Emtricitabine (Capsules) Instructions for Use

Marketing Authorization Holder

Biocad, JSC (Russia)

Manufactured By

Jiangsu Tasly Diyi Pharmaceutical, Co., Ltd. (China)

Labeled By

Biocad, JSC (Russia)

ATC Code

J05AF09 (Emtricitabine)

Active Substance

Emtricitabine

Dosage Form

Emtricitabine

Capsules 200 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Capsules are hard gelatin, size No. 1, with a light blue opaque cap and a white opaque body; the capsule contents are a white or almost white powder.

Excipients: microcrystalline cellulose – 137.75 mg, crospovidone – 7 mg, magnesium stearate – 1.75 mg, povidone – 3.5 mg.

Composition of the gelatin capsule: gelatin, titanium dioxide (E 171), brilliant blue dye (E 133).

10 pcs. – blister packs (3) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Emtricitabine is a synthetic nucleoside, an analog of cytidine, which is phosphorylated by cellular enzymes to emtricitabine 5′-triphosphate.

Emtricitabine 5′-triphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5′-triphosphate and through incorporation into the nascent viral DNA, which leads to chain termination.

Emtricitabine 5′-triphosphate is a weak inhibitor of DNA polymerases α, β, ε, and mitochondrial DNA polymerase γ.

Antiviral activity

The antiviral activity of emtricitabine against laboratory and donor strains of HIV-1 was evaluated in lymphoblastoid cell lines (MAGI-CCR5 cell line) and peripheral blood mononuclear cells.

The EC₅₀ (EC₅₀ – the concentration of the drug required to suppress 50% of viruses) ranged from 0.0013 to 0.64 µmol (0.0003-0.158 mg/ml).

Emtricitabine exhibited antiviral activity against HIV-1 subtypes A, B, C, D, E, F, and G in cell culture (EC₅₀ was 0.007-0.075 µmol) and showed selective inhibitory activity against some HIV-2 strains (EC₅₀ was 0.007-1.5 µmol).

In studies of drug combinations of 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 additive synergistic effect was observed.

The antiviral activity of emtricitabine in vivo was studied in two clinical trials in which patients received emtricitabine monotherapy at a dose of 25-400 mg/day for 10-14 days.

A dose-dependent antiviral effect was observed with a mean reduction in HIV-1 RNA of 1.3 log₁₀ at a dose of 25 mg once daily and 1.7 log₁₀ and 1.9 log₁₀ at a dose of 200 mg once or twice daily.

Resistance

Emtricitabine-resistant HIV strains have been isolated from cell culture and in vivo.

Genotypic analysis of these strains showed that reduced susceptibility to emtricitabine was associated with a mutation in the HIV reverse transcriptase gene at codon 184, which in turn led to the substitution of the amino acid methionine with valine or isoleucine (M184V/I).

Emtricitabine-resistant HIV strains were detected in some patients receiving emtricitabine as monotherapy or in combination with other antiretroviral drugs.

In a clinical trial, viral strains in 37/5% of treatment-naive patients with virological failure had reduced susceptibility to emtricitabine.

Genotypic analysis of these strains showed that reduced susceptibility to emtricitabine was associated with the M184V/I mutation in the HIV reverse transcriptase gene.

Resistance analysis of isolated HIV-1 strains was performed in all patients with confirmed virological failure (HIV-1 RNA >400 copies/ml by week 144 or earlier) participating in the clinical trial and receiving emtricitabine, tenofovir, and efavirenz or zidovudine/lamivudine and efavirenz.

Mutations conferring resistance to efavirenz were most frequently observed, with similar numbers between treatment groups.

The M184V amino acid substitution mutation, associated with resistance to emtricitabine and lamivudine, was observed in 2 of 19 patients receiving emtricitabine and tenofovir and in 10 of 29 patients receiving lamivudine/zidovudine.

Based on standard genotypic analysis throughout the 144-week study 934, no patient developed the HIV-1 K65R mutation.

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 susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, and nevirapine).

HIV-1 strains with the K65R mutation, induced in vivo by abacavir, didanosine, tenofovir, and zalcitabine, showed reduced susceptibility to the inhibitory effect of emtricitabine.

Viruses with mutations leading to reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine.

HIV-1 with the 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.

Pharmacokinetic parameters were similar in these populations.

Absorption and bioavailability

After oral administration, emtricitabine is rapidly absorbed, reaching peak concentration in 1-2 hours.

After multiple oral administration of 200 mg of emtricitabine to 20 HIV-infected patients, the steady-state C_max of emtricitabine was 1.8±07 µg/ml and AUC was 10.0±3.1 µg·h/ml.

The mean steady-state plasma concentration 24 hours after administration was 0.09 µg/ml.

When emtricitabine is administered orally as capsules on an empty stomach, the absolute bioavailability is 93%.

After multiple administration of emtricitabine in the dose range of 25-200 mg, pharmacokinetic parameters increased proportionally with increasing dose.

Effect of food on absorption

Emtricitabine capsules can be taken with or without food.

When emtricitabine capsules were taken with a high-fat meal, the systemic exposure (AUC) of emtricitabine did not change, while C_max decreased by 29%.

Distribution

The binding of emtricitabine to human plasma proteins in vitro is less than 4% and is independent of concentration over the range of 0.02-200 µg/ml.

The mean ratio of drug concentration in plasma to blood is approximately 1.0.

The mean ratio of drug concentration in seminal fluid to plasma is approximately 4.0.

Metabolism

In vitro studies have shown that emtricitabine does not inhibit CYP450 isoenzymes.

After administration of radiolabeled ¹⁴C-emtricitabine, approximately 86% is excreted in the urine and approximately 14% in the feces.

13% of the administered dose was found in the urine as putative metabolites.

The biotransformation of emtricitabine involves oxidation of the thiol group to form 3′-sulfoxide diastereomers (approximately 9% of the dose) and conjugation with glucuronic acid to form 2′-O-glucuronide (approximately 4% of the dose).

Other metabolites were not identified.

Excretion

The renal clearance of emtricitabine exceeded the creatinine clearance, indicating combined elimination of emtricitabine by glomerular filtration and active tubular secretion.

Competitive interactions for renal clearance with other compounds that are also excreted by the kidneys are possible.

Pharmacokinetics in special patient groups

Gender

The pharmacokinetic parameters of emtricitabine were similar in men and women.

Race

No pharmacokinetic differences were reported with the use of emtricitabine among different racial groups.

Elderly age

There are insufficient data to adequately assess the pharmacokinetics in elderly patients.

Hepatic impairment

The pharmacokinetics of emtricitabine in patients with hepatic impairment have not been studied.

However, since emtricitabine is not significantly metabolized by liver enzymes, the effect of hepatic impairment on the pharmacokinetics of emtricitabine is likely to be negligible.

Pediatric age

The pharmacokinetics of emtricitabine capsules were studied in HIV-infected children in 2 age groups (Table 1).

Based on AUC values, it was shown that the use of emtricitabine in children at a dose of 6 mg/kg (maximum 200 mg in capsules) provides plasma concentrations similar to those in adult patients taking the drug at the recommended dose of 200 mg.

Table 1. Pharmacokinetic parameters of emtricitabine capsules in children of different age groups

Renal impairment

In adult patients with creatinine clearance less than 50 ml/min or with end-stage renal disease requiring dialysis, the C_max and AUC of emtricitabine increased due to reduced renal clearance, which requires an increase in the dosing interval in such patients (see section “Dosage Adjustment”).

The effect of renal impairment on the pharmacokinetics of emtricitabine in children has not been studied.

Indications

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

ICD codes

Dosage Regimen

Orally, regardless of meals.

Adults: the recommended dose is 1 capsule of 200 mg orally once daily.

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

If swallowing a whole capsule is not possible, as well as children older than 3 months and weighing less than 33 kg should receive Emtricitabine as an oral solution.

Antiretroviral therapy is generally indicated for life.

The duration of therapy with Emtricitabine is determined individually by the attending physician.

Dosage regimen adjustment

Renal impairment

When emtricitabine is administered to patients with renal impairment, a significant increase in drug exposure is observed.

In patients with CrCl <50 ml/min, it is recommended to increase the dosing interval, using the recommendations outlined in Table 2.

Table 2. Dose adjustment of emtricitabine in patients with renal impairment

The safety and efficacy of these recommendations for adjusting the dosing interval in patients with renal impairment have not been clinically evaluated.

In these patients, renal function should be continuously monitored.

In children, the adjustment of the dosing interval for emtricitabine capsules should be based on the same principles as for adults.

Adverse Reactions

More than 2000 HIV-infected patients received Emtricitabine as monotherapy or in combination with other antiretroviral drugs for periods ranging from 10 days to 200 weeks in clinical trials.

Since the conditions of clinical trials vary significantly, the frequency of observed adverse events in a clinical trial of a drug cannot be directly compared with the frequency of adverse reactions observed in clinical trials of another drug and may not reflect the level of adverse events observed in practice.

For a large number of the phenomena listed below, it is not reliably known whether they are related to the action of a wide range of commonly prescribed drugs for the treatment of HIV infection, or whether the reported adverse reactions are the result of the pathological processes underlying the disease.

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

Studies 301A and 303

The most frequent adverse reactions observed in patients receiving Emtricitabine in combination with other antiretroviral agents included headache, diarrhea, nausea, and rash, which were generally mild to moderate in severity.

Approximately 1% of patients discontinued the drug due to these adverse reactions.

All adverse events were reported with similar frequency in patients receiving combination therapy with emtricitabine or other antiretroviral regimens, except for skin discoloration, which was observed more frequently in patients taking Emtricitabine.

Skin discoloration, manifested as hyperpigmentation of the palms and/or soles, was moderate and asymptomatic.

The mechanism of this phenomenon and its clinical significance are unknown.

Table 3. Adverse reactions observed in ≥3% of patients in different treatment groups in studies 301A and 303

¹– non-nucleoside reverse transcriptase inhibitor

²– protease inhibitor

³ – rash cases included pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and allergic reactions

Laboratory abnormalities in these studies were observed with similar frequency in patients receiving Emtricitabine and in the comparison groups (Table 4).

Table 4. Significant laboratory abnormalities (grades 3 and 4) observed in ≥1% of patients in different treatment groups in studies 301A and 303

¹– ULN – upper limit of normal

Study 934

Study 934 included 511 antiretroviral-naive patients who received Emtricitabine and tenofovir in combination with efavirenz (n=257) or zidovudine/lamivudine in combination with efavirenz (n=254). The adverse effects observed in this study are generally consistent with data from other studies of antiretroviral-naive or treatment-experienced patients (Table 5).

Table 5. Selected Treatment-Emergent Adverse Reactions¹ of Grades 2-4 Reported in ≥5% of Patients in Any Treatment Arm in Study 934 (0-144 Weeks)

¹ – Adverse reaction rates are based on treatment-emergent adverse events, regardless of relationship to study drug.

² – From Week 96 to Week 144 of the study, patients received the fixed-dose combination tablet containing tenofovir disoproxil fumarate and Emtricitabine instead of these two agents as separate formulations.

³ – Rash included events characterized as exfoliative, generalized, macular, maculopapular, pruritic, and vesicular.

Significant laboratory abnormalities observed in this study are presented in Table 6.

Table 6. Significant Laboratory Abnormalities Reported in ≥1% of Patients in Any Treatment Arm in Study 934 (0-144 Weeks)

¹ – From Week 96 to Week 144 of the study, patients received the fixed-dose combination tablet containing tenofovir disoproxil fumarate and Emtricitabine instead of these two agents as separate formulations.

Pediatric Patients

The assessment of adverse reactions is based on data from an open-label, uncontrolled study, 203, in which 116 HIV-1 infected pediatric patients received Emtricitabine for 48 weeks. Overall, the safety profile in pediatric patients was comparable to that in adult patients. Hyperpigmentation was observed more frequently in children. An additional adverse event reported in children was anemia.

In children who received emtricitabine therapy for 48 weeks, adverse events, regardless of causality, included the following: infections (44%), hyperpigmentation (32%), increased cough (28%), vomiting (23%), otitis media (23%), rash (21%), rhinitis (20%), diarrhea (20%), fever (18%), pneumonia (15%), gastroenteritis (11%), abdominal pain (10%), anemia (7%). Treatment-emergent Grade 3-4 laboratory abnormalities occurred in 9% of children and included elevated amylase >2 ULN (n=4), neutropenia <750/mm³(n=3), elevated ALT >5 ULN (n=2), creatine phosphokinase >4 ULN (n=2) and single cases of elevated bilirubin (>3 ULN), gamma-glutamyltransferase (>10 ULN), lipase (>2.5 ULN), decreased hemoglobin (<70 g/L), and decreased glucose (<4 g/L).

Contraindications

• Hypersensitivity to the components of the drug;
• Lactation period;
• Children weighing less than 33 kg (for this dosage form).

Use with caution

• Elderly age;
• Renal failure with CrCl less than 50 ml/min.

Use in Pregnancy and Lactation

No increase in the frequency of fetal malformations was recorded in embryofetal toxicity studies of emtricitabine in mice at drug exposures (AUC) approximately 60 times higher, and in rabbits approximately 120 times higher than the human AUC at the recommended daily dose of emtricitabine. However, adequate and well-controlled studies of emtricitabine use in pregnant women have not been conducted. Given the inability to fully extrapolate in vivo data to the human reproductive system, Emtricitabine should be used in pregnant women only for vital indications.

Nursing Women

HIV-infected women are advised not to breastfeed to prevent the risk of postnatal HIV transmission. It is not known whether Emtricitabine is excreted in human milk. Due to the risk of HIV transmission and the potential for serious adverse reactions in the nursing infant, mothers should not breastfeed during therapy with the drug.

Use in Renal Impairment

Administration of emtricitabine to patients with renal impairment results in a significant increase in drug exposure.

An increased dosing interval is recommended for patients with creatinine clearance less than 50 ml/min or with end-stage renal disease requiring dialysis.

Pediatric Use

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

The efficacy and safety of emtricitabine in patients aged 3 months to 21 years were studied in 3 open-label, non-randomized clinical trials. The drug was administered to 169 infected patients. The pharmacokinetics of emtricitabine were also studied in 20 neonates born to HIV-infected mothers. All neonates were HIV-negative at the end of the study. However, these data are insufficient to evaluate the efficacy of emtricitabine for the prevention of mother-to-child transmission of the virus, as well as for the treatment of HIV-infected neonates.

Geriatric Use

Clinical studies of emtricitabine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Special Precautions

General

Emtricitabine should not be administered concurrently with drugs that contain Emtricitabine or with drugs that contain lamivudine (due to its similarity to emtricitabine). These drugs include Emtriva (Emtricitabine), Atripla (efavirenz/Emtricitabine/tenofovir), Combivir (lamivudine/zidovudine), Epivir (lamivudine), Epivir-HBV (lamivudine), Epzicom (abacavir/lamivudine), Trizivir (abacavir/lamivudine/zidovudine).

Lactic acidosis/hepatomegaly with steatosis

The use of nucleoside analogues, including emtricitabine, alone or in combination with other antiretroviral agents, has been associated with reports of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Most of these cases have occurred in women. Obesity and prolonged nucleoside exposure may be risk factors. Nucleoside analogues should be used with particular caution in patients with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with the drug should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients co-infected with HIV and hepatitis B virus

All HIV-infected patients should be tested for the presence of chronic hepatitis B before initiating antiretroviral therapy. Emtricitabine is not approved for the treatment of chronic infection caused by hepatitis B virus (HBV), and the safety and efficacy of emtricitabine have not been established for patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HIV and HBV and discontinue Emtricitabine. In some patients treated with emtricitabine, exacerbations of hepatitis B were accompanied by hepatic decompensation and liver failure. In patients co-infected with HIV and HBV who discontinue emtricitabine, liver function should be monitored closely with both clinical and laboratory follow-up for at least several months. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Fat redistribution

Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance.” The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune reconstitution syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Emtricitabine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds to treatment may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves’ disease, polymyositis, Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

Patient information

To avoid complications, Emtricitabine should be used under the supervision of a physician experienced in the management of HIV-infected patients.

Patients should be warned not to use other drugs on their own concurrently. Irregular use of the drug may lead to the development of viral resistance and reduced treatment efficacy.

Patients should be informed that therapy with Emtricitabine does not reduce the risk of transmitting HIV to others through sexual contact or blood transfusion and, therefore, does not eliminate the need to observe appropriate precautions.

Effect on ability to drive and operate machinery

No studies on the effects of the drug on the ability to drive and use machines have been performed. Patients should be informed about possible dizziness during treatment with emtricitabine.

Overdose

No antidote is known.

There is limited clinical experience with emtricitabine at doses higher than the therapeutic dose. In one pharmacology study, 11 patients received Emtricitabine at a dose of 1200 mg. No severe adverse reactions were reported.

The effects of higher doses of emtricitabine are unknown. In case of overdose, the patient should be monitored for evidence of toxicity, and standard supportive treatment applied if necessary.

Hemodialysis removes approximately 30% of the emtricitabine dose over a 3-hour hemodialysis period starting 1.5 hours after emtricitabine ingestion (blood flow rate 400 ml/min, dialysate flow rate 600 ml/min). The ability of peritoneal dialysis to remove emtricitabine has not been studied.

Drug Interactions

At in vitro concentrations 14-fold higher than in vivo concentrations, Emtricitabine did not inhibit the metabolism of drugs metabolized by the following human CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Emtricitabine did not inhibit the glucuronidation process mediated by uridine 5′-diphospho-glucuronosyltransferase enzyme. Based on these data and the known elimination pathway of emtricitabine, the potential for emtricitabine to interact with other drugs via the CYP system is low.

In studies conducted in healthy volunteers, no clinically significant drug interactions were observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, or zidovudine.

Storage Conditions

The drug should be stored in a dry place, protected from light, out of the reach of children, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription only.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.