SUSTIVA

Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (<10 microgram/mL).

Capsules: SUSTIVA is available as capsules for oral administration containing either 50 mg or 200 mg of efavirenz and the following inactive ingredients: lactose monohydrate, magnesium stearate, sodium lauryl sulfate, and sodium starch glycolate. The capsule shell contains the following inactive ingredients and dyes: gelatin, sodium lauryl sulfate, titanium dioxide, and/or yellow iron oxide. The capsule shells may also contain silicon dioxide. The capsules are printed with ink containing carmine 40 blue, FD&C Blue No. 2, and titanium dioxide.

Tablets: SUSTIVA is available as film-coated tablets for oral administration containing 600 mg of efavirenz and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The film coating contains Opadry Yellow and Opadry Clear. The tablets are polished with carnauba wax and printed with purple ink, Opacode WB.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Absorption

Peak efavirenz plasma concentrations of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in C_max 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 C_max, mean C_min, 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 C_max was 12.9 ± 3.7 μM (mean ± SD), steady-state C_min was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•h.

Effect of Food on Oral Absorption:

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

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 C_max of efavirenz relative to the exposures achieved under fasted conditions. [See Dosage and Administration (2) and Patient Counseling Information (17) .]

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.

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 K_i 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 (K_i 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 C_max, AUC, and C_min 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 (7.1) .

12.4 Microbiology

Mechanism of Action

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

Antiviral Activity in Cell Culture

The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90-95% (EC_90-95) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. Efavirenz demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group O viruses. Efavirenz demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the NNRTIs delavirdine and nevirapine, NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz was not antagonistic with adefovir, used for the treatment of hepatitis B virus infection, or ribavirin, used in combination with interferon for the treatment of hepatitis C virus infection.

Resistance

In cell culture

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

Clinical studies

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

Cross-Resistance

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Mutagenesis

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

Impairment of Fertility

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

13.2 Animal Toxicology

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

14 CLINICAL STUDIES

14.1 Adults

Study 006, a randomized, open-label trial, compared SUSTIVA (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or SUSTIVA (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years [range 18-81], 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm³ and the median baseline HIV-1 RNA level was 4.8 log₁₀ copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 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.

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.

A Kaplan-Meier analysis of time to treatment failure through 72 weeks demonstrates a longer duration of virologic suppression (HIV RNA <500 copies/mL) in the SUSTIVA-containing treatment arms.

14.2 Pediatric Patients

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

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Capsules

SUSTIVA^® (efavirenz) capsules are available as follows:

Capsules 200 mg are gold color, reverse printed with “SUSTIVA” on the body and imprinted “200 mg” on the cap.

      Bottles of 90      NDC 0056-0474-92

Capsules 50 mg are gold color and white, printed with “SUSTIVA” on the gold color cap and reverse printed “50 mg” on the white body.

      Bottles of 30      NDC 0056-0470-30

16.2 Tablets

SUSTIVA^® (efavirenz) tablets are available as follows:

Tablets 600 mg are yellow, capsular-shaped, film-coated tablets, with “SUSTIVA” printed on both sides.

      Bottles of 30      NDC 0056-0510-30

16.3 Storage

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

17 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, patients should be advised to report to their doctor the use of any other prescription, or nonprescription medication

General Information for Patients

Patients should be informed that SUSTIVA is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician while taking SUSTIVA.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

• • Do not share 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. It is not known if SUSTIVA can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.

Dosing Instructions

Patients should be advised 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. Patients should be advised to take SUSTIVA on an empty stomach, preferably at bedtime. Taking SUSTIVA with food increases efavirenz concentrations and may increase the frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Dosage and Administration (2) and Adverse Reactions (6.1) ]. Healthcare providers should assist parents or caregivers in determining the best SUSTIVA dosing schedule for infants and young children.

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

Nervous System Symptoms

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

Psychiatric Symptoms

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

Rash

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

Reproductive Risk Potential

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

Fat Redistribution

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

SUSTIVA is a registered trademark of Bristol-Myers Squibb Pharma Company, ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC, PRAVACHOL is a registered trademark of ER Squibb & Sons, LLC, and REYATAZ is a registered trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners.

Distributed by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

SUSTIVA^® (efavirenz) capsules made in India.

© Bristol-Myers Squibb Company 2014

Patient Information

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 must 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.

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 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. You should not become pregnant while taking SUSTIVA and for 12 weeks after stopping treatment with SUSTIVA.
•   Females who are able to become pregnant must use 2 effective forms of birth control during treatment and for 12 weeks after stopping treatment with SUSTIVA. A barrier form of birth control must 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.
• •are breastfeeding or plan to breastfeed. You should not breastfeed if you have HIV because of the risk of passing HIV to your baby. Do not breastfeed if you take SUSTIVA. SUSTIVA can pass into your breast milk. It is not known if this could harm your baby. Talk with your doctor about the best way to feed your baby.

Tell your doctor 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.

Especially tell your doctor if you take any of the medicines below:

The following medicines may need to be replaced with another medicine during your treatment with SUSTIVA:

• •boceprevir (Victrelis)
• •carbamazepine (Carbatrol, Tegretol, Tegretol-XR, Equetro, Teril, Epitol)
• •clarithromycin (Biaxin, Biaxin XL)
• •itraconazole (Sporanox, Onmel)
• •posaconazole (Noxafil)
• •saquinavir mesylate (Invirase)
• •atazanavir sulfate (REYATAZ)

If you take any of the following medicines during treatment with SUSTIVA, your doctor may need to change the dose of the medicine or change the dose of SUSTIVA, or your doctor may need to monitor you more closely:

• •calcium channel blockers such as diltiazem (Cardizem, Cardizem CD, Cardizem LA, Tiazac, Cartia XT, Dilacor XR, Dilt-CD, Diltzac, Taztia XT), verapamil (Covera-HS, Calan, Calan SR, Verelan, Verelan PM), felodipine (Plendil), nicardipine (Cardene, Cardene SR), or nifedipine (Adalat CC, Afeditab CR, Procardia, Procardia XL)
• •the cholesterol-lowering medicines atorvastatin (Lipitor), pravastatin sodium (PRAVACHOL), or simvastatin (Zocor)
• •immunosuppressant medicines such as cyclosporine (Gengraf, Neoral, Sandimmune), tacrolimus (Prograf, Astagraf XL), or sirolimus (Rapamune)
• •artemether/lumefantrine (Coartem)
• •atazanavir sulfate (REYATAZ)
• •bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL, Forfivo XL, Zyban)
• •indinavir (Crixivan)
• •lopinavir/ritonavir (Kaletra)
• •ritonavir (Norvir)
• •maraviroc (Selzentry)
• •methadone (Dolophine, Methadose)
• •rifabutin (Mycobutin)
• •rifampin (Rifadin, Rimactane, Rifamate, Rifater)
• •sertraline (Zoloft)
• •voriconazole (Vfend). Your doses of both Vfend and SUSTIVA may need to be changed.
• •raltegravir (Isentress)
• •telaprevir (Incivek)
• •warfarin (Coumadin, Jantoven)
• •phenytoin (Dilantin)
• •ketoconazole (Nizoral)

Ask your doctor or pharmacist if you are not sure if your medicine is one that is listed above.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

Your doctor and your pharmacist can tell you if you can take these medicines with SUSTIVA. Do not start any new medicines while you are taking SUSTIVA without first talking with your doctor or pharmacist. You can ask your doctor or pharmacist for a list of medicines that can interact with SUSTIVA.

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 should 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 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
  • •feel anxious or restless
  • •have thoughts of hurting yourself (suicide) or have tried to hurt yourself or others
  • •are not able to tell the difference between what is true or real and what is false or unreal
  • •do not trust other people
  • •hear or see things that are not real
• • 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. 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 sleeping
  • •trouble concentrating
  • •drowsiness
  • •unusual dreams
•  If you have dizziness, trouble concentrating or drowsiness, do not drive a car, use machinery, or do anything that needs you to be alert.
• • 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
  • •fever
  • •swelling of your face
  • •blisters or skin lesions
  • •peeling skin
  • •mouth sores
  • •red or inflamed eyes, like “pink eye” (conjunctivitis)
• • Liver problems, including liver failure and death. If you have liver problems, including hepatitis B or C infection or take another medicine that can cause liver problems, your doctor may do blood tests to check your liver before you start SUSTIVA and during treatment. Liver problems can also happen in people without a history of liver problems. 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)
  • •your urine turns dark
  • •your bowel movements (stools) turn light in color
  • •you don’t feel like eating food for several days or longer
  • •you feel sick to your stomach (nausea)
  • •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:

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.



This Patient Information has been approved by the U.S. Food and Drug Administration.

Distributed by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

SUSTIVA^® (efavirenz) capsules made in India.

© Bristol-Myers Squibb Company 2014

Revised: May 2014

1320416A0
510230013IN12

SUSTIVA is a registered trademark of Bristol-Myers Squibb Pharma Company, ATRIPLA is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC, PRAVACHOL is a registered trademark of ER Squibb & Sons, LLC, and REYATAZ is a registered trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners.

Instructions for Use

SUSTIVA (sus-TEE-vah)

efavirenz
capsules

Preparing a dose of SUSTIVA using the capsule sprinkle method

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

Important Information:

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

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

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

• •paper towels
• •small spoon
• • small clean container (such as a small cup or bowl)
• •soft food such as applesauce, grape jelly, or yogurt

How should I store SUSTIVA capsules?

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

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

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

Distributed by:

Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

SUSTIVA^® (efavirenz) capsules made in India.

Issued: May 2013

1320416A0
510230013IN12

SUSTIVA 50 mg capsules Representative Packaging

See How Supplied section for a complete list of available packages of SUSTIVA.

NDC 0056-0470-30      30 Capsules
SUSTIVA ^®      Rx only
(efavirenz) capsules
50 mg
Each capsule contains 50 mg of efavirenz.
DOSAGE: For dosage and full prescribing
information, read accompanying package
insert.
Note to pharmacist: Do not cover
ALERT box with pharmacy label.
ALERT: Find out about medicines that
should NOT be taken with SUSTIVA ^®