Efavirenz

Contraindications

Previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions)

Cautions

Hepatic impairment; not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary

Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity; among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease; weigh risk/benefit if AST/ALT >5 xULN

Redistribution of fat may occur (cushingoid appearance)

Risk of serious psychiatric events (eg, depression, suicidality, paranoia, manic episodes); immediate medical evaluation recommended for serious psychiatric symptoms such as severe depression or suicidal ideation; there have been occasional postmarketing reports of death by suicide, delusions, psychosis-like behavior and catatonia; a causal relationship to the use of efavirenz cannot be determined from these reports

CNS symptoms reported (eg, dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, and hallucinations); nervous system symptoms (NSS) are frequent and usually begin 1-2 days after initiating therapy and resolve in 2-4 weeks; dosing at bedtime may improve tolerability; NSS are not predictive of onset of psychiatric symptoms

Risk of skin rash - discontinue if severe rash associated wtih blistering, desquamation, mucosal involvement, or fever

Use caution in history of seizures

Total cholesterol and triglyceride elevations may occur; monitor before therapy and periodically thereafter

Women should avoid pregnancy; use 2 forms of contraception including a barrier method; postmarketing reports of contraceptive failure in patients on efavirenz while on an implantable hormonal contraceptive; avoid administration in first trimester of pregnancy as fetal harm may occur

Risk of immune reconstitution syndrome if used in combination with other antiretroviral drugs; immune reconstitution syndrome may necessitate further evaluation and treatment

Autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment

Not for use as a single agent or add on as a sole agent to a failing regimen; consider potential for cross-resistance when choosing other agents

Not recommended with ATRIPLA, which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin

Consider alternatives in patients taking other medications with known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes

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

Mechanism of Action

Non-nucleoside reverse transcriptase inhibitor (NNRTI) against HIV-1

Absorption

Peak Plasma Time: 2.5-4 hr

Metabolism

Metabolized by liver CYP3A4 and CYP2B6

Inhibits: CYP2C9; CYP2C19, and CYP3A4 (in vitro)

Induces: CYP3A4 (in vivo)

Elimination

Half-Life: 41 hr ± 20 hr

Excretion: Urine (14-34%); feces (16-61%)

Distribution

Protein binding: 99% (albumin)

Efavirenz is also used with other medications to help prevent infection in healthcare workers or other people who were accidentally exposed to HIV. Talk to your doctor about the possible risks of using this medication for your condition.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Efavirenz is an antiviral medicine that prevents human immunodeficiency virus (HIV) cells from multiplying in your body.

Efavirenz is used to treat HIV, the virus that can cause acquired immunodeficiency syndrome (AIDS). Efavirenz is not a cure for HIV or AIDS.

Efavirenz may also be used for purposes not listed in this medication guide.

Do not take efavirenz together with Atripla (combination efavirenz, emtricitabine, and tenofovir), unless your doctor tells you to.

You should not use this medicine if you have ever had a severe allergic reaction to efavirenz. Do not take efavirenz together with Atripla (combination efavirenz, emtricitabine, and tenofovir), unless your doctor tells you to.

Some medicines can cause unwanted or dangerous effects when used with efavirenz. Your doctor may need to change your treatment plan if you use any of the following drugs:

• midazolam, pimozide, St. John's wort; or
• ergot medicine--dihydroergotamine, ergotamine, ergonovine, methylergonovine.

Using any of these medicines while you are taking efavirenz can cause serious medical problems or death.

To make sure efavirenz is safe for you, tell your doctor if you have:

• liver disease (including hepatitis B or C);
• seizures or epilepsy;
• a history of mental illness, injection drug use, or taking an anti-psychotic medicine;
• high cholesterol or triglycerides; or
• if you have ever taken delavirdine (Rescriptor) or nevirapine (Viramune) and they were not effective in treating your condition.

Do not use efavirenz if you are pregnant. It could harm the unborn baby. Use two forms of birth control, including a barrier form (such as a condom or diaphragm with spermicide gel) while you are taking efavirenz, and for at least 12 weeks after your treatment ends. Tell your doctor if you become pregnant during treatment.

Hormonal contraception (birth control pills, injections, implants, skin patches, and vaginal rings) may not be effective enough to prevent pregnancy during your treatment.

Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Dosage Forms And Strengths

• 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.

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

Storage And Handling

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

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. [print code] Revised: Oct 2016

Do not use efavirenz if you are pregnant. It could harm the unborn baby. Use two forms of birth control, including a barrier form (such as a condom or diaphragm with spermicide gel) while you are taking efavirenz, and for at least 12 weeks after your treatment ends. Tell your doctor if you become pregnant during treatment.

Efavirenz may cause serious psychiatric symptoms including confusion, severe depression, suicidal thoughts, aggression, extreme fear, hallucinations, or unusual behavior. Contact your doctor at once if you have any of these side effects, even if you have had them before.

Do not take efavirenz with cisapride (Propulsid), pimozide (Orap), midazolam (Versed), triazolam (Halcion), or ergot medicines such as dihydroergotamine (D.H.E. 45), ergonovine (Ergotrate), ergotamine (Ergomar, Cafergot, Wigraine), or methylergonovine (Methergine). These drugs can cause life-threatening side effects if you use them while you are taking efavirenz.

There are many other medicines that can interact with efavirenz, or make it less effective. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Taking this medication will not prevent you from passing HIV to other people. Talk with your doctor about safe methods of preventing HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Efavirenz must be given in combination with other antiviral medications and it should not be used alone. Your disease may become resistant to efavirenz if you do not take it in combination with other HIV medicines your doctor has prescribed.

Take efavirenz on an empty stomach at bedtime.

To make swallowing easier, you may open an efavirenz capsule and sprinkle the medicine into a spoonful of applesauce, yogurt, or grape jelly. You may also mix the medicine with infant formula if you are giving the medicine to a baby. Swallow the mixture right away. Do not save it for later use.

After taking efavirenz using the sprinkle method, do not eat for the next 2 hours. Efavirenz mixed with infant formula should be given to the baby right away. But do not feed the baby any more formula for at least 2 hours afterward.

Efavirenz comes with instructions for mixing the capsule contents with soft food or infant formula. Follow these directions carefully. Ask your pharmacist if you have any questions.

Do not crush, chew, or break an efavirenz tablet. Swallow it whole with liquid.

While using efavirenz, you may need frequent blood tests.

Efavirenz can cause you to have a false positive drug screening test. If you provide a urine sample for drug screening, tell the laboratory staff that you are taking efavirenz.

If a child is using this medicine, tell your doctor if the child has any changes in weight. Efavirenz doses are based on weight in children, and any changes may affect your child's dose.

Take efavirenz regularly to get the most benefit. Get your prescriptions refilled before you run out of medicine completely. Skipping doses may increase the risk of your virus becoming resistant to antiviral medicine.

Store at room temperature away from moisture and heat.

Read the medication guide provided with all your medications. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).1 2 3 12 14

• Pharmacologically related to other NNRTIs (e.g., delavirdine, etravirine, nevirapine, rilpivirine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.1 2 3 6 12 14 52 53 212 215

• Active against HIV-1; inactive against HIV-2.1 3

• Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.1 3

• HIV-1 with reduced susceptibility to efavirenz have been selected in vitro and have emerged during therapy with the drug.1 3 9 14 18 18

• Strains of HIV-1 resistant to efavirenz may be cross-resistant to some other NNRTIs (e.g., delavirdine, nevirapine).3 9 10 18 32 50 200 201 1 215

• Cross-resistance between efavirenz and NRTIs unlikely since the drugs bind at difference sites on reverse transcriptase and have difference mechanisms of action.1 3 9 10 32 Cross-resistance between efavirenz and PIs unlikely since the drugs have different target enzymes and mechanisms of action.1 32

In the U.S.

• Sustiva

Available Dosage Forms:

• Tablet
• Solution
• Capsule

Therapeutic Class: Antiretroviral Agent

Pharmacologic Class: Non-Nucleoside Reverse Transcriptase Inhibitor

Refer to adult dosing.

Store at 25°C (77°F); excursion permitted to 15°C to 30°C (59°F to 86°F).

Data not available

Comments: This drug is highly protein-bound; significant removal via dialysis is not likely.

Administration advice:
-Administer on an empty stomach (bedtime preferable); administration with food increases drug levels and may increase rate of side effects.
-Administer at bedtime to improve tolerability of CNS side effects.
-Do not crush tablets; swallow tablets intact with liquid.
-Capsules can be swallowed intact with liquid or administered using the sprinkle method.
-For patients unable to swallow capsules or tablets, the capsule contents can be administered with a small amount (1 to 2 teaspoons) of food; consult the manufacturer product information regarding administration using the sprinkle method.
-Consult the manufacturer product information regarding missed doses.

Reconstitution/preparation techniques:
-The manufacturer product information should be consulted regarding preparation for the capsule sprinkle method of administration.

General:
-This drug should always be used in combination with other antiretroviral agents; it should not be used as a single agent to treat HIV-1.
-This drug should not be added on as a sole agent to a failing regimen.

Monitoring:
-General: Pregnancy testing (before starting this drug)
-Hepatic: Liver enzymes (before and during therapy)
-Metabolic: Triglycerides and cholesterol (before and periodically during therapy)

Patient advice:
-This drug may impair mental abilities needed to perform potentially hazardous tasks (e.g., driving, operating machinery); CNS effects may be additive if used with alcohol or psychoactive drugs. Avoid hazardous tasks if CNS symptoms (e.g., dizziness, impaired concentration, drowsiness) occur.

Efavirenz is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its molecular formula is C14H9ClF3NO2 and its structural formula is:

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

Efavirenz is available as capsules for oral administration containing either 50 mg or 200 mg of Efavirenz USP and the following inactive ingredients: lactose monohydrate, magnesium stearate, sodium lauryl sulfate and sodium starch glycolate (potato). The capsule shell contains gelatin, silicon dioxide and sodium lauryl sulfate. In addition 50 mg contains titanium dioxide and yellow iron oxide, and 200 mg contains yellow iron oxide. The capsules are printed with edible ink containing black iron oxide and shellac.

Adults

Study 006, a randomized, open-label trial, compared Efavirenz (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or Efavirenz (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 to 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.

a        Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 or Week 168.

b        Includes patients who rebounded, patients who were on study at Week 48 and failed to achieve confirmed HIV-1 RNA <400 copies/mL at time of discontinuation, and patients who discontinued due to lack of efficacy.

c        Includes consent withdrawn, lost to follow-up, noncompliance, never treated, missing data, protocol violation, death, and other reasons. Patients with HIV-1 RNA levels <400 copies/mL who chose not to continue in the voluntary extension phases of the study were censored at date of last dose of study medication.

For patients treated with Efavirenz + zidovudine + lamivudine, Efavirenz + 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 to 76], 74% Caucasian, 88% male) received NRTIs in combination with Efavirenz (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or Efavirenz (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.

*    For some patients, Week 56 data were used to confirm the status at Week 48.

a        Subjects achieved virologic response (two consecutive viral loads <500 copies/mL) and maintained it through Week 48.

b       Includes viral rebound and failure to achieve confirmed <500 copies/mL by Week 48.

c        See Adverse Reactions (6.1) for a safety profile of these regimens.

d       Includes loss to follow-up, consent withdrawn, noncompliance.

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 Efavirenz-containing treatment arms.

Pediatric Patients

Study AI266922 is an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz 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 Efavirenz. 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 Efavirenz 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 Efavirenz. 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 Efavirenz 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 Efavirenz. 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%.