Efavirenz is a human immunodeficiency virus type 1 (HIV-1) specific, non-nucleoside reverse transcriptase inhibitor (NNRTI). Efavirenz is chemically described as (S)-6-chloro-(cyclopropylethynyl)-1, 4-dihydro-4-(trifluoromethyl)-2H-3, 1-benzoxazin-2-one. Its empirical formula is C14 H9 ClF3 NO2. Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (<10 µg/mL).
Mechanism of action: Efavirenz is a non-nucleoside reverse transcriptase (RT) inhibitor of human immunodeficiency virus type 1 (HIV-1). Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 RT. HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma, and delta are not inhibited by Efavirenz.
Pharmacokinetics: Food increases the absorption of Efavirenz. A mean increase of 28% for AUC and 79% for Cmax is seen when administered with food. Total protein binding is 99%. Elimination half-life is 52 to 76 hours after a single dose. Efavirenz is metabolized in the liver via the cytochrome P450 system (P450CYP3A4 and P450CYP2B6). Efavirenz can induce its own metabolism. Renal excretion is 14% to 34%. The majority is excreted as changed drug. Excretion in feces is 16 % to 61%.
Efavirenz in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection.
|Table. 1 Pediatric dose of Efavirenz oral solution to be administered once daily|
3 years to < 5 years
aged 5 years or more
|13 to < 15||12||9|
|15 to < 20||13||10|
|20 to < 25||15||12|
Efavirenz is contraindicated in patients with clinically significant hypersensitivity to any of its components. 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).
|Table 2. Drugs That Should Not Be Co-administered With Efavirenz|
|Drug Class||Drugs Within Class Not To Be Coadministered With Efavirenz|
|GI Motility Agents||cisapride|
|Established Drug Interactions|
|Drug Name||Effect||Clinical Comment|
|Clarithromycin||Decreased clarithromycin concentration||Increased 14-OH metabolite concentration Plasma concentrations decreased by Efavirenz; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving Efavirenz and clarithromycin. No dose adjustment of Efavirenz is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs, following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with Efavirenz.|
|Indinavir||Decreased indinavir concentration||Increase indinavir dose from 800 mg to 1000 mg every 8 hours.|
|Methadone||Decreased methadone concentration||Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.|
|Ethinyl estradiol||Increased ethinyl estradiol concentration||Plasma concentrations increased by Efavirenz (Efavirenz); clinical significance unknown. Because the potential interaction of Efavirenz with oral contraceptives has not been fully characterized, a reliable method of barrier contraception should be used in addition to oral contraceptives.|
|Rifabutin||Decreased rifabutin concentration||Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.|
|Rifampin||Decreased Efavirenz concentration||Clinical significance of reduced Efavirenz concentrations unknown.|
|Ritonavir||Increased ritonavir concentration||Increased Efavirenz concentration Combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when Efavirenz is used in combination with ritonavir.|
|Saquinavir||Decreased saquinavir concentration||Should not be used as sole protease inhibitor in combination with Efavirenz|
|Other potentially clinically significant drug or herbal product interactions with Efavirenz|
|Anticoagulants: Warfarin||Plasma concentrations and effects potentially increased or decreased by Efavirenz|
|Anticonvulsants: Phenytoin, Phenobarbital ,Carbamazepine||Potential for reduction in anticonvulsant and/or Efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.|
|Antifungals: Itraconazole, Ketoconazole||Drug interaction studies with Efavirenz and these imidazole and triazole antifungals have not been conducted. Efavirenz has the potential to decrease plasma concentrations of itraconazole and ketoconazole.|
|Anti-HIV protease inhibitors:|
| No pharmacokinetic data are available.
Efavirenz has the potential to decrease serum concentrations of amprenavir.
|Non-nucleoside reverse transcriptase inhibitors||No studies have been performed with other NNRTIs.|
|St John's wort (hypericum perforatum)||Expected to substantially decrease plasma levels of Efavirenz; has not been studied in combination with Efavirenz.|
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. Increases in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving Efavirenz. Other side effects are allergic reactions, asthenia, abnormal coordination, ataxia, convulsions, hypoesthesia, paraesthesia, neuropathy, tremor, gynaecomastia, constipation, malabsorption, flushing, palpitations, hepatic enzyme increase, hepatic failure, hypercholesterolaemia, hypertriglyceridaemia, arthralgia, myalgia, myopathy aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, dyspnoea, erythema multiforme, nail disorders, skin discoloration, Stevens-Johnson Syndrome, abnormal vision, tinnitus
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.