Prescribing Information:

For the use of a Registered Medical Practitioner or Hospital or Laboratory only.

Efavirenz Oral Solution


Composition:

EFCURE SOLUTION
Each ml contains:Efavirenz - 30 mg

Description:

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).


Clinical pharmacology:

  • 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%.


Indication:

Efavirenz in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection.


Dosage and Administration:

Table.1 describes the dose of Efavirenz oral solution for pediatric patients 3 years of age and older.

Table. 1 Pediatric dose of Efavirenz oral solution to be administered once daily
Body Weight(Kg)Children
3 years to < 5 years
Children
aged 5 years or more
Dose (ml)
13 to < 15 12 9
15 to < 20 13 10
20 to < 25 15 12

Contraindications:

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).


Warnings and Precautions:

General: 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: Patients should be informed that rash is another common side effect seen with Efavirenz. However, these rashes usually go away without any change in treatment. In a small number of patients, rash may be serious. Patients should be advised that they should contact their physician promptly if they develop a rash.

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 and were not predictive of subsequent onset of the less frequent psychiatric symptoms. 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.

Convulsions: Convulsions have been observed infrequently in patients receiving Efavirenz, generally in the presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin, carbamazepine and Phenobarbital, may require periodic monitering of plasma levels. Caution must be taken in any patient with a history of seizures.

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 persistent elevations of serum transaminases to greater than 5 times the upper limit of normal range, 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.

Cholesterol: Monitoring of cholesterol and triglycerides should be considered in patients treated with Efavirenz.

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.

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.

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 table 2.

Table 2. Drugs That Should Not Be Co-administered With Efavirenz
Drug Class  Drugs Within Class Not To Be Coadministered With Efavirenz
Antihistamines   astemizole
Benzodiazepines   midazolam, triazolam
GI Motility Agents   cisapride
Anti-Migraine   ergot derivatives
Established Drug Interactions
Drug Name EffectClinical 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.
IndinavirDecreased indinavir concentration Increase indinavir dose from 800 mg to 1000 mg every 8 hours.
MethadoneDecreased 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.
RifabutinDecreased 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, KetoconazoleDrug 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:
Saquinavir/ritonavir combination

Amprenavir

No pharmacokinetic data are available.

Efavirenz has the potential to decrease serum concentrations of amprenavir.

Non-nucleoside reverse transcriptase inhibitorsNo 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.

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. 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


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.


Storage:


Presentation: