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SUSTIVA

 * Generic Name: efavirenz
 * Brand Name: Sustiva
 * Drug Class: HIV, NNRTIs

Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 11/28/2023

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DRUG SUMMARY

WHAT IS SUSTIVA?

Sustiva (efavirenz) is an antiviral medication used to treat HIV, which causes
the acquired immunodeficiency syndrome (AIDS). Sustiva is not a cure for HIV or
AIDS.

WHAT ARE SIDE EFFECTS FOR SUSTIVA?

Sustiva may cause serious side effects including:

 * hives,
 * difficulty breathing,
 * swelling of your face, lips, tongue, or throat,
 * fever,
 * sore throat,
 * burning eyes,
 * skin pain,
 * red or purple skin rash with blistering and peeling,
 * seizure,
 * hallucinations,
 * trouble concentrating,
 * trouble speaking or moving (may occur months or years after beginning the
   medicine),
 * dizziness,
 * drowsiness,
 * confusion,
 * trouble concentrating,
 * strange dreams,
 * insomnia,
 * problems with speech,
 * difficulties with your balance or muscle movement,
 * anxiety,
 * paranoia,
 * unusual behavior,
 * feeling sad or hopeless,
 * suicidal thoughts,
 * nausea,
 * stomach pain,
 * loss of appetite,
 * dark urine,
 * clay-colored stools,
 * yellowing of the skin or eyes (jaundice),
 * night sweats,
 * swollen glands,
 * cold sores,
 * cough,
 * wheezing,
 * diarrhea,
 * weight loss,
 * difficulty swallowing,
 * problems with balance or eye movement,
 * weakness,
 * prickly feeling,
 * swelling in your neck or throat (enlarged thyroid),
 * menstrual changes, and
 * impotence

Get medical help right away, if you have any of the symptoms listed above.

Common side effects of Sustiva include:

 * dizziness,
 * trouble sleeping (insomnia),
 * drowsiness,
 * unusual dreams,
 * trouble concentrating,
 * nausea,
 * vomiting,
 * stomach pain,
 * diarrhea,
 * constipation,
 * cough,
 * blurred vision,
 * headache,
 * tired feeling,
 * spinning sensation,
 * problems with balance or coordination,
 * muscle or joint pain, or
 * changes in the shape or location of body fat (especially in your arms, legs,
   face, neck, breasts, and waist).

Many of these side effects may begin 1-2 days after starting Sustiva and usually
go away in 2-4 weeks. Tell your doctor if you have rare but serious side effects
of Sustiva including signs of liver problems such as:

 * persistent nausea or vomiting,
 * stomach or abdominal pain,
 * severe tiredness,
 * yellowing eyes or skin, or
 * dark urine

Seek medical care or call 911 at once if you have the following serious side
effects:

 * Serious eye symptoms such as sudden vision loss, blurred vision, tunnel
   vision, eye pain or swelling, or seeing halos around lights;
 * Serious heart symptoms such as fast, irregular, or pounding heartbeats;
   fluttering in your chest; shortness of breath; and sudden dizziness,
   lightheartedness, or passing out;
 * Severe headache, confusion, slurred speech, arm or leg weakness, trouble
   walking, loss of coordination, feeling unsteady, very stiff muscles, high
   fever, profuse sweating, or tremors.

This document does not contain all possible side effects and others may occur.
Check with your physician for additional information about side effects.

DOSAGE FOR SUSTIVA

The recommended adult dosage of Sustiva is 600 mg orally, once daily, in
combination with a protease inhibitor and/or nucleoside analogue reverse
transcriptase inhibitors (NRTIs).

WHAT DRUGS, SUBSTANCES, OR SUPPLEMENTS INTERACT WITH SUSTIVA?

Sustiva may interact with:

 * cyclosporine,
 * itraconazole,
 * sirolimus,
 * tacrolimus,
 * St. John's wort,
 * voriconazole,
 * blood thinners,
 * cholesterol medications,
 * antibiotics,
 * heart or blood pressure medications,
 * other HIV medicines, or
 * seizure medications

Tell your doctor all medications you use.

SUSTIVA DURING PREGNANCY AND BREASTFEEDING

Sustiva is not recommended for use during pregnancy. It may harm a fetus,
especially if taken during the first 3 months of pregnancy. Women of
childbearing age should have a pregnancy test before starting this medication.
Consult your doctor about using at least 2 forms of birth control (such as
condoms with birth control pills) during treatment and for 3 months after the
end of treatment. If you become pregnant or think you may be pregnant, tell your
doctor immediately. It is unknown if Sustiva passes into breast milk. Because
breast milk can transmit HIV, do not breastfeed.

ADDITIONAL INFORMATION

Our Sustiva (efavirenz) Side Effects Drug Center provides a comprehensive view
of available drug information on the potential side effects when taking this
medication.


FDA DRUG INFORMATION

 * Drug Description
 * Indications & Dosage
 * Side Effects
 * Drug Interactions
 * Warnings & Precautions
 * Overdose & Contraindications
 * Clinical Pharmacology
 * Medication Guide


DESCRIPTION FOR SUSTIVA

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-dihydro4-(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.




USES FOR SUSTIVA

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.


DOSAGE FOR SUSTIVA

HEPATIC FUNCTION

Monitor hepatic function prior to and during treatment with SUSTIVA [see
WARNINGS AND PRECAUTIONS].

SUSTIVA is not recommended in patients with moderate or severe hepatic
impairment (Child Pugh B or C) [see WARNINGS AND PRECAUTIONS and Use In Specific
Populations].

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]. Dosing at bedtime
may improve the tolerability of nervous system symptoms [see WARNINGS AND
PRECAUTIONS, ADVERSE REACTIONS, and Patient Counseling Information]. 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].

CONCOMITANT ANTIRETROVIRAL THERAPY

SUSTIVA must be given in combination with other antiretroviral medications [see
INDICATIONS AND USAGE, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL
PHARMACOLOGY].

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 must not be broken [see
DRUG INTERACTIONS (Table 5) and CLINICAL PHARMACOLOGY , Tables 7 and 8)].

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 ( Table 5) and CLINICAL PHARMACOLOGY (Table 8)].

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]. 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].

Table 1: SUSTIVA Dosing in Pediatric Patients

Patient Body Weight SUSTIVA Daily Dose Number of Capsulesa or Tabletsb and
Strength to Administer 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 a Capsules can be administered intact or as sprinkles [see
DOSAGE AND ADMINISTRATION].
b Tablets must not be crushed.



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 should 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 of
reconstituted room temperature infant formula in a small container 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 minutes 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).


HOW SUPPLIED

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.

STORAGE AND HANDLING

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

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

STORAGE

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

Distributed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA. Revised:
Nov 2023


SIDE EFFECTS FOR SUSTIVA

The most significant adverse reactions observed in patients treated with SUSTIVA
are:

 * psychiatric symptoms [see WARNINGS AND PRECAUTIONS]
 * nervous system symptoms [see WARNINGS AND PRECAUTIONS]
 * rash [see WARNINGS AND PRECAUTIONS]
 * hepatotoxicity [see WARNINGS AND PRECAUTIONS]

CLINICAL TRIALS EXPERIENCE

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.

ADVERSE REACTIONS IN ADULTS

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.

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 2.

Table 2: Selected Treatment-Emergenta Adverse Reactions of Moderate or Severe
Intensity Reported in ≥2% of SUSTIVA-Treated Patients in Studies 006 and ACTG
364

Adverse Reactions Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients
Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
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 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% 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.



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 3 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]. The frequencies of specific
central and peripheral nervous system symptoms are provided in Table 2.

Table 3: 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) % 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 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.



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].

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 4.

Table 4: Selected Grade 3-4 Laboratory Abnormalities Reported in ≥2% of
SUSTIVA-Treated Patients in Studies 006 and ACTG 364

Variable Limit Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients
Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
SUSTIVAa + ZDV/LAM
(n=412) 180 weeksb SUSTIVAa + Indinavir
(n=415) 102 weeksb Indinavir + ZDV/LAM
(n=401) 76 weeksb SUSTIVAa + Nelfinavir + NRTIs
(n=64) 71.1 weeksb SUSTIVAa + NRTIs
(n=65) 70.9 weeksb Nelfinavir + NRTIs
(n=66) 62.7 weeksb 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% a SUSTIVA provided as 600
mg once daily.
b Median duration of treatment.
cIsolated 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.



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].

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].

ADVERSE REACTIONS IN PEDIATRIC PATIENTS

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.

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].

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]

Central and Peripheral Nervous System: abnormal coordination, ataxia,
encephalopathy, 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.

Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia

Musculoskeletal: arthralgia, myalgia, myopathy

Psychiatric: aggressive reactions, agitation, delusions, emotional lability,
mania, neurosis, paranoia, psychosis, suicide, catatonia

Respiratory: dyspnea

Skin and Appendages: erythema multiforme, photoallergic dermatitis,
Stevens-Johnson syndrome

Special Senses: abnormal vision, tinnitus


DRUG INTERACTIONS FOR SUSTIVA

POTENTIAL FOR SUSTIVA TO AFFECT OTHER DRUGS

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.

POTENTIAL FOR OTHER DRUGS TO AFFECT SUSTIVA

Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin)
would be expected to increase the clearance of efavirenz resulting in lowered
plasma concentrations [see DOSAGE AND ADMINISTRATION].

QT PROLONGING DRUGS

There is limited information available on the potential for a pharmacodynamic
interaction between SUSTIVA and drugs that prolong the QTc interval. QTc
prolongation has been observed with the use of efavirenz [see CLINICAL
PHARMACOLOGY]. Consider alternatives to SUSTIVA when coadministered with a drug
with a known risk of Torsade de Pointes.

ESTABLISHED AND OTHER POTENTIALLY SIGNIFICANT DRUG INTERACTIONS

Drug interactions with SUSTIVA are summarized in Table 5. For pharmacokinetics
data, [see CLINICAL PHARMACOLOGY] Tables 7 and 8. This table includes
potentially significant interactions, but is not all inclusive.

Table 5: 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 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
↓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. Protease inhibitor: Lopinavir/ritonavir
↓lopinavir* Lopinavir/ritonavir once daily dosing is not recommended when
coadministered with SUSTIVA.
The dose of lopinavir/ritonavir must be increased when coadministered with
SUSTIVA. See the lopinavir/ritonavir prescribing information for dose
adjustments of lopinavir/ritonavir when coadministered with efavirenz in adult
and pediatric patients. Protease inhibitor: Ritonavir ↑ritonavir*
↑efavirenz* Monitor for elevation of liver enzymes and for adverse clinical
experiences (e.g., dizziness, nausea, paresthesia) when SUSTIVA is
coadministered with ritonavir. Protease inhibitor: Saquinavir ↓ saquinavir*
Appropriate doses of the combination of SUSTIVA and saquinavir/ritonavir with
respect to safety and efficacy have not been established. 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.
Hepatitis C antiviral agents Boceprevir ↓ boceprevir* Concomitant administration
of boceprevir with SUSTIVA is not recommended because it may result in loss of
therapeutic effect of boceprevir. Elbasvir/Grazoprevir ↓elbasvir
↓ grazoprevir Coadministration of SUSTIVA with elbasvir/grazoprevir is
contraindicated [see CONTRAINDICATIONS] because it may lead to loss of virologic
response to elbasvir/grazoprevir. Pibrentasvir/Glecaprevir ↓ pibrentasvir
↓ glecaprevir Coadministration of SUSTIVA is not recommended because it may lead
to reduced therapeutic effect of pibrentasvir/glecaprevir. Simeprevir
↓simeprevir* ↔efavirenz* Concomitant administration of simeprevir with SUSTIVA
is not recommended because it may result in loss of therapeutic effect of
simeprevir. Velpatasvir/ Sofosbuvir ↓velpatasvir Coadministration of SUSTIVA and
sofosbuvir/velpatasvir is not recommended because it may result in loss of
therapeutic effect of sofosbuvir/velpatasvir. Velpatasvir /Sofosbuvir/
/Voxilaprevir ↓velpatasvir ↓voxilaprevir Coadministration of SUSTIVA and
sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in
loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir. Other agents
Anticoagulant: Warfarin ↑ or
↓warfarin Monitor INR and adjust warfarin dosage if necessary. 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
Sertraline ↓bupropion* ↓sertraline* Increases in bupropion dosage should be
guided by clinical response. Bupropion dose should not exceed the maximum
recommended dose. Increases in sertraline dosage should be guided by clinical
response. Antifungals: Voriconazole ↓ voriconazole*
↑ efavirenz* SUSTIVA and voriconazole should not be coadministered at standard
doses. 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 must not be broken [see DOSAGE AND ADMINISTRATION and CLINICAL
PHARMACOLOGY, Tables 7 and 8)]. Itraconazole ↓itraconazole* ↓hydroxyitraconazole
* Consider alternative antifungal treatment because no dose recommendation for
itraconazole can be made. Ketoconazole ↓ketoconazole Consider alternative
antifungal treatment because no dose recommendation for ketoconazole can be
made. Posaconazole ↓posaconazole* Avoid concomitant use unless the benefit
outweighs the risks. Anthelmintic: Praziquantel ↓praziquantel Coadministration
with efavirenz is not recommended due to significant decrease in plasma
concentrations of praziquantel, with risk of treatment failure due to increased
hepatic metabolism by efavirenz. Anti-infective: Clarithromycin ↓
clarithromycin*
↑14-OH metabolite* Consider alternatives to macrolide antibiotics because of the
risk of QT interval prolongation. Antimycobacterials: Rifabutin Rifampin ↓
rifabutin*
↓efavirenz* Increase daily dose of rifabutin by 50%. Consider doubling the
rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Increase SUSTIVA to 800 mg once daily when coadministered with rifampin to
patients weighing 50 kg or more. Antimalarials: Artemether/ lumefantrine
Atovaquone/ proguanil ↓artemether*
↓dihydroartemisinin*
↓lumefantrine*
↓ atovaquone
↓proguanil Consider alternatives to artemether/lumefantrine because of the risk
of QT interval prolongation. Concomitant administration is not recommended.
Calcium channel blockers: Diltiazem Others (e.g., felodipine, nicardipine,
nifedipine, verapamil) ↓diltiazem*
↓ desacetyl diltiazem*
↓N-monodesmethyl diltiazem*
↓calcium channel blocker 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. When
coadministered with SUSTIVA, dosage adjustment of calcium channels blocker may
be needed and 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 should be used in
addition to hormonal contraceptives. Implant Etonogestrel ↓etonogestrel A
reliable method of barrier contraception should be used in addition to hormonal
contraceptives. 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 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* Monitor for signs of methadone withdrawal and
increase methadone dose if required to alleviate withdrawal symptoms. * 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.



DRUGS WITHOUT CLINICALLY SIGNIFICANT INTERACTIONS WITH SUSTIVA

No dosage adjustment is recommended when SUSTIVA is given with the following:
aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine,
fluconazole, lorazepam, nelfinavir, nucleoside reverse transcriptase inhibitors
(abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate,
zidovudine), paroxetine, and raltegravir.

CANNABINOID TEST INTERACTION

Efavirenz does not bind to cannabinoid receptors. False-positive urine
cannabinoid test results have been reported with some screening assays in
uninfected and HIV-infected subjects receiving efavirenz. Confirmation of
positive screening tests for cannabinoids by a more specific method is
recommended.


WARNINGS FOR SUSTIVA

Included as part of the PRECAUTIONS section.


PRECAUTIONS FOR SUSTIVA

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. The most prominent effect of efavirenz at steady
state is induction of CYP3A and CYP2B6 [see DOSAGE AND ADMINISTRATION and DRUG
INTERACTIONS].

QTC PROLONGATION

QTc prolongation has been observed with the use of efavirenz [see DRUG
INTERACTIONS and CLINICAL PHARMACOLOGY]. Consider alternatives to SUSTIVA when
coadministered with a drug with a known risk of Torsade de Pointes or when
administered to patients at higher risk of Torsade de Pointes.

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 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 (e.g., with rifampin), since efavirenz is one of its active
ingredients.

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. Postmarketing cases of catatonia have
also been reported and may be associated with increased efavirenz exposure.
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].

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 (Table 3)]. 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]. Dosing at
bedtime may improve the tolerability of these nervous system symptoms [see
DOSAGE AND ADMINISTRATION].

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.

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired
consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur
months to years after beginning efavirenz therapy. Some events of late-onset
neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which
are associated with increased efavirenz levels despite standard dosing of
SUSTIVA. Patients presenting with signs and symptoms of serious neurologic
adverse experiences should be evaluated promptly to assess the possibility that
these events may be related to efavirenz use, and whether discontinuation of
SUSTIVA is warranted.

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.

EMBRYO-FETAL TOXICITY

Efavirenz may cause fetal harm when administered during the first trimester to a
pregnant woman. Advise females of reproductive potential who are receiving
SUSTIVA to avoid pregnancy [see Use In Specific Populations].

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]. 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 (e.g., 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]. 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 generally 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 (e.g., Stevens-Johnson syndrome), alternative therapy should
be considered [see CONTRAINDICATIONS].

HEPATOTOXICITY

Postmarketing cases of hepatitis, including fulminant hepatitis progressing to
liver failure requiring transplantation or resulting in death, have been
reported in patients treated with SUSTIVA. Reports have included patients with
underlying hepatic disease, including coinfection with hepatitis B or C, and
patients without pre-existing hepatic disease or other identifiable risk
factors.

SUSTIVA is not recommended for patients with moderate or severe hepatic
impairment. Careful monitoring is recommended for patients with mild hepatic
impairment receiving SUSTIVA [see ADVERSE REACTIONS and Use In Specific
Populations].

Monitoring of liver enzymes before and during treatment is recommended for all
patients [see DOSAGE AND ADMINISTRATION]. Consider discontinuing SUSTIVA in
patients with persistent elevations of serum transaminases to greater than five
times the upper limit of the normal range.

Discontinue SUSTIVA if elevation of serum transaminases is accompanied by
clinical signs or symptoms of hepatitis or hepatic decompensation.

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]. Caution should 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].

LIPID ELEVATIONS

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

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
jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further
evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré
syndrome, and autoimmune hepatitis) 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.

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.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (PATIENT
INFORMATION and Instructions for Use).

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, advise patients to report to
their doctor the use of any other prescription or nonprescription medication.

GENERAL INFORMATION FOR PATIENTS

Inform patients 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.

Advise patients to avoid doing things that can spread HIV-1 infection to others.

 * Do not share or reuse 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 safer sex by
   using a latex or polyurethane condom to lower the chance of sexual contact
   with semen, vaginal secretions, or blood.
 * Do not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can
   be passed to the baby in breast milk.

DOSING INSTRUCTIONS

Advise patients to take SUSTIVA every day as prescribed. If a patient forgets to
take SUSTIVA, tell the patient to take the missed dose right away, unless it is
almost time for the next dose. Advise the patient not to take 2 doses at one
time and to take the next dose at the regularly scheduled time. Advise the
patient to ask a healthcare provider if he/she needs help in planning the best
times to take his/her medicine.

SUSTIVA must always be used in combination with other antiretroviral drugs.
Advise patients 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 and ADVERSE
REACTIONS]. 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 and FDA-approved patient labeling
(Patient Information and Instructions for Use)]. Patients should call their
healthcare provider or pharmacist if they have any questions.

NERVOUS SYSTEM SYMPTOMS

Inform patients 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]. Dosing at bedtime may improve the tolerability of these symptoms,
which are likely to improve with continued therapy. Alert patients to the
potential for additive effects when SUSTIVA is used concomitantly with alcohol
or psychoactive drugs. Instruct patients that if they experience NSS they should
avoid potentially hazardous tasks such as driving or operating machinery.

Inform patients that there is a risk of developing late-onset neurotoxicity,
including ataxia and encephalopathy which may occur months to years after
beginning SUSTIVA therapy [see WARNINGS AND PRECAUTIONS].

PSYCHIATRIC SYMPTOMS

Inform patients that serious psychiatric symptoms including severe depression,
suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like
symptoms and catatonia have been reported in patients receiving SUSTIVA [see
WARNINGS AND PRECAUTIONS]. If they experience severe psychiatric adverse
experiences they should seek immediate medical evaluation. Advise patients to
inform their physician of any history of mental illness or substance abuse.

RASH

Inform patients that a common side effect is rash [see WARNINGS AND
PRECAUTIONS]. Rashes usually go away without any change in treatment. However,
since rash may be serious, advise patients to contact their physician promptly
if rash occurs.

HEPATOTOXICITY

Inform patients to watch for early warning signs of liver inflammation or
failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as
well as later signs such as jaundice, confusion, abdominal swelling, and
discolored feces, and to consult their health care professional without delay if
such symptoms occur [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

FEMALES OF REPRODUCTIVE POTENTIAL

Advise females of reproductive potential to use effective contraception as well
as a barrier method during treatment with SUSTIVA and for 12 weeks after
discontinuing SUSTIVA. Advise patients to contact their healthcare provider if
they plan to become pregnant, become pregnant, or if pregnancy is suspected
during treatment with SUSTIVA [see WARNINGS AND PRECAUTIONS and Use In Specific
Populations].

PREGNANCY EXPOSURE REGISTRY

Advise patients that there is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to SUSTIVA during pregnancy [see Use In
Specific Populations].

FAT REDISTRIBUTION

Inform patients 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].

NONCLINICAL TOXICOLOGY

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.

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].

USE IN SPECIFIC POPULATIONS

PREGNANCY

PREGNANCY EXPOSURE REGISTRY

There is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to SUSTIVA during pregnancy. Physicians are encouraged to register
patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

RISK SUMMARY

There are retrospective case reports of neural tube defects in infants whose
mothers were exposed to efavirenz-containing regimens in the first trimester of
pregnancy. Prospective pregnancy data from the Antiretroviral Pregnancy Registry
are not sufficient to adequately assess this risk. Available data from the
Antiretroviral Pregnancy Registry show no difference in the risk of overall
major birth defects compared to the background rate for major birth defects of
2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital
Defects Program (MACDP). Although a causal relationship has not been established
between exposure to efavirenz in the first trimester and neural tube defects,
similar malformations have been observed in studies conducted in monkeys at
doses similar to the human dose. In addition, fetal and embryonic toxicities
occurred in rats, at a dose ten times less than the human exposure at
recommended clinical dose. Because of the potential risk of neural tube defects,
efavirenz should not be used in the first trimester of pregnancy. Advise
pregnant women of the potential risk to a fetus.

DATA

Human Data

There are retrospective postmarketing reports of findings consistent with neural
tube defects, including meningomyelocele, all in infants of mothers exposed to
efavirenz-containing regimens in the first trimester.

Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of
approximately 1000 live births following exposure to efavirenz-containing
regimens (including over 800 live births exposed in the first trimester), there
was no difference between efavirenz and overall birth defects compared with the
background birth defect rate of 2.7% in the U.S. reference population of the
Metropolitan Atlanta Congenital Defects Program. As of the interim APR report
issued December 2014, the prevalence of birth defects following first-trimester
exposure was 2.3% (95% CI: 1.4%-3.6%). 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. This case also included severe oblique facial clefts and
amniotic banding, which have a known association with anophthalmia.

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 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, microphthalmia 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.

LACTATION

RISK SUMMARY

The Centers for Disease Control and Prevention recommend that HIV-infected
mothers not breastfeed their infants to avoid risking postnatal transmission of
HIV. Because of the potential for HIV transmission in breastfed infants, advise
women not to breastfeed.

FEMALES AND MALES OF REPRODUCTIVE POTENTIAL

Because of potential teratogenic effects, pregnancy should be avoided in women
receiving SUSTIVA [see Use In Specific Populations].

PREGNANCY TESTING

Females of reproductive potential should undergo pregnancy testing before
initiation of SUSTIVA.

CONTRACEPTION

Females of reproductive potential should use effective contraception during
treatment with SUSTIVA and for 12 weeks after discontinuing SUSTIVA due to the
long half-life of efavirenz. Barrier contraception should always be used in
combination with other methods of contraception. Hormonal methods that contain
progesterone may have decreased effectiveness [see DRUG INTERACTIONS].

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, CLINICAL PHARMACOLOGY, and Clinical Studies]. 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 and ADVERSE REACTIONS].

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 for dosing recommendations for pediatric patients.

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.

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 and
CLINICAL PHARMACOLOGY].


OVERDOSE INFORMATION FOR SUSTIVA

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.


CONTRAINDICATIONS FOR SUSTIVA

 * SUSTIVA is contraindicated in patients with previously demonstrated
   clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome,
   erythema multiforme, or toxic skin eruptions) to any of the components of
   this product.
 * Coadministration of efavirenz with elbasvir and grazoprevir is
   contraindicated [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].


CLINICAL PHARMACOLOGY FOR SUSTIVA

MECHANISM OF ACTION

Efavirenz is an antiviral drug [see Microbiology].

PHARMACODYNAMICS

CARDIAC ELECTROPHYSIOLOGY

The effect of SUSTIVA on the QTc interval was evaluated in an open-label,
positive and placebo controlled, fixed single sequence 3-period, 3-treatment
crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The
mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the
administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax
observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between
efavirenz concentration and QTc prolongation was observed. Based on the
concentration-QTc relationship, the mean QTc prolongation and its upper bound
90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6
genotype following the administration of 600 mg daily dose for 14 days [see
WARNINGS AND PRECAUTIONS].

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/high­caloric 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 and Patient Counseling Information].

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 and Patient Counseling Information].

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 6 by weight ranges that correspond to the recommended doses.

Table 6: 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 and 2C19
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. 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 7 (effect of efavirenz on other drugs) and Table 8
(effect of other drugs on efavirenz). For information regarding clinical
recommendations see DRUG INTERACTIONS.

Table 7: 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) 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 720 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 500/125 mg tablet
q12h x 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd x 9
days 600 mg qd x 9 days 11,7c 19 ↔d ↓ 19%d
(↓ 36-↑ 3%) ↓ 39%d
(3-62%) ↑ 12%d
(2-23%) ↔d ↓ 10%d (↓ 22-↑ 4%) 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 Metabolite AG-1402 750 mg q8h x 7 days 600 mg qd x 7 days 10
↑21%
(10-33%) ↑20%
(8-34%) ↔ ↓40%
(30-48%) ↓ 37%
(25-48%) ↓43%
(21-59%) Ritonavir 500 mg q12h x 8 days After AM dose 600 mg qd x 10 days 11
↑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%) Simeprevir 150 mg qd x 14 days 600 mg qd x 14 days 23 ↓ 51%
(↓ 46-↓ 56%) ↓ 71%
(↓ 67-↓ 74%) ↓ 91%
(↓ 88-↓ 92%) Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↑22%
(4-42%) ↔ NA Clarithromycin 14-OH metabolite 500 mg q12h x 7 days 400 mg qd x 7
days 11 ↓ 26%
(15-35%) ↓ 39%
(30-46%) ↓ 53%
(42-63%) ↑ 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 Artemether/ lumefantrine Artemether 20
mg/ lumefantrine 120 mg tablets
(6 4-tablet doses over 3 days) 600 mg qd x 26 days 12 Artemether ↓ 21% ↓ 51% NA
dihydroartemisinin ↓ 38% ↓46% NA Lumefantrine ↔ ↓ 21% 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 Epoxide metabolite 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%) ↔ ↔ ↓ 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-monodes-methyl diltiazem ↓ 28%
(7-44%) ↓37%
(17-52%) ↓37%
(17-52%) Ethinyl estradiol/ Norgestimate Ethinyl estradiol Norelgestromin
Levonorgestrel 0.035 mg/0.25 mg x 14 days 600 mg qd x 14 days 21 ↔ ↔ ↔ 21 ↓ 46%
(39-52%) ↓ 64%
(62-67%) ↓ 82%
(79-85%) 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 Hydroxy- bupropion 150 mg single dose
(sustained-release) 600 mg qd x 14 days 13 ↓ 34%
(21-47%) ↓55%
(48-62%) NA ↑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%) ↑ 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.



Table 8: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin

Coadministered Drug Dose Efavirenz Dose Number of Subjects Efavirenz (mean %
change) Cmax (90% CI) AUC (90% CI) Cmin (90% CI) 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 x10 days 600 mg qd x10 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 Simeprevir 150 mg qd x 14 days 600 mg qd x 14 days 23 ↔ ↓ 10%
(5-15%) ↓ 13%
(7-19%) 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
Artemether/ Lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets
(6 4-tablet doses over 3 days) 600 mg qd x 26 days 12 ↔ ↓17% 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%) ↔ ↔ ↑ 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.



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.

CLINICAL STUDIES

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 9. 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 9: Outcomes of Randomized Treatment Through 48 and 168 Weeks, Study 006

Outcome SUSTIVA + ZDV+ LAM
(n=422) SUSTIVA + IDV
(n=429) IDV + ZDV + LAM
(n=415) Week 48 Week 168 Week 48 Week 168 Week 48 Week 168 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/mm ) Observed subjects (n) (279) (205) (256)
(158) (228) (129) Mean change from baseline 190 329 191 319 180 329 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.
cIncludes 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.



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 (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 10. Plasma HIV RNA levels
were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit of
quantification of 500 copies/mL.

Table 10: Outcomes of Randomized Treatment Through 48 Weeks, Study ACTG 364*

Outcome SUSTIVA + NFV + NRTIs
(n=65) SUSTIVA + NRTIs
(n=65) NFV + NRTIs
(n=66) 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% * 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 for a safety profile of these regimens.
d Includes loss to follow-up, consent withdrawn, noncompliance.



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.

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 antiretroviral­naive 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 antiretroviral­naive 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%.


PATIENT INFORMATION FOR SUSTIVA

SUSTIVA®
(sus-TEE-vah)
(efavirenz) capsules

SUSTIVA®
(sus-TEE-vah)
(efavirenz) tablets

Important: Ask your doctor or pharmacist about medicines that should not be
taken with SUSTIVA. For more information, see the section “What should I tell my
doctor before taking SUSTIVA?”

Read this Patient Information before you start taking SUSTIVA and each time you
get a refill. There may be new information. This information does not take the
place of talking with your doctor about your medical condition or treatment.

What is SUSTIVA?

SUSTIVA is a prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine
used with other antiretroviral medicines to treat HIV-1 infection in adults and
in children who are at least 3 months old and who weigh at least 7 pounds 12
ounces (3.5 kg). HIV is the virus that causes AIDS (Acquired Immune Deficiency
Syndrome).

It is not known if SUSTIVA is safe and effective in children younger than 3
months of age or who weigh less than 7 pounds 12 ounces (3.5 kg).

When used with other antiretroviral medicines to treat HIV-1 infection, SUSTIVA
may help:

 * reduce the amount of HIV-1 in your blood. This is called viral load.
 * increase the number of CD4+ (T) cells in your blood that help fight off other
   infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may
help improve your immune system. This may reduce your risk of death or getting
infections that can happen when your immune system is weak (opportunistic
infections).

SUSTIVA does not cure HIV-1 infection or AIDS. You should keep taking HIV-1
medicines to control HIV-1 infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV-1 infection to others:

 * Do not share or reuse 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 safer sex by
   using a latex or polyurethane condom to lower the chance of sexual contact
   with any body fluids such as semen, vaginal secretions, or blood.

Ask your doctor if you have any questions about how to prevent passing HIV to
other people.

Who should not take SUSTIVA?

Do not take SUSTIVA if you are allergic to efavirenz or any of the ingredients
in SUSTIVA. See the end of this leaflet for a complete list of ingredients in
SUSTIVA.

Do not take SUSTIVA if you are currently taking elbasvir and grazoprevir
(ZEPATIER ®).

What should I tell my doctor before taking SUSTIVA?

Before taking SUSTIVA, tell your doctor if you have any medical conditions and
in particular, if you:

 * have a heart condition
 * have ever had a mental health problem
 * have ever used street drugs or large amounts of alcohol
 * have liver problems, including hepatitis B or C virus infection
 * have a history of seizures
 * are pregnant or plan to become pregnant. SUSTIVA may harm your unborn baby.
   If you are able to become pregnant your healthcare provider should do a
   pregnancy test before you start SUSTIVA. You should not become pregnant while
   taking SUSTIVA and for 12 weeks after stopping treatment with SUSTIVA.
   * Females who are able to become pregnant should use 2 effective forms of
     birth control during treatment and for 12 weeks after stopping treatment
     with SUSTIVA. A barrier form of birth control should always be used along
     with another type of birth control.
   * Barrier forms of birth control may include latex or polyurethane condom,
     contraceptive sponge, diaphragm with spermicide, and cervical cap.
   * Hormonal forms of birth control, such as birth control pills, injections,
     vaginal rings, or implants may not work during treatment with SUSTIVA.
   * Talk to your doctor about forms of birth control that may be used during
     treatment with SUSTIVA.
   * Pregnancy Registry. There is a pregnancy registry for women who take
     antiretroviral medicines during pregnancy. The purpose of this registry is
     to collect information about the health of you and your baby. Talk to your
     doctor about how you can take part in this registry.
   * Do not breastfeed if you take SUSTIVA.
   * You should not breastfeed if you have HIV because of the risk of passing
     HIV to your baby.

Tell your doctor and pharmacist about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal supplements.

SUSTIVA may affect the way other medicines work, and other medicines may affect
how SUSTIVA works, and may cause serious side effects. If you take certain
medicines with SUSTIVA, the amount of SUSTIVA in your body may be too low and it
may not work to help control your HIV infection. The HIV virus in your body may
become resistant to SUSTIVA or other HIV medicines that are like it.

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

Tell your doctor and pharmacist about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal supplements.
Some medicines interact with SUSTIVA.

Keep a list of your medicines to show your doctor and pharmacist.

 * You can ask your doctor or pharmacist for a list of medicines that interact
   with SUSTIVA.
 * Do not start taking a new medicine without telling your doctor. Your doctor
   can tell you if it is safe to take SUSTIVA with other medicines.

How should I take SUSTIVA?

 * Take SUSTIVA exactly as your doctor tells you to.
 * Do not change your dose or stop taking SUSTIVA unless your doctor tells you
   to.
 * Stay under the care of your doctor during treatment with SUSTIVA.
 * SUSTIVA must be used with other antiretroviral medicines.
 * Take SUSTIVA 1 time each day.
 * SUSTIVA comes as tablets or capsules.
 * SUSTIVA tablets must not be broken.
 * Swallow SUSTIVA tablets or capsules whole with liquid.

How and when to take SUSTIVA.

 * You should take SUSTIVA on an empty stomach at bedtime. Taking SUSTIVA with
   food increases the amount of medicine in your body. Some side effects may
   bother you less if you take SUSTIVA on an empty stomach and at bedtime.
 * Your child’s doctor will prescribe the right dose of SUSTIVA based on your
   child’s weight.
 * If you have difficulty swallowing tablets or capsules, tell your doctor. Your
   doctor may recommend 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 to learn the right way to take SUSTIVA using the
   capsule sprinkle method.
 * 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.
 * 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 take too much SUSTIVA, call your doctor or go to the nearest hospital
   emergency room right away.
 * When your SUSTIVA supply starts to run low, get more from your doctor or
   pharmacy. It is important not to run out of SUSTIVA. The amount of HIV-1 in
   your blood may increase if the medicine is stopped for even a short time. The
   virus may become resistant to SUSTIVA and harder to treat.

What are the possible side effects of SUSTIVA?

SUSTIVA may cause serious side effects, including:

 * Serious mental health problems can happen in people who take SUSTIVA. Tell
   your doctor right away if you have any of the following symptoms:
   * feel sad or hopeless
   * do not trust other people
   * feel anxious or restless
   * hear or see things that are not real
   * have thoughts of hurting yourself (suicide) or have tried to hurt yourself
     or others
   * are not able to move or speak normally
   * are not able to tell the difference between what is true or real and what
     is false or unreal
 * Nervous system symptoms are common in people who take SUSTIVA and can be
   severe. These symptoms usually begin during the first or second day of
   treatment with SUSTIVA and usually go away after 2 to 4 weeks of treatment.
   Some symptoms may occur months to years after beginning SUSTIVA therapy.
   These symptoms may become worse if you drink alcohol, take a medicine for
   mental health problems, or use certain street drugs during treatment with
   SUSTIVA. Symptoms may include:
   * dizziness
   * trouble concentrating
   * trouble sleeping
   * drowsiness
   * unusual dreams
   * lack of coordination or difficulty with balance

If you have dizziness, trouble concentrating or drowsiness, do not drive a car,
use machinery, or do anything that needs you to be alert.

Some nervous system symptoms (e.g., confusion, slow thoughts and physical
movement, and delusions [false beliefs] or hallucinations [seeing or hearing
things that others do not see or hear]) may occur months to years after
beginning SUSTIVA therapy. Promptly contact your health care provider should any
of these symptoms occur.

 * Skin rash is common with SUSTIVA but can sometimes be severe. Skin rash
   usually goes away without any change in treatment. If you develop a rash with
   any of the following symptoms, tell your doctor right away:
   * skin rash, with or without itching
   * peeling skin
   * mouth sores
   * fever
   * swelling of your face
   * red or inflamed eyes, like “pink eye” (conjunctivitis)
   * blisters or skin lesions
 * Liver problems, including liver failure and death can happen in people who
   take SUSTIVA. Liver problems can happen in people without a history of liver
   problems. Your doctor will do blood tests to check your liver before you
   start SUSTIVA and during treatment. Tell your doctor right away if you get
   any of the following symptoms:
   * your skin or the white part of your eyes turns yellow (jaundice)
   * you don’t feel like eating food for several days or longer
   * you feel sick to your stomach (nausea)
   * your urine turns dark
   * your bowel movements (stools) turn light in color
   * you have lower stomach area (abdominal) pain
 * Seizures can happen in people who take SUSTIVA. Seizures are more likely to
   happen if you have had seizures in the past. Tell your doctor if you have had
   a seizure or if you take a medicine to help prevent seizures.
 * Changes in your immune system (Immune Reconstitution Syndrome) can happen
   when you start taking HIV-1 medicines. Your immune system may get stronger
   and begin to fight infections that have been hidden in your body for a long
   time. Tell your doctor if you start having new symptoms after starting your
   HIV-1 medicine.
 * Changes in body fat can happen in people who take HIV-1 medicine. These
   changes may include increased amount of fat in the upper back and neck
   (“buffalo hump”), breast, and around the main part of your body (trunk). Loss
   of fat from the legs, arms, and face may also happen. The cause and long-term
   health effects of these conditions are not known.

The most common side effects of SUSTIVA include:

 * abnormal dreams
 * rash
 * tiredness
 * dizziness
 * nausea
 * trouble sleeping
 * headache
 * vomiting
 * difficulty concentrating

Some patients taking SUSTIVA have experienced increased levels of lipids
(cholesterol and triglycerides) in the blood. Tell your doctor if you have any
side effect that bothers you or that does not go away.

These are not all the possible side effects of SUSTIVA. For more information,
ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.

How should I store SUSTIVA?

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

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

General information about SUSTIVA

Medicines are sometimes prescribed for purposes other than those listed in a
Patient Information leaflet. 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 that you have. It may harm them.

If you would like more information, talk with your doctor. You can ask your
pharmacist or doctor for information about SUSTIVA that is written for health
professionals. For more information, go to www.sustiva.com or call
1-800-321-1335.

What are the ingredients in SUSTIVA?

Active ingredient: efavirenz

Inactive ingredients: SUSTIVA capsules: lactose monohydrate, magnesium stearate,
sodium lauryl sulfate, and sodium starch glycolate. The capsule shell contains
gelatin, sodium lauryl sulfate, titanium dioxide, and/or yellow iron oxide. The
capsule shell may also contain silicon dioxide. The capsules are printed with
ink containing carmine 40 blue, FD&C Blue No. 2, and titanium dioxide.

SUSTIVA tablets: croscarmellose sodium, hydroxypropyl cellulose, lactose
monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl
sulfate. The tablet film coating contains Opadry Yellow and Opadry Clear. The
tablets are polished with carnauba wax and printed with purple ink, Opacode WB.

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
 * teaspoon for measuring
 * small spoon for stirring and feeding
 * 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.

Figure 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).

Figure B





Step 5. Hold the SUSTIVA capsule 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).

Figure 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).

Figure 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.

Figure E





Step 7. Sprinkle the contents of the SUSTIVA capsule onto the food (see Figure
F).

 * Check the capsule shells to make sure they are empty.
 * Throw away the empty capsule shells.

Figure 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 should be completed within 30 minutes of mixing the medicine
(see Figure G).

Figure G





Step 8. Use the small spoon to gently mix the capsule contents and food together
(see Figure H). Sprinkles will not dissolve. Mixture will look grainy but should
not be lumpy.

Figure H





Step 9. Use the small spoon to give or take the food and capsule contents
mixture. 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 with the small spoon to mix with any capsule contents that may still
be in the container.

Step 11. Use the small spoon to give or take the food and capsule contents
mixture. Make sure all of the mixture is swallowed.

Step 12. Wash the container and spoons. Throw away the paper towel and clean the
work surface. Wash your hands.

Preparing a dose of SUSTIVA mixed with infant formula using the capsule sprinkle
method

To make sure that your baby gets all of the medicine, do not give SUSTIVA
capsule contents to your baby in a bottle.

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

 * paper towels
 * teaspoon for stirring and measuring
 * small clean container (such as a small cup or bowl) (see Figure I).
 * 10 mL oral dosing syringe (ask your pharmacist for this) (see Figure I).
 * infant formula at room temperature.

Figure I





Step 1. Prepare the infant formula according to the directions on the infant
formula package. You will use about 1 ounce of the formula to give the medicine.
Any remaining formula should not be given to the child for 2 hours.

Step 2. 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 3. Wash and dry your hands well.

Step 4. Pour 2 teaspoons of room temperature infant formula into the container
(see Figure J).

Figure J





Step 5. 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 K).

Figure K





Step 6. Hold the SUSTIVA capsule in a sideways  (horizontal) position directly
over the container with the infant formula. Hold each end of the SUSTIVA capsule
between your thumbs and index (pointer) fingers (see Figure L).

Figure L





Step 7. Use your thumb and index finger to pinch near the end of the overlapping
part of the SUSTIVA capsule (see Figure M).

Figure M





Then, carefully twist both ends of the SUSTIVA capsule in opposite directions to
open it (see Figure N). Be careful not to spill the capsule contents or spread
it in the air.

Figure N





Step 8. Sprinkle the contents of the SUSTIVA capsule onto the infant formula
(see Figure O).

 * Check the capsule shells to make sure they are empty.
 * Throw away the empty capsule shells.

Figure O





If the total prescribed dose is more than 1 capsule, follow Steps 5 through 8
for each capsule. Do not add more infant formula.

Steps 9 through 12 should be completed within 30  minutes of mixing the
medicine (see Figure P).

Figure P





Step 9. Hold the container with one hand. With your other hand, use the teaspoon
to gently mix the capsule contents and the infant formula (see Figure Q).
Sprinkles will not dissolve. Mixture will look grainy but should not be lumpy.

Figure Q





Step 10. To draw up all of the mixture into the oral dosing syringe:

 * Check that the plunger is completely pushed into barrel of the syringe (see
   Figure R).

Figure R







 * Place the tip of the syringe into the mixture in the container (see Figure
   S).

Figure S





 * Slowly pull back on the plunger and draw up all of the mixture (see Figure
   T).

Figure T





Step 11. Place the tip of the syringe in your baby’s mouth along the inner
cheek (see Figure U). Slowly push on the plunger to give your baby all of the
mixture.

Figure U





Step 12. To make sure all of the medicine is given to your baby:

 * Repeat Step 4 above.
 * Stir with a teaspoon.
 * Then, repeat Steps 10 and 11 above (see Figure V).

Figure V





Step 13. Remove the plunger from the oral dosing syringe. Wash the container,
teaspoon, and oral dosing syringe. Allow the plunger and the syringe barrel to
dry before putting them back together.

Step 14. Throw away the paper towel and clean the work surface. 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.


FROM

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WE CARE ABOUT YOUR PRIVACY

We and our 65 partners store and/or access information on a device, such as
unique IDs in cookies to process personal data. You may accept or manage your
choices by clicking below, including your right to object where legitimate
interest is used, or at any time in the privacy policy page. These choices will
be signaled to our partners and will not affect browsing data.


WE AND OUR PARTNERS PROCESS DATA TO PROVIDE:

Use precise geolocation data. Actively scan device characteristics for
identification. Store and/or access information on a device. Personalised
advertising and content, advertising and content measurement, audience research
and services development. List of Partners (vendors)

I Accept Show Purposes



ABOUT YOUR PRIVACY

We process your data to deliver content or advertisements and measure the
delivery of such content or advertisements to extract insights about our
website. We share this information with our partners on the basis of consent and
legitimate interest. You may exercise your right to consent or object to a
legitimate interest, based on a specific purpose below or at a partner level in
the link under each purpose. These choices will be signaled to our vendors
participating in the Transparency and Consent Framework.
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MANAGE CONSENT PREFERENCES

STRICTLY NECESSARY COOKIES

Always Active

These cookies are necessary for the website to function and cannot be switched
off in our systems. They are usually only set in response to actions made by you
which amount to a request for services, such as setting your privacy
preferences, logging in or filling in forms. You can set your browser to block
or alert you about these cookies, but some parts of the site will not then work.
These cookies do not store any personally identifiable information.

TARGETING COOKIES

Targeting Cookies

These cookies may be set through our site by our advertising partners. They may
be used by those companies to build a profile of your interests and show you
relevant adverts on other sites. They do not store directly personal
information, but are based on uniquely identifying your browser and internet
device. If you do not allow these cookies, you will experience less targeted
advertising.

PERFORMANCE COOKIES

Performance Cookies

These cookies allow us to count visits and traffic sources so we can measure and
improve the performance of our site. They help us to know which pages are the
most and least popular and see how visitors move around the site. All
information these cookies collect is aggregated and therefore anonymous. If you
do not allow these cookies we will not know when you have visited our site, and
will not be able to monitor its performance.

FUNCTIONAL COOKIES

Functional Cookies

These cookies enable the website to provide enhanced functionality and
personalisation. They may be set by us or by third party providers whose
services we have added to our pages. If you do not allow these cookies then some
or all of these services may not function properly.

STORE AND/OR ACCESS INFORMATION ON A DEVICE 53 PARTNERS CAN USE THIS PURPOSE

Store and/or access information on a device

Cookies, device or similar online identifiers (e.g. login-based identifiers,
randomly assigned identifiers, network based identifiers) together with other
information (e.g. browser type and information, language, screen size, supported
technologies etc.) can be stored or read on your device to recognise it each
time it connects to an app or to a website, for one or several of the purposes
presented here.

List of IAB Vendors‎ | View Illustrations 

PERSONALISED ADVERTISING AND CONTENT, ADVERTISING AND CONTENT MEASUREMENT,
AUDIENCE RESEARCH AND SERVICES DEVELOPMENT 60 PARTNERS CAN USE THIS PURPOSE

Personalised advertising and content, advertising and content measurement,
audience research and services development

 * USE LIMITED DATA TO SELECT ADVERTISING 50 PARTNERS CAN USE THIS PURPOSE
   
   Switch Label
   
   Advertising presented to you on this service can be based on limited data,
   such as the website or app you are using, your non-precise location, your
   device type or which content you are (or have been) interacting with (for
   example, to limit the number of times an ad is presented to you).
   
   View Illustrations 
   Object to Legitimate Interests Remove Objection

 * CREATE PROFILES FOR PERSONALISED ADVERTISING 41 PARTNERS CAN USE THIS PURPOSE
   
   Switch Label
   
   Information about your activity on this service (such as forms you submit,
   content you look at) can be stored and combined with other information about
   you (for example, information from your previous activity on this service and
   other websites or apps) or similar users. This is then used to build or
   improve a profile about you (that might include possible interests and
   personal aspects). Your profile can be used (also later) to present
   advertising that appears more relevant based on your possible interests by
   this and other entities.
   
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 * USE PROFILES TO SELECT PERSONALISED ADVERTISING 41 PARTNERS CAN USE THIS
   PURPOSE
   
   Switch Label
   
   Advertising presented to you on this service can be based on your advertising
   profiles, which can reflect your activity on this service or other websites
   or apps (like the forms you submit, content you look at), possible interests
   and personal aspects.
   
   View Illustrations 

 * CREATE PROFILES TO PERSONALISE CONTENT 14 PARTNERS CAN USE THIS PURPOSE
   
   Switch Label
   
   Information about your activity on this service (for instance, forms you
   submit, non-advertising content you look at) can be stored and combined with
   other information about you (such as your previous activity on this service
   or other websites or apps) or similar users. This is then used to build or
   improve a profile about you (which might for example include possible
   interests and personal aspects). Your profile can be used (also later) to
   present content that appears more relevant based on your possible interests,
   such as by adapting the order in which content is shown to you, so that it is
   even easier for you to find content that matches your interests.
   
   View Illustrations 

 * USE PROFILES TO SELECT PERSONALISED CONTENT 12 PARTNERS CAN USE THIS PURPOSE
   
   Switch Label
   
   Content presented to you on this service can be based on your content
   personalisation profiles, which can reflect your activity on this or other
   services (for instance, the forms you submit, content you look at), possible
   interests and personal aspects. This can for example be used to adapt the
   order in which content is shown to you, so that it is even easier for you to
   find (non-advertising) content that matches your interests.
   
   View Illustrations 

 * MEASURE ADVERTISING PERFORMANCE 55 PARTNERS CAN USE THIS PURPOSE
   
   Switch Label
   
   Information regarding which advertising is presented to you and how you
   interact with it can be used to determine how well an advert has worked for
   you or other users and whether the goals of the advertising were reached. For
   instance, whether you saw an ad, whether you clicked on it, whether it led
   you to buy a product or visit a website, etc. This is very helpful to
   understand the relevance of advertising campaigns.
   
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   Object to Legitimate Interests Remove Objection

 * MEASURE CONTENT PERFORMANCE 16 PARTNERS CAN USE THIS PURPOSE
   
   Switch Label
   
   Information regarding which content is presented to you and how you interact
   with it can be used to determine whether the (non-advertising) content e.g.
   reached its intended audience and matched your interests. For instance,
   whether you read an article, watch a video, listen to a podcast or look at a
   product description, how long you spent on this service and the web pages you
   visit etc. This is very helpful to understand the relevance of
   (non-advertising) content that is shown to you.
   
   View Illustrations 
   Object to Legitimate Interests Remove Objection

 * UNDERSTAND AUDIENCES THROUGH STATISTICS OR COMBINATIONS OF DATA FROM
   DIFFERENT SOURCES 35 PARTNERS CAN USE THIS PURPOSE
   
   Switch Label
   
   Reports can be generated based on the combination of data sets (like user
   profiles, statistics, market research, analytics data) regarding your
   interactions and those of other users with advertising or (non-advertising)
   content to identify common characteristics (for instance, to determine which
   target audiences are more receptive to an ad campaign or to certain
   contents).
   
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   Object to Legitimate Interests Remove Objection

 * DEVELOP AND IMPROVE SERVICES 49 PARTNERS CAN USE THIS PURPOSE
   
   Switch Label
   
   Information about your activity on this service, such as your interaction
   with ads or content, can be very helpful to improve products and services and
   to build new products and services based on user interactions, the type of
   audience, etc. This specific purpose does not include the development or
   improvement of user profiles and identifiers.
   
   View Illustrations 
   Object to Legitimate Interests Remove Objection

 * USE LIMITED DATA TO SELECT CONTENT 8 PARTNERS CAN USE THIS PURPOSE
   
   Switch Label
   
   Content presented to you on this service can be based on limited data, such
   as the website or app you are using, your non-precise location, your device
   type, or which content you are (or have been) interacting with (for example,
   to limit the number of times a video or an article is presented to you).
   
   View Illustrations 
   Object to Legitimate Interests Remove Objection

List of IAB Vendors‎

USE PRECISE GEOLOCATION DATA 16 PARTNERS CAN USE THIS PURPOSE

Use precise geolocation data

With your acceptance, your precise location (within a radius of less than 500
metres) may be used in support of the purposes explained in this notice.

List of IAB Vendors‎

ACTIVELY SCAN DEVICE CHARACTERISTICS FOR IDENTIFICATION 7 PARTNERS CAN USE THIS
PURPOSE

Actively scan device characteristics for identification

With your acceptance, certain characteristics specific to your device might be
requested and used to distinguish it from other devices (such as the installed
fonts or plugins, the resolution of your screen) in support of the purposes
explained in this notice.

List of IAB Vendors‎

ENSURE SECURITY, PREVENT AND DETECT FRAUD, AND FIX ERRORS 50 PARTNERS CAN USE
THIS PURPOSE

Always Active

Your data can be used to monitor for and prevent unusual and possibly fraudulent
activity (for example, regarding advertising, ad clicks by bots), and ensure
systems and processes work properly and securely. It can also be used to correct
any problems you, the publisher or the advertiser may encounter in the delivery
of content and ads and in your interaction with them.

List of IAB Vendors‎ | View Illustrations 

DELIVER AND PRESENT ADVERTISING AND CONTENT 47 PARTNERS CAN USE THIS PURPOSE

Always Active

Certain information (like an IP address or device capabilities) is used to
ensure the technical compatibility of the content or advertising, and to
facilitate the transmission of the content or ad to your device.

List of IAB Vendors‎ | View Illustrations 

MATCH AND COMBINE DATA FROM OTHER DATA SOURCES 41 PARTNERS CAN USE THIS PURPOSE

Always Active

Information about your activity on this service may be matched and combined with
other information relating to you and originating from various sources (for
instance your activity on a separate online service, your use of a loyalty card
in-store, or your answers to a survey), in support of the purposes explained in
this notice.

List of IAB Vendors‎

LINK DIFFERENT DEVICES 36 PARTNERS CAN USE THIS PURPOSE

Always Active

In support of the purposes explained in this notice, your device might be
considered as likely linked to other devices that belong to you or your
household (for instance because you are logged in to the same service on both
your phone and your computer, or because you may use the same Internet
connection on both devices).

List of IAB Vendors‎

IDENTIFY DEVICES BASED ON INFORMATION TRANSMITTED AUTOMATICALLY 41 PARTNERS CAN
USE THIS PURPOSE

Always Active

Your device might be distinguished from other devices based on information it
automatically sends when accessing the Internet (for instance, the IP address of
your Internet connection or the type of browser you are using) in support of the
purposes exposed in this notice.

List of IAB Vendors‎
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