Medicinal Products

EFAVIRENZ MYLAN 600 mg

Generic drug of Sustiva
Therapeutic class: Infectiology - Parasitology
Active ingredients: Efavirenz
laboratory: Mylan

Coated tablet
Box of 30 blister packs of 1
All forms

Indication

Efavirenz is indicated in combination with other antiretrovirals for the treatment of Human Immunodeficiency Virus (HIV-1) infection in adults, adolescents, and children over 3 years of age. more.

Efavirenz has not been adequately studied in patients with advanced HIV disease, especially in patients with CD4 cell counts <50 cells / mm3 or with previous protease inhibitor IP) failed. Although no cross-resistance between efavirenz and PIs has been documented, there is currently insufficient data on the efficacy of PIs used after failure of treatment including efavirenz.

For a summary of clinical and pharmacodynamic information, see section 5.1 Pharmacodynamic properties .

Dosage EFAVIRENZ MYLAN 600 mg Film-coated tablet Box of 30 blister packs of 1

Treatment should be initiated by a specialist physician in the management of HIV infection.

Concurrent antiretroviral therapy

EFAVIRENZ MYLAN should be taken in combination with other antiretroviral medicinal products (see section 4.5).

It is recommended to take EFAVIRENZ MYLAN on an empty stomach. An increase in efavirenz concentrations following administration of EFAVIRENZ MYLAN with food may result in an increase in the frequency of adverse reactions (see Warnings and Precautions and Pharmacokinetic Properties sections).

To improve the tolerance of adverse reactions affecting the nervous system, it is recommended to take EFAVIRENZ MYLAN at bedtime (see section 4.8).

Adults and adolescents over 40 kg

The recommended dose of EFAVIRENZ MYLAN in combination with nucleoside reverse transcriptase inhibitors (NRTIs) with or without IP (see section 4.5) is 600 mg orally in one single dose. daily intake.

EFAVIRENZ MYLAN film-coated tablets are not suitable for children weighing less than 40 kg. Efavirenz is marketed in other formulations for these patients. Refer to the summaries of product characteristics for formulations adapted to pediatric dosages (3 to 17 years).

Dosage adjustment

If EFAVIRENZ MYLAN is co-administered with voriconazole, the maintenance dose of voriconazole should be increased to 400 mg every 12 hours and the dose of EFAVIRENZ MYLAN should be reduced by 50% or 300 mg once daily. If treatment with voriconazole is discontinued, the initial dose of EFAVIRENZ MYLAN should be restored (see section 4.5).

If EFAVIRENZ MYLAN is co-administered with rifampicin, an increase in the dose of EFAVIRENZ MYLAN to 800 mg / day may be considered (see section 4.5).

Special populations

Renal Insufficiency: The pharmacokinetics of efavirenz have not been studied in patients with renal impairment. However, since less than 1% of the efavirenz dose is excreted unchanged in the urine, renal impairment is expected to have minimal impact on the elimination of efavirenz (see section 4.4). of employment ).

Hepatic impairment: Patients with mild hepatic disease may be treated at the usual recommended dose of efavirenz. Dose-dependent adverse effects of these patients, especially those affecting the nervous system, should be carefully monitored (see sections 4.3 and 4.4 ).

Against indications

Hypersensitivity to the active substance or to any of the excipients.

Efavirenz should not be administered to patients with severe hepatic impairment (Child Pugh Class C) (see section 5.2 ).

Efavirenz should not be administered concomitantly with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (eg, ergotamine, dihydroergotamine, ergonovine, and methylergonovine) because of the competitive binding of efavirenz to CYP3A4, with efavirenz likely to inhibit their metabolism and lead to potentially harmful or life-threatening side effects (eg rhythm, prolonged sedation or respiratory distress) (see section Interactions with other medicinal products and other forms of interaction ).

Herbal preparations containing St. John's Wort ( Hypericum perforatum ) should not be used in combination with efavirenz due to the risk of decreased plasma concentrations and reduced clinical efficacy of efavirenz (see section Interactions with other drugs and other forms of interaction ).

Adverse effects Efavirenz Mylan

at. Summary of the job security profile

Efavirenz has been studied in more than 9, 000 patients. In a subgroup of 1, 008 adult patients who received efavirenz 600 mg daily in combination with PIs and / or NRTIs in controlled clinical studies, the most commonly reported adverse reactions, and less moderate, were the following in at least 5% of patients: rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%). The most notorious side effects seen with efavirenz are rashes and symptoms affecting the nervous system. Symptoms affecting the nervous system usually begin shortly after initiation of treatment and usually resolve after the first 2 to 4 weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme, psychiatric adverse events including severe depression, suicide death, psychosis-like behavior and seizures have been reported in some patients treated with efavirenz, Administration of EFAVIRENZ MYLAN with food may increase efavirenz exposure and may increase the incidence of adverse reactions (see Warnings and Precautions ) section.

The long-term safety profile of treatments containing efavirenz was evaluated in a controlled clinical trial (Study 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). In this study, analysis of long-term use data for efavirenz did not reveal any new safety concerns.

b. Summary table of adverse effects

Adverse events of moderate to severe intensity may be treatment-related (based on investigator judgment) and reported in clinical trials evaluating antiretroviral combination therapy with efavirenz at the recommended dose (n = 1, 008). ) are listed below. Adverse events observed with antiretroviral therapy with efavirenz after the drug has been on the market are also listed in italics. Frequency is defined using the following convention: very common (≥ 1/10); frequent (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10 000 to <1/1000); or very rare (<1 / 10, 000).

Immune system disorders

Rare

hypersensitivity

Psychiatric disorders

Frequent

Abnormal dreams, anxiety, depression, insomnia 1

Rare

Emotional leniency, aggressive behavior, confusion, euphoria, hallucination, manic reactions, paranoid reactions, psychosis 2, suicide attempt, suicidal idea 1

Rare

Delirium 3, neurosis 3, suicide 1.3

Nervous system disorders

Frequent

Disorders of cerebellar coordination and balance 2, disturbances in concentration (3.6%), dizziness (8.5%), headache (5.7%), drowsiness (2.0%) 1

Rare

Agitation, amnesia, ataxia, abnormal coordination, convulsions, thought disorders 1, tremor 2

Eye disorders

Rare

Blurred vision

Affections of the ear and labyrinth

Rare

Tinnitus 2, vertigo

Vascular disorders

Rare

Congestive puffs 2

Gastrointestinal disorders

Frequent

Abdominal pain, diarrhea, nausea, vomiting

Rare

pancreatitis

Hepatobiliary disorders

Rare

Acute hepatitis

Rare

Hepatic insufficiency 1, 3

Skin and subcutaneous tissue disorders

Very common

Rashes (11.6%) 1

Frequent

itching

Rare

Erythema multiforme, Stevens-Johnson syndrome 1

Rare

allergic photo dermatitis 1, 3

Disorders of reproductive organs and breast

Rare

gynecomastia

General disorders and administration site conditions

Frequent

Tired

1 see section "c. Description of some adverse effects "for more details.

2 These side effects were identified during post-marketing surveillance of the drug; however, frequencies were determined using data from 16 clinical trials (n = 3969).

3 These adverse effects were identified in the post-marketing surveillance of the drug but were not reported as drug-related effects for efavirenz-treated patients in 16 clinical trials. The "rare" frequency category has been defined according to the European guideline " A Guideline on Summary of Product Characteristics (SmPC) (rev 2, Sept 2009)" based on an estimate of the upper limit of the 95% confidence for 0 events taking into account the number of patients treated with efavirenz in these clinical trials (n = 3, 969).

c. Description of some adverse effects

Rash: In clinical studies, 26% of patients treated with 600 mg efavirenz experienced rash compared with 17% of control patients. In 18% of patients treated with efavirenz, rash was considered treatment-related. Less than 1% of patients treated with efavirenz experienced severe rash and 1.7% discontinued treatment due to these rashes. The incidence of erythema multiforme and Stevens-Johnson syndrome was approximately 0.1%.

Rashes are usually mild to moderate maculopapular and appear in the first two weeks of treatment with efavirenz. In most patients, these rashes disappear after one month despite the continuation of efavirenz. It is possible to re-administer efavirenz after treatment interruption due to rash. In this case, it is recommended to use appropriate antihistamines and / or corticosteroids.

The number of patients who have received efavirenz after discontinuing other antiretrovirals in the NNRTI class is limited. Based primarily on retrospective cohort data from the published literature, reported recurrent skin rash rates following a change in treatment of nevirapine by efavirenz ranged from 13% to 18%, and are comparable to patients treated with efavirenz in clinical trials (see Warnings and Precautions ).

Psychiatric Disorders: Serious psychiatric-like adverse events have been reported in patients treated with efavirenz. In controlled studies, the frequency of serious specific psychiatric effects is detailed below:

Treatment with efavirenz

(N = 1008)

Treatment control

(N = 637)

- severe depression

1.6%

0.6%

- suicidal idea

0.6%

0.3%

- non-fatal suicide attempt

0.4%

0%

- aggressive behaviour

0.4%

0.3%

paranoid reactions

0.4%

0.3%

- manic reactions

0.1%

0%

Patients with a history of psychiatric disorders may be at increased risk of developing these psychiatric-type adverse events with a range of frequencies ranging from 0.3% for manic reactions to 2.0% for both depression and depression. severe and suicidal ideation. Post-marketing surveillance of suicide deaths, delusions and psychotic-type behavior has also been reported.

Symptoms affecting the nervous system: In controlled clinical trials, commonly reported adverse reactions include, but are not limited to, dizziness, insomnia, drowsiness, impaired concentration, and dream disturbance.

Nervous systemic symptoms of moderate to severe intensity were observed in 19% (2% of whom were severe) of patients receiving efavirenz compared to 9% (1% of whom were severe) of patients receiving control regimens. In clinical studies, 2% of patients treated with efavirenz discontinued treatment due to such symptoms.

These usually appear during the first two days of treatment and often disappear after 2 to 4 weeks. In a study in non-HIV infected subjects, the median time to onset of a nervous system symptom is one hour and the median duration is 3 hours. Neurologic symptoms may occur more frequently when efavirenz is taken in combination with food because of possible increased plasma concentrations of efavirenz (see section 5.2 ). Bedtime seems to improve the tolerance of these symptoms and may be recommended during the first few weeks of treatment and in patients who continue to have these symptoms (see section 4.2 ). Dose reduction or fractionation has not been shown to provide any benefit.

Long-term data analysis showed that beyond 24 weeks of treatment, the incidence of nervous system symptoms in patients treated with efavirenz was generally similar to those in the control arm.

Hepatic impairment: Some of the post-marketing reports of hepatic insufficiency, including cases in patients without pre-existing liver disease or other identifiable risk factors, were fulminant hepatitis, which in some cases have progressed to a transplant or a death.

Immune Restoration Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral combination therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may occur (see section 5.2). caution and precautions for use ).

Lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy has been associated with a redistribution of body fat (lipodystrophy) in HIV-infected patients, including peripheral and facial subcutaneous adipose tissue loss. increased intra-abdominal and visceral fat mass, breast hypertrophy and retro-cervical fat mass accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactataemia (see Warnings and Precautions ).

Osteonecrosis : Cases of osteonecrosis have been reported, particularly in patients with known risk factors, advanced HIV-related disease, or combination therapy with long-term antiretrovirals. Their frequency of occurrence is not known (see section Warnings and Precautions ).

Anomalies in biological tests

Hepatic enzymes : increases in aspartate aminotransferases (ASAT) and alanine aminotransferases (ALT) above five times the upper limit of normal values ​​were observed in 3% of 1, 008 patients treated with 600 mg efavirenz (5%). 8% after long-term treatment in Study 006). Similar increases were observed in patients in the control arm (5% after long-term treatment). Increases in gamma-glutamyl transferase (GGT) beyond five times the upper limit of normal values ​​were observed in 4% of all patients treated with 600 mg efavirenz and 1.5 to 2 % of patients in the control arm (7% of patients treated with efavirenz and 3% of patients treated in the control arm after long-term treatment). In patients receiving efavirenz, isolated increases in gamma-glutamyl transferase may reflect enzyme induction. According to long-term data from Study 006, 1% of patients in each arm of the study discontinued treatment due to liver or biliary disorders.

Amylase : in clinical studies, in a subgroup of 1, 008 patients, asymptomatic increases in serum amylase levels greater than one and a half times the upper limit of normal values ​​were observed in 10% of patients treated with efavirenz and in 6% of patients in the control group. The clinical significance of asymptomatic increases in serum amylase levels is unknown.

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

Interaction with tests for cannabinoids : Efavirenz does not bind to cannabinoid receptors. In urinary tests, false positives have been reported in uninfected volunteers who received efavirenz. There were false positives only with the CEDIA DAU THC Multi-Concentrations method that is used for screening, and not with the other tests for cannabinoids, including the tests used to confirm positive results.

d. Pediatric population

In children, side effects were generally similar to those in adults. Rash has been reported more frequently in children (in a clinical study including 57 children who received efavirenz for a 48 week period, rash was reported in 46% of them) and were often more severe in adults (a severe skin rash was reported in 5.3% of children). Prophylaxis with appropriate antihistamines may be recommended before starting treatment with efavirenz.

Although disorders affecting the nervous system are difficult to report in young children, they appear to be less common in children and generally moderate. In a clinical study of 57 children, symptoms of moderate intensity affecting the nervous system appeared in 3.5% of them: it was mainly dizziness. No children had severe symptoms or discontinuation due to neurological symptoms.

e. Other special populations

Hepatic enzymes in patients co-infected with hepatitis B or C : according to long-term data from study 006, 137 patients in the arms including efavirenz (median duration of treatment: 68 weeks) and 84 patients in the control arm (median duration: 56 weeks) were positive for Hepatitis B (Positive Surface Antigen) and / or Hepatitis C (Positive Hepatitis C Antibody) screening. Among patients co-infected in Study 006, increases in ASAT beyond five times the upper limit of normal values ​​were observed in 13% of patients treated with efavirenz and in 7% of patients in the control arm. and increases in ALT beyond five times the upper limit of normal values ​​were observed in 20% and 7%, respectively. Among co-infected patients, 3% of those treated with efavirenz and 2% of those in the control arm discontinued treatment due to liver diseases (see Warnings and precautions for use ).

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals declare any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (Ansm) and the network of Regional Pharmacovigilance Centers - Website: www.ansm.sante.fr.

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