Efavirenz-Nanolek, 600 mg 30 pcs

Pharmacokinetics:

Intake:

In healthy volunteers, the maximum plasma concentration (Cmax) of efavirenz of 1.6-9.1 μmol/L was reached 5 h after a single oral dose of 100 to 1600 mg. Dose-dependent increase in Cmax and area under curve “concentration – time” (AUC) was observed when taking the drug in doses up to 1600 mg; herewith there was no dose-proportional increase of these parameters, therefore, it can be assumed that at higher doses absorption decreases. The time of reaching maximum plasma concentration (3-5 hours) did not change after multiple doses of the drug, and the equilibrium plasma concentration was reached after 6-7 days.

When a single dose of Efavirenz in healthy volunteers in form of film-coated tablets with high fat content in a meal was observed to increase AUC by 28% and Cmax by 79% in comparison with these figures when the preparation was taken on an empty stomach.

Distribution:

Efavirenz is highly bound to plasma proteins (approximately 99.5-99.75%), especially to albumin. In HIV-infected patients (N = 9) who received efavirenz in doses of 200 to 600 mg once daily for at least one month, the drug concentration in cerebrospinal fluid was 0.26 to 1.19% (0.69% on average) of the corresponding concentration in blood plasma. This figure is approximately 3 times higher than concentration of non-protein bound (free) fraction of efavirenz in blood plasma.

Metabolism:

Clinical and in vitro studies using human liver microsomes have shown that efavirenz is metabolized primarily by the cytochrome P450 system to hydroxylated derivatives, which then bind to glucuronic acid to form glucuronides. Generally, these metabolites are inactive against HIV-1. In vitro studies suggest that CYP3A4 and CYP2B6 are the main isoenzymes that metabolize efavirenz and that efavirenz inhibits 2C9, 2C19 and 3A4 cytochrome P450 isoenzymes. In in vitro studies efavirenz did not inhibit CYP2E1 isoenzyme and inhibited CYP2D6 and CYP1A2 isoenzymes only at concentrations much higher than those used in clinical practice. Plasma exposure of efavirenz may increase in patients homozygous for the G516T gene polymorphism of CYP2B6 isoenzyme. Clinical significance of this change is unknown; however, the possibility of increased risk of development and increased severity of adverse reactions of efavirenz cannot be excluded.

Efavirenz has been shown to induce the CYP3A4 and CYP2B6 isoenzymes, resulting in induction of its own metabolism, which may be clinically expressed in some patients. When multiple doses of efavirenz 200-400 mg per day were administered to healthy volunteers for 10 days, less cumulation of efavirenz (22-42% lower than suggested values) and shorter half-life – 40-55 h (half-life of a single dose is 52-76 h) were observed. Efavirenz has also been shown to induce isoform 1A1 of uridine diphosphate-glucuronyltransferase (UDF-GT1A1), so plasma concentrations of raltegravir, which is a substrate of UDF-GT1A1, are reduced when used concurrently with efavirenz.

Although in in vitro studies efavirenz inhibited CYP2C9 and CYP2C19 isoenzymes, in vivo studies both increased and decreased exposure of substrates of these enzymes were observed when concomitantly used with efavirenz. The ultimate effect of this interaction has not been established.

Efavirenz has a relatively long half-life, which is at least 52 hours after a single dose and 40-55 hours after multiple doses.

Approximately 14-34% of the dose of efavirenz taken is excreted by the kidneys, less than 1% of the dose of efavirenz is excreted unchanged by the kidneys.

Pharmacokinetics in special patient groups

Hepatic impairment

A two-fold increase in half-life of efavirenz was observed with single drug administration in one patient with severe hepatic impairment (Child-Pugh class C), which indicates an increased degree of cumulation in these cases. There was no significant effect of liver damage on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh class A) compared to patients in the control group. There are currently insufficient data to conclude whether moderate to severe hepatic impairment (Child-Pugh grades B and C) affects the pharmacokinetics of efavirenz (see Caution).

Prenal impairment

The pharmacokinetics of efavirenz in patients with renal impairment have not been studied, but because less than 1% of the dose of efavirenz is excreted unchanged by the kidneys, renal impairment should not significantly affect efavirenz excretion (see section “Cautionary Note”).

Gender and race

The pharmacokinetic parameters of efavirenz are similar in men and women as well as in patients of different racial backgrounds.

Elderly patients

No pharmacokinetic differences were found in patients 65 years of age or older and younger patients, although clinical trials of efavirenz have not included a sufficient number of patients 65 years of age or older.

Children

The use of efavirenz in children less than 3 months of age or weighing less than 3.5 kg has not been studied.

The pharmacokinetic parameters of efavirenz in children and adults were similar. In 49 children who received a dose of efavirenz equivalent to 600 mg (dose was calculated based on body weight), Cmax was 14.1 µM, Cmin was 5.6 µM and the area under the concentration-time curve was 216 µM per hour.

Indications

Active ingredient

Composition

Each film-coated tablet contains:

The active ingredient:

Efavirenz 600 mg;

Excipients:

Microcrystalline cellulose 240.00 mg,

croscarmellose sodium 60.00 mg,

Hyprolose 38.40 mg,

p> sodium lauryl sulfate 12.00 mg,

lactose monohydrate 237.60 mg,

magnesium stearate 12.00 mg;

Shell composition: Opadray Yellow 15B82855 18.00 mg (hypromellose 3cP, hypromellose 6cP, titanium dioxide, macrogol 400, talc, iron oxide yellow dye, polysorbate 80).

Interaction

Exposure of efavirenz may be increased when the drug is used concomitantly with some drugs (e.g., ritonavir) or food products (e.g., grapefruit juice) that inhibit CYP3A4 or CYP2B6 isoenzymes. Preparations based on Ginkgo biloba extract, which induce these isoenzymes, may lead to a decrease in plasma concentration of efavirenz.

Contraindicated combination therapy

. Concomitant use of efavirenz with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil and ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergometrine and methylergometrine) is contraindicated since inhibiting their metabolism with efavirenz can cause serious, life-threatening consequences (see See section “Contraindications”).

Other interactions

The interactions between efavirenz and HIV protease inhibitors, antiretroviral drugs other than HIV protease inhibitors, and between efavirenz and drugs other than antiretrovirals are shown in Table 2 below.

An increase in the index value is indicated by the “↑” arrow, a decrease in the value by the “↓” arrow, and if the index remains unchanged by the “↔” arrow; if the drug was administered every 8 or 12 h, it is indicated by “k8h” or “k12h”. If necessary, 90% and 95% confidence intervals are presented in parentheses. Studies have generally been performed on healthy volunteers unless other information is specifically stated.

Table 2. Interactions between efavirenz and other drugs

Drugs divided by pharmacotherapeutic group (dose)

The effect on serum drug concentration.

The mean change in AUC, Cmax, Cmin values (%) and confidence intervals, if applicablea (mechanism)

Recommendations for possible concomitant use with efavirenz

Antimicrobial drugs

Antiretroviral medicines

HIV protease inhibitors

Atazanavir/ritonavir/efavirenz

(400 mg once daily/100 mg once daily/ 600 mg once daily, weights taken with meals)

Atazanavir (afternoon):

AUC: ↔ (↓9 to ↑10)

Cmax: ↑17%* (↑8 to ↑27)

Cmin: ↓42%* (↑31 to ↓51)

Concurrent use of efavirenz with atazanavir/ritonavir is not recommended. If concomitant use of atazanavir with NIOT is required, consideration should be given to increasing the dose of atazanavir to 400 mg and ritonavir to 200 mg, in combination with efavirenz, with close clinical monitoring.

Atazanavir/ritonavir/efavirenz

(400 mg once daily/200 mg once daily/600 mg once daily, all taken with meals)

Atazanavir (afternoon):

AUC: ↔*/** (↓10 to ↑2 6)

Cmax: ↔*/** (↓5 to ↑26)

Cmin: ↑12%*/** (↓16 to ↑49)

(CYP3A4 induction.)

* When compared with atazanavir 300 mg/ritonavir 100 mg once daily in the evening without efavirenz. This reduction in atazanavir Cmin may adversely affect atazanavir efficacy

**based on historical comparison.

Darunavir/ritonavir/efavirenz

(300 mg 2 times daily*/100 mg 2 times daily/ 600 mg once daily)

* below the recommended dose.

The same results are expected when used at the recommended doses.

Darunavir:

AUC: ↓13%

Cmin: ↓31%

Cmax: ↓31%

(induction of CYP3A4)

Efavirenz:

AUC: ↑21%

Cmin: ↑17%

Cmax: ↑15%

(CYP3A4 inhibition)

Special Instructions

Efavirenz should not be used as a single drug to treat HIV infection, nor should it be added as a single drug to an ineffective therapy regimen. As with other NNRTIs, viral resistance can develop rapidly when efavirenz is used in monotherapy. When selecting new antiretrovirals for use in combination with efavirenz, the possibility of cross-resistance of the virus should be considered (see section on Pharmacodynamics).

The use of efavirenz concomitantly with tablet medications with fixed combinations of efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended unless a dose adjustment is required (for example, when concomitantly used with rifampicin).

The concomitant use of efavirenz with preparations based on Ginkgo biloba extract is not recommended.

When prescribing drugs for concomitant use with Efavirenz-NANOLEC®, the physician should refer to the instructions for medical use of these drugs.

With ART, the risk of transmission of HIV to others through sexual intercourse or blood cannot be ruled out. Because of this, appropriate precautions should be taken.

Companion antiretroviral therapy: If any antiretroviral drug in a combination ART regimen is withdrawn due to suspected intolerance, all antiretrovirals should be considered for simultaneous withdrawal. All antiretrovirals that have been discontinued should be restarted as soon as symptoms of intolerance have disappeared. Interrupted monotherapy and sequential re-treatment with antiretrovirals are not recommended because of the increased likelihood of emergence of therapy-resistant virus.

There is limited experience with efavirenz in patients who have had other NNRTI class antiretrovirals withdrawn (see side effects).

Efavirenz is not recommended in patients who have previously developed life-threatening skin reactions (e.g., Stevens-Johnson syndrome) while taking other NNRTIs.

Mental symptoms: There are data on the occurrence of mental adverse events in patients taking efavirenz. Patients with a history of mental disorders are at increased risk of serious mental adverse events. In particular, severe depression was most frequently observed in patients with a history of depression. There are also post-registration data on cases of severe depression, death by suicide, delirium, and psychosis-like behavior.

Patients should be warned that if they develop symptoms such as severe depression, psychosis, or suicidal ideation, they should inform their physician immediately. The physician should determine if these symptoms may be related to taking efavirenz, and if this relationship is confirmed, assess the balance between the risk to the patient of continuing therapy and the potential benefit of taking the drug (see Caution section).

Synopsis

Contraindications

– Hypersensitivity to any of the components of the drug;

– Severe hepatic impairment (Child-Pugh functional class C) (see sections “Pharmacological properties” and “Pharmacokinetics of special patient groups. Pharmacological properties” and “Pharmacokinetics in special patient groups”);

– children with a body weight less than 40 kg (for the given dosage form and dosage form);

– concomitant use with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine or methyl ergonovine), since competitive interaction of efavirenz with the CYP3A4 isoenzyme may inhibit the metabolism of these drugs and lead to serious and/or life-threatening adverse reactions (e.g. arrhythmias, prolonged sedation or respiratory depression) (see section “Interaction with other drugs”).

– concomitant use with preparations/ herbal products containing Hypericum perforatum, since plasma concentrations of efavirepz are reduced and, consequently, the clinical effect (see “Interaction with other medicinal products”).

Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

– Patients with a history of psychiatric disorders who are at high risk of developing serious adverse psychiatric events;

Patients with a history of mild to moderate liver disease;

Patients with a history of seizures/patients taking concomitant anticonvulsants that are metabolized preferentially in the liver, such as phenytoin, carbamazepine, and phenobarbital (periodic monitoring of their blood concentrations is necessary);

– when concomitant use of efavirenz and artemether/lumefantrine.

Side effects

The frequency of adverse events is categorized as follows: very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10000, < 1/1000); very rare (< 1/10000).

Immune system disorders

Infrequent: hypersensitivity.

Metabolic disorders

Often: hypertriglyceridemia.

Infrequent: hypercholesterolemia.

Mental disorders

Often: abnormal dreams, anxiety, depression, insomnia.

Infrequent: tendency to affect, aggressiveness, confusion, moodiness with tendency to euphoria, hallucinations, mania, paranoid behavior, psychosis, suicide attempt, suicidal intentions.

Rarely: delirium, neurosis, death by suicide.

Nervous system disorders

Often: cerebellar coordination and balance disorders, attention disorders, dizziness, headaches, drowsiness.

Infrequent: anxious agitation, amnesia, ataxia, impaired coordination of movements, seizures, impaired thinking, tremor.

Visual organ disorders

Infrequent: blurred vision.

Hearing organ and labyrinth disorders

Infrequent: tinnitus, vertigo.

Respiratory system disorders

Rarely: dyspnea.

Vascular disorders

Infrequent: “rushes” of blood to the skin of the face.

Gastrointestinal disorders

Often: abdominal pain, diarrhea, nausea, vomiting.

Infrequent: pancreatitis.

Hepatic and biliary tract disorders

Often: increased aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) activity.

Infrequent: acute hepatitis.

Rarely: liver failure.

Dermal and subcutaneous tissue disorders

very often: skin rash.

Often: skin itching.

Infrequent: erythema multiforme, Stevens-Johnson syndrome.

Rarely: photoallergic dermatitis.

Gender and breast disorders

Infrequent: gynecomastia.

General disorders

Often: increased fatigue.

Description of individual adverse events

Skin rash. In clinical trials, skin rash was observed in 26% of patients taking efavirenz at a dose of 600 mg, compared to 17% of patients in control groups. Skin rash was associated with taking efavirenz in 18% of patients, with 1.7% of patients discontinuing the drug due to the onset of a skin rash. The incidence of erythema multiforme and Stevens-Johnson syndrome was approximately 0.1%.
Cases of skin rash were reported in 59 of 182 children (32%) treated with efavirenz in 3 clinical trials with an average duration of 123 weeks. In 6 children, the rash was severe. Appropriate antihistamine therapy as prophylaxis may be recommended before starting efavirenz therapy in children. A mild to moderate maculopapular skin rash usually develops and appears within the first two weeks of starting efavirenz therapy. In most patients, the skin rash disappears when therapy with efavirenz is continued for one month. Efavirenz may be re-prescribed to patients who discontinued it because of a skin rash. When resuming therapy with efavirenz, it is also recommended that appropriate H1-histamine receptor blockers and/or corticosteroids be taken.

There is limited experience with efavirenz in patients who have discontinued therapy with other NRTIs. The rate of skin rash recurrence after switching from nevirapine therapy to efavirenz therapy, mainly estimated from published retrospective data, was 13% to 18%, and is comparable to the rate found in patients taking efavirenz in clinical trials (see Special Instructions).

Mental Symptoms. Serious adverse psychiatric events have been observed in some patients taking efavirenz. In controlled clinical trials, the incidence of selected serious adverse psychiatric events was as follows: severe depression 1.6% in the group of patients receiving combined ART with efavirenz and 0.6% in the control group of patients, suicidal intentions 0.6% and 0.3%, non-fatal suicide attempts 0.4% and 0%, aggressive behavior 0.4% and 0.3%, paranoid reactions 0.4% and 0.3%, manic reactions 0.1% and 0% respectively.

Patients with a history of psychiatric disorders are at increased risk of developing these serious adverse psychiatric events, with the incidence of each of the above phenomena ranging from 0.3% for manic reactions to 2.0% for severe depression and suicidal ideation. Suicidal deaths, delusional disorders, and psychosis-like behavior were also reported in the post-registration period.

Nervous system symptoms. The following adverse reactions have been frequently observed in patients taking efavirenz in a dose of 600 mg in controlled clinical trials: dizziness, insomnia, somnolence, attention deficit disorder, nightmares. Other adverse events have also been observed. Moderate to severe nervous system symptoms were observed in 19% of patients (severe – in 2%), whereas in patients receiving control therapy the rate was 9% (severe – in 1%). During clinical trials, 2% of patients receiving efavirenz discontinued therapy because of the above symptoms.

Nervous system symptoms were usually observed within the first or second day after initiation of therapy and in most cases disappeared within the first 2-4 weeks. In a study involving uninfected volunteers, a representative nervous system symptom occurred an average of 1 h after drug administration and lasted an average of 3 h. Nervous system symptoms developed more frequently if efavirenz was taken with meals. This may be due to increased plasma concentrations of efavirenz under such conditions (see Pharmacokinetics). In order to improve the tolerability of the drug for these symptoms during the first weeks of therapy, it is recommended to take the drug before bedtime. This regimen is also recommended for patients who continue to have these symptoms (see Administration and Dosage). Decreasing the dose or taking the daily dose in portions usually does not produce a favorable effect.

Analysis of data on long-term use of the drug showed that after 24 weeks of therapy the incidence of first-onset nervous system symptoms in patients taking efavirenz was generally similar to that in the control group.

Hepatic failure. Several cases of hepatic failure were reported in the post-registration follow-up period, including cases without a history of liver disease or other identified risk factors. These cases were characterized by a fulminant course; in a number of cases liver transplantation was required or patient death was reported.

The immune reconstitution syndrome. HIV-infected patients with severe immunodeficiency may have an increased risk of inflammatory reactions to inactive or residual opportunistic infections at the start of combination ART (see Special Instructions).

Lipodystrophy and metabolic disorders: Combination ART is associated with redistribution of body fat (lipodystrophy) in HIV-infected patients, including depletion of peripheral and facial subcutaneous fat, accumulation in the intraperitoneal space, internal organs, posterior neck (“buffalo hump”) and hypertrophy of the breasts.

Combination ART may cause metabolic abnormalities such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia (see Special Instructions).

Osteonecrosis. Cases of osteonecrosis have been observed, predominantly in patients with well known risk factors, with long-term HIV infection, and in patients who have been on long-term combination ART. However, the incidence of this complication has not been established (see Special Instructions).

Laboratory indices

Children and adolescents

The type and frequency of adverse events in children are generally comparable to those observed in adult patients, except for skin rash, which is more common in children (46% of children) than in adults and more severe (severe skin rash was observed in 5.3% of children). In order to prevent the rash, it may be reasonable to prescribe appropriate H1-histamine receptor blockers to children before starting efavirenz therapy. Although nervous system symptoms in young children are difficult to detect, it is believed that such symptoms in children are less frequent and usually mild. In 3.5% of patients there were moderate nervous system symptoms, mostly dizziness. No child had severe symptoms and did not require discontinuation of therapy due to nervous system symptoms.

Other special patient groups

Hepatic enzyme activity in patients concurrently infected with hepatitis B or C

Overdose

Pregnancy use

There have been no adequate and controlled clinical studies involving pregnant women. In the post-registration period, there have been reports of the use of efavirenz as part of combination antiretroviral therapy (ART) in the first trimester of pregnancy. No specific features (increased incidence) of neonatal malformations have been reported. Only a few reports contained information on cases of neural tube defects, including meningomyelocele. Most of these reports were retrospective, and causality has not been studied.

Efavirenz has been shown to be excreted with the breast milk of lactating women. There is insufficient information on the effect of efavirenz on newborns and infants. Breastfeeding is not recommended for women taking efavirenz during lactation. Breastfeeding is not recommended for HIV-infected mothers under any circumstances to prevent HIV transmission.