Medicinal Products

EFAVIRENZ CRISTERS 600 mg

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

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Indication

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

Esfavirenz has not been sufficiently studied in patients at an advanced stage of HIV disease, particularly in patients with CD4 cell counts <50 cells / mm3 or with prior treatment with CRP inhibitors. proteases (IP) have failed. Although no resistance crossed between Šfavirenz and PIs has been documented, there is currently insufficient data on the effectiveness of combination therapy with PI used after treatment failure including Žfavirenz.

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

Dosage EFAVIRENZ CRISTERS 600 mg tablet film boast of 30

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

Esfavirenz has not been sufficiently studied in patients at an advanced stage of HIV disease, particularly in patients with CD4 cell counts <50 cells / mm3 or with prior treatment with CRP inhibitors. proteases (IP) have failed. Although no resistance crossed between Šfavirenz and PIs has been documented, there is currently insufficient data on the effectiveness of combination therapy with PI used after treatment failure including Žfavirenz.

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

Against indications

Hypersensitivity to the active substance or to any of the excipients listed under Composition .

Patients with severe hepatic insufficiency (Child Pugh, Class C) (see Proprietary pharmacokinetics section).

Co-administration with terfenadine, astimizole, cisapride, midazolam, triazolam, pimozide, benpridil, or ergot alkaloids (eg ergotamine, dihydroergotamine, ergonovine and methylergonovine) due to the concomitant uptake of šfavirenz on CYP3A4 because Šfavirenz may inhibit metabolism and cause undesirable, potentially life-threatening or fatal effects [eg rhythm disorders, sedation prolonged or respiratory distress] (see section Interactions with other medicinal products and other forms of interaction ).

Herbal preparations containing St. John's wort ( hypericum perforatum ) due to the risk of decreased plasma concentrations and reduced clinical efficacy of Žfavirenz (see section 4.5). Interactions with other medicinal products and other forms of interaction ).

Adverse effects Efavirenz Cristers

Summary of the job security profile

Esfavirenz has been studied in over 9, 000 patients. In a subgroup of 1, 008 adult patients receiving 600 mg of esfavirenz daily in combination with PIs and / or NRTIs in controlled clinical trials, the most commonly reported adverse effects, and at least 5% of patients: skin breakdown (11.6%), dizziness (8.5%), nausea (8.0%), cephalosa (5.7%) and fatigue (5.5%). The most common undesirable effects observed with Žfavirenz are skin 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 undesirable effects including severe depression, death by suicide, behavior similar to psychosis and seizures have been reported in some patients treated by Úfavirenz Administration of esfavirenz with food may increase exposure to esfavirenz and may result in increased frequency of adverse effects (see Warnings and Precautions section ).

The long-term tolerability profile of treatments including Žfavirenz was assessed in a controlled clinical trial (Study 006) in which patients were treated with Žfavirenz + zidovudine + lamivudine (n = 412, median duration: 180). weeks), Úfavirenz + indinavir (n = 415, median duration: 102 weeks), or indinavir + zidovudine + lamivudine (n = 401, median duration: 76 weeks). In this study, the analysis of data on the long-term use of šfavirenz did not reveal any new problems of tolerance.

Summary table of undesirable effects

The undesirable effects of moderate severity were possibly related to treatment (based on investigator judgment) and reported in clinical trials evaluating antiretroviral combination therapy including esfavirenz at the recommended dosage (n = 1). 1, 008) are listed below. Adverse effects observed with antiretroviral therapy with Äšfavirenz following the marketing of the medicinal product are also listed in italics. Frequency is defined using the following convention: very common (≥ 1/10); frequent (≥ 1/100 to "<1/10); not very frequent (≥ 1/1000 Ã "<1/100); rare (≥ 1/10 000 to <1/1000); or very rare (<1 / 10, 000).

Immune system disorders

Not very frequent

HypersensibilitÚ

Metabolism and nutrition disorders

frÚquent

little frequent

HypertriglyceridÚmie *

HypercholesterolÚmie *

Psychiatric disorders

FrÚquent

Abnormal findings, anxiety, depression, insomnia *

Not very frequent

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

AT

Rare

Describing, necrosis, suicide,

Nervous System Affections

FrÚquent

disorders of co-ordination and balance of cerebellar origin, concentration disorders (3.6%), dizziness (8.5%), cephalosis (5.7%), somnolence (2.0%) ) *

Not very frequent

Agitation, amnesia, ataxia, abnormal coordination, convulsions, disturbances of thought *, tremor ¥

Eye disorders

Not very frequent

Blurred vision

Affections of the ear and labyrinth

Not very frequent

Tinnitus, vertigo

AT

Vascular disorders

Not very frequent

Congestive puffs à ¥

Gastrointestinal disorders

FrÚquent

Abdominal pain, diarrhea, nausea, vomiting

Not very frequent

PancrÚatite

Hospital diseases

FrÚquent

Not very frequent

Increased aspartate aminotransferase (AST) *, increased alanine aminotransferase (ALT) *, increased gamma-glutamyltransferase (GGT) *

Acute hepatitis

Rare

Hepatic insufficiency ¥, *

Skin and subcutaneous tissue disorders

Very good

Cutaneous eruptions (11.6%) *

AT

FrÚquent

itching

Not very frequent

ÚrythÞme multiforme, Stevens-Johnson syndrome *

Rare

allergic photo dermatitis ¥

Disorders of reproductive organs and breast

Not very frequent

GynÚcomastie

General disorders and administration site abnormalities

FrÚquent

Tired

*, à ¢, see section ½ Description of some undesirable effects? for more details.

Description of certain undesirable effects

Information on post marketing surveillance

These undesirable effects have been identified during post market surveillance of the drug; however, the frequency of occurrence of these undesirable effects was determined from data from 16 clinical trials (n = 3, 969).

§ These undesirable effects have been identified during postmarketing surveillance but have not been reported as drug-related effects in patients treated with Úfavirenz and included in one of the 16 trials. clinics. The frequency category "rare" has been defined according to the European recommendations on the Product Characteristics Summary "Guideline on Summary of Product Characteristics (SmPC) (version 2, Sept 2009)" based on an estimate of the upper limit. the 95% confidence interval for 0 events taking into account the number of patients treated with esfavirenz in these clinical trials (n = 3, 969).

Skin rashes

In clinical studies, 26% of patients treated with 600 mg of esfavirenz experienced skin rashes compared with 17% of patients in the control groups. In 18% of patients treated with Úfavirenz, skin rashes were considered to be related to treatment. Less than 1% of patients treated with Úfavirenz experienced severe skin rashes and 1.7% of patients discontinued treatment due to these events. The incidence of multiform erythema and Stevens-Johnson syndrome is about 0.1%.

Skin eruptions are usually of the maculopapular type, and appear in the first two weeks of treatment with esfavirenz. In most patients, these eruptions disappear after one month, despite the continuation of esfavirenz. It is possible to administer esfavirenz after treatment interruption due to rash. In this case, it is recommended to use appropriate antihistamines and / or corticosteroids.

The number of patients who received æfavirenz after discontinuing use of other antiretroviral drugs in the NNRTI class is limited. Mainly based on retrospective cohort data extracted from the published literature, recurring skin rash reporting rates following a change in treatment of nevirapine by Äšfavirenz ranged from 13% to 18%, and are comparable to observed in patients treated with esfavirenz in clinical trials (see Warnings and Precautions section ).

Psychiatric disorders

Serious psychiatric-like adverse effects have been reported in patients treated with esfavirenz. In some studies, the frequency of serious specific psychiatric effects is detailed below:

Treatment with Úfavirenz

(N = 1008)

Controlled treatment

(N = 635)

- serious 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 psychiatric disorders may have an increased risk of developing these psychiatric-type adverse effects with a range of frequencies ranging from 0.3% for manic reactions to 2.0% for both serious depression and suicidal ideation. It has also been reported during the post-market surveillance of cases of suicide deaths, deaths and psychotic-type behaviors.

Symptoms affecting the nervous system

In controlled clinical trials, undesirable effects commonly reported include, but are not limited to, dizziness, insomnia, drowsiness, impaired concentration, and impaired renal function. Symptoms affecting the nervous system of moderate severity were observed in 19% (of which 2% were severe) of patients receiving efavirenz compared to 9% (1% of whom were patients) of patients receiving treatment. In clinical studies, 2% of patients treated with æfavirenz discontinued treatment because of such symptoms.

These usually appear during the first two days of treatment and often disappear after 2 to 4 weeks. During a study in subjects not infected with HIV, the median delay of onset of a symptom affecting the nervous system is one hour and its median duration is 3 hours. Neurologic symptoms may occur more frequently when šfavirenz is taken in combination with food, due to possible increased plasma concentrations of Úfavirenz (see Proprietary Pharmacokinetic ). Taking at bedtime seems to improve the tolerance of these symptoms and can be recommended during the first weeks of treatment and in patients continuing to present these symptoms (see section 4.2). It has not been shown that reducing or splitting the doses provided any benefit whatsoever.

Long-term data analysis showed that, beyond 24 weeks of treatment, the incidence of symptom onset affecting the nervous system in patients treated with esfavirenz was generally similar to those of the controlled arm.

Hepatic insufficiency

Some of the reports of hepatic insufficiency reported following the marketing of the drug, including cases in patients without pre-existing liver disease or other identifiable risk factors, have been fulminant hepatitis, which in some cases have evolved. to a transplant or a death.

Immune Restoration Syndrome

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

Lipodystrophy and metabolic abnormalities

Antiretroviral combination therapy has been associated with a redistribution of body fat (lipodystrophy) in patients infected with HIV, including loss of peripheral and subcutaneous adipose tissue, increased body mass intra-abdominal and visceral fat, breast hypertrophy and fat mass accumulation at the cervical level (buffalo hump).

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

OstÚonÚcrose

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

Anomalies in biological tests

Liver enzymes : ASAT and ALAT increases above five times the upper limit of normal values ​​were observed in 3% of the 1, 008 patients treated with 600 mg of esfavirenz (5% to 8% after treatment). long term in study 006). Similar increases were observed in patients in the controlled arm (5% after long-term treatment). Increases in GGT beyond five times the upper limit of normal values ​​were observed in 4% of all patients treated with 600 mg of esfavirenz and in 1.5 to 2% of patients in the controlled arms (7% of patients treated with Úfavirenz and 3% of patients treated in the controlled arm after long-term treatment). In patients receiving šfavirenz, 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 hepatic 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 ффfirenz and at 6% of patients of the control group. The clinical significance of asymptomatic increases in serum amylase levels is unknown.

Lipids : Increases in total cholesterol of 10 - 20% have been observed in some uninfected volunteers receiving Žfavirenz. In clinical studies in naive patients using antiretroviral therapy including esfavirenz, total cholesterol, HDL-cholesterol and triglycerides increased after 48 weeks of treatment (21-31%, 23-34, respectively). % 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 ​​can be influenced by factors such as the duration of treatment and other components of antiretroviral therapy.

Pediatric population

In children, undesirable effects are generally similar to those of adults. Skin eruptions have been reported more frequently in children (in a clinical study including 57 children who received İfavirenz for a 48-week period, 46% of them had skin rashes) and were often more only in adults (a severe cutaneous rash was reported in 5.3% of children). Prophylactic treatment with appropriate antihistamines may be recommended before the start of treatment with Úfavirenz. Although disorders affecting the nervous system are difficult to report in young children, they seem to be less frequent in children and generally moderated. In a clinical study conducted on 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 treatment interruptions due to neurologic symptoms.

Other special populations

Hepatic enzymes in patients co-infected with hepatitis B or C : according to the long-term data from study 006, 137 patients in the arms including Žfavirenz (median duration of treatment: 68 weeks) and 84 patients in the control arm (median duration: 56 weeks) were positive when screening for hepatitis B (positive surface Antigen) and / or hepatitis C (positive anti-hepatitis C antibody). Among co-infected patients in study 006, increases in ASAT beyond five times the upper limit of normal values ​​were observed in 13% of patients treated with ﯯ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ And in 7% of patients in the control, and increases in ALATs greater than five times the upper limit of normal values ​​were observed in 20% and 7%, respectively. Among co-infected patients, 3% of those treated with Žfavirenz and 2% of those on the controlled arm discontinued treatment due to liver diseases (see Warnings and Precautions section ).

Declaration of suspected undesirable effects

The declaration of undesirable effects suspected after authorization of the drug is important. It allows continuous monitoring of the beneficial / risk ratio of the drug. Healthcare professionals declare any suspected adverse effects via the national system of declaration: 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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