Viranz

Efavirenz.

Each tablet contains Efavirenz 600 mg.

Pharmacology: Pharmacodynamics: Efavirenz is a selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) with respect to template, primer or nucleoside triphosphates, with a small component of competitive inhibition. HIV-2 RT and human cellular DNA polymerases alpha, beta, gama and omega are not inhibited by concentrations of efavirenz well in excess of those achieved clinically.
Pharmacokinetics: Metabolism: Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism. The degree of CYP3A4 induction is expected to be similar between a 400 mg and 600 mg dose of efavirenz based on pharmacokinetic interaction studies in which daily 400 mg or 600 mg efavirenz doses in combination with indinavir did not appear to cause any further reduction of indinavir compared to a 200 mg dose of efavirenz.
Elimination: Efavirenz has a relatively long terminal half-life of 52 to 76 hours after single doses and 40 - 55 hours after multiple doses. Approximately 14 - 34% of a radiolabelled dose of efavirenz was recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz.

Efavirenz are indicated in antiviral combination treatment of HIV-1 infected adults,adolescents and children.

Adults: The recommended dosage of efavirenz in combination with a protese inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs) is 600 mg orally, once daily. Efavirenz may be taken with or without food, as desired.
In order to improve the tolerability of nervous system side effects, bedtime dosing is recommended during the first two to four weeks of therapy and in patients who continue to experience these symptoms.
Concomitant antiretroviral therapy: Efavirenz must be given in combination with other antiretroviral medications.
Adolescents and children (17 years and under): The recommended dose of Efavirenz in combination with a protease inhibitor and/or NRTIs for patients 17 years of age and under is described in Table as follows. Efavirenz capsules or tablets should only be administered to children who are able to reliably swallow capsules or tablets. Efavirenz capsules or tablets may be taken with or without food, as desired. Efavirenz has not been adequately studied in children under the age of 3 years or children weighing less than 13 kg. (See table.)

Click on icon to see table/diagram/image

Route of administration: Oral.

Symptoms and Treatment of Overdose: 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 of it from blood.

Efavirenz is contraindicated in patients with clinically significant hypersensitivity to any of its components.
Efavirenz should not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot derivatives because competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious and/or life-threatening adverse events (e.g., cardiac arrhythmias, prolonged sedation or respiratory depression).
Efavirenz must not be administered concurrently with the standard doses of voriconazole because efavirenz significantly decreases voriconazole plasma concentrations while voriconazole also significantly increases efavirenz plasma concentrations.

Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events.
When prescribing drugs concomitantly with Efavirenz, physicians should refer to the corresponding manufacturer's product circular.
If any antiretroviral medication in a combination regimen is interrupted because of suspected intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral medications. The antiretroviral medications should be restarted at the same time upon resolution of the intolerance symptoms. Intermittent monotherapy and sequential reintroduction of antiretroviral agents is not advisable because of the increased potential for selection of drug-resistant mutant virus.
Malformations have been observed in foetuses from efavirenz-treated animals; therefore, pregnancy should be avoided in women receiving Efavirenz. Barrier contraception should always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives).
Rash: Mild-to-moderate rash has been reported in clinical trials with Efavirenz and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.14%. Efavirenz should 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 drug resistant virus.
Psychiatric symptoms: Psychiatric adverse experiences have been reported in patients treated with efavirenz. Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse experiences. There have also been post-marketing reports of death by suicide, delusions and psychosis-like behaviour, although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients should be advised that if they experience these symptoms they should contact their doctor immediately 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.
Nervous system symptoms: Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming are frequently reported undesirable effects in patients receiving efavirenz 600 mg daily in clinical studies. 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 if they do occur, these common symptoms are likely to improve with continued therapy and are not predictive of subsequent onset of any of the less frequent psychiatric symptoms.
Seizures: Convulsions have been observed rarely in patients receiving efavirenz, generally in the presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant medicinal products primarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. In a drug interaction study, carbamazepine plasma concentrations were decreased when carbamazepine was co-administered with efavirenz. Caution must be taken in any patient with a history of seizures.
Effect of food: The administration of Efavirenz with food may increase efavirenz exposure and may lead to an increase in the frequency of undesirable effects. This effect may be more evident for the tablets than for the hard capsules. Taking Efavirenz on an empty stomach, preferably at bedtime, can be considered.
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy (CART), including Efavirenz. During the initial phase of treatment, a patient whose immune system responds to CART may mount an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment.
Special populations: Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution should be exercised in administering Efavirenz to patients with liver disease.
The pharmacokinetics of efavirenz has not been studied in patients with renal insufficiency; however, less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
Insufficient numbers of elderly patients have been evaluated in clinical studies to determine whether they respond differently than younger patients.
Efavirenz has not been evaluated in children below 3 years of age or who weigh less than 13 kg. Evidence exists indicating that efavirenz may have altered pharmacokinetics in very young children. For this reason, efavirenz oral solution should not be given to children less than 3 years of age.
Liver enzymes: In patients with known or suspected history of Hepatitis B or C infection and in patients treated with other medications associated with liver toxicity monitoring of liver enzymes is recommended. In patients with persistant elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with Efavirenz needs to be weighed against the unknown risks of significant liver toxicity.
Lipids: Monitoring of lipid levels should be considered in patients treated with Efavirenz.

Pregnancy should be avoided in women treated with efavirenz. Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz. Efavirenz should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus and there are no other appropriate treatment options. If a woman takes efavirenz during the first trimester of pregnancy or becomes pregnant while taking efavirenz, the patient should be informed of the potential harm to the foetus.
There are no adequate and well-controlled studies of efavirenz in pregnant women. It is known whether efavirenz is excreted in human milk. Since animal data suggest that the substance may be passed into breast milk. It is recommended that mothers taking efavirenz do not breast-feed their infants. It is recommended that HIV-infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Like all medicines, efavirenz tablets can have side effects. When treating HIV infection, it is not always possible to tell whether some of the undesirable effects that occur are caused by efavirenz tablets, by other medicines the patients are taking at the same time or by the HIV disease. For this reason it is very important that the patient inform the doctor about any changes in the patient health.
Mild-to-moderate rash may occur when taking efavirenz tablets but it usually resolves with continued therapy.
Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming may occur during the first one or two days of therapy and generally resolve after the first 2 - 4 weeks. These side effects may be reduced if the patient take efavirenz tablets at bedtime on an empty stomach. If the patient have these common side effects, such as dizziness, it does not mean that the patient will also have serious psychiatric problems, such as severe depression, strange thoughts, or angry behavior. Tell the doctor right away if any of these side effects continue or if they bother the patient. It is possible that these symptoms may be more severe if efavirenz tablets are used with alcohol or mood altering (street) drugs. If the patients are dizzy, have trouble concentrating, or are drowsy, avoid activities that may be dangerous, such as driving or operating machinery.
Changes in body fat develop in some patients taking anti-HIV medicine. These changes may include an increased amount of fat in the upper back and neck ("buffalo hump"), in the breasts, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these fat changes are not known.
Other common side effects include tiredness, upset stomach, vomiting and diarrhea.

Efavirenz is an inducer of CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with Efavirenz.
Concomitant Antiretroviral Agents: Amprenavir: when amprenavir (1200 mg every 12 hours) was given with efavirenz (600 mg once daily) in HIV-infected subjects. While the clinical significance of decreased amprenavir concentrations has not been established, the magnitude of the observed pharmacokinetic interaction should be taken into consideration when choosing a regimen containing both efavirenz and amprenavir.
Fosamprenavir calsium: For coadministration with fosamprenavir and ritonavir, the prescribing information for fosamprenavir calcium should be consulted.
Atazanavir: Coadministration of efavirenz 600mg with atazanavir resulted in substantial decreases in atazanavir exposure, necessitating dosage adjustment of atazanavir in combination with ritonavir. Efavirenz concentrations when co-administered with atazanavir and low-dose ritonavir were similar to efavirenz alone, based on comparison with historical data.
Indinavir: The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Ritonavir: When Efavirenz 600 mg (given once daily at bedtime) and ritonavir 500 mg (given every 12 hours) was studied the combination was not well tolerated and was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paraesthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when Efavirenz is used in combination with ritonavir.
Saquinavir: Use of Efavirenz in combination with sequinavir as the sole protease inhibitor is not recommended.
Antimicrobial Agents: Rifamycins: Rifamycins reduced efavirenz. The dose of Efavirenz should be increased to 800 mg/day when taken with rifampin. No dose adjustment of rifampin is recommended when given with Efavirenz. Rifabutin had no significant effect on the pharmacokinetics of efavirenz. The daily dose of rifabutin should be increased by 50% when administered with efavirenz and that the rifabutin dose may be doubled for regimens in which rifabutin is given two or three times a week in combination with efavirenz.
Clarithromycin: Coadministration of 400 mg of Efavirenz once daily with clarithromycin given as 500 mg every 12 hours for seven days resulted in a significant effect of efavirenz. Develop rash while receiving Efavirenz and clarithromycin. No dose adjustment of Efavirenz is recommended when given with clarithromycin. Alternative to clarithromycin should be considered.
Antifungal agents: Voriconazole: Coadministration of 400 mg of Efavirenz (400 mg orally once daily) with voriconazole (200 mg orally every 12 hours) in uninfected volunteers resulted in a 2 way interaction.
Itraconazole: Coadministration of efavirenz (600 mg orally once daily) with itraconazole (200 mg orally every 12 hours). Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
Lipid-lowering agents: Coadministration of efavirenz with the HMG-CoA reductase inhibitors atorvastatin, pravastatin, or simvastatin has been shown to reduce the plasma concentration of the statin in uninfected volunteers. Cholesterol levels should be periodically monitored. Dosage adjustments of statins may be required.
Anticonvulsants: Carbamazepine: Coadministration of efavirenz (600 mg orally once daily) with carbamazepine (400 mg once daily) in uninfected volunteers resulted in a two-way interaction. There are no data with coadministration of higher doses of either medicinal product; therefore, no dose recommendation can be made, and alternative anticonvulsant treatment should be considered.
Other anticonvulsants: No data are available on the potential interactions of efavirenz with phenytoin, Phenobarbital, or other anticonvulsants that are substrates of CYP450 isozymes.
Other Drug Interactions: Oral Contraceptives: 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.
Methadone: Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.
St.John's wort (Hypericum perforatum): Patients on efavirenz should not concomitantly use products containing St. John's wort (Hypericum perforatum) since it may be expected to result in reduced plasma concentrations of efavirenz. This effect is due to an induction of CYP3A4 and may result in loss of therapeutic effect and development of resistance.
Antidepressants: There were no clinically significant effects on pharmacokinetic parameters when paroxetine and efavirenz were coadministered. No dose adjustments are necessary for either efavirenz or paroxetine when these drugs are coadministered. The dose of sertraline should be increased when administered with efavirenz to compensate for the induction of sertraline metabolism by efavirenz. Sertraline dose increases should be guided by clinical response.
Cetirizine: No dose adjustments are necessary for either efavirenz or cetirizine when these drugs are coadministered.
Lorazepam: No dose adjustment is necessary for either efavirenz or lorazepam when these drugs are co-administered.
Calcium channel blockers: Diltiazem dose adjustments should be guided by clinical response (refer to the product circular for diltiazem).
No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of the CYP3A4 enzyme (eg, verapamil, felodepine, nifedipine, nicardipine). When efavirenz is administered concomitantly with one of these agents, there is a potential for reduction in the plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the corresponding manufacturer's product circular for the calcium channel blocker).
Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected volunteers who received Efavirenz. False positive test result have only been observed with the CEDIA DAU Multi-level THC assay, which is used for screening, and have not been observed with other cannabinoid assays tested including tests used for confirmation of positive results.

Store below 30°C. Store in the original package.
Shelf-Life: 36 months.

Antivirals

J05AG03 - efavirenz ; Belongs to the class of non-nucleoside reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

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