Emtricitabine - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Means for the treatment of HIV infection

Included in the formulation

Emtitab®

pills inwards

FARMASINTEZ, JSC (Irkutsk) Russia

Emtricitabine

capsules inwards

BIOCAD, CJSC Russia

АТХ:

J.05.A.F.09 Emtricitabine

Pharmacodynamics:

Emtricitabine is a synthetic nucleoside, an analog of cytidine, phosphorylated by cellular enzymes up to emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits HIV-1 reverse transcriptase activity by competing with the natural substrate deoxytidine 5'-triphosphate and through incorporation into the resulting viral DNA, which leads to chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of α-, β-, ε-polymerase DNA and mitochondrial DNA γ-polymerase.

Antiviral activity

The antiviral activity of emtricitabine against laboratory and donor HIV-1 strains was evaluated in colonies of lymphoblastoid cells (MAGI-CCR5 cell line) and peripheral blood mononuclear cells. EU₅₀ (EU₅₀ - the concentration of the drug necessary to suppress 50% of the viruses) was in the range from 0.0013 to 0.64 μmol (0.0003-0.158 mg / ml).

Emtricitabine has shown antiviral activity relative to the culture of the cells of HIV-1 subtypes A, B, C, D, E, F and G (EU₅₀ was 0.007-0.075 μmol) and showed selective inhibitory effect on some strains of HIV-2 (EU₅₀ was 0.007-1.5 μmol).

In studies of drug combinations, emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine) and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir) an additional synergistic effect was observed.

Antiviral activity of emtricitabine in vivo was studied in two clinical studies in which patients received monotherapy with emtricitabine at a dose of 25-400 mg per day for 10-14 days. A dose-dependent antiviral effect was observed with an average decrease in HIV-1 RNA by 1.3 log₁₀ in a dose of 25 mg once a day and at 1.7 log₁₀and 1.9 log₁₀ in a dose of 200 mg 1 or 2 times a day.

Resistance

From cell culture and in vivo Emtricitabine-resistant HIV strains were isolated. A genotypic analysis of these strains showed that a decrease in sensitivity to emtricitabine was associated with a mutation of the HIV reverse transcriptase gene in codon 184, which in turn led to a substitution of the amino acid methionine for valine or isoleucine (M184V / I).

Emtricitabine-resistant strains of HIV were found in some patients who took emtricitabine in monotherapy or in combination with other antiretroviral drugs. In a clinical study, viral strains in 37/5% of previously untreated patients with virologic failure had a reduced sensitivity to emtricitabine. Genotypic analysis of these strains showed that the decrease in sensitivity to emtricitabine was associated with mutation M184V / I in the reverse transcriptase gene of HIV.

Assay for resistance of HIV-1 isolated strains was performed in all patients with confirmed virological failure (HIV-1 RNA> 400 copies / ml or 144 to week earlier) participating in a clinical trial and receiving emtricitabine, tenofovir and efavirenz either zidovudine / lamivudine and efavirenz. The most frequently observed mutations of resistance to efavirenz, the number of which was similar between treatment groups. Amino acid substitution mutation M184V, associated with resistance to lamivudine and emtricitabine was observed in 2 of the 19 patients receiving emtricitabine and tenofovir, and in 10 of 29 patients receiving lamivudine / zidovudine. Based on standard genotypic analysis, during a 144-week study of 934, no patient identified a mutation of HIV-1 K65R.

Cross-resistance

Cross-resistance to certain nucleoside reverse transcriptase inhibitors has been identified. Emtricitabine-resistant strains (M184V / I) were cross-resistant to lamivudine and zalcitabine, but retained the sensitivity of cell cultures to didanosine, stavudine, tenofovir, zidovudine and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz and nevirapine). HIV-1 strains that had a K65R mutation caused in vivo by abacavir, didanosine, tenofovir, and zalcitabine showed reduced sensitivity to the inhibitory effect of emtricitabine. Viruses with mutations leading to a decrease in sensitivity to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y / F, K219Q / E) or didanosine (L74V), retained sensitivity to emtricitabine. HIV-1 with a K103N mutation associated with resistance to non-nucleoside reverse transcriptase inhibitors was sensitive to emtricitabine.

Pharmacokinetics:

The pharmacokinetic properties of emtricitabine were evaluated in healthy volunteers and HIV-infected individuals. The pharmacokinetics were similar in these populations.

Absorption and bioavailability

After oral administration emtricitabine is rapidly absorbed, reaching a peak concentration after 1-2 hours. After repeated oral administration of 200 mg of emtricitabine, 20 HIV-infected patients have a stable maximum concentrationEmtricitabine was 1.8 ± 0.7 μg / ml and the AUC was 10.0 ± 3.1 μg-h / ml. The mean steady plasma concentration at 24 hours after administration was 0.09 μg / ml. With oral administration of emtricitabine in the form of capsules on an empty stomach, the absolute bioavailability is 93%. After repeated administration of emtricitabine in the dose range of 25-200 mg, the pharmacokinetic parameters increased in proportion to the dose increase.

Effect of food on absorption

Capsules of emtricitabine can be taken regardless of food intake. With the simultaneous administration of emtricitabine capsules with fatty foods, the systemic exposure of emtricitabine did not change, while the maximum concentrationdecreased by 29%.

Distribution

The binding of emtricitabine to human plasma proteins in vitro is less than 4% and is independent of the concentration that exceeds the range of 0.02-200 μg / ml. The average plasma / blood plasma concentration is approximately 1.0.The average ratio of drug concentration in the seminal fluid and plasma is approximately 4.0.

Metabolism

In vitro studies, it has been shown that emitricitabine does not inhibit the isoenzymes of the CYP450 system. After the administration of radiolabeled 14^from-emitritabine approximately 86% of it excreted in the urine and approximately 14% - with feces. 13% of the administered dose was detected in urine in the form of putative metabolites. Biotransformation of emtricitabine involves the oxidation of the thiol group to form the 3-sulfoxide diastereomers (about 9% of the dose) and conjugation with glucuronic acid to form 2-O-glucuronide (approximately 4% dose). Other metabolites have not been identified.

Excretion

Renal clearance of emtricitabine exceeded the creatinine clearance, which indicates a combined elimination of emtricitabine by glomerular filtration and active tubular secretion. A competitive relationship is possible for renal clearance with other compounds, which are also excreted by the kidneys.

Indications:

Treatment of HIV-1 infection in adults and children (as part of combined antiretroviral therapy).

ICD-10

I.B20-B24.B24 Disease caused by human immunodeficiency virus [HIV], unspecified

Contraindications:

Hypersensitivity to the components of the drug; lactation period; children weighing less than 33 kg.

Carefully:

With caution: the elderly; Renal failure with creatinine clearance less than 50 ml / min.

Pregnancy and lactation:

Adequate controlled studies of the use of emtricitabine in pregnant women have not been conducted. Considering the impossibility of full extrapolation of data in vivo on the human reproductive system, use emtricitabine in pregnant women is possible only for life indications.

HIV-infected women are not recommended to breast-feed to prevent the risk of postnatal HIV transmission. It is not known whether the emtricitabine in the female milk. Because of the risk of HIV transmission and the possibility of severe adverse reactions in the newborn, mothers should not breast-feed during therapy with the drug.

Dosing and Administration:

Inside, regardless of food intake.

Adults: recommended dose - 1 capsule 200 mg orally once a day.

Children weighing more than 33 kg, who can swallow the whole capsule: the recommended dose is 1 capsule 200 mg orally once a day.

If it is not possible to swallow an entire capsule, and children older than 3 months and weighing less than 33 kg should receive emtricitabine in the form of a solution for oral administration. Antiretroviral therapy is shown, as a rule, throughout life. Duration of drug therapy emtricitabine is determined individually by the attending physician.

Correction of the dosing regimen

Renal insufficiency

When emtricitabine is prescribed, a significant increase in the effect of the drug is observed in patients with renal insufficiency. In patients with creatinine clearance <50 ml / min, it is recommended to increase the interval of drug administration using the recommendations in Table 1.

Table 1. Correction of the dose of emtricitabine in patients with renal insufficiency

	Creatinine clearance, ml / min
	> 50 ml / min	30-49 ml / min	15-29 ml / min	<15 ml / min or hemodialysis
Capsules 200 mg	200 mg every 24 hours	200mg every 48h	200 mg every 72 hours	200 mg every 96 h

The safety and effectiveness of these recommendations for correcting the intervals between doses of the drug in patients with renal insufficiency was not clinically evaluated. These patients should be constantly monitored kidney function.In children, correction of the interval for taking emtricitabine capsules should be done according to the same principles as for adults.

Side effects:

The most common side effects (> 10% regardless of severity) that were observed in patients receiving emtricitabine in combination with other aitiretrovirals in 3 large-scale controlled clinical trials, were headache, diarrhea, nausea, fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, cough and rhinitis.

The most frequent adverse reactions observed in patients who received emtricitabine in combination with other antiretroviral agents, included headache, diarrhea, nausea and rash, which were usually mild or moderate. About 1% of patients stopped taking the drug in connection with these adverse reactions. All adverse events were recorded at the same frequency in patients who received combination therapy with emtricitabine or other antiretroviral regimens, except for skin discoloration that was observed with a higher frequency in patients taking emtricitabine. The change in skin color, manifested by hyperpigmentation of the palms and / or soles, was mild and asymptomatic. The mechanism of this phenomenon and its clinical significance are unknown.

Overdose:

The antidote is not known.

There is limited clinical experience with the use of emtricitabine in doses exceeding the therapeutic dose. In one pharmacological study, 11 patients received emtricitabine in a dose of 1200 mg. The development of serious adverse reactions has not been reported.

The effect of taking higher doses of emtricitabine is not known. In case of an overdose, the patient should be monitored to identify possible signs of toxicity, in the event of which standard maintenance therapy is performed.

With hemodialysis, about 30% of emtricitabine is released within a 3-hour period of hemodialysis, started 1.5 hours after taking emtricitabine (blood flow rate 400 ml / min, dialysate flow rate 600 ml / min). The possibility of excretion of emtricitabine by peritoneal dialysis has not been studied.

Interaction:

Emtricitabine should not be given concomitantly with drugs that contain emtricitabine or with drugs that contain lamivudine (due to its similarity to emtricitabine).

Special instructions:

Lactatacidosis / hepatomegaly with steatosis

When nucleoside analogues, including emtricitabine, were used in the form of monotherapy or in conjunction with other antiretroviral drugs, there were reports of the occurrence of lactic acidosis and severe liver enlargement with steatosis, including lethal cases. The majority of such cases were observed in women. Obesity and the use of long-acting nucleosides can be risk factors. With special care, nucleoside analogs should be used in patients with known risk factors for liver disease, but such cases have been reported in patients without known risk factors. If the patient has clinical or laboratory signs of lactic acidosis or obvious hepatotoxicity (which may include liver enlargement and steatosis, even if there is no pronounced increase in the level of transamiaasis), treatment with the drug should be discontinued.

Patients who are simultaneously infected with HIV and hepatitis B virus

It is recommended that all HIV-infected patients be tested for chronic hepatitis B before initiating antiretroviral therapy. Emtricitabine is not approved for the treatment of chronic infection caused by the hepatitis B virus (HBV), nor is the safety and efficacy of emtricitabine established for patients simultaneously infected with the hepatitis B virus and HIV. There was a pronounced sharp exacerbation of hepatitis B in patients simultaneously infected with HIV and HBV who stopped using emtricitabine. In some patients who received treatment with emtricitabine, exacerbation of hepatitis B was accompanied by hepatic decompensation and liver damage. In patients who are simultaneously infected with HIV and HBV who have stopped using emtricitabine, liver function should be monitored by clinical and laboratory methods, at least for several months. If necessary, hepatitis B should be treated.

Distribution of adipose tissue

Patients receiving antiretroviral therapy were observed to redistribute / accumulate adipose tissue of the body, including obesity in the abdomen,dorsocervical fat deposition ("bison hump"), loss of adipose tissue on the limbs, fat loss on the face, breast enlargement and "Cushingoid appearance." The mechanism of development and the long-term effects of these changes are not known. Causal link is not established.

Immune Recovery Syndrome

Immune-Reduction Syndrome was reported in patients who received combination antiretroviral therapy, including emtricitabine. In the initial phase of combined antiretroviral treatment in patients whose immune system responds to treatment, it is possible to develop an inflammatory response to delayed or residual opportunistic infections (infections caused by Mycobacterium avium, cytomegalovirus infection, pneumonia caused by Pneumocystis jirovecii, or tuberculosis), which may require further examination and treatment.

Autoimmune diseases (for example, Graves' disease, polymyositis, Guillain-Barre syndrome), which occurred under conditions of immune recovery, have also been reported. However, the time of appearance of these diseases varies considerably and can be observed many months after the start of treatment.

Information for patients

To avoid complications emtricitabine apply under the supervision of a doctor with experience in managing HIV-infected patients.

Patients should be warned that they should not simultaneously use other drugs themselves. Irregular intake of the drug may lead to the development of resistance to the virus and reduce the effectiveness of treatment.

Patients should be informed that emtricitabine therapy does not reduce the risk of HIV transmission to other people during sexual intercourse or blood transfusion, and therefore does not negate the need for appropriate precautions.

Patients should be informed of possible dizziness in the treatment of emtricitabine.

Instructions

Emtricitabine (Emtricitabinum)