STOCRIN * is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1).

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

Adults: The recommended dosage of STOCRIN in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs) is 600 mg orally, once daily. STOCRIN 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 (see X. SIDE EFFECTS).

Concomitant Antiretroviral Therapy: STOCRIN must be given in combination with other antiretroviral medications (see IX. and XXI. DRUG INTERACTIONS).

Adolescents and children (17 years and under): The recommended dose of STOCRIN in combination with a protease inhibitor and/or NRTIs for patients 17 years of age and under is described in Table 1. STOCRIN capsules or tablets should only be administered to children who are able to reliably swallow capsules or tablets. STOCRIN capsules, tablets and oral solution may be taken with or without food, as desired. STOCRIN has not been adequately studied in children under the age of 3 years or children weighing less than 13 Kg. STOCRIN tablets are not suitable for children weighing less than 40 kg, STOCRIN capsules or oral solution are available for these patients.

Table 1
Pediatric Dose to be Administered Once Daily

* STOCRIN oral solution is less bioavailable than the hard capsule on a mg per mg basis of efavirenz. The dose recommendations above have been adjusted to take into account the difference in bioavailability.

STOCRIN is contraindicated in patients with clinically significant hypersensitivity to any of its components.

STOCRIN should not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, 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].

STOCRIN must not be used as a single agent to treat HIV or added on as a sole agent to a failing
regimen.

When prescribing drugs concomitantly with STOCRIN, 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 (see VI. PREGNANCY and XIXd. Development); therefore, pregnancy should be avoided in women receiving STOCRIN. Barrier contraception should always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives) (see IX. and XXI. DRUG INTERACTIONS).

Skin Rash: Mild-to-moderate rash has been reported in clinical trials with STOCRIN and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 1% of patients treated with STOCRIN. The incidence of erythema multiforme or Stevens-Johnson Syndrome was 0.14%. STOCRIN should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with STOCRIN is discontinued, consideration should also be given to interrupting therapy with other anti-retroviral agents to avoid development of drug resistant virus (see X. SIDE EFFECTS).

Rash was reported in 26 of 57 children (46%) treated with STOCRIN and was severe in 3 patients (5%). Prophylaxis with appropriate antihistamines prior to initiating therapy with STOCRIN in children may be considered.

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 occasional post-marketing 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. 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 (see X. SIDE EFFECTS).

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 (see X. SIDE EFFECTS ). Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2 to 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.

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 STOCRIN to patients with liver disease.

The pharmacokinetics of efavirenz have 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.

STOCRIN 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.

Convulsions have been observed rarely in patients receiving efavirenz, including in the presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolised by the liver, such as carbamazepine, phenytoin and phenobarbital, may require periodic monitoring 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 the normal range, the benefit of continued therapy with STOCRIN needs to be weighed against the unknown risks of significant liver toxicity. (See X. SIDE EFFECTS.)

Cholesterol: Monitoring of cholesterol should be considered in patients treated with STOCRIN (see X. SIDE EFFECTS).

(For animal data, see Alternative Section XIXe.)

There are no adequate and well controlled studies in pregnant women. Efavirenz should not be used during pregnancy unless clearly necessary (the potential benefit to the mother outweighs the potential risk to the foetus and there are no other appropriate treatment options). Pregnancy should be avoided in women receiving efavirenz. Barrier contraception should always be used in combination with other methods of contraception (for example oral or other hormonal contraceptives).

It is not 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 recommend that HIV-infected women do not breast feed their infants under any circumstances in order to avoid transmission of HIV.

(For alternative version, see Alternative Section XX.)

STOCRIN has not been studied in pediatric patients below 3 years of age or who weigh less than 13 Kg. STOCRIN tablets are not suitable for children weighing less than 40 kg, STOCRIN capsules or oral solution are available for these patients.

(For alternative version including all drug interaction studies, see Alternative Section XXI.)

Efavirenz is an inducer of CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with STOCRIN.

Indinavir: When indinavir (800 mg every 8 hours) was given with STOCRIN, the indinavir AUC and Cmax were decreased by approximately 31% and 16%, respectively as a result of enzyme induction. Therefore, the dose of indinavir should be increased from 800 mg to 1000 mg every 8 hours when STOCRIN and indinavir are coadministered. No adjustment of the dose of
STOCRIN is necessary when given with indinavir.

Ritonavir: When STOCRIN 600 mg (given once daily at bedtime) and ritonavir 500 mg (given every 12 hours) was studied in uninfected volunteers 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 STOCRIN is used in combination with ritonavir.

Saquinavir: When saquinavir (1200 mg given 3 times a day, soft gel formulation) was given with STOCRIN, the saquinavir AUC and Cmax were decreased by 62% and 45-50%, respectively. Use of STOCRIN in combination with saquinavir as the sole protease inhibitor is not recommended.

Rifamycins: Rifampin reduced efavirenz AUC by 26% and Cmax by 20% in 12 uninfected volunteers. The dose of STOCRIN should be increased to 800 mg/day when taken with rifampin. No dose adjustment of rifampin is recommended when given with STOCRIN. Rifabutin has not been studied in combination with STOCRIN. In one study in uninfected volunteers, efavirenz induced a reduction in rifabutin Cmax and AUC by 32% and 38% respectively and increased rifabutin clearance. Rifabutin had no significant effect on the pharmacokinetics of efavirenz. These data suggest that 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 STOCRIN once daily with clarithromycin given as 500 mg every 12 hours for seven days resulted in a significant effect of efavirenz on the pharmacokinetics of clarithromycin. The AUC and Cmax of clarithromycin decreased 39% and 26%, respectively, while the AUC and Cmax of the clarithromycin hydroxymetabolite were increased 34% and 49%, respectively, when used in combination with STOCRIN. The clinical significance of these changes in clarithromycin plasma levels is not known. In uninfected volunteers 46% developed rash while receiving STOCRIN and clarithromycin. No dose adjustment of STOCRIN is recommended when given with clarithromycin. Alternatives to clarithromycin should be considered.

Oral Contraceptives: Only the ethinylestradiol component of oral contraceptives has been studied. The AUC following a single dose of ethinylestradiol was increased (37%) by efavirenz. No significant changes were observed in Cmax of ethinylestradiol. The clinical significance of these effects is not known. No effect of a single dose of ethinylestradiol on efavirenz Cmax or AUC was observed. 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.

Anticonvulsants: Drug interactions studies have not been conducted between efavirenz and anticonvulsants. When efavirenz is administered concomitantly with anticonvulsants such as carbamazepine, phenytoin or phenobarbital there is the potential for reduction in the plasma concentrations of each agent; therefore, periodic monitoring of plasma levels may be required.

Methadone: In a study of HIV-infected IV drug users, co-administration of efavirenz with methadone resulted in decreased plasma levels of methadone and signs of opiate withdrawal. The 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.

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.

Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected volunteers who received STOCRIN. False positive test results 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.

Efavirenz was generally well tolerated in clinical trials. Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 patients who received 600-mg efavirenz daily in combination with protease inhibitors and/or NRTIs in controlled clinical studies, the most frequently reported treatment-related undesirable effects of at least moderate severity reported in at least 5% of patients were rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%). Nausea was reported with a higher frequency in the control groups. The most notable undesirable effects associated with efavirenz are rash and nervous system symptoms (see V. PRECAUTIONS.)

Other, less frequent, clinically significant treatment-related undesirable effects reported in all clinical trials include: allergic reaction, abnormal coordination, ataxia, confusion, stupor, vertigo, vomiting, diarrhoea, hepatitis, impaired concentration, insomnia, anxiety, abnormal dreams, somnolence, depression, abnormal thinking, agitation, amnesia, delirium, emotional lability, euphoria, hallucination, and psychosis.

Additional undesirable effects reported in post-marketing surveillance include neurosis paranoid reaction, convulsions, pruritus, abdominal pain and blurred vision.

The type and frequency of undesirable effects in children was generally similar to that of adult patients with the exception that rash was reported more frequently in children and was more often of higher grade than in adults.

Rash: In clinical trials, 26% of patients treated with 600 mg of STOCRIN experienced skin rash compared with 17% of patients treated in control groups. Skin rash was considered treatment-related in 18% of patients treated with STOCRIN. Severe rash occurred in less than 1% of patients treated with STOCRIN and 1.7% discontinued therapy because of rash. The incidence of erythema multiforme or Stevens-Johnson Syndrome was 0.14%.

Rash was reported in 26 of 57 children (46%) treated with efavirenz and was severe in 3 patients (5%). Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered.

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first two weeks of initiating therapy with STOCRIN. In most patients rash resolves with continuing therapy with STOCRIN within one month. STOCRIN can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when STOCRIN is restarted (see V. PRECAUTIONS).

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

Psychiatric Symptoms: Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1,008 patients treated with regimens containing efavirenz for an average of 1.6 years and 635 patients treated with control regimens for an average of 1.3 years, the frequency of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, were: severe depression (1.6%, 0.6%), suicidal ideation (0.6%, 0.3%), non-fatal suicide attempts (0.4%, 0%), aggressive behavior (0.4%, 0.3%), paranoid reactions (0.4%, 0.3%) and manic reactions (0.1%, 0%). Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse experiences, with the frequency of each of the above events ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation. There have also been occasional post-marketing 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.

Nervous System Symptoms: Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration, and abnormal dreaming are frequently reported side effects in patients receiving STOCRIN 600 mg daily in clinical trials. In controlled clinical trials where 600 mg STOCRIN was administered with other antiretroviral agents, 19.4% of patients experienced nervous system symptoms of moderate-to-severe intensity compared to 9% of patients receiving control regimens. These symptoms were severe in 2.0% of patients receiving STOCRIN 600 mg daily and in 1.3% of patients receiving control regimens. In clinical trials 2.1% of patients treated with 600 mg of STOCRIN discontinued therapy because of nervous system symptoms.

Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2-4 weeks. In one clinical study, the monthly prevalence of nervous system symptoms of at least moderate severity between weeks 4 and 48, ranged from 5%-9% in patients treated with regimens containing efavirenz and 3%-5% in patients treated with the control regimen. In a study of uninfected volunteers, a representative nervous system symptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Dosing at bedtime improves the tolerability of these symptoms and is recommended during the first weeks of therapy and in patients who continue to experience these symptoms (see III. DOSAGE AND ADMINISTRATION). Dose reduction or splitting the daily dose has not been shown to provide benefit and is not recommended.

Laboratory Abnormalities:
Liver enzymes: Elevations of AST and ALT to greater than five times the upper limit of the normal range were seen in 3% of 1,008 patients treated with 600 mg of efavirenz. Similar elevations were seen in patients treated with control regimens. In 156 patients treated with 600 mg of efavirenz who were seropositive for Hepatitis B and/or C, 7% developed AST levels and 8% developed ALT levels greater than five times the upper limit of the normal range. In 91 patients seropositive for Hepatitis B and/or C treated with control regimens, 5% developed AST elevations and 4% developed ALT elevations to these levels. Elevations of GGT to greater than five times the upper limit of the normal range were observed in 4% of all patients treated with 600 mg of efavirenz and in 10% of patients seropositive for Hepatitis B or C. In patients treated with control regimens, the incidence of GGT elevations to this level was 1.5-2%, irrespective of Hepatitis B or C serology. Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity (see V. PRECAUTIONS).

Lipids: Increases in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving efavirenz. Increases in non-fasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed in patients treated with efavirenz+ZDV+3TC and of approximately 40% and 35%, in patients treated with efavirenz+IDV. The effects of efavirenz on triglycerides and LDL were not well-characterized. The clinical significance of these findings is unknown. (see V. PRECAUTIONS).

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.

Treatment of overdose with STOCRIN 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 drug. There is no specific antidote for overdose with STOCRIN. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.

To be filled in locally.