Efavirenz - Efavirenz capsule

Efavirenz capsules in combination with other antiretroviral agents are 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.

• Efavirenz capsules should be taken orally once daily on an empty stomach, preferably at bedtime. (
  2 DOSAGE AND ADMINISTRATION

  • Efavirenz capsules should be taken orally once daily on an empty stomach, preferably at bedtime.
  • Recommended adult dose: 600 mg.
  • With voriconazole, increase voriconazole maintenance dose to 400 mg every 12 hours and decrease efavirenz dose to 300 mg once daily using the capsule formulation. (2.2)
  • With rifampin, increase efavirenz capsules dose to 800 mg once daily for patients weighing 50 kg or more. (2.2)
  • Pediatric dosing is based on weight. (2.3)

  2.1 Hepatic Function

  
  
  

  Monitor hepatic function prior to and during treatment with efavirenz capsules

  [see Warnings and Precautions (5.9)]

  .
  
  
  
  Efavirenz capsules are not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C)

  [see Warnings and Precautions (5.9)and Use in Specific Populations (8.6)]

  .

  2.2 Adults

  The recommended dosage of efavirenz capsules is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz capsules with food may lead to an increase in frequency of adverse reactions

  [see Clinical Pharmacology (12.3)].

  Dosing at bedtime may improve the tolerability of nervous system symptoms

  [see

  Warnings and Precautions (5.6)

  ,

  Adverse Reactions (6.1)

  , and

  Patient Counseling Information (17)

  ].

  Efavirenz capsules should be swallowed intact with liquid. For patients who cannot swallow capsules, the capsule sprinkle method of administration is recommended

  [see

  Dosage and Administration (2.4)

  ].

  Concomitant Antiretroviral Therapy

  Efavirenz capsules must be given in combination with other antiretroviral medications

  [see

  Indications and Usage (1)

  ,

  Warnings and Precautions (5.3)

  ,

  Drug Interactions (7.1)

  , and

  Clinical Pharmacology (12.3)

  ]

  .

  Dosage Adjustment

  If efavirenz capsules are coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz 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).
  
  
  
  If efavirenz capsules are coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz capsules to 800 mg once daily is recommended

  [see

  Drug Interactions (7.1, Table 5

  ) and

  Clinical Pharmacology (12.3, Table 8)

  ].

  2.3 Pediatric Patients

  It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of efavirenz capsules for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg

  [see Clinical Pharmacology (12.3)]

  . The recommended dosage of efavirenz capsules for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration

  [see Dosage and Administration (2.4)].

  
  
  

  Table 1: Efavirenz Capsules Dosing in Pediatric Patients

  Patient Body Weight	Efavirenz Capsules Daily Dose	Number of Capsulesaand 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	three 200 mg capsules

  ^aCapsules can be administered intact or as sprinkles

  [see Dosage and Administration (2.4)].

  2.4 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, 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 efavirenz capsules-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 efavirenz residue, and administered to the patient. The efavirenz capsules-food or -formula mixture should be administered within 30 minutes of mixing. No additional food should be consumed for 2 hours after administration of efavirenz capsules.
  
  
  
  Further patient instructions on the capsule sprinkle method of administration are provided in the FDA-approved patient labeling (see Patient Informationand Instructions for Use).
  )
• Recommended adult dose: 600 mg. (
  2.2 Adults

  The recommended dosage of efavirenz capsules is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz capsules with food may lead to an increase in frequency of adverse reactions

  [see Clinical Pharmacology (12.3)].

  Dosing at bedtime may improve the tolerability of nervous system symptoms

  [see

  Warnings and Precautions (5.6)

  ,

  Adverse Reactions (6.1)

  , and

  Patient Counseling Information (17)

  ].

  Efavirenz capsules should be swallowed intact with liquid. For patients who cannot swallow capsules, the capsule sprinkle method of administration is recommended

  [see

  Dosage and Administration (2.4)

  ].

  Concomitant Antiretroviral Therapy

  Efavirenz capsules must be given in combination with other antiretroviral medications

  [see

  Indications and Usage (1)

  ,

  Warnings and Precautions (5.3)

  ,

  Drug Interactions (7.1)

  , and

  Clinical Pharmacology (12.3)

  ]

  .

  Dosage Adjustment

  If efavirenz capsules are coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz 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).
  
  
  
  If efavirenz capsules are coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz capsules to 800 mg once daily is recommended

  [see

  Drug Interactions (7.1, Table 5

  ) and

  Clinical Pharmacology (12.3, Table 8)

  ].
  )
• With voriconazole, increase voriconazole maintenance dose to 400 mg every 12 hours and decrease efavirenz dose to 300 mg once daily using the capsule formulation.
  2.2 Adults

  The recommended dosage of efavirenz capsules is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz capsules with food may lead to an increase in frequency of adverse reactions

  [see Clinical Pharmacology (12.3)].

  Dosing at bedtime may improve the tolerability of nervous system symptoms

  [see

  Warnings and Precautions (5.6)

  ,

  Adverse Reactions (6.1)

  , and

  Patient Counseling Information (17)

  ].

  Efavirenz capsules should be swallowed intact with liquid. For patients who cannot swallow capsules, the capsule sprinkle method of administration is recommended

  [see

  Dosage and Administration (2.4)

  ].

  Concomitant Antiretroviral Therapy

  Efavirenz capsules must be given in combination with other antiretroviral medications

  [see

  Indications and Usage (1)

  ,

  Warnings and Precautions (5.3)

  ,

  Drug Interactions (7.1)

  , and

  Clinical Pharmacology (12.3)

  ]

  .

  Dosage Adjustment

  If efavirenz capsules are coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz 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).
  
  
  
  If efavirenz capsules are coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz capsules to 800 mg once daily is recommended

  [see

  Drug Interactions (7.1, Table 5

  ) and

  Clinical Pharmacology (12.3, Table 8)

  ].
• With rifampin, increase efavirenz capsules dose to 800 mg once daily for patients weighing 50 kg or more.
  2.2 Adults

  The recommended dosage of efavirenz capsules is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz capsules with food may lead to an increase in frequency of adverse reactions

  [see Clinical Pharmacology (12.3)].

  Dosing at bedtime may improve the tolerability of nervous system symptoms

  [see

  Warnings and Precautions (5.6)

  ,

  Adverse Reactions (6.1)

  , and

  Patient Counseling Information (17)

  ].

  Efavirenz capsules should be swallowed intact with liquid. For patients who cannot swallow capsules, the capsule sprinkle method of administration is recommended

  [see

  Dosage and Administration (2.4)

  ].

  Concomitant Antiretroviral Therapy

  Efavirenz capsules must be given in combination with other antiretroviral medications

  [see

  Indications and Usage (1)

  ,

  Warnings and Precautions (5.3)

  ,

  Drug Interactions (7.1)

  , and

  Clinical Pharmacology (12.3)

  ]

  .

  Dosage Adjustment

  If efavirenz capsules are coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz 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).
  
  
  
  If efavirenz capsules are coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz capsules to 800 mg once daily is recommended

  [see

  Drug Interactions (7.1, Table 5

  ) and

  Clinical Pharmacology (12.3, Table 8)

  ].
• Pediatric dosing is based on weight. 
  2.3 Pediatric Patients

  It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of efavirenz capsules for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg

  [see Clinical Pharmacology (12.3)]

  . The recommended dosage of efavirenz capsules for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration

  [see Dosage and Administration (2.4)].

  
  
  

  Table 1: Efavirenz Capsules Dosing in Pediatric Patients

  Patient Body Weight	Efavirenz Capsules Daily Dose	Number of Capsulesaand 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	three 200 mg capsules

  ^aCapsules can be administered intact or as sprinkles

  [see Dosage and Administration (2.4)].

Efavirenz capsules USP 50 mg are Yellow/White size ‘4’ hard gelatin capsules imprinted with ‘D’ on yellow cap and ‘72’ on white body with black edible ink filled with white to off-white colored powder.



Efavirenz capsules USP 100 mg are White/White size ‘2’ hard gelatin capsules imprinted with ‘D’ on white cap and ‘71’ on white body with black edible ink filled with white to off-white colored powder.



Efavirenz capsules USP 200 mg are Yellow/Yellow size ‘0EL’ hard gelatin capsules imprinted with ‘D’ on yellow cap and ‘36’ on yellow body with black edible ink filled with white to off-white colored powder.

• Lactation
  :
  Breastfeeding not recommended. (
  8.2 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:
  Pregnancy testing and contraception are recommended. (
  8.3 Females and Males of Reproductive Potential

  
  
  

  Because of potential teratogenic effects, pregnancy should be avoided in women receiving efavirenz

  [see Use in Specific Populations (8.1)].

  
  
  

  Pregnancy Testing

  
  
  

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

  
  
  

  Contraception

  
  
  

  Females of reproductive potential should use effective contraception during treatment with efavirenz and for 12 weeks after discontinuing efavirenz 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 (7.1)]

  .
  )
• Hepatic impairment:
  Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. (
  8.6 Hepatic Impairment

  Efavirenz 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 efavirenz to these patients

  [see

  Warnings and Precautions (5.9)

  and

  Clinical Pharmacology (12.3)

  ]

  .
  )
• Pediatric patients:
  The incidence of rash was higher than in adults. (
  5.8 Rash

  In controlled clinical trials, 26% (266/1008) of adult patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups

  [see

  Adverse Reactions (6.1)]

  . Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with efavirenz. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult patients treated with efavirenz 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 efavirenz

  [see Adverse Reactions (6.2)].

  Two pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 28 days (range 3 to 1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz in pediatric patients should be considered.
  
  
  
  Efavirenz can generally be reinitiated in patients interrupting therapy because of rash. Efavirenz 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 (4)].
  ,
  6.2 Postmarketing Experience

  The following adverse reactions have been identified during postapproval use of efavirenz. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  
  
  

  Body as a Whole:

  allergic reactions, asthenia, redistribution/accumulation of body fat

  [see

  Warnings and Precautions (5.13)]

  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
  ,
  8.4 Pediatric Use

  The safety, pharmacokinetic profile, and virologic and immunologic responses of efavirenz were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients 3 months to 21 years of age in three open-label clinical trials

  [see

  Adverse Reactions (6.2)

  ,

  Clinical Pharmacology (12.3)

  , and

  Clinical Studies (14.2)

  ].

  The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of a higher frequency of rash, including a higher frequency of Grade 3 or 4 rash, in pediatric patients compared to adults

  [see

  Warnings and Precautions (5.8)

  and

  Adverse Reactions (6.2)

  ].

  
  
  

  Use of efavirenz 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 efavirenz have not been evaluated in this age group and there is a risk of developing HIV resistance if efavirenz is underdosed. See

  Dosage and Administration (2.2)

  for dosing recommendations for pediatric patients.
  )

• QTc
  prolongation:
  Consider alternatives to efavirenz in patients taking other medications with a known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. (
  5.2 QTc Prolongation

  QTc prolongation has been observed with the use of efavirenz

  [see

  Drug Interactions (7.3

  ,

  7.4

  ) and

  Clinical Pharmacology (12.2)

  ]

  . Consider alternatives to efavirenz 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.
  )
• Do not use as a single agent
  or add on as a sole agent to a failing regimen. Consider potential for cross-resistance when choosing other agents. (
  5.3 Resistance

  Efavirenz 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.
  )
• Not recommended with ATRIPLA, which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. (
  5.4 Coadministration with Related Products

  Coadministration of efavirenz 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.
  )
• Serious psychiatric symptoms:
  Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. (
  5.5 Psychiatric Symptoms

  Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz 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 efavirenz 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 efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control- treated patients. One percent of efavirenz-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 efavirenz 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 efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits

  [see

  Adverse Reactions (6.1)].

  
  
  
  ,
  17 PATIENT COUNSELING INFORMATION

  Advise the patient to read the FDA-approved patient labeling .

  
  
  

  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 Efavirenz Capsules.

  
  
  

  Efavirenz 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 efavirenz 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 efavirenz.

  
  
  

  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 efavirenz every day as prescribed. If a patient forgets to take efavirenz, 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.

  
  
  

  Efavirenz must always be used in combination with other antiretroviral drugs. Advise patients to take efavirenz on an empty stomach, preferably at bedtime. Taking efavirenz 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 efavirenz dosing schedule for infants and young children.
  
  
  
  For adult and pediatric patients who cannot swallow capsules, 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

  
  
  

  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 efavirenz

  [see

  Warnings and Precautions (5.6)

  ].

  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 efavirenz 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 efavirenz therapy

  [see

  Warnings and Precautions (5.6)

  ]

  .
  
  
  
  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 efavirenz

  [see

  Warnings and Precautions (5.5)

  ].

  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 (5.8)

  ].

  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 (5.9)

  and

  Adverse Reactions (6.1)

  ]

  .
  
  
  
  Females of Reproductive Potential

  
  
  

  Advise females of reproductive potential to use effective contraception as well as a barrier method during treatment with efavirenz and for 12 weeks after discontinuing efavirenz. Advise patients to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with efavirenz

  [see

  Warnings and Precautions (5.7)

  and

  Use in Specific Populations (8.1

  ,

  8.3

  )]

  .

  
  
  

  Pregnancy Exposure Registry

  
  
  

  Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy

  [see

  Use in Specific Populations (8.1)

  ]

  .

  
  
  

  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 (5.13)

  ].
  
  

  
  
  Dispense with Patient Information available at:

  www.aurobindousa.com/medication-guides
  )
• Nervous system symptoms
  (NSS):
  NSS are frequent and usually begin 1 to 2 days after initiating therapy and resolve in 2 to 4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. (
  5.6 Nervous System Symptoms

  Fifty-three percent (531/1008) of patients receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens

  [see Adverse Reactions (6.1, Table 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 to 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 efavirenz and from 3% to 5% in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms

  [see Warnings and Precautions (5.5)].

  Dosing at bedtime may improve the tolerability of these nervous system symptoms

  [see Dosage and Administration (2)]

  .

  
  
  

  Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-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 efavirenz. 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 efavirenz is warranted.

  
  
  

  Patients receiving efavirenz should be alerted to the potential for additive central nervous system effects when efavirenz 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.
  ,
  6.1 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 efavirenz 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 efavirenz-treated patients in two controlled clinical trials are presented in Table 2.

  
  
  

  Table 2: Selected Treatment-Emergent^aAdverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364

  	Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients			Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
  Adverse Reactions	Efavirenzb+ ZDV/LAM (n=412) 180 weeksc	Efavirenzb+ Indinavir (n=415) 102 weeksc	Indinavir + ZDV/LAM (n=401) 76 weeksc	Efavirenzb+ Nelfinavir + NRTIs (n=64) 71.1 weeksc	Efavirenzb+ NRTIs (n=65) 70.9 weeksc	Nelfinavir + NRTIs (n=66) 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%

  ^aIncludes 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.

  ^bEfavirenz provided as 600 mg once daily.

  ^cMedian duration of treatment.

  ^dIncludes 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 efavirenz 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 (5.6)]

  . 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 Symptoms^a,b

  
  
  

  Percent of Patients with:	Efavirenz 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

  ^aIncludes events reported regardless of causality.

  ^bData 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 efavirenz. In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with efavirenz 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 efavirenz 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 efavirenz-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz-treated patients and 0.3% for control groups

  [see Warnings and Precautions (5.8)]

  .

  
  
  

  Experience with efavirenz 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 efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.

  
  
  

  Laboratory Abnormalities

  
  
  

  Selected Grade 3 to 4 laboratory abnormalities reported in ≥2% of efavirenz-treated patients in two clinical trials are presented in Table 4.

  
  
  

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

  		Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients			Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
  Variable	Limit	Efavirenza + ZDV/LAM (n=412) 180 weeksb	Efavirenza + Indinavir (n=415) 102 weeksb	Indinavir + ZDV/LAM (n=401) 76 weeksb	Efavirenza + Nelfinavir + NRTIs (n=64) 71.1 weeksb	Efavirenza+ 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%

  ^aEfavirenz provided as 600 mg once daily.

  ^bMedian duration of treatment.

  ^cIsolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity.

  ^dNonfasting.

  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 efavirenz-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 efavirenz 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 efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders

  [see Warnings and Precautions (5.9)]

  .

  
  
  

  Lipids

  
  
  

  Increases from baseline in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + 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 efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown

  [see Warnings and Precautions (5.11)]

  .

  
  
  

  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 efavirenz 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 (i.e., more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash

  [see Warnings and Precautions (5.8)]

  .
  ,
  17 PATIENT COUNSELING INFORMATION

  Advise the patient to read the FDA-approved patient labeling .

  
  
  

  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 Efavirenz Capsules.

  
  
  

  Efavirenz 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 efavirenz 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 efavirenz.

  
  
  

  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 efavirenz every day as prescribed. If a patient forgets to take efavirenz, 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.

  
  
  

  Efavirenz must always be used in combination with other antiretroviral drugs. Advise patients to take efavirenz on an empty stomach, preferably at bedtime. Taking efavirenz 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 efavirenz dosing schedule for infants and young children.
  
  
  
  For adult and pediatric patients who cannot swallow capsules, 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

  
  
  

  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 efavirenz

  [see

  Warnings and Precautions (5.6)

  ].

  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 efavirenz 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 efavirenz therapy

  [see

  Warnings and Precautions (5.6)

  ]

  .
  
  
  
  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 efavirenz

  [see

  Warnings and Precautions (5.5)

  ].

  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 (5.8)

  ].

  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 (5.9)

  and

  Adverse Reactions (6.1)

  ]

  .
  
  
  
  Females of Reproductive Potential

  
  
  

  Advise females of reproductive potential to use effective contraception as well as a barrier method during treatment with efavirenz and for 12 weeks after discontinuing efavirenz. Advise patients to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with efavirenz

  [see

  Warnings and Precautions (5.7)

  and

  Use in Specific Populations (8.1

  ,

  8.3

  )]

  .

  
  
  

  Pregnancy Exposure Registry

  
  
  

  Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy

  [see

  Use in Specific Populations (8.1)

  ]

  .

  
  
  

  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 (5.13)

  ].
  
  

  
  
  Dispense with Patient Information available at:

  www.aurobindousa.com/medication-guides
  )
• Embryo-Fetal Toxicity:
  Avoid administration in the first trimester of pregnancy as fetal harm may occur. (
  5.7 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 efavirenz to avoid pregnancy

  [see Use in Specific Populations (8.1and 8.3)].
  ,
  8.1 Pregnancy

  Pregnancy Exposure Registry

  
  
  

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz 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% to 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.
  )
• Hepatotoxicity:
  Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease. (
  5.9 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 efavirenz. 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.
  
  
  
  Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving efavirenz

  [see

  Adverse Reactions (6.1)

  and

  Use in Specific Populations (8.6)

  ].
  
  
  
  

  Monitoring of liver enzymes before and during treatment is recommended for all patients

  [see

  Dosage and Administration (2.1)

  ]

  . Consider discontinuing efavirenz in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range.
  
  
  
  Discontinue efavirenz if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation.
  ,
  6.1 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 efavirenz 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 efavirenz-treated patients in two controlled clinical trials are presented in Table 2.

  
  
  

  Table 2: Selected Treatment-Emergent^aAdverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364

  	Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients			Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
  Adverse Reactions	Efavirenzb+ ZDV/LAM (n=412) 180 weeksc	Efavirenzb+ Indinavir (n=415) 102 weeksc	Indinavir + ZDV/LAM (n=401) 76 weeksc	Efavirenzb+ Nelfinavir + NRTIs (n=64) 71.1 weeksc	Efavirenzb+ NRTIs (n=65) 70.9 weeksc	Nelfinavir + NRTIs (n=66) 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%

  ^aIncludes 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.

  ^bEfavirenz provided as 600 mg once daily.

  ^cMedian duration of treatment.

  ^dIncludes 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 efavirenz 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 (5.6)]

  . 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 Symptoms^a,b

  
  
  

  Percent of Patients with:	Efavirenz 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

  ^aIncludes events reported regardless of causality.

  ^bData 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 efavirenz. In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with efavirenz 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 efavirenz 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 efavirenz-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz-treated patients and 0.3% for control groups

  [see Warnings and Precautions (5.8)]

  .

  
  
  

  Experience with efavirenz 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 efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.

  
  
  

  Laboratory Abnormalities

  
  
  

  Selected Grade 3 to 4 laboratory abnormalities reported in ≥2% of efavirenz-treated patients in two clinical trials are presented in Table 4.

  
  
  

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

  		Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients			Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
  Variable	Limit	Efavirenza + ZDV/LAM (n=412) 180 weeksb	Efavirenza + Indinavir (n=415) 102 weeksb	Indinavir + ZDV/LAM (n=401) 76 weeksb	Efavirenza + Nelfinavir + NRTIs (n=64) 71.1 weeksb	Efavirenza+ 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%

  ^aEfavirenz provided as 600 mg once daily.

  ^bMedian duration of treatment.

  ^cIsolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity.

  ^dNonfasting.

  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 efavirenz-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 efavirenz 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 efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders

  [see Warnings and Precautions (5.9)]

  .

  
  
  

  Lipids

  
  
  

  Increases from baseline in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + 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 efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown

  [see Warnings and Precautions (5.11)]

  .

  
  
  

  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 efavirenz 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 (i.e., more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash

  [see Warnings and Precautions (5.8)]

  .
  ,
  8.6 Hepatic Impairment

  Efavirenz 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 efavirenz to these patients

  [see

  Warnings and Precautions (5.9)

  and

  Clinical Pharmacology (12.3)

  ]

  .
  )
• Rash:
  Rash usually begins within 1 to 2 weeks after initiating therapy and resolves within 4 weeks. Discontinue if severe rash develops. (
  5.8 Rash

  In controlled clinical trials, 26% (266/1008) of adult patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups

  [see

  Adverse Reactions (6.1)]

  . Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with efavirenz. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult patients treated with efavirenz 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 efavirenz

  [see Adverse Reactions (6.2)].

  Two pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 28 days (range 3 to 1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz in pediatric patients should be considered.
  
  
  
  Efavirenz can generally be reinitiated in patients interrupting therapy because of rash. Efavirenz 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 (4)].
  ,
  6.1 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 efavirenz 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 efavirenz-treated patients in two controlled clinical trials are presented in Table 2.

  
  
  

  Table 2: Selected Treatment-Emergent^aAdverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364

  	Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients			Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
  Adverse Reactions	Efavirenzb+ ZDV/LAM (n=412) 180 weeksc	Efavirenzb+ Indinavir (n=415) 102 weeksc	Indinavir + ZDV/LAM (n=401) 76 weeksc	Efavirenzb+ Nelfinavir + NRTIs (n=64) 71.1 weeksc	Efavirenzb+ NRTIs (n=65) 70.9 weeksc	Nelfinavir + NRTIs (n=66) 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%

  ^aIncludes 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.

  ^bEfavirenz provided as 600 mg once daily.

  ^cMedian duration of treatment.

  ^dIncludes 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 efavirenz 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 (5.6)]

  . 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 Symptoms^a,b

  
  
  

  Percent of Patients with:	Efavirenz 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

  ^aIncludes events reported regardless of causality.

  ^bData 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 efavirenz. In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with efavirenz 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 efavirenz 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 efavirenz-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz-treated patients and 0.3% for control groups

  [see Warnings and Precautions (5.8)]

  .

  
  
  

  Experience with efavirenz 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 efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.

  
  
  

  Laboratory Abnormalities

  
  
  

  Selected Grade 3 to 4 laboratory abnormalities reported in ≥2% of efavirenz-treated patients in two clinical trials are presented in Table 4.

  
  
  

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

  		Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients			Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
  Variable	Limit	Efavirenza + ZDV/LAM (n=412) 180 weeksb	Efavirenza + Indinavir (n=415) 102 weeksb	Indinavir + ZDV/LAM (n=401) 76 weeksb	Efavirenza + Nelfinavir + NRTIs (n=64) 71.1 weeksb	Efavirenza+ 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%

  ^aEfavirenz provided as 600 mg once daily.

  ^bMedian duration of treatment.

  ^cIsolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity.

  ^dNonfasting.

  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 efavirenz-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 efavirenz 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 efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders

  [see Warnings and Precautions (5.9)]

  .

  
  
  

  Lipids

  
  
  

  Increases from baseline in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + 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 efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown

  [see Warnings and Precautions (5.11)]

  .

  
  
  

  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 efavirenz 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 (i.e., more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash

  [see Warnings and Precautions (5.8)]

  .
  ,
  17 PATIENT COUNSELING INFORMATION

  Advise the patient to read the FDA-approved patient labeling .

  
  
  

  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 Efavirenz Capsules.

  
  
  

  Efavirenz 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 efavirenz 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 efavirenz.

  
  
  

  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 efavirenz every day as prescribed. If a patient forgets to take efavirenz, 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.

  
  
  

  Efavirenz must always be used in combination with other antiretroviral drugs. Advise patients to take efavirenz on an empty stomach, preferably at bedtime. Taking efavirenz 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 efavirenz dosing schedule for infants and young children.
  
  
  
  For adult and pediatric patients who cannot swallow capsules, 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

  
  
  

  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 efavirenz

  [see

  Warnings and Precautions (5.6)

  ].

  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 efavirenz 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 efavirenz therapy

  [see

  Warnings and Precautions (5.6)

  ]

  .
  
  
  
  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 efavirenz

  [see

  Warnings and Precautions (5.5)

  ].

  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 (5.8)

  ].

  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 (5.9)

  and

  Adverse Reactions (6.1)

  ]

  .
  
  
  
  Females of Reproductive Potential

  
  
  

  Advise females of reproductive potential to use effective contraception as well as a barrier method during treatment with efavirenz and for 12 weeks after discontinuing efavirenz. Advise patients to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with efavirenz

  [see

  Warnings and Precautions (5.7)

  and

  Use in Specific Populations (8.1

  ,

  8.3

  )]

  .

  
  
  

  Pregnancy Exposure Registry

  
  
  

  Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy

  [see

  Use in Specific Populations (8.1)

  ]

  .

  
  
  

  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 (5.13)

  ].
  
  

  
  
  Dispense with Patient Information available at:

  www.aurobindousa.com/medication-guides
  )
• Convulsions:
  Use caution in patients with a history of seizures. (
  5.10 Convulsions

  Convulsions have been observed in adult and pediatric patients receiving efavirenz, generally in the presence of known medical history of seizures

  [s

  ee

  Nonclinical Toxicology (13.2)

  ].

  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 (7.1)

  ]

  .
  )
• Lipids:
  Total cholesterol and triglyceride elevations. Monitor before therapy and periodically thereafter. (
  5.11 Lipid Elevations

  Treatment with efavirenz has resulted in increases in the concentration of total cholesterol and triglycerides

  [see Adverse Reactions (6.1)].

  Cholesterol and triglyceride testing should be performed before initiating efavirenz therapy and at periodic intervals during therapy.
  )
• Immune reconstitution syndrome:
  May necessitate further evaluation and treatment. (
  5.12 Immune Reconstitution Syndrome

  Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz. 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.
  )
• Redistribution/accumulation of body fat:
  Observed in patients receiving antiretroviral therapy. (
  5.13 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.
  ,
  17 PATIENT COUNSELING INFORMATION

  Advise the patient to read the FDA-approved patient labeling .

  
  
  

  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 Efavirenz Capsules.

  
  
  

  Efavirenz 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 efavirenz 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 efavirenz.

  
  
  

  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 efavirenz every day as prescribed. If a patient forgets to take efavirenz, 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.

  
  
  

  Efavirenz must always be used in combination with other antiretroviral drugs. Advise patients to take efavirenz on an empty stomach, preferably at bedtime. Taking efavirenz 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 efavirenz dosing schedule for infants and young children.
  
  
  
  For adult and pediatric patients who cannot swallow capsules, 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

  
  
  

  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 efavirenz

  [see

  Warnings and Precautions (5.6)

  ].

  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 efavirenz 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 efavirenz therapy

  [see

  Warnings and Precautions (5.6)

  ]

  .
  
  
  
  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 efavirenz

  [see

  Warnings and Precautions (5.5)

  ].

  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 (5.8)

  ].

  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 (5.9)

  and

  Adverse Reactions (6.1)

  ]

  .
  
  
  
  Females of Reproductive Potential

  
  
  

  Advise females of reproductive potential to use effective contraception as well as a barrier method during treatment with efavirenz and for 12 weeks after discontinuing efavirenz. Advise patients to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with efavirenz

  [see

  Warnings and Precautions (5.7)

  and

  Use in Specific Populations (8.1

  ,

  8.3

  )]

  .

  
  
  

  Pregnancy Exposure Registry

  
  
  

  Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy

  [see

  Use in Specific Populations (8.1)

  ]

  .

  
  
  

  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 (5.13)

  ].
  
  

  
  
  Dispense with Patient Information available at:

  www.aurobindousa.com/medication-guides
  )