ASPEN EFAVIRENZ 600 mg (tablets)
(and dosage form):
ASPEN EFAVIRENZ 600 mg (tablets)
ASPEN EFAVIRENZ 600 mg: Each tablet contains 600 mg Efavirenz.
A.20.2.8 Antiviral agents.
Mechanism of action:
Efavirenz is a selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 HIV-1. Efavirenz diffuses into the cell where it binds adjacent to the active site of reverse transcriptase. This produces a conformational change in the enzyme and inhibits its function. Efavirenz is a noncompetitive 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, gamma and delta are not inhibited by concentrations of efavirenz.
In vitro HIV susceptibility:
The clinical significance of in vitro susceptibility of HIV-1 to efavirenz has not been established. The in vitro antiviral activity of efavirenz was assessed in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures enriched from PBMCs. The 90 to 95% inhibitor concentration (IC90-95) of efavirenz for wild type laboratory adapted strains and clinical isolates ranged from 1,7 to 25 nM. Efavirenz demonstrated synergistic activity in cell culture in combination with the nucleoside analogue reverse transcriptase inhibitors (NRTIs), zidovudine (ZDV) or didanosine (ddi), or the protease inhibitor, indinavir (IDV).
Resistance: HIV-1 isolates with reduced susceptibility to efavirenz (greater than 380- fold increase in IC90) compared to baseline can emerge in vitro. Phenotypic changes in evaluable HIV-1 isolates and genotypic changes in plasma virus from selected patients treated with efavirenz in combination with IDV or with ZDV plus lamivudine were monitored. One or more RT mutations at amino acid positions 100, 101, 103, 108, 190 and 225, were observed in all 62 patients with a frequency of at least 10% compared to baseline. The mutation at RT amino acid position 103 (lysine to asparagines) was the most frequently observed (greater or equal to 90%). A mean loss in susceptibility (IC90) to efavirenz of 47-fold was observed in 26 clinical isolates. Five clinical isolates were evaluated for both genotypic and phenotypic changes from baseline. Decreases in efavirenz susceptibility (range from 9 to greater than 312-fold increase in IC90) were observed for these isolates in vitro compared to baseline. All 5 isolates possessed at least one of the efavirenz-associated RT mutations. The clinical relevance of phenotypic and genotypic changes associated with efavirenz therapy has not been established.
Cross resistance: Rapid emergence of HIV-1 strains that are cross-resistant to nonnucleoside RT inhibitors has been observed in vitro. Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant to nevirapine and delavirdine in vitro compared to baseline. Clinically derived ZDV-resistant HIV-1 isolated and tested in vitro retained susceptibility to efavirenz. Cross-resistance between efavirenz and HIV protease inhibitors is unlikely because of the different enzyme targets involved.
Absorption: Peak efavirenz plasma concentrations of 1,6 9,1 microM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses.
Steady state plasma concentrations are reached in 6 7 days.
Distribution: Efavirenz is very highly bound (approximately 99,5 99,75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients who received efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0,26 to 1,19% (mean 0,69%) of the corresponding plasma concentration. This proportion is approximately three-fold higher than the nonprotein-bound (free) fraction of efavirenz in plasma.
Metabolism: Efavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are inactive against HIV-1. CYP3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism.
Elimination: Efavirenz has a 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 16 61% was recovered in faeces, mainly in the form of metabolites.
The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic 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.
Gender and Race: Pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied.
Geriatric use: Pharmacokinetics of efavirenz have not been studied in subjects aged 65 and over to establish whether they respond differently.
Paediatric use: In 49 paediatric patients receiving the equivalent of a 600 mg dose of efavirenz (dose adjusted from calculated body size based on weight), steady state Cmax was 14,2 microM, steady state Cmin was 5,6 microM, and AUC was 218 microM h. The pharmacokinetics of efavirenz in paediatric patients were similar to adults.
ASPEN EFAVIRENZ, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infected adults, adolescents and children weighing 13 kg and above, and/or 3 years and above.
ASPEN EFAVIRENZ 600 mg tablets are indicated in combination with other antiretroviral agents for treatment of HIV-1 infected adults, adolescents and children weighing greater than or equal to 40 kg.
ASPEN EFAVIRENZ is contra-indicated in patients with hypersensitivity to ASPEN EFAVIRENZ or any of its components.
ASPEN EFAVIRENZ 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].
Pregnancy and lactation (see PREGNANCY AND LACTATION).
Children less than 3 years or weighing less than 13 kg.
ALERT: Find out about medicines that should NOT be taken with ASPEN EFAVIRENZ (see CONTRA-INDICATIONSand SIDE-EFFECTS AND SPECIAL PRECAUTIONS).
Resistant viruses emerge rapidly when ASPEN EFAVIRENZ is administered as monotherapy, therefore, ASPEN EFAVIRENZ must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen.
Serious nervous system and psychiatric symptoms have been reported.
ASPEN EFAVIRENZ is an inducer of CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co-administered with ASPEN EFAVIRENZ.
Indinavir: When indinavir (800 mg every 8 hours) was given with ASPEN EFAVIRENZ (200 mg every 24 hours), the indinavir AUC and Ctrough 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 ASPEN EFAVIRENZ and indinavir are co-administered. No adjustment of the dose of ASPEN EFAVIRENZ is necessary when given with indinavir.
Ritonavir: When ASPEN EFAVIRENZ 600 mg (given once daily at bedtime) and ritonavir 500 mg (given every 12 hours) were studied in infected volunteers, the combination was not well tolerated and was associated with a higher frequency of adverse clinical experiences (for example, dizziness, nausea, paraesthesia and elevated liver enzymes occurred).
Monitoring of liver enzymes is recommended when ASPEN EFAVIRENZ is used in combination with ritonavir.
Saquinavir: When saquinavir (1,200 mg given 3 times a day, soft capsule formulation) was given with ASPEN EFAVIRENZ the saquinavir AUC and Cmax were decreased by 62% and 50% respectively. Use of ASPEN EFAVIRENZ in combination with saquinavir as the sole PI is not recommended.
Rifamycins: Rifampicin reduced ASPEN EFAVIRENZ AUC by 26% and Cmax by 20% in 12 uninfected volunteers. The dose of efavirenz must be increased to 800 mg/day when taken with rifampin. No dose adjustment of rifampicin is recommended when given with ASPEN EFAVIRENZ. Rifabutin has not been studied in combination with ASPEN EFAVIRENZ.
Clarithromycin: Co-administration of 400 mg of ASPEN EFAVIRENZ 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 active clarithromycin hydroxymetabolite were increased 34% and 49%, respectively, when used in combination with ASPEN EFAVIRENZ. The clinical significance of these changes in clarithromycin plasma levels is not known. In uninfected volunteers 46% developed rash while receiving ASPEN EFAVIRENZ and clarithromycin. No dose adjustment of ASPEN EFAVIRENZ is recommended when given with clarithromycin.
Alternatives to clarithromycin may be considered. Oral contraceptives: Only the ethinyloestradiol component of oral contraceptives has been studied. The AUC following a single dose of ethinyloestradiol was increased (37%) after multiple dosing of ASPEN EFAVIRENZ. No significant changes were observed in Cmax of ethinyloestradiol. The clinical significance of these effects is not known. No effect of a single dose of ethinyloestradiol on efavirenz Cmax or AUC was observed. Because the potential interaction of ASPEN EFAVIRENZ with oral contraceptives has not been fully characterised, a reliable method of barrier contraception must be used in addition to oral contraceptives.
Methadone: Co-administration of ASPEN EFAVIRENZ with methadone, in HIV-infected IV drug users, 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 Johns Wort (Hypericum perforatum): Patients on ASPEN EFAVIRENZ should not concomitantly use products containing St. Johns Wort (Hypericum perforatum) since it may be expected to result in reduced plasma concentrations of ASPEN 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: ASPEN EFAVIRENZ does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected volunteers who received ASPEN EFAVIRENZ. 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.
PREGNANCY AND LACTATION:
The use of ASPEN EFAVIRENZ during pregnancy is not recommended, as teratogenicity has been noted. Malformations have been observed in foetuses from ASPEN EFAVIRENZ-treated monkeys that received doses, which resulted in plasma drug concentrations similar to those in humans given 600 mg/day; therefore pregnancy should be avoided in women receiving ASPEN EFAVIRENZ. Barrier contraception should always be used in combination with other methods of contraception (e.g. oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing prior to initiation of ASPEN EFAVIRENZ. (see CONTRAINDICATIONS).
The safety in lactation has not been established. Since animal data suggest that the substance may be passed into breast milk, it is recommended that mothers taking ASPEN EFAVIRENZ do not breast-feed their infants. It is recommended that HIVinfected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
DOSAGE AND DIRECTIONS FOR USE:
Adults: The recommended dosage of ASPEN EFAVIRENZ in combination with a protease inhibitor, and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs) is 600 mg orally, once daily. ASPEN EFAVIRENZ may be taken on an empty stomach, preferably at bedtime.
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 SIDE-EFFECTS).
Concomitant Antiretroviral Therapy: ASPEN EFAVIRENZ must be given in combination with other antiretroviral medications (see INTERACTIONS).
Adolescents and children (17 years and under): ASPEN EFAVIRENZ may be taken on an empty stomach, at bedtime. ASPEN EFAVIRENZ 600 mg can only be used in adults and children who weigh greater than or equal to 40 kg.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Body as a whole general disorder:
The following side-effects have been reported and frequencies are unknown: Redistribution/accumulation of body fat.
Autonomic nervous system symptoms:
Frequent: Dizziness, headache.
Less frequent: Impaired concentration, somnolence, abnormal dreams, insomnia and anorexia. Abnormal coordination, ataxia, convulsions, hypoesthesia, paraesthesia.
The following side-effects have been reported and frequencies are unknown: Neuropathy.
Less frequent: Vomiting, diarrhoea, dyspepsia and abdominal pain.
The following side-effects have been reported and frequencies are unknown: Constipation and malabsorption.
Liver and biliary system disorders:
The following side-effects have been reported and frequencies are unknown: Hepatic failure.
Musculoskeletal system disorders:
The following side-effects have been reported and frequencies are unknown: Myopathy.
Skin and appendages disorders:
Frequent: Rash and increased swelling.
Less frequent: Erythema multiforme and Stevens- Johnson Syndrome.
The following side-effects have been reported and frequencies are unknown: Nail disorders and skin discolouration. The type and frequency of side-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.
Adverse clinical experiences of moderate to severe intensity observed in less than 2% of patients receiving efavirenz in all Phase II/III studies and considered at least possibly related or of unknown relationship to treatment are listed below by body system:
Body as a whole general disorder:
Pain, alcohol intolerance, allergic reaction, asthenia, hot flushes, influenza-like symptoms, malaise, pain, and syncope.
Autonomic nervous system symptoms:
Aggravated depression, agitation, amnesia, anxiety, apathy, appetite increased, confusion, emotional lability, euphoria, hallucination, impaired coordination, impotence, libido decreased, libido increased, neuralgia, paraesthesia, peripheral neuropathy, speech disorder, tremor and vertigo.
Gastritis, gastroenteritis and gastro-oesophageal reflux.
Special senses other, disorders:
Tinnitus, abnormal vision and taste perversion.
Cardiovascular disorders, general:
Flushing, palpitations and tachycardia.
Liver and biliary system disorders:
Hepatitis and hepatic enzyme increase.
Metabolic and nutritional disorders:
Weight gain and weight loss.
Musculoskeletal system disorders:
Arthralgia and myalgia.
Respiratory system disorders:
Asthma, sinusitis, and upper respiratory tract infections.
Skin and appendages disorders:
Acne, alopecia, eczema, folliculitis, seborrhea, skin exfoliation and urticaria.
Raised liver enzyme values have occurred, particularly in patients with viral hepatitis.
Raised serum-cholesterol and triglyceride concentrations have been reported.
Elevations of AST and ALT to greater than five times the upper limit of the normal range were seen in patients treated with 600 mg of ASPEN EFAVIRENZ. Similar elevations were seen in patients treated with control regimens. In 156 patients treated with 600 mg of ASPEN EFAVIRENZ who were sero-positive 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 sero-positive 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 ASPEN EFAVIRENZ and in 10% of patients sero-positive for Hepatitis B or C. In patients treated with control regimens, the incidence of GGT elevations to this level was 1,5 to 2% irrespective of Hepatitis B or C serology. Isolated elevations of GGT in patients receiving ASPEN EFAVIRENZ may reflect enzyme induction not associated with liver toxicity (see SPECIAL PRECAUTIONS).
Increases in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving ASPEN EFAVIRENZ. Increases in non-fasting total cholesterol and HDL of approximately 20% and 25%, respectively were observed in patients treated with efavirenz+SDV+3TC and of approximately 40% and 35%, in patients treated with ASPEN EFAVIRENZ+IDV. The effects of ASPEN EFAVIRENZ on triglycerides and LDL were not well characterized. The clinical significance of these findings is unknown (see SPECIAL PRECAUTIONS).
Alert: Find out about medicines that should not be taken with ASPEN EFAVIRENZ.
ASPEN EFAVIRENZ must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen.
When prescribing medications concomitantly with ASPEN EFAVIRENZ, medical practitioners should refer to the corresponding manufacturers 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.
Skin Rash: Mild-to-moderate rash has been reported with ASPEN EFAVIRENZ use and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. ASPEN EFAVIRENZ should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with ASPEN EFAVIRENZ is discontinued, consideration should also be given to interrupting therapy with other antiretroviral agents to avoid development of drug resistant virus (see SIDE-EFFECTS). Prophylaxis with appropriate antihistamines prior to initiating therapy with ASPEN EFAVIRENZ in children may be considered.
Nervous System Symptoms: Nervous system symptoms have been reported with ASPEN EFAVIRENZ use (see SIDE-EFFECTS). In addition, there have been reports of psychosis-like reactions, such as delusions and inappropriate behaviour (including aggressive reactions), predominantly in patients with a history of mental illness or substance abuse. Severe acute depression (including suicidal ideation/attempts) has also been infrequently reported in both ASPEN EFAVIRENZ-treated and control-treated patients, particularly in patients with a previous history of depression. Patients should be advised that if they experience these symptoms they should contact their doctor immediately because discontinuation of ASPEN EFAVIRENZ may be required.
Special Populations: Because of the extensive cytochrome P450-mediated metabolism of ASPEN EFAVIRENZ and limited clinical experience in patients with chronic liver disease, caution should be exercised in administering ASPEN EFAVIRENZ to patients with liver disease. 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 ASPEN EFAVIRENZ needs to be weighed against the unknown risks of significant liver toxicity (see SIDE- EFFECTS).
Cholesterol: Monitoring of cholesterol and triglycerides should be considered in patients treated with ASPEN EFAVIRENZ (see SIDE-EFFECTS).
Paediatric use: ASPEN EFAVIRENZ has not been studied in paediatric patients below 3 years of age or who weigh less than 13 kg. Therefore, ASPEN EFAVIRENZ is not recommended in this group.
Effects on ability to drive and use machines: ASPEN EFAVIRENZ may cause dizziness, impaired-concentration, and/or drowsiness. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms and involuntary muscle contractions. Treatment of overdose with ASPEN EFAVIRENZ should consist of general supportive measure, including monitoring of vital signs and observation of the patients clinical status.
Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with ASPEN EFAVIRENZ. Since ASPEN EFAVIRENZ is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.
ASPEN EFAVIRENZ 600 mg tablets: Off-white coloured, oval, biconvex, film coated tablets.
ASPEN EFAVIRENZ 600 mg tablets will be available in white opaque high density polyethylene (HDPE) bottles sealed with a white, tear off, tamper evident, low density polyethylene (LDPE) cap.
White, high density polyethylene (HDPE) bottles closed with a white polypropylene closure which has an induction sealing wad.
The pack size is 30 tablets.
Store below 30ºC. Protect from light. Keep in a well closed container.
KEEP OUT OF REACH OF CHILDREN.
ASPEN EFAVIRENZ 600 mg: 42/20.2.8/0026
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
Building 12, Healthcare Park
Woodlands Drive, Woodmead
DATE OF PUBLCATION OF THIS PACKAGE INSERT:
10 August 2007
New addition to this site: February 2008
Source: Pharmaceutical Industry
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