Contraindications
Efavir is contraindicated in patients with clinically significant hypersensitivity to the active substance or to any of the excipients.
Efavirenz should not be used in patients with severe hepatic impairment (Child Pugh Grade C).
Efavirenz must not be administered concurrently with astemizole, cisapride, midazolam, triazolam or ergot alkaloids because competition for the cytochrome P450 3A4 enzyme by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious and/or life-threatening adverse events (for example, cardiac arrhythmias, prolonged sedation or respiratory depression).

Warnings and Precautions
Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors, resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agent(s) to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance.
Psychiatric symptoms
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. These include severe depression, suicidal ideation/attempts, aggressive behaviour, paranoid reactions and manic reactions. Patients with a prior history of psychiatric disorders appear to be at greater risk for these psychiatric adverse experiences. 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 risk of continued therapy outweighs the benefits.
Rash
Rash associated with blistering, moist desquamation or ulceration has been reported in clinical trials. The incidence of erythema multiforme or Stevens-Johnson Syndrome was approximately 0.1%. The median time to onset of rash in adults was 11 days and the median duration 16 days. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Efavirenz must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with efavirenz is discontinued, consideration should also be given to interrupting therapy with other antiretroviral agents to avoid development of resistant virus.
Nervous system symptoms
These include dizziness, insomnia, impaired concentration, somnolence, abnormal dreams and hallucinations.
Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2-4 weeks. Patients should be informed that these common symptoms were likely to improve with continued therapy. Dosing at bedtime seems to improve the tolerability of these symptoms and can be recommended during the first weeks of therapy and in patients who continue to experience these symptoms. Patients should be altered 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.
Liver enzymes
In patients with known or suspected history of hepatitis B or C infection and in patients treated with other mediations associated with liver toxicity, monitoring of liver enzymes is recommended. In patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of normal, the benefit of continued therapy with efavirenz needs to be weighed against the unknown risks of significant liver toxicity.
Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution must be exercised in administering efavirenz to these patients.
Renal impairment
The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency. However, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
Cholesterol
Monitoring of cholesterol should be considered in patients treated with efavirenz.

Drug Interactions
Efavirenz is an inducer of CYP3A4 in vivo. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19 and 3A4 isoenzymes in the range of observed efavirenz concentrations. Coadministration of efavirenz with drugs primarily metabolized by these isoenzymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs.
Drugs which induce CYP3A4 activity (e.g. Phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interactions with efavirenz are summarized in the following table:

Table: Drugs That Should Not Be Coadministered with Efavirenz

Indinavir
It is recommended to increase the dose of indinavir from 800 mg every 8 hours to 1000 mg every 8 hours when efavirenz and indinavir are co-administered.
Nelfinavir
No dose adjustment is necessary when nelfinavir is administered in combination with efavirenz.
Amprenavir
Efavirenz has the potential to decrease serum concentrations of amprenavir.
Ritonavir
The combination of ritonavir and efavirenz was associated with a higher frequency of adverse clinical experiences (for example, dizziness, nausea, paraesthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when efavirenz is used in combination with ritonavir.
Saquinavir
When saquinavir (1,200 mg q 8 h, soft capsule formulation) was given with efavirenz, the saquinavir AUC and Cmax were decreased by 62% and 50% respectively. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended.
Saquinavir/Ritonavir
No data is available on the potential interactions of efavirenz with the combination of saquinavir and ritonavir.
Rifampin
Rifampin (600 mg daily) reduced efavirenz AUC by 26% and Cmax by 20% in 12 uninfected volunteers. The clinical significance of the reduced efavirenz levels is not known. No dose adjustment of rifampin is recommended when given with efavirenz.
Clarithromycin
Efavirenz significantly affects the pharmacokinetics of clarithromycin. 46% of uninfected volunteers developed rash while receiving efavirenz and clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered.
Oral contraceptives
Because the potential interaction of efavirenz with oral contraceptives has not been fully characterized, a reliable method of barrier contraception must be used in addition to oral contraceptives.
Pregnancy
Category C. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations. Because teratogenic effects have been seen in primates at efavirenz exposures similar to those seen in the clinic at the recommended dose, pregnancy should be avoided in women receiving efavirenz. Barrier contraception should always be used in combination with the other methods of contraception (e.g. oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing prior to initiation of efavirenz.
There are no adequate and well-controlled studies in pregnant women. Efavirenz should be used during pregnancy only if the potential benefit justifies the potential role to the fetus, such as in pregnant women without other therapeutic options.
Lactation
Since animal data suggests that efavirenz may be passed into breast milk, it is recommended that mothers taking efavirenz do not breast feed their infants. It has also been recommended that HIV-infected women do not breast feed their infants in order to avoid transmission of HIV.

Side effects
The most significant adverse events observed in patients treated with efavirenz are nervous system symptoms, psychiatric symptoms and rash.
A few cases of pancreatitis have been described, 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. Increases in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving efavirenz. Additional post-marketing surveillance data reveals the following side effects:
Body as a Whole: allergic reactions, asthenia
Central and Peripheral Nervous System:
abnormal coordination, ataxia, convulsions, hypoesthesia, paresthesia, neuropathy, tremor
Endocrine: gynaecomastia
Gastrointestinal: constipation, malabsorption
Cardiovascular: flushing, palpitations
Liver and Biliary System: hepatic enzyme increase, hepatic failure
Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia
Musculoskeletal: arthralgia, myalgia, myopathy
Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide
Respiratory: dyspnea
Skin and Appendages: erythema multiforme, nail disorders, skin discoloration, Stevens-Johnson Syndrome.
Special Senses: abnormal vision, tinnitus

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

Presentation
Efavir-200 Container of 30 capsules