dosage
and Administration (2) and Patient
Counseling Information (17.3).

Distribution

Efavirenz is highly bound (approximately
99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected
patients (n=9) who received SUSTIVA 200 to 600 mg once daily for at least
one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean
0.69%) of the corresponding plasma concentration. This proportion is approximately
3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.

Metabolism

Studies in humans and in vitro studies
using human liver microsomes have demonstrated that efavirenz is principally
metabolized by the cytochrome P450 system to hydroxylated metabolites with
subsequent glucuronidation of these hydroxylated metabolites. These metabolites
are essentially inactive against HIV-1. The in vitro studies
suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz
metabolism. Efavirenz has been shown to induce
CYP enzymes, resulting in the induction of its own metabolism. Multiple doses
of 200-400 mg per day for 10 days resulted in a lower than predicted extent
of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours
(single dose half-life 52-76 hours).

Elimination

Efavirenz has a terminal half-life
of 52-76 hours after single doses and 40-55 hours after multiple doses. A
one-month mass balance/excretion study was conducted using 400 mg per day
with a 14C-labeled dose administered on Day 8.
Approximately 14-34% of the radiolabel was recovered in the urine and 16-61%
was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled
drug was in the form of metabolites. Efavirenz accounted for the majority
of the total radioactivity measured in feces.

Special Populations

Gender and race: The
pharmacokinetics of efavirenz in patients appear to be similar between men
and women and among the racial groups studied.Renal
impairment: The pharmacokinetics of efavirenz have not been studied
in patients with renal insufficiency; however, less than 1% of efavirenz is
excreted unchanged in the urine, so the impact of renal impairment on efavirenz
elimination should be minimal.Hepatic impairment: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics.

Drug Interaction Studies

Efavirenz has been shown in
vivo to cause hepatic enzyme induction, thus increasing the biotransformation
of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have
shown that efavirenz inhibited CYP isozymes 2C9, 2C19, and 3A4 with Ki values
(8.5-17 μM) in the range of observed efavirenz plasma concentrations. In in
vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6
and CYP1A2 (Ki values 82-160 μM) only at concentrations
well above those achieved clinically. The inhibitory effect on CYP3A is expected
to be similar between 200-mg, 400-mg, and 600-mg doses of efavirenz. Coadministration
of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A isozymes
may result in altered plasma concentrations of the coadministered drug. Drugs
which induce CYP3A activity would be expected to increase the clearance of
efavirenz resulting in lowered plasma concentrations.Drug
interaction studies were performed with efavirenz and other drugs likely to
be coadministered or drugs commonly used as probes for pharmacokinetic interaction.
The effects of coadministration of efavirenz on the Cmax,
AUC, and Cmin are summarized in Table 8 (effect of
efavirenz on other drugs) and Table 9 (effect of other drugs on efavirenz).
For information regarding clinical recommendations see Contraindications (4.2) and Drug Interactions (7.1).Table 8: Effect of Efavirenz on Coadministered Drug Plasma Cmax,
AUC, and CminCoadministered
DrugDoseEfavirenz
DoseNumber of SubjectsCoadministered
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.Atazanavir400 mg qd with a
light meal d 1‑20600 mg qd with a
light meal d 7‑2027↓ 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 meal600 mg qd 2 h after atazanavir and
ritonavir d 7‑2013↑ 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%)Indinavir1000 mg q8h x 10 days600 mg qd x 10 days20  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/   ritonavir400/100 mg capsuleq12h
x 9 days600 mg qd x 9 days11,7c↔d↓ 19%d(↓ 36-↑ 3%)↓ 39%d(3-62%) 600/150 mg tabletq12h
x 10 days withefavirenz compared to400/100 mg q12h
alone600 mg qd x 9 days23↑ 36%d(28-44%)↑ 36%d(28-44%)↑ 32%d(21-44%)Nelfinavir750 mg q8h x 7 days600 mg qd x 7 days10↑ 21%(10-33%)↑ 20%(8-34%)↔   Metabolite      AG-1402 ↓ 40%(30-48%)↓ 37%(25-48%)↓ 43%(21-59%)Ritonavir500 mg q12h x 8 days600 mg qd x 10 days11     After AM dose↑ 24%(12-38%)↑ 18%(6-33%)↑ 42%(9-86%)e    After PM dose↔↔↑ 24%(3-50%)eSaquinavir   SGCf1200 mg q8h x 10 days600 mg qd x 10 days12↓ 50%(28-66%)↓ 62%(45-74%)↓ 56%(16-77%)eLamivudine150 mg q12h x 14 days600 mg qd x 14 days9↔↔↑ 265%(37-873%)Tenofovirg300 mg qd 600 mg qd x 14 days29↔↔↔Zidovudine300 mg q12h x 14 days600 mg qd x 14 days9↔↔↑ 225%(43-640%)Maraviroc100 mg bid600 mg qd12↓ 51%(37-62%)↓ 45%(38-51%)↓ 45%(28-57%)Raltegravir400 mg single dose600 mg qd9↓ 36%(2-59%)↓ 36%(20-48%)↓ 21%(↓ 51-↑ 28%)Boceprevir800 mg tid x 6 days600 mg qd x 16 daysNA↓ 8%(↓ 22-↑ 8%)↓ 19%(11-25%)↓ 44%(26-58%)Telaprevir750 mg q8h x 10 days600 mg qd x 20 days21↓ 9%(↓ 18-↑ 2%)↓ 26%(16-35%)↓ 47%(35-56%)Azithromycin600 mg single dose400 mg qd x 7 days14↑ 22%(4-42%)↔NAClarithromycin500 mg q12h x 7 days400 mg qd x 7 days11↓ 26%(15-35%)↓ 39%(30-46%)↓ 53%(42-63%)   14-OH metabolite ↑ 49%(32-69%)↑ 34%(18-53%)↑ 26%(9-45%)Fluconazole200 mg x 7 days400 mg qd x 7 days10↔↔↔Itraconazole200 mg q12h x 28 days600 mg qd x 14 days18↓ 37%(20-51%)↓ 39%(21-53%)↓ 44%(27-58%)   Hydroxy-itraconazole ↓ 35%(12-52%)↓ 37%(14-55%)↓ 43%(18-60%)Posaconazole400 mg (oral suspension) bid x 10 and 20 days400 mg qd x 10 and 20 days11↓ 45%(34-53%)↓ 50%(40-57%)NARifabutin300 mg qd x 14 days600 mg qd x 14 days9↓ 32%(15-46%)↓ 38%(28-47%)↓ 45%(31-56%)Voriconazole400 mg po q12h x 1 day, then 200
mg po q12h x 8 days400 mg qd x 9 daysNA↓ 61%h↓ 77%hNA 300 mg po q12h days 2‑7300 mg qd x 7 days NA↓ 36%i(21-49%)↓ 55%i(45-62%)NA 400 mg po q12h days 2‑7300 mg qd x 7 daysNA↑ 23%i(↓ 1-↑ 53%)↓ 7%i(↓ 23-↑ 13%)NAAtorvastatin10 mg qd x 4 days600 mg qd x 15 days14↓ 14%(1-26%)↓ 43%(34-50%)↓ 69%(49-81%)   Total active   (including   metabolites) ↓ 15%(2-26%)↓ 32%(21-41%)↓ 48%(23-64%)Pravastatin40 mg qd x 4 days600 mg qd x 15 days13↓ 32%(↓ 59-↑ 12%)↓ 44%(26-57%)↓ 19%(0-35%)Simvastatin40 mg qd x 4 days600 mg qd x 15 days14↓ 72%(63-79%)↓ 68%(62-73%)↓ 45%(20-62%)   Total active   (including   metabolites) ↓ 68%(55-78%)↓ 60%(52-68%)NAjCarbamazepine200 mg qd x 3 days,
200 mg bid x 3 days, then 400 mg qd x 29 days600 mg qd x 14 days12↓ 20%(15-24%)↓ 27%(20-33%)↓ 35%(24-44%)Epoxide metabolite ↔↔↓ 13%(↓ 30-↑ 7%)Cetirizine10 mg single dose600 mg qd x 10 days11↓ 24%(18-30%)↔NADiltiazem240 mg x 21 days600 mg qd x 14 days13↓ 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/
   Norgestimate0.035 mg/0.25 mg x 14 days600 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%)Lorazepam2 mg single dose600 mg qd x 10 days12↑ 16%(2-32%)↔NAMethadoneStablemaintenance
35-100 mg daily600 mg qd x 14-21 days11↓ 45%(25-59%)↓ 52%(33-66%)NABupropion150 mg single dose(sustained-release)600 mg qd x 14 days13↓ 34%(21-47%)↓ 55%(48-62%)NA   Hydroxy-   bupropion ↑ 50%(20-80%)↔NAParoxetine20 mg qd x 14 days600 mg qd x 14 days16↔↔↔Sertraline50 mg qd x 14 days600 mg qd x 14 days13↓ 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 DrugDoseEfavirenz DoseNumber of SubjectsCmax(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.Indinavir800 mg q8h x 14 days200 mg qd x 14 days11↔↔↔Lopinavir/   ritonavir400/100 mg q12h x
9 days600 mg qd x 9 days11,12a↔↓ 16%(↓ 38-↑ 15%)↓ 16%(↓ 42-↑ 20%)Nelfinavir750 mg q8h x 7 days600 mg qd x 7 days10↓ 12%(↓ 32-↑ 13%)b↓ 12%(↓ 35-↑ 18%)b↓ 21%(↓ 53-↑ 33%)Ritonavir500 mg q12h x 8 days600 mg qd x 10 days9↑ 14%(4-26%)↑ 21%(10-34%)↑ 25%(7-46%)bSaquinavir   SGCc1200 mg q8h x 10 days600 mg qd x 10 days13↓ 13%(5-20%)↓ 12%(4-19%)↓ 14%(2-24%)bTenofovird300 mg qd600 mg qd x 14 days30↔↔↔Boceprevir800 mg tid x 6 days600 mg qd x 16 daysNA↑ 11%(2-20%)↑ 20%(15-26%)NATelaprevir750 mg q8h x 10 days600 mg qd x 20 days21↓ 16%(7-24%)↓ 7%(2-13%)↓ 2%(↓ 6-↑ 2%)Telaprevir, coadministered with tenofovir disoproxil fumarate (TDF)1125 mg q8h x 7 days600 mg efavirenz/300 mg TDF qd x 7 days15↓ 24%(15-32%)↓ 18%(10-26%)↓ 10%(↓ 19-↑ 1%)1500 mg q12h x 7 days600 mg efavirenz/300 mg TDF qd x 7 days16↓ 20%(14-26%)↓ 15%(9-21%)↓ 11%(4-18%)Azithromycin600 mg single dose400 mg qd x 7 days14↔↔↔Clarithromycin500 mg q12h x 7 days400 mg qd x 7 days12↑ 11%(3-19%)↔↔Fluconazole200 mg x7 days400 mg qd x 7 days10↔↑ 16%(6-26%)↑ 22%(5-41%)Itraconazole200 mg q12h x 14 days600 mg qd x 28 days16↔↔↔Rifabutin300 mg qd x 14 days600 mg qd x 14 days11↔↔↓ 12%(↓ 24-↑ 1%)Rifampin600 mg x7 days600 mg qd x 7 days12↓ 20%(11-28%)↓ 26%(15-36%)↓ 32%(15-46%)Voriconazole400 mg po q12hx
1 day, then 200 mg po q12hx 8 days400 mg qd x 9 daysNA↑ 38%e↑ 44%eNA   300 mg po q12h days
2-7300 mg qd x 7 daysNA↓ 14%f(7-21%)↔fNA   400 mg po q12h days
2-7300 mg qd x 7 daysNA↔f↑ 17%f(6-29%)NAAtorvastatin10 mg qd x4 days600 mg qd x 15 days14↔↔↔Pravastatin40 mg qd x4 days600 mg qd x 15 days11↔↔↔Simvastatin40 mg qd x4 days600 mg qd x 15 days14↓ 12%(↓ 28-↑ 8%)↔↓ 12%(↓ 25-↑ 3%)Aluminum hydroxide
400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg30 mL single dose400 mg single dose17↔↔NACarbamazepine200 mg qd x 3 days,
200 mgbid x 3 days, then 400 mg qd x 15 days600 mg qd x 35 days 14↓ 21%(15-26%)↓ 36%(32-40%)↓ 47%(41-53%)Cetirizine10 mg single dose600 mg qd x 10 days11↔↔↔Diltiazem240 mg x14 days600 mg qd x 28 days12↑ 16%(6-26%)↑ 11%(5-18%)↑ 13%(1-26%)Famotidine40 mg single dose400 mg single dose17↔↔NAParoxetine20 mg qd x 14 days600 mg qd x 14 days12↔↔↔Sertraline50 mg qd x
14 days600 mg qd x 14 days13↑ 11%(6-16%)↔↔

Mechanism Of Action

Efavirenz (EFV) is an NNRTI of HIV-1.
EFV activity is mediated predominantly by noncompetitive inhibition of HIV-1
reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by EFV.

Antiviral Activity In Cell Culture

The concentration of EFV inhibiting
replication of wild-type laboratory adapted strains and clinical isolates
in cell culture by 90-95% (EC90-95) ranged from 1.7
to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells
(PBMCs), and macrophage/monocyte cultures. EFV demonstrated antiviral activity
against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F,
G, J, N), but had reduced antiviral activity against group O viruses. EFV
demonstrated additive antiviral activity without cytotoxicity against HIV-1
in cell culture when combined with the NNRTIs delavirdine (DLV) and nevirapine
(NVP), NRTIs (abacavir, didanosine, emtricitabine, lamivudine [LAM], stavudine,
tenofovir, zalcitabine, zidovudine [ZDV]), PIs (amprenavir, indinavir [IDV],
lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide.
EFV demonstrated additive to antagonistic antiviral activity in cell culture
with atazanavir. EFV was not antagonistic with adefovir, used for the treatment
of hepatitis B virus infection, or ribavirin, used in combination with interferon
for the treatment of hepatitis C virus infection.

In Cell Culture

In cell culture, HIV-1 isolates with
reduced susceptibility to EFV (>380-fold increase in EC90 value)
emerged rapidly in the presence of drug. Genotypic characterization of these
viruses identified single amino acid substitutions L100I or V179D, double
substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in
RT.

Clinical Studies

Clinical isolates with reduced susceptibility
in cell culture to EFV have been obtained. One or more RT substitutions at
amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 were
observed in patients failing treatment with EFV in combination with IDV, or
with ZDV plus LAM. The mutation K103N was the most frequently observed. Long-term
resistance surveillance (average 52 weeks, range 4-106 weeks) analyzed 28
matching baseline and virologic failure isolates. Sixty-one percent (17/28)
of these failure isolates had decreased EFV susceptibility in cell culture
with a median 88-fold change in EFV susceptibility (EC50 value)
from reference. The most frequent NNRTI substitution to develop in these patient
isolates was K103N (54%). Other NNRTI substitutions that developed included
L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and
M230I/L (11%).

Cross-Resistance

Cross-resistance among NNRTIs has been
observed. Clinical isolates previously characterized as EFV-resistant were
also phenotypically resistant in cell culture to DLV and NVP compared to baseline.
DLV- and/or NVP-resistant clinical viral isolates with NNRTI resistance-associated
substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X,
P225H, F227L, or M230L) showed reduced susceptibility to EFV in cell culture.
Greater than 90% of NRTI-resistant clinical isolates tested in cell culture
retained susceptibility to EFV.

Carcinogenesis

Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0,
25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose.

Mutagenesis

Efavirenz tested negative in a battery of in
vitro and in vivo genotoxicity assays. These included bacterial
mutation assays in S. typhimurium and E. coli,
mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay.

Impairment Of Fertility

Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately ≤0.15 times that in humans at the recommended clinical dose.

13.2 Animal Toxicology

Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values
4- to 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.9)].

14 Clinical Studies

Study 006, a randomized, open-label trial, compared SUSTIVA (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or SUSTIVA (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years [range 18-81], 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm3 and the median baseline HIV-1 RNA level was 4.8 log10 copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 10. Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) versions of the AMPLICOR HIV-1 MONITOR assay. During the study, version 1.5 of the assay was introduced in Europe to enhance detection of non-clade B virus.Table 10: Outcomes of Randomized Treatment Through 48 and 168 Weeks,
Study 006 SUSTIVA
+ ZDV+ LAM(n=422) SUSTIVA
+ IDV(n=429) IDV
+ ZDV + LAM(n=415)OutcomeWeek 48Week 168Week 48Week 168Week 48Week 168a  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.Respondera69%48%57%40%50%29%Virologic failureb6%12%15%20%13%19%Discontinued for adverse events7%8%6%8%16%20%Discontinued for other reasonsc17%31%22%32%21%32%CD4+ cell count (cells/mm3)   Observed subjects (n)(279)(205)(256)(158)(228)(129)   Mean change
from   baseline190329191319180329For 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*OutcomeSUSTIVA +
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/mLa71%63%41%HIV-1 RNA ≥500 copies/mLb17%34%54%CDC Category C Event2%0%0%Discontinuations
for adverse eventsc3%3%5%Discontinuations
for other reasonsd8%0%0%A Kaplan-Meier analysis of time to treatment failure
through 72 weeks demonstrates a longer duration of virologic suppression (HIV
RNA <500 copies/mL) in the SUSTIVA-containing treatment arms.

16.1 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.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.

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 54868-4668-0

16.3 Storage

SUSTIVA capsules and SUSTIVA tablets
should be stored at 25° C (77° F); excursions permitted to 15°–30° C (59°–86°
F) [see USP Controlled Room Temperature].

17 Patient Counseling Information

See FDA-approved patient labeling (Patient Information).

17.1 Drug Interactions

A statement to patients and healthcare
providers is included on the product’s bottle labels:ALERT: Find
out about medicines that should NOT be taken with SUSTIVA.SUSTIVA may interact with some drugs; therefore, patients should
be advised to report to their doctor the use of any other prescription, nonprescription
medication, or herbal products, particularly St. John’s wort.

17.2 General Information For Patients

  • Patients should be informed that SUSTIVA is not a cure for HIV-1 infection and patients may continue to experience
  • Illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician while taking SUSTIVA.Patients should be advised to avoid doing things that can spread HIV-1 infection to others.Do not share needles or other injection equipment.Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.Do not breast-feed. It is not known if SUSTIVA can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk.

17.3 Dosing Instructions

Patients should be advised to take SUSTIVA
every day as prescribed. SUSTIVA must always be used in combination with other
antiretroviral drugs. Patients should be advised to take SUSTIVA on an empty
stomach, preferably at bedtime. Taking SUSTIVA with food increases efavirenz
concentrations and may increase the frequency of adverse reactions. Dosing
at bedtime may improve the tolerability of nervous system symptoms [see Dosage
and Administration (2) and Adverse
Reactions (6.1)].

17.4 Nervous System Symptoms

Patients should be informed that central
nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration,
drowsiness, and abnormal dreams are commonly reported during the first weeks
of therapy with SUSTIVA [see Warnings and Precautions (5.5)].
Dosing at bedtime may improve the tolerability of these symptoms, which are
likely to improve with continued therapy. Patients should be alerted to the
potential for additive effects when SUSTIVA is used concomitantly with alcohol
or psychoactive drugs. Patients should be instructed that if they experience
NSS they should avoid potentially hazardous tasks such as driving or operating
machinery.

17.5 Psychiatric Symptoms

Patients should be informed that serious
psychiatric symptoms including severe depression, suicide attempts, aggressive
behavior, delusions, paranoia, and psychosis-like symptoms have been reported
in patients receiving SUSTIVA [see Warnings and Precautions (5.4)]. If they experience severe
psychiatric adverse experiences they should seek immediate medical evaluation.
Patients should be advised to inform their physician of any history of mental
illness or substance abuse.

17.6 Rash

Patients should be informed that a
common side effect is rash [see Warnings and Precautions (5.7)]. Rashes usually go away without any change in treatment. However,
since rash may be serious, patients should be advised to contact their physician
promptly if rash occurs.

17.7 Reproductive Risk Potential

Women receiving SUSTIVA should be
instructed to avoid pregnancy [see Warnings and Precautions (5.6)]. A reliable form of barrier
contraception must always be used in combination with other methods of contraception,
including oral or other hormonal contraception. Because of the long half-life
of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation
of SUSTIVA is recommended. Women should be advised to notify their physician
if they become pregnant or plan to become pregnant while taking SUSTIVA. If
this drug is used during the first trimester of pregnancy, or if the patient
becomes pregnant while taking this drug, she should be apprised of the potential
harm to the fetus.

17.8 Fat Redistribution

Patients should be informed that redistribution
or accumulation of body fat may occur in patients receiving antiretroviral
therapy and that the cause and long-term health effects of these conditions
are not known [see Warnings and Precautions (5.12)].

Other

Distributed by:Physicians Total Care, Inc.Tulsa, OK      74146

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