Generic drug of the therapeutic class: Infectiology - Parasitology
Active ingredients: Efavirenz, Emtricitabine, Tenofovir disoproxil
laboratory: Bms And Gilead Sciences

Coated tablet
Box of 1 bottle of 30
All forms

Indication

Atripla is a fixed combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate indicated for the treatment of human immunodeficiency virus (HIV-1) infection in virologically controlled adults (with HIV-1 RNA <50 copies / ml) with antiretroviral combination therapy for more than 3 months. Patients should not have experienced virologic failure with prior antiretroviral therapy and it should be established that these patients have not archived, prior to initiating their first antiretroviral therapy, mutant viral strains conferring significant resistance to antiretroviral therapy. one of the three components of Atripla (see sections 4.4 Special warnings and precautions for use and Pharmacodynamic properties ).

The demonstration of Atripla's benefit is primarily based on 48-week data from a clinical study in which patients with stable virologic control, treated with antiretroviral combination therapy, changed their treatment for Atripla (see section 5.1 ). . No clinical trial data are currently available with Atripla in treatment-naive or heavily pretreated patients.

There is no data available on the combination of Atripla with other antiretroviral agents.

Dosage ATRIPLA 600 mg / 200 mg / 245 mg Film-coated tablet Box of 1 vial of 30

Treatment should be initiated by physicians experienced in the management of human immunodeficiency virus (HIV) infection.

Dosage

Adults: The recommended dose of Atripla is one tablet taken once a day orally.

Administration mode

It is recommended to swallow the Atripla tablet whole with water.

It is recommended that Atripla be taken on an empty stomach, as concomitant use of food may increase efavirenz exposure and may increase the incidence of side effects (see sections 4.4 Special warnings and precautions for use and adverse reactions). ). In order to improve the safety of efavirenz in terms of undesirable effects on the nervous system, it is recommended to take the drug at bedtime (see section 4.8 ).

It is expected that after administration of Atripla on an empty stomach, tenofovir exposure will be approximately 35% less than that of the individual tenofovir disoproxil fumarate component taken with food (see section 5.2 ). In virologically controlled patients, the clinical relevance of this reduction may be expected to be limited (see section 5.1 ). Additional data on the clinical translation of the decrease in pharmacokinetic exposure are expected.

Children and adolescents: Atripla should not be used in children under the age of 18 due to the lack of data on safety and effectiveness.

Elderly: An insufficient number of older adults have been evaluated in clinical studies with Atripla components to determine if these patients respond differently to younger patients. Caution is advised when prescribing Atripla to the elderly, bearing in mind the greater frequency of decreased hepatic or renal function in these patients.

Dosage Adjustment: A supplemental dose of efavirenz of 200 mg / day (800 mg total) is recommended when rifampicin is co-administered with Atripla (see section 4.5, Interactions with other medicinal products and other forms of interaction ).

Renal Insufficiency: Atripla is not recommended in patients with moderate or severe renal impairment (creatinine clearance (CrCl) <50 ml / min). Patients with moderate or severe renal impairment require an adjustment of the interval of administration of emtricitabine and tenofovir disoproxil fumarate that can not be achieved with the fixed-combination tablet (see sections 4.4 and 4.4). precautions for use and pharmacokinetic properties ).

Hepatic impairment: The pharmacokinetics of Atripla have not been studied in patients with hepatic impairment. Patients with mild-to-moderate hepatic disease (Child-Pugh-Turcotte (CPT), grade A or B) may be treated with the usual recommended dose of Atripla (see section 4.3). Contraindications, Special Warnings and Precautions use and pharmacokinetic properties ). Adverse reactions, particularly those related to efavirenz affecting the nervous system, should be carefully monitored in these patients (see sections Contraindications and special warnings and precautions for use ).

If Atripla is discontinued in patients co-infected with HIV and HBV, these patients should be closely monitored for signs of hepatitis exacerbation (see section 4.4 Special warnings and precautions for use ).

It is important to take Atripla regularly so you do not forget a catch. If you miss a dose of Atripla within 12 hours of the usual time, patients should be advised to take the missed dose immediately. If it has been noted more than 12 hours after the usual set time, patients should be advised not to take the missed dose and to take their next dose at the usual time.

If discontinuation of the administration of any component of Atripla is indicated or if a dose modification is required, individual formulations of efavirenz, emtricitabine and tenofovir disoproxil fumarate are available. Please refer to the Summary of Product Characteristics for these drugs.

If treatment with Atripla is discontinued, the long half-life of efavirenz should be taken into account (see Pharmacokinetic properties ) and the long intracellular half-lives of tenofovir and emtricitabine should be taken into account. Because of the interindividual variability of these parameters and because of the possibility of resistance development, current recommendations for the therapeutic management of HIV should be consulted, and the reason for stopping treatment should be taken into consideration.

Against indications

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

Atripla should not be administered to patients with severe hepatic impairment (CPT, grade C) (see section 5.2 ).

Atripla 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 cytochrome P450 (CYP) 3A4, which may inhibit their metabolism and lead to potentially serious and / or prognostic adverse effects. vital (eg, arrhythmias, 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 Atripla due to the risk of decreased plasma concentrations and reduced clinical efficacy of efavirenz (see section 4.8). other drugs and other forms of interaction ).

Efavirenz significantly decreased plasma concentrations of voriconazole and voriconazole significantly increased plasma concentrations of efavirenz. Since Atripla is a fixed combination, the dose of efavirenz can not be changed; therefore, voriconazole and Atripla should not be co-administered (see section Interactions with other medicinal products and other forms of interaction ).

Atripla side effects

The evaluation of the adverse effects of the Atripla fixed combination is based on the following experience:

• a 48-week clinical study with Atripla (see Table 2)

• a clinical study in which efavirenz, emtricitabine and tenofovir disoproxil fumarate were co-administered (see Table 3).

• clinical studies and post-marketing experience of individual Atripla components (see Table 4).

In Tables 2, 3 and 4, adverse effects are presented in descending order of severity within each frequency group. Frequencies are defined as very common (≥ 1/10), frequent (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100).

Adverse effects observed during clinical experience with Atripla

In an open-label, 48-week, randomized clinical trial in HIV-infected patients with effective virologic control with their current antiretroviral therapy, patients either changed their treatment for Atripla (n = 203) or continued their original antiretroviral therapy (n = 97). The treatment-emergent adverse events considered as possibly or probably related to the study drugs, reported in patients treated with Atripla in Study AI266073, are presented in Table 2 by system organ class and frequency.

Table 2: All Adverse Events Emerging During Treatment and Regarded as Possibly or Probably Linked to Atripla, Reported in Study AI266073 (48 Weeks)

Atripla (n = 203)

Metabolism and nutrition disorders:

Frequent

Anorexia

Rare

Fat redistribution, hypertriglyceridemia, weight loss, increased appetite

Psychiatric disorders:

Frequent

Nightmares, depression, depressed mood, anxiety, insomnia, mood changes, abnormal dreams, sleep disorders

Rare

Mental confusion, disorientation, change of personality, changing mood, decreased libido

Nervous system disorders:

Very common

Dizzying sensations

Frequent

Drowsiness, headache

Rare

Inconsistent speech

Eye disorders:

Rare

Blurred vision, altered depth of field of vision

Affections of the ear and labyrinth:

Rare

Dizziness

Vascular disorders:

Frequent

Hot flashes

Gastrointestinal disorders:

Diarrhea, nausea

Rare

Acute pancreatitis, vomiting, oral paresthesia, oral hypoaesthesia, flatulence, dry mouth

Hepatobiliary disorders:

Rare

Acute hepatitis

Skin and subcutaneous tissue disorders:

Frequent

Rash, night sweats

Rare

itching

Musculoskeletal and systemic disorders:

Rare

myalgia

Renal and urinary disorders:

Frequent

Increased blood creatinine

Disorders of the reproductive organs and the breast:

Rare

Increased breast size

General disorders and administration site defects:

Frequent

Fatigue, increased energy

Rare

Abnormal sensation, excitement, chills

Undesirable effects observed during clinical experience with efavirenz + emtricitabine + tenofovir disoproxil fumarate

The following data are from a clinical study (GS-01-934) in which efavirenz, emtricitabine and tenofovir disoproxil fumarate were administered concomitantly, regardless of food intake, in their individual or the form of a fixed combination of emtricitabine and tenofovir disoproxil fumarate with efavirenz.

The selected adverse events emerging during treatment that are considered to be possibly or probably related to the study drugs reported in this clinical study in patients after 144 weeks of treatment are presented in Table 3 by organ system class and by frequency.

Table 3: Selected adverse reactions that emerged during treatment and were considered possibly or probably related to the study drugs (efavirenz, emtricitabine and tenofovir disoproxil fumarate) in the 144-week GS-01-934 study

Efavirenz + emtricitabine + tenofovir fumarate

disoproxil

(n = 257)

Hematological and lymphatic system disorders:

Rare

neutropenia

Nervous system disorders:

Very common

Dizzying sensations

Frequent

Drowsiness, stupor, lethargy, headache, attention deficit disorder

Rare

Amnesia, ataxia, balance disorder, dysgeusia

Eye disorders:

Rare

Blurry vision

Affections of the ear and labyrinth:

Frequent

Dizziness

Respiratory, thoracic and mediastinal disorders:

Rare

dyspnoea

Gastrointestinal disorders:

Very common

nausea

Frequent

Diarrhea, vomiting, abdominal pain, flatulence, abdominal distension, dry mouth

Rare

Dyspepsia

Skin and subcutaneous tissue disorders:

Very common

rash

Frequent

Pruritus, hyperpigmentation of the skin, dermatitis

Rare

Urticaria, dry skin, eczema

Metabolism and nutrition disorders:

Frequent

Decreased appetite, increased appetite

Rare

Hypertriglyceridaemia, anorexia

Vascular disorders:

Frequent

Hot flashes

General disorders and administration site defects:

Frequent

Fatigue, fever

Rare

Asthenia, feeling drunk

Psychiatric disorders:

Very common

Abnormal dreams

Frequent

Nightmares, depression, insomnia, sleep disorders, euphoric mood

Rare

Paranoid reaction, psychomotor agitation, delirium, mental confusion, anxiety, aggressive behavior, nervousness, disorientation

Biological abnormalities: Liver enzymes: In a 144-week clinical study (GS-01-934), increases in aspartate aminotransferase (AST> 5 times the upper limit of normal) and alanine aminotransferase (ALT> 5-fold) the upper limit of normal) were reported in 3% and 2%, respectively, of patients treated with efavirenz, emtricitabine and tenofovir disoproxil fumarate (n = 257) and in 3% and 3% of patients treated with efavirenz and zidovudine / lamivudine in fixed combination (n = 254).

Side effects associated with individual components of Atripla

Adverse events from clinical studies and post-marketing experience with each of the individual components of Atripla in combination antiretrovirals are listed in Table 4 below by organ system class and frequency.

The most notorious side effects reported in clinical studies with efavirenz are rashes and symptoms affecting the nervous system. Administration of efavirenz with food may increase efavirenz exposure and may increase the incidence of adverse reactions (see section 4.4 ). After marketing tenofovir disoproxil fumarate, urinary and renal disorders have been reported, including renal failure, proximal tubulopathy (including cases of Fanconi syndrome), acute tubular necrosis, and nephrogenic diabetes insipidus.

Table 4: Adverse Events Associated with Individual Atripla Components Based on Clinical Trial Data and Post Marketing Pharmacovigilance

efavirenz

emtricitabine

Tenofovir Fumarate Disoproxil

Hematological and lymphatic system disorders:

Frequent

neutropenia

Rare

Anemia

Nervous system disorders:

Very common

headaches

Dizzying sensations

Frequent

Drowsiness, Headache, Attention Deficit, Dizziness

Dizzying sensations

Rare

Convulsion, amnesia, thought disorders, ataxia, coordination disorders, agitation

Not known *

Cerebellar disorders of coordination and balance

Eye disorders:

Rare

Blurry vision

Affections of the ear and labyrinth:

Rare

Dizziness

Respiratory, thoracic and mediastinal disorders:

Not known *

dyspnoea

Gastrointestinal disorders:

Very common

Diarrhea, nausea

Diarrhea, vomiting, nausea

Frequent

diarrhea,

vomiting, abdominal pain, nausea

Increased amylase including pancreatic amylase, increased serum lipase, vomiting, abdominal pain, dyspepsia

Flatulence

Rare

Acute pancreatitis

Not known *

pancreatitis

efavirenz

emtricitabine

Tenofovir Fumarate Disoproxil

Renal and urinary disorders:

Not known *

Renal insufficiency (acute and chronic), acute tubular necrosis, proximal renal tubulopathy, including Fanconi syndrome, nephritis, acute interstitial nephritis, nephrogenic diabetes insipidus, hypercreatininemia, proteinuria

Skin and subcutaneous tissue disorders:

Very common

Rash (all grades, 18%)

Frequent

itching

Allergic reaction, vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discolouration (dyschromia due to increased pigmentation)

Rare

Stevens-Johnson syndrome, erythema multiforme, severe rash (<1%)

Not known *

Photoallergic dermatitis

rash

Musculoskeletal and systemic disorders:

Very common

Increased creatine kinase

Not known *

Rhabdomyolysis, osteomalacia (manifested by bone pain and may in rare cases promote the occurrence of fractures), muscle weakness, myopathy

Metabolism and nutrition disorders:

Very common

hypophosphatemia

Frequent

Hyperglycemia, hypertriglyceridemia

Not known *

Lactic acidosis, hypokalemia

General disorders and administration site defects:

Frequent

Tired

Pain, asthenia

Not known *

Asthenia

efavirenz

emtricitabine

Tenofovir Fumarate Disoproxil

Immune system disorders:

Rare

hypersensitivity

Hepatobiliary disorders:

Frequent

Increased serum ASAT and / or elevated serum ALT, hyperbilirubinemia

Uncommon Acute hepatitis

Not known *

Hepatic insufficiency

Hepatitis, increased rate of

transaminases, hepatic steatosis

Disorders of reproductive organs and breast

:

Rare

gynecomastia

Psychiatric disorders:

Frequent

Depression (severe

Abnormal dreams,

in 1.6% of cases),

insomnia

anxiety, dreams

abnormal, insomnia

Rare

Suicide attempt, suicidal ideation, manic reaction, paranoid reaction, hallucination, euphoria, emotional lability, confusion, aggressive behavior

Not known *

Suicide, psychosis, delirium, neurosis

* These adverse effects have been identified in the context of postmarketing pharmacovigilance and their frequency is not known.

The following undesirable effects, presented above by organ class, may occur following proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested by bone pain and may in rare cases promote the occurrence of fractures), hypokalemia, muscle weakness, myopathy and hypophosphatemia. In the absence of proximal renal tubulopathy, these effects are not considered to be causally associated with tenofovir disoproxil fumarate therapy.

Rash with Efavirenz: The rash is usually maculopapular, mild to moderate, occurring within the first two weeks of treatment with efavirenz. In most patients, these rashes disappear after one month despite the continuation of efavirenz. In clinical studies, 1.7% of patients treated with efavirenz discontinued treatment due to rash occurrence. It is possible to re-administer efavirenz after treatment interruption due to rash. Appropriate antihistamines and / or corticosteroids are recommended when taking efavirenz.

The number of patients who received efavirenz after discontinuing other antiretrovirals in the non-nucleoside reverse transcriptase inhibitor class (NNRTIs) is limited. Nineteen patients who discontinued nevirapine due to rash were treated with efavirenz. Nine of these patients developed mild-to-moderate rash while taking efavirenz and two patients discontinued efavirenz due to rash.

Psychiatric Symptoms with Efavirenz: Patients with a history of psychiatric disorders are at increased risk of serious psychiatric adverse events (shown in the Efavirenz column of Table 4) with a frequency of effects of 0.3% for manic reactions and 2% for both severe depression and suicidal ideation.

Symptoms affecting the nervous system with efavirenz: In controlled clinical studies, moderate to severe nervous system symptoms were observed in 19.4% of patients versus 9.0% of patients receiving arm treatments. control. These symptoms were severe in 2.0% of patients receiving efavirenz 600 mg daily and in 1.3% of patients receiving control treatments. In clinical studies, 2.1% of patients treated with 600 mg efavirenz discontinued treatment due to symptoms affecting the nervous system.

Symptoms affecting the nervous system usually appear during the first two days of treatment and often disappear after the first 2 to 4 weeks of treatment. These symptoms affecting the nervous system may occur more frequently when efavirenz is taken concomitantly with food, due to possible increased plasma concentrations of efavirenz (see section Pharmacokinetic properties ). The bedtime dose seems to improve the tolerance to these symptoms (see section Dosage and method of administration ).

Analysis of data from a long-term clinical study (median follow-up: 180 weeks, 102 weeks, and 76 weeks for patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir and indinavir + zidovudine + lamivudine, respectively) showed that beyond 24 weeks of treatment, incidences of nervous system symptoms in efavirenz-treated patients were generally similar to those in the control arm.

Lactic acidosis: Cases of lactic acidosis, usually associated with fatty liver, have been reported with the administration of nucleoside analogues (see section 4.4 ).

Patients co-infected with HIV / HBV or HCV: Only a limited number of patients were co-infected with HBV (n = 13) or HCV (n = 26) in study GS-01-934. The adverse event profile of efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients co-infected with HIV / HBV or HIV / HCV was similar to that observed in HIV-infected patients without HIV. -infection. However, as expected for this patient population, increases in ASAT and ALT levels were more frequent than in the general HIV-infected population.

Amylase: In clinical studies, asymptomatic increases in serum amylase> 1.5 times the upper limit of normal were observed in 10% of patients treated with efavirenz and in 6% of patients in the group control. The clinical significance of asymptomatic increases in serum amylase levels is unknown.

Lipids, lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactataemia (see section special guard and precautions for use ).

Combination antiretroviral therapy has been associated with a redistribution of body fat (lipodystrophy) in HIV-infected patients, including loss of subcutaneous peripheral and facial adipose tissue, increased body fat intra-abdominal and visceral, breast hypertrophy and accumulation of fat mass at the cervical level (buffalo hump) (see section 4.4. Special warnings and precautions for use ).

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

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

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 4.4 ).

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