Efavirenz HEXAL

Efavirenz HEXAL is indicated in antiviral combination treatment of human immunodeficiency virus-1 (HIV-1) infected adults, adolescents and children 3 months of age and older and weighing at least 3.5 kg.

Efavirenz HEXAL has not been adequately studied in patients with advanced HIV disease, namely in patients with CD4 counts < 50 cells/mm³, or after failure of protease inhibitor (PI) containing regimens. Although cross-resistance of efavirenz with PIs has not been documented, there are at present insufficient data on the efficacy of subsequent use of PI based combination therapy after failure of regimens containing Efavirenz HEXAL.

Efavirenz HEXAL is indicated in antiviral combination treatment of human immunodeficiency virus-1 (HIV-1) infected adults, adolescents and children 3 years of age and older.

Efavirenz HEXAL has not been adequately studied in patients with advanced HIV disease, namely in patients with CD4 counts < 50 cells/mm³, or after failure of protease inhibitor (PI) containing regimens.

Although cross-resistance of Efavirenz HEXAL with PIs has not been documented, there are at present insufficient data on the efficacy of subsequent use of PI based combination therapy after failure of regimens containing Efavirenz HEXAL.

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Efavirenz must be given in combination with other antiretroviral medicines.

In order to improve the tolerability of nervous system adverse reactions, bedtime dosing is recommended.

Adults

The recommended dose of efavirenz in combination with nucleoside analogue reverse transcriptase inhibitors (NRTIs) with or without a PI is 600 mg orally, once daily.

Dose adjustment

If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose must be increased to 400 mg every 12 hours and the efavirenz dose must be reduced by 50%, i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dose of efavirenz should be restored.

If efavirenz is coadministered with rifampicin to patients weighing 50 kg or more, an increase in the dose of efavirenz to 800 mg/day may be considered.

Children and adolescents (3 months to 17 years)

The recommended dose of efavirenz in combination with a PI and/or NRTIs for patients between 3 months and 17 years of age is described in Table 1. Efavirenz intact hard capsules must only be administered to children who are able to reliably swallow hard capsules.

Table 1: Paediatric dose to be administered once daily*

Special populations

Renal impairment

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.

Hepatic impairment

Patients with mild liver disease may be treated with their normally recommended dose of efavirenz. Patients should be monitored carefully for dose-related adverse reactions, especially nervous system symptoms.

Paediatric population

The safety and efficacy of efavirenz in children below the age of 3 months or weighing less than 3.5 kg have not been established. No data are available.

Method of administration

It is recommended that efavirenz be taken on an empty stomach. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions.

Patients who cannot swallow

Capsule sprinkle: for patients at least 3 months old and weighing at least 3.5 kg who cannot swallow capsules, the capsule contents can be administered with a small amount of food using the capsule sprinkle method of administration. No additional food should be consumed for up to 2 hours after administration of efavirenz..

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Efavirenz HEXAL must be given in combination with other antiretroviral medicines.

In order to improve the tolerability of nervous system adverse reactions, bedtime dosing is recommended.

Adults and adolescents over 40 kg

The recommended dose of Efavirenz HEXAL in combination with nucleoside analogue reverse transcriptase inhibitors (NRTIs) with or without a PI is 600 mg orally, once daily.

Efavirenz HEXAL film-coated tablets are not suitable for children weighing less than 40 kg. Other Efavirenz HEXAL-containing formulations are available for these patients.

Dose adjustment

If Efavirenz HEXAL is coadministered with voriconazole, the voriconazole maintenance dose must be increased to 400 mg every 12 hours and the Efavirenz HEXAL dose must be reduced by 50%, i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dose of Efavirenz HEXAL should be restored.

If Efavirenz HEXAL is coadministered with rifampicin to patients weighing 50 kg or more, an increase in the dose of Efavirenz HEXAL to 800 mg/day may be considered

As the product is not divisible, other formulations have to be used for enabling these dose adjustments.

Special populations

Renal impairment

The pharmacokinetics of Efavirenz HEXAL have not been studied in patients with renal insufficiency; however, less than 1% of an Efavirenz HEXAL dose is excreted unchanged in the urine, so the impact of renal impairment on Efavirenz HEXAL elimination should be minimal.

Hepatic impairment

Patients with mild liver disease may be treated with their normally recommended dose of Efavirenz HEXAL. Patients should be monitored carefully for dose-related adverse reactions, especially nervous system symptoms.

Method of administration

It is recommended that Efavirenz HEXAL be taken on an empty stomach. The increased Efavirenz HEXAL concentrations observed following administration of Efavirenz HEXAL with food may lead to an increase in frequency of adverse reactions.

Patients with severe hepatic impairment (Child Pugh Class C).

Co-administraion with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine) because competition for CYP3A4 by efavirenz could result in inhibition of metabolism and create the potential for serious and/or life-threatening adverse reactions [for example, cardiac arrhythmias, prolonged sedation or respiratory depression].

Herbal preparations containing St. John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz.

Patients with:

- a family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms, or with any other clinical condition known to prolong the QTc interval.

- a history of symptomatic cardiac arrythmias or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction.

- severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia.

Patients taking drugs that are known to prolong the QTc interval (proarrythmic).

These drugs include:

- antiarrhythmics of classes IA and III,

- neuroleptics, antidepressive agents,

- certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, imidazole and triazole antifungal agents,

- certain non-sedating antihistamines (terfenadine, astemizole),

- cisapride,

- flecainide,

- certain antimalarials,

- methadone.

Patients with severe hepatic impairment (Child Pugh Class C).

Co-administraion with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine) because competition for CYP3A4 by Efavirenz HEXAL could result in inhibition of metabolism and create the potential for serious and/or life-threatening adverse reactions [for example, cardiac arrhythmias, prolonged sedation or respiratory depression].

Herbal preparations containing St. John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of Efavirenz HEXAL.

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

Co-administration of efavirenz with the fixed combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate is not recommended unless needed for dose adjustment (for example, with rifampicin).

Concomitant use of Ginkgo biloba extracts is not recommended.

When prescribing medicinal products concomitantly with efavirenz, physicians should refer to the corresponding Summary of Product Characteristics.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

If any antiretroviral medicinal product in a combination regimen is interrupted because of suspected intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral medicinal products. The antiretroviral medicinal products 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 resistant virus.

Rash

Mild-to-moderate rash has been reported in clinical studies with efavirenz 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 efavirenz. The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%. Efavirenz must 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 resistant virus.

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Efavirenz is not recommended for patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking another NNRTI.

Psychiatric symptoms

Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with a prior history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions. In particular, severe depression was more common in those with a history of depression. There have also been post-marketing reports of severe depression, death by suicide, delusions, psychosis-like behaviour and catatonia. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation, 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 adverse reactions 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 in adult and paediatric 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.

Hepatic events

A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. Liver enzyme monitoring should be considered for patients without pre-existing hepatic dysfunction or other risk factors.

QTc Prolongation

QTc prolongation has been observed with the use of efavirenz.

Consider alternatives to efavirenz for coadministration with a drug with a known risk of Torsade de Pointes or when to be administered to patients at higher risk of Torsade de Pointes.

Effect of food

The administration of efavirenz with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions. It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Weight and metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Special populations

Liver disease

Efavirenz is contraindicated in patients with severe hepatic impairment and not recommended in patients with moderate hepatic impairment because of insufficient data to determine whether dose adjustment is necessary. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution must be exercised in administering efavirenz to patients with mild hepatic impairment. Patients should be monitored carefully for dose-related adverse reactions, especially nervous system symptoms. Laboratory tests should be performed to evaluate their liver disease at periodic intervals.

The safety and efficacy of efavirenz has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse reactions. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease or persistent 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 potential risks of significant liver toxicity. In such patients, interruption or discontinuation of treatment must be considered.

In patients treated with other medicinal products associated with liver toxicity, monitoring of liver enzymes is also recommended. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Renal insufficiency

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. There is no experience in patients with severe renal failure and close safety monitoring is recommended in this population.

Elderly patients

Insufficient numbers of elderly patients have been evaluated in clinical studies to determine whether they respond differently than younger patients.

Paediatric population

Efavirenz has not been evaluated in children below 3 months of age or who weigh less than 3.5 kg. Therefore, efavirenz should not be given to children less than 3 months of age.

Rash was reported in 59 of 182 children (32%) treated with efavirenz and was severe in six patients. Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Efavirenz HEXAL must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when Efavirenz HEXAL is administered as monotherapy. The choice of new antiretroviral agent(s) to be used in combination with Efavirenz HEXAL should take into consideration the potential for viral cross-resistance.

Co-administration of Efavirenz HEXAL with the fixed combination tablet containing Efavirenz HEXAL, emtricitabine, and tenofovir disoproxil fumarate is not recommended unless needed for dose adjustment (for example, with rifampicin).

Concomitant use of Ginkgo biloba extracts is not recommended.

When prescribing medicinal products concomitantly with Efavirenz HEXAL, physicians should refer to the corresponding Summary of Product Characteristics.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

If any antiretroviral medicinal product in a combination regimen is interrupted because of suspected intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral medicinal products. The antiretroviral medicinal products 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 resistant virus.

Rash

Mild-to-moderate rash has been reported in clinical studies with Efavirenz HEXAL 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 Efavirenz HEXAL. The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%. Efavirenz HEXAL must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with Efavirenz HEXAL is discontinued, consideration should also be given to interrupting therapy with other antiretroviral agents to avoid development of resistant virus.

Experience with Efavirenz HEXAL in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Efavirenz HEXAL is not recommended for patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking another NNRTI.

Psychiatric symptoms

Psychiatric adverse reactions have been reported in patients treated with Efavirenz HEXAL. Patients with a prior history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions. In particular, severe depression was more common in those with a history of depression. There have also been post-marketing reports of severe depression, death by suicide, delusions and psychosis-like behaviour. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately to assess the possibility that the symptoms may be related to the use of Efavirenz HEXAL, 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 adverse reactions in patients receiving Efavirenz HEXAL 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 in patients receiving Efavirenz HEXAL, 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 HEXAL. Caution must be taken in any patient with a history of seizures.

Hepatic events

A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. Liver enzyme monitoring should be considered for patients without pre-existing hepatic dysfunction or other risk factors.

Effect of food

The administration of Efavirenz HEXAL with food may increase Efavirenz HEXAL exposure and may lead to an increase in the frequency of adverse reactions. It is recommended that Efavirenz HEXAL be taken on an empty stomach, preferably at bedtime.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Lipodystrophy and metabolic abnormalities

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Special populations

Liver disease

Efavirenz HEXAL is contraindicated in patients with severe hepatic impairment and not recommended in patients with moderate hepatic impairment because of insufficient data to determine whether dose adjustment is necessary. Because of the extensive cytochrome P450-mediated metabolism of Efavirenz HEXAL and limited clinical experience in patients with chronic liver disease, caution must be exercised in administering Efavirenz HEXAL to patients with mild hepatic impairment. Patients should be monitored carefully for dose-related adverse reactions, especially nervous system symptoms. Laboratory tests should be performed to evaluate their liver disease at periodic intervals.

The safety and efficacy of Efavirenz HEXAL has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse reactions. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease or persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with Efavirenz HEXAL needs to be weighed against the potential risks of significant liver toxicity. In such patients, interruption or discontinuation of treatment must be considered.

In patients treated with other medicinal products associated with liver toxicity, monitoring of liver enzymes is also recommended. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Renal insufficiency

The pharmacokinetics of Efavirenz HEXAL have not been studied in patients with renal insufficiency; however, less than 1% of an Efavirenz HEXAL dose is excreted unchanged in the urine, so the impact of renal impairment on Efavirenz HEXAL elimination should be minimal. There is no experience in patients with severe renal failure and close safety monitoring is recommended in this population.

Elderly patients

Insufficient numbers of elderly patients have been evaluated in clinical studies to determine whether they respond differently than younger patients.

Paediatric population

Efavirenz HEXAL has not been evaluated in children below 3 years of age or who weigh less than 13 kg. Therefore, Efavirenz HEXAL should not be given to children less than 3 years of age.

Rash was reported in 26 of 57 children (46%) treated with Efavirenz HEXAL during a 48-week period and was severe in three patients. Prophylaxis with appropriate antihistamines prior to initiating therapy with Efavirenz HEXAL in children may be considered.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Individuals with these conditions may take another, lactose free Efavirenz HEXAL formulation, which is free from lactose.

Efavirenz may cause dizziness, impaired concentration, and/or somnolence. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Efavirenz HEXAL may cause dizziness, impaired concentration, and/or somnolence. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Summary of the safety profile

Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 adult patients who received 600 mg efavirenz daily in combination with PIs and/or NRTIs in controlled clinical studies, the most frequently reported adverse reactions 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%). The most notable adverse reactions associated with efavirenz are rash and nervous system symptoms. Nervous system symptoms usually begin soon after therapy onset and generally resolve after the first 2 - 4 weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; psychiatric adverse reactions including severe depression, death by suicide, and psychosis like behaviour; and seizures have been reported in patients treated with efavirenz. The administration of efavirenz with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions.

The long-term safety profile of efavirenz-containing regimens was evaluated in a controlled trial (006) in which patients received efavirenz + zidovudine + lamivudine (n = 412, median duration 180 weeks), efavirenz + indinavir (n = 415, median duration 102 weeks), or indinavir + zidovudine + lamivudine (n = 401, median duration 76 weeks). Long-term use of efavirenz in this study was not associated with any new safety concerns.

Tabulated list of adverse reactions

Adverse reactions of moderate or greater severity with at least possible relationship to treatment regimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommended dose in combination therapy (n = 1,008) are listed below. Also listed in italics are adverse reactions observed post-marketing in association with efavirenz-containing antiretroviral treatment regimens. Frequency is defined using the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); or very rare (< 1/10,000).

*,†,‡ See section Description of selected adverse reactions for more details.

Description of selected adverse reactions

Information regarding post-marketing surveillance

†These adverse reactions were identified through post-marketing surveillance; however, the frequencies were determined using data from 16 clinical trials (n=3,969).

‡These adverse reactions were identified through post-marketing surveillance but not reported as drug-related events for efavirenz-treated patients in 16 clinical trials. The frequency category of "rare" was defined per A Guideline on Summary of Product Characteristics (SmPC) (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of patients treated with efavirenz in these clinical trials (n=3,969).

Rash

In clinical studies, 26% of patients treated with 600 mg of efavirenz experienced skin rash compared with 17% of patients treated in control groups. Skin rash was considered treatment related in 18% of patients treated with efavirenz. Severe rash occurred in less than 1% of patients treated with efavirenz, and 1.7% discontinued therapy because of rash. The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%.

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

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Reported rates of recurrent rash following a switch from nevirapine to efavirenz therapy, primarily based on retrospective cohort data from published literature, range from 13 to 18%, comparable to the rate observed in patients treated with efavirenz in clinical studies.

Psychiatric symptoms

Serious psychiatric adverse reactions have been reported in patients treated with efavirenz. In controlled trials, the frequency of specific serious psychiatric events were:

Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions with frequencies ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation. There have also been post-marketing reports of death by suicide, delusions, psychosis-like behaviour and catatonia.

Nervous system symptoms

In clinical controlled trials, frequently reported adverse reactions included, but were not limited to dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. Nervous system symptoms of moderate-to-severe intensity were experienced by 19% (severe 2%) of patients compared to 9% (severe 1%) of patients receiving control regimens. In clinical studies 2% of patients treated with efavirenz discontinued therapy due to such 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 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. Nervous system symptoms may occur more frequently when efavirenz is taken concomitantly with meals possibly due to increased efavirenz plasma levels. 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. Dose reduction or splitting the daily dose has not been shown to provide benefit.

Analysis of long-term data showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the control arm.

Hepatic failure

A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.

Laboratory test abnormalities

Liver enzymes: elevations of AST and ALT to greater than five times the upper limit of the normal range (ULN) were seen in 3% of 1,008 patients treated with 600 mg of efavirenz (5-8% after long-term treatment in study 006). Similar elevations were seen in patients treated with control regimens (5% after long-term treatment). Elevations of GGT to greater than five times ULN were observed in 4% of all patients treated with 600 mg of efavirenz and 1.5-2% of patients treated with control regimens (7% of efavirenz-treated patients and 3% of control-treated patients after long-term treatment). Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction. In the long-term study (006), 1% of patients in each treatment arm discontinued because of liver or biliary system disorders.

Amylase: in the clinical trial subset of 1,008 patients, asymptomatic increases in serum amylase levels greater than 1.5 times the upper limit of normal were seen in 10% of patients treated with efavirenz and 6% of patients treated with control regimens. The clinical significance of asymptomatic increases in serum amylase is unknown.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

Paediatric population

Undesirable effects in children were generally similar to those of adult patients. Rash was reported more frequently in children (59 of 182 (32%) treated with efavirenz) and was more often of higher grade than in adults (severe rash was reported in 6 of 182 (3.3%) of children). Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered..

Other special populations

Liver enzymes in hepatitis B or C co-infected patients: in the long-term data set from study 006, 137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among co-infected patients in study 006, elevations in AST to greater than five times ULN developed in 13% of efavirenz-treated patients and in 7% of controls, and elevations in ALT to greater than five times ULN developed in 20% and 7%, respectively. Among co-infected patients, 3% of those treated with efavirenz and 2% in the control arm discontinued because of liverdisorders.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse via:

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Summary of the safety profile

Efavirenz HEXAL has been studied in over 9,000 patients. In a subset of 1,008 adult patients who received 600 mg Efavirenz HEXAL daily in combination with PIs and/or NRTIs in controlled clinical studies, the most frequently reported adverse reactions 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%). The most notable adverse reactions associated with Efavirenz HEXAL are rash and nervous system symptoms. Nervous system symptoms usually begin soon after therapy onset and generally resolve after the first 2 - 4 weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; psychiatric adverse reactions including severe depression, death by suicide, and psychosis like behaviour; and seizures have been reported in patients treated with Efavirenz HEXAL. The administration of Efavirenz HEXAL with food may increase Efavirenz HEXAL exposure and may lead to an increase in the frequency of adverse reactions.

The long-term safety profile of Efavirenz HEXAL-containing regimens was evaluated in a controlled trial (006) in which patients received Efavirenz HEXAL + zidovudine + lamivudine (n = 412, median duration 180 weeks), Efavirenz HEXAL + indinavir (n = 415, median duration 102 weeks), or indinavir + zidovudine + lamivudine (n = 401, median duration 76 weeks). Long-term use of Efavirenz HEXAL in this study was not associated with any new safety concerns.

Tabulated list of adverse reactions

Adverse reactions of moderate or greater severity with at least possible relationship to treatment regimen (based on investigator attribution) reported in clinical trials of Efavirenz HEXAL at the recommended dose in combination therapy (n = 1,008) are listed below. Also listed in italics are adverse reactions observed post-marketing in association with Efavirenz HEXAL-containing antiretroviral treatment regimens. Frequency is defined using the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); or very rare (< 1/10,000).

*, †,‡ See section Description of selected adverse reactions for more details.

Description of selected adverse reactions

Information regarding post-marketing surveillance

†These adverse reactions were identified through post-marketing surveillance; however, the frequencies were determined using data from 16 clinical trials (n=3,969).

‡These adverse reactions were identified through post-marketing surveillance but not reported as drug-related events for Efavirenz HEXAL-treated patients in 16 clinical trials. The frequency category of "rare" was defined per A Guideline on Summary of Product Characteristics (SmPC) (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of patients treated with Efavirenz HEXAL in these clinical trials (n=3,969).

Rash

In clinical studies, 26% of patients treated with 600 mg of Efavirenz HEXAL experienced skin rash compared with 17% of patients treated in control groups. Skin rash was considered treatment related in 18% of patients treated with Efavirenz HEXAL. Severe rash occurred in less than 1% of patients treated with Efavirenz HEXAL, and 1.7% discontinued therapy because of rash. The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%.

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

Experience with Efavirenz HEXAL in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Reported rates of recurrent rash following a switch from nevirapine to Efavirenz HEXAL therapy, primarily based on retrospective cohort data from published literature, range from 13 to 18%, comparable to the rate observed in patients treated with Efavirenz HEXAL in clinical studies.

Psychiatric symptoms

Serious psychiatric adverse reactions have been reported in patients treated with Efavirenz HEXAL. In controlled trials, the frequency of specific serious psychiatric events were:

Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions with frequencies ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation. There have also been post-marketing reports of death by suicide, delusions and psychosis-like behaviour.

Nervous system symptoms

In clinical controlled trials, frequently reported adverse reactions included, but were not limited to dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. Nervous system symptoms of moderate-to-severe intensity were experienced by 19% (severe 2%) of patients compared to 9% (severe 1%) of patients receiving control regimens. In clinical studies 2% of patients treated with Efavirenz HEXAL discontinued therapy due to such 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 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. Nervous system symptoms may occur more frequently when Efavirenz HEXAL is taken concomitantly with meals possibly due to increased Efavirenz HEXAL plasma levels. 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. Dose reduction or splitting the daily dose has not been shown to provide benefit.

Analysis of long-term data showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among Efavirenz HEXAL-treated patients were generally similar to those in the control arm.

Hepatic failure

A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Lipodystrophy and metabolic abnormalities

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.

Laboratory test abnormalities:

Liver enzymes: elevations of AST and ALT to greater than five times the upper limit of the normal range (ULN) were seen in 3% of 1,008 patients treated with 600 mg of Efavirenz HEXAL (5-8% after longterm treatment in study 006). Similar elevations were seen in patients treated with control regimens (5% after long-term treatment). Elevations of GGT to greater than five times ULN were observed in 4% of all patients treated with 600 mg of Efavirenz HEXAL and 1.5-2% of patients treated with control regimens (7% of Efavirenz HEXAL-treated patients and 3% of control-treated patients after long-term treatment). Isolated elevations of GGT in patients receiving Efavirenz HEXAL may reflect enzyme induction. In the long-term study (006), 1% of patients in each treatment arm discontinued because of liver or biliary system disorders.

Amylase: in the clinical trial subset of 1,008 patients, asymptomatic increases in serum amylase levels greater than 1.5 times the upper limit of normal were seen in 10% of patients treated with Efavirenz HEXAL and 6% of patients treated with control regimens. The clinical significance of asymptomatic increases in serum amylase is unknown.

Lipids: increases in total cholesterol of 10 - 20% have been observed in some uninfected volunteers receiving Efavirenz HEXAL. In clinical trials of various Efavirenz HEXAL-containing regimens in treatment naïve patients, total cholesterol, HDL-cholesterol, and triglycerides increased over 48 weeks of treatment (21 - 31%, 23 - 34%, and 23 - 49%, respectively). The proportion of patients with a total cholesterol/HDL-cholesterol ratio greater than 5 was unchanged. The magnitude of changes in lipid levels may be influenced by factors such as duration of therapy and other components of the antiretroviral regimen.

Paediatric population

Undesirable effects in children were generally similar to those of adult patients. Rash was reported more frequently in children (in a clinical study including 57 children who received Efavirenz HEXAL during a 48-week period, rash was reported in 46%) and was more often of higher grade than in adults (severe rash was reported in 5.3% of children). Prophylaxis with appropriate antihistamines prior to initiating therapy with Efavirenz HEXAL in children may be considered. Although nervous system symptoms are difficult for young children to report, they appear to be less frequent in children and were generally mild. In the study of 57 children, 3.5% of patients experienced nervous system symptoms of moderate intensity, predominantly dizziness. No child had severe symptoms or had to discontinue because of nervous system symptoms.

Other special populations

Liver enzymes in hepatitis B or C co-infected patients: in the long-term data set from study 006, 137 patients treated with Efavirenz HEXAL-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among co-infected patients in study 006, elevations in AST to greater than five times ULN developed in 13% of Efavirenz HEXAL-treated patients and in 7% of control, and elevations in ALT to greater than five times ULN developed in 20% and 7%, respectively. Among co-infected patients, 3% of those treated with Efavirenz HEXAL and 2% in the control arm discontinued because of liver disorders.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

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.

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 HEXAL 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 HEXAL. There is no specific antidote for overdose with Efavirenz HEXAL. Since Efavirenz HEXAL is highly protein bound, dialysis is unlikely to remove significant quantities of it from blood.

Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase inhibitors. ATC code: J05AG03

Mechanism of action

Efavirenz is a NNRTI of HIV-1. Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases (α, β, γ or δ).

Cardiac Electrophysiology

The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days.

Antiviral activity

The free concentration of efavirenz required for 90 to 95% inhibition of wild type or zidovudine-resistant laboratory and clinical isolates in vitro ranged from 0.46 to 6.8 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures.

Resistance

The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to that observed against wild type viral strains. The single substitutions which led to the highest resistance to efavirenz in cell culture correspond to a leucine-to-isoleucine change at position 100 (L100I, 17 to 22-fold resistance) and a lysine-to-asparagine at position 103 (K103N, 18 to 33-fold resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing K103N in addition to other amino acid substitutions in RT.

K103N was the most frequently observed RT substitution in viral isolates from patients who experienced a significant rebound in viral load during clinical studies of efavirenz in combination with indinavir or zidovudine + lamivudine. This mutation was observed in 90% of patients receiving efavirenz with virological failure. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N. The pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of the other antiviral medicines used in combination with efavirenz.

Cross resistance

Cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture demonstrated that the K103N substitution confers loss of susceptibility to all three NNRTIs. Two of three delavirdine-resistant clinical isolates examined were cross-resistant to efavirenz and contained the K103N substitution. A third isolate which carried a substitution at position 236 of RT was not cross-resistant to efavirenz.

Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical studies who showed evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteen isolates previously characterised as efavirenz-resistant were also resistant to nevirapine and delavirdine. Five of these NNRTI-resistant isolates were found to have K103N or a valine-to-isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment failure isolates tested remained sensitive to efavirenz in cell culture and were also sensitive to nevirapine and delavirdine.

The potential for cross resistance between efavirenz and PIs is low because of the different enzyme targets involved. The potential for cross-resistance between efavirenz and NRTIs is low because of the different binding sites on the target and mechanism of action.

Clinical efficacy

Efavirenz has not been studied in controlled studies in patients with advanced HIV disease, namely with CD4 counts < 50 cells/mm³, or in PI or NNRTI experienced patients. Clinical experience in controlled studies with combinations including didanosine or zalcitabine is limited.

Two controlled studies (006 and ACTG 364) of approximately one year duration with efavirenz in combination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit of quantification of the assay and increased CD4 lymphocytes in antiretroviral therapy-naïve and NRTI-experienced HIV-infected patients. Study 020 showed similar activity in NRTI-experienced patients over 24 weeks. In these studies the dose of efavirenz was 600 mg once daily; the dose of indinavir was 1,000 mg every 8 hours when used with efavirenz and 800 mg every 8 hours when used without efavirenz. The dose of nelfinavir was 750 mg given three times a day. The standard doses of NRTIs given every 12 hours were used in each of these studies.

Study 006, a randomized, open-label trial, compared efavirenz + zidovudine + lamivudine or efavirenz + indinavir with indinavir + zidovudine + lamivudine in 1,266 patients who were required to be efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell count was 341 cells/mm³ and the mean baseline HIV-RNA level was 60,250 copies/ml. Efficacy results for study 006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found in Table 3. In the analysis of responder rates (the non-completer equals failure analysis [NC = F]), patients who terminated the study early for any reason, or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA above 50 or above 400 copies/ml at the missing time points.

Table 3: Efficacy results for study 006

^a NC = F, noncompleter = failure.

^b C.I., confidence interval.

^c S.E.M., standard error of the mean.

^d EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir.

Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with EFV+IDV, 196 patients with EFV+ZDV+3TC and 127 patients with IDV+ZDV+3TC, respectively), suggest durability of response in terms of proportions of patients with HIV RNA < 400 copies/ml, HIV RNA < 50 copies/ml and in terms of mean change from baseline CD4 cell count.

Efficacy results for studies ACTG 364 and 020 are found in Table 4. Study ACTG 364 enrolled 196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled 327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowed to change their patient's NRTI regimen upon entry into the study. Responder rates were highest in patients who switched NRTIs.

Table 4: Efficacy results for studies ACTG 364 and 020

^a NC = F, noncompleter = failure.

^b EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir; NRTI, nucleoside reverse transcriptase inhibitor; NFV, nelfinavir.

^c C.I., confidence interval for proportion of patients in response.

^d S.E.M., standard error of the mean.

---, not performed.

Paediatric population

Study AI266922 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz HEXAL in combination with didanosine and emtricitabine in antiretroviral-naive and -experienced paediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 years) were treated with Efavirenz HEXAL. At baseline, median plasma HIV-1 RNA was 5.88 log₁₀ copies/mL, median CD4+ cell count was 1144 cells/mm³, and median CD4+ percentage was 25%. The median time on study therapy was 132 weeks; 27% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in CD4+ count at 48 weeks was 215 cells/mm³ and the median increase in CD4+ percentage was 6%.

Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz HEXAL in combination with didanosine and emtricitabine in paediatric patients who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 9.6 years) were dosed with Efavirenz HEXAL. At baseline, median plasma HIV-1 RNA was 4.8 log₁₀ copies/mL, median CD4+ cell count was 367 cells/mm³, and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm³ and the median increase in CD4+ percentage was 13%.

Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz HEXAL in combination with nelfinavir and an NRTI in antiretroviral-naive and NRTI-experienced paediatric patients. One hundred two patients 3 months to 16 years of age (median 5.7 years) were treated with Efavirenz HEXAL. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log₁₀ copies/mL, median CD4+ cell count was 755 cells/mm³, and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 128 cells/mm³ and the median increase in CD4+ percentage was 5%.

Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase inhibitors.

ATC code: J05AG03

Mechanism of action

Efavirenz HEXAL is a NNRTI of HIV-1. Efavirenz HEXAL is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases (α, β, γ or δ).

Antiviral activity

The free concentration of Efavirenz HEXAL required for 90 to 95% inhibition of wild type or zidovudine-resistant laboratory and clinical isolates in vitro ranged from 0.46 to 6.8 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures.

Resistance

The potency of Efavirenz HEXAL in cell culture against viral variants with amino acid substitutions at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to that observed against wild type viral strains. The single substitutions which led to the highest resistance to Efavirenz HEXAL in cell culture correspond to a leucine-to-isoleucine change at position 100 (L100I, 17 to 22-fold resistance) and a lysine-to-asparagine at position 103 (K103N, 18 to 33-fold resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing K103N in addition to other amino acid substitutions in RT.

K103N was the most frequently observed RT substitution in viral isolates from patients who experienced a significant rebound in viral load during clinical studies of Efavirenz HEXAL in combination with indinavir or zidovudine + lamivudine. This mutation was observed in 90% of patients receiving Efavirenz HEXAL with virological failure. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N. The pattern of amino acid substitutions in RT associated with resistance to Efavirenz HEXAL was independent of the other antiviral medications used in combination with Efavirenz HEXAL.

Cross resistance

Cross resistance profiles for Efavirenz HEXAL, nevirapine and delavirdine in cell culture demonstrated that the K103N substitution confers loss of susceptibility to all three NNRTIs. Two of three delavirdine-resistant clinical isolates examined were cross-resistant to Efavirenz HEXAL and contained the K103N substitution. A third isolate which carried a substitution at position 236 of RT was not cross-resistant to Efavirenz HEXAL.

Viral isolates recovered from PBMCs of patients enrolled in Efavirenz HEXAL clinical studies who showed evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteen isolates previously characterised as Efavirenz HEXAL-resistant were also resistant to nevirapine and delavirdine. Five of these NNRTI-resistant isolates were found to have K103N or a valine-toisoleucine substitution at position 108 (V108I) in RT. Three of the Efavirenz HEXAL treatment failure isolates tested remained sensitive to Efavirenz HEXAL in cell culture and were also sensitive to nevirapine and delavirdine.

The potential for cross resistance between Efavirenz HEXAL and PIs is low because of the different enzyme targets involved. The potential for cross-resistance between Efavirenz HEXAL and NRTIs is low because of the different binding sites on the target and mechanism of action.

Clinical efficacy

Efavirenz HEXAL has not been studied in controlled studies in patients with advanced HIV disease, namely with CD4 counts < 50 cells/mm³, or in PI or NNRTI experienced patients. Clinical experience in controlled studies with combinations including didanosine or zalcitabine is limited.

Two controlled studies (006 and ACTG 364) of approximately one year duration with Efavirenz HEXAL in combination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit of quantification of the assay and increased CD4 lymphocytes in antiretroviral therapy-naïve and NRTI-experienced HIV-infected patients. Study 020 showed similar activity in NRTI-experienced patients over 24 weeks. In these studies the dose of Efavirenz HEXAL was 600 mg once daily; the dose of indinavir was 1,000 mg every 8 hours when used with Efavirenz HEXAL and 800 mg every 8 hours when used without Efavirenz HEXAL. The dose of nelfinavir was 750 mg given three times a day. The standard doses of NRTIs given every 12 hours were used in each of these studies.

Study 006, a randomized, open-label trial, compared Efavirenz HEXAL + zidovudine + lamivudine or Efavirenz HEXAL + indinavir with indinavir + zidovudine + lamivudine in 1,266 patients who were required to be Efavirenz HEXAL-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell count was 341 cells/mm³ and the mean baseline HIV-RNA level was 60,250 copies/ml. Efficacy results for study 006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found in Table 2. In the analysis of responder rates (the non-completer equals failure analysis [NC = F]), patients who terminated the study early for any reason, or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA above 50 or above 400 copies/ml at the missing time points.

Table 2: Efficacy results for study 006

^a NC = F, noncompleter = failure.

^b C.I., confidence interval.

^c S.E.M., standard error of the mean.

^d EFV, Efavirenz HEXAL; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir.

Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with EFV+IDV, 196 patients with EFV+ZDV+3TC and 127 patients with IDV+ZDV+3TC, respectively), suggest durability of response in terms of proportions of patients with HIV RNA < 400 copies/ml, HIV RNA < 50 copies/ml and in terms of mean change from baseline CD4 cell count.

Efficacy results for studies ACTG 364 and 020 are found in Table 3. Study ACTG 364 enrolled 196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled 327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowed to change their patient's NRTI regimen upon entry into the study. Responder rates were highest in patients who switched NRTIs.

Table 3: Efficacy results for studies ACTG 364 and 020

^a NC = F, noncompleter = failure.

^b EFV, Efavirenz HEXAL; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir; NRTI, nucleoside reverse transcriptase inhibitor; NFV, nelfinavir.

^c C.I., confidence interval for proportion of patients in response.

^d S.E.M., standard error of the mean.

---, not performed.

Paediatric population

ACTG 382 is an ongoing uncontrolled study of 57 NRTI-experienced paediatric patients (3 - 16 years) which characterises the pharmacokinetics, antiviral activity and safety of Efavirenz HEXAL in combination with nelfinavir (20 - 30 mg/kg given three times a day) and one or more NRTIs. The starting dose of Efavirenz HEXAL was the equivalent of a 600 mg dose (adjusted from calculated body size based on weight). The response rate, based on the NC = F analysis of the percentage of patients with plasma HIV-RNA < 400 copies/ml at 48 weeks was 60% (95%, C.I. 47, 72), and 53% (C.I. 40, 66) based on percentage of patients with plasma HIV-RNA < 50 copies/ml. The mean CD4 cell counts were increased by 63 ± 34.5 cells/mm³ from baseline. The durability of the response was similar to that seen in adult patients.

Absorption

Peak efavirenz plasma concentrations of 1.6 - 9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose related increases in C_max and AUC were seen for doses up to 1,600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. Time to peak plasma concentrations (3 - 5 hours) did not change following multiple dosing and steady-state plasma concentrations were reached in 6 - 7 days.

In HIV infected patients at steady state, mean C_max, mean C_min, and mean AUC were linear with 200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily, steady state C_max was 12.9 ± 3.7 μM (29%) [mean ± S.D. (% C.V.)], steady state C_min was 5.6 ± 3.2 μM (57%), and AUC was 184 ± 73 μM·h (40%).

Effect of food

The bioavailability of a single 600 mg dose of efavirenz hard capsules in uninfected volunteers was increased 22% and 17%, respectively, when given with a meal of high fat or normal composition, relative to the bioavailability of a 600 mg dose given under fasted conditions.

Bioavailability of hard capsule contents mixed with food vehicles

In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg hard capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly, yogurt or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions.

Distribution

Efavirenz is highly bound (approximately 99.5 - 99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n = 9) 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 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.

Biotransformation

Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism and that it inhibited P450 isozymes 2C9, 2C19, and 3A4. In in vitro studies efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically.

Efavirenz plasma exposure may be increased in patients with the homozygous G516T genetic variant of the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however, the potential for an increased frequency and severity of efavirenz-associated adverse events cannot be excluded.

Efavirenz has been shown to induce CYP3A4 and CYP2B6, resulting in the induction of its own metabolism, which may be clinically relevant in some patients. In uninfected volunteers, multiple doses of 200 - 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22 - 42% lower) and a shorter terminal half-life compared with single dose administration (see below). Efavirenz has also been shown to induce UGT1A1. Exposures of raltegravir (a UGT1A1 substrate) are reduced in the presence of efavirenz.

Although in vitro data suggest that efavirenz inhibits CYP2C9 and CYP2C19, there have been contradictory reports of both increased and decreased exposures to substrates of these enzymes when coadministered with efavirenz in vivo. The net effect of coadministration is not clear.

Elimination

Efavirenz has a relatively long terminal half-life of at least 52 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.

Hepatic impairment

In a single-dose study, half life was doubled in the single patient with severe hepatic impairment (Child Pugh Class C), indicating a potential for a much greater degree of accumulation. A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics.

Gender, race, elderly

Although limited data suggest that females as well as Asian and Pacific Island patients may have higher exposure to efavirenz, they do not appear to be less tolerant of efavirenz. Pharmacokinetic studies have not been performed in the elderly.

Paediatric population

The pharmacokinetic parameters for efavirenz at steady state in paediatric patients were predicted by a population pharmacokinetic model and are summarized in Table 5 by weight ranges that correspond to the recommended doses.

Table 5: Predicted steady-state pharmacokinetics of efavirenz (capsules/capsule sprinkles) in HIV-infected paediatric patients

Absorption

peak Efavirenz HEXAL plasma concentrations of 1.6 - 9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose related increases in Cmax and AUC were seen for doses up to 1,600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. Time to peak plasma concentrations (3 - 5 hours) did not change following multiple dosing and steady-state plasma concentrations were reached in 6 - 7 days.

In HIV infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were linear with 200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving Efavirenz HEXAL 600 mg once daily, steady state Cmax was 12.9 ± 3.7 μM (29%) [mean ± S.D. (% C.V.)], steady state Cmin was 5.6 ± 3.2 μM (57%), and AUC was 184 ± 73 μM-h (40%).

Effect of food

The AUC and Cmax of a single 600 mg dose of Efavirenz HEXAL film-coated tablets in uninfected volunteers was increased by 28% (90% CI: 22-33%) and 79% (90% CI: 58-102%), respectively, when given with a high fat meal, relative to when given under fasted conditions.

Distribution

Efavirenz HEXAL is highly bound (approximately 99.5 - 99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n = 9) who received Efavirenz HEXAL 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 3-fold higher than the non-protein-bound (free) fraction of Efavirenz HEXAL in plasma.

Biotransformation

Studies in humans and in vitro studies using human liver microsomes have demonstrated that Efavirenz HEXAL is principally metabolised by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsible for Efavirenz HEXAL metabolism and that it inhibited P450 isozymes 2C9, 2C19, and 3A4. In in vitro studies Efavirenz HEXAL did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically.

Efavirenz HEXAL plasma exposure may be increased in patients with the homozygous G516T genetic variant of the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however, the potential for an increased frequency and severity of Efavirenz HEXAL-associated adverse events cannot be excluded.

Efavirenz HEXAL has been shown to induce CYP3A4 and CYP2B6, resulting in the induction of its own metabolism, which may be clinically relevant in some patients. In uninfected volunteers, multiple doses of 200 - 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22 - 42% lower) and a shorter terminal half-life compared with single dose administration (see below). Efavirenz HEXAL has also been shown to induce UGT1A1. Exposures of raltegravir (a UGT1A1 substrate) are reduced in the presence of Efavirenz HEXAL.

Although in vitro data suggest that Efavirenz HEXAL inhibits CYP2C9 and CYP2C19, there have been contradictory reports of both increased and decreased exposures to substrates of these enzymes when coadministered with Efavirenz HEXAL in vivo. The net effect of coadministration is not clear.

Elimination

Efavirenz HEXAL has a relatively long terminal half-life of at least 52 hours after single doses and 40 - 55 hours after multiple doses. Approximately 14 - 34% of a radiolabelled dose of Efavirenz HEXAL was recovered in the urine and less than 1% of the dose was excreted in urine as unchanged Efavirenz HEXAL.

Hepatic impairment

In a single-dose study, half life was doubled in the single patient with severe hepatic impairment (Child Pugh Class C), indicating a potential for a much greater degree of accumulation. A multiple-dose study showed no significant effect on Efavirenz HEXAL pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects Efavirenz HEXAL pharmacokinetics.

Gender, race, elderly

Although limited data suggest that females as well as Asian and Pacific Island patients may have higher exposure to Efavirenz HEXAL, they do not appear to be less tolerant of Efavirenz HEXAL. Pharmacokinetic studies have not been performed in the elderly.

Paediatric population

In 49 paediatric patients receiving the equivalent of a 600 mg dose of Efavirenz HEXAL (dose adjusted from calculated body size based on weight), steady state Cmax was 14.1 μM, steady state Cmin was 5.6 μM, and AUC was 216 μM-h. The pharmacokinetics of Efavirenz HEXAL in paediatric patients were similar to adults.

Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays.

Efavirenz induced foetal resorptions in rats. Malformations were observed in 3 of 20 foetuses/ newborns from efavirenz-treated cynomolgus monkeys given doses resulting in plasma efavirenz concentrations similar to those seen in humans. Anencephaly and unilateral anophthalmia with secondary enlargement of the tongue were observed in one foetus, microophthalmia was observed in another foetus, and cleft palate was observed in a third foetus. No malformations were observed in foetuses from efavirenz-treated rats and rabbits.

Biliary hyperplasia was observed in cynomolgus monkeys given efavirenz for > 1 year at a dose resulting in mean AUC values approximately 2-fold greater than those in humans given the recommended dose. The biliary hyperplasia regressed upon cessation of dosing. Biliary fibrosis has been observed in rats. Non-sustained convulsions were observed in some monkeys receiving efavirenz for > 1 year, at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.

Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female mice, but not in male mice. The mechanism of tumour formation and the potential relevance for humans are not known.

Carcinogenicity studies in male mice, male and female rats were negative. While the carcinogenic potential in humans is unknown, these data suggest that the clinical benefit of efavirenz outweighs the potential carcinogenic risk to humans.

Efavirenz HEXAL was not mutagenic or clastogenic in conventional genotoxicity assays.

Efavirenz HEXAL induced foetal resorptions in rats. Malformations were observed in 3 of 20 foetuses/ newborns from Efavirenz HEXAL-treated cynomolgus monkeys given doses resulting in plasma Efavirenz HEXAL concentrations similar to those seen in humans. Anencephaly and unilateral anophthalmia with secondary enlargement of the tongue were observed in one foetus, microophthalmia was observed in another foetus, and cleft palate was observed in a third foetus. No malformations were observed in foetuses from Efavirenz HEXAL-treated rats and rabbits.

Biliary hyperplasia was observed in cynomolgus monkeys given Efavirenz HEXAL for > 1 year at a dose resulting in mean AUC values approximately 2-fold greater than those in humans given the recommended dose. The biliary hyperplasia regressed upon cessation of dosing. Biliary fibrosis has been observed in rats. Non-sustained convulsions were observed in some monkeys receiving Efavirenz HEXAL for > 1 year, at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.

Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female mice, but not in male mice. The mechanism of tumour formation and the potential relevance for humans are not known.

Carcinogenicity studies in male mice, male and female rats were negative. While the carcinogenic potential in humans is unknown, these data suggest that the clinical benefit of Efavirenz HEXAL outweighs the potential carcinogenic risk to humans.

No special requirements for disposal.

Use in the paediatric population

For patients at least 3 months old and weighing at least 3.5 kg who cannot swallow capsules, the capsule contents can be administered with a small amount (1-2 teaspoons) of food using the capsule sprinkle method of administration. Patients and caregivers must be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. It is recommended to hold the capsule with the cap facing up and to pull the cap away from the body of the capsule, and to mix the capsule contents with food in a small container. The mixture should be administered as soon as possible, but no more than 30 minutes after mixing. After administration of the efavirenz-food mixture, an additional small amount (approximately 2 teaspoons) of food must be added to the empty mixing container, stirred to disperse any remaining residue of the medicinal product, and administered to the patient. No additional food should be consumed for up to 2 hours after administration of efavirenz.

Any unused product or waste material should be disposed of in accordance with local requirements.