Emtritab^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmsintez OJSC (Russia)

ATC Code

J05AF09 (Emtricitabine)

Active Substance

Emtricitabine (Rec.INN registered by WHO)

Dosage Form

Emtritab®

Film-coated tablets, 200 mg: 30, 60, 90, 100, or 120 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oval, biconvex; on the cross-section, the tablet is white or white with a yellowish tint.

Excipients: pregelatinized starch – 12 mg, colloidal silicon dioxide (aerosil brand A-300) – 2 mg, croscarmellose sodium – 12 mg, lactose – 118 mg, magnesium stearate – 4 mg, microcrystalline cellulose – 40 mg.

Film coating composition: hypromellose – 8.7 mg, copovidone – 0.3 mg, macrogol 6000 – 1.74 mg, talc – 0.3 mg, titanium dioxide – 0.96 mg.

10 pcs. – contour cell packaging (3) – cardboard packs (1) – group packaging.
10 pcs. – contour cell packaging (6) – cardboard packs (1) – group packaging.
10 pcs. – contour cell packaging (10) – cardboard packs (1) – group packaging.
30 pcs. – polymer jars*(1) – cardboard packs.
60 pcs. – polymer jars* (1) – cardboard packs.
90 pcs. – polymer jars* (1) – cardboard packs.
120 pcs. – polymer jars* (1) – cardboard packs.

* with first opening control

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; nucleoside and nucleotide reverse transcriptase inhibitors

Pharmacological Action

It is a synthetic nucleoside analogue of cytidine. It 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.

In cell culture, emtricitabine exhibited antiviral activity against HIV-1 subtypes A, B, C, D, E, F, G (EC₅₀ was 0.007-0.075 µmol), as well as a suppressive effect on some HIV-2 strains (EC₅₀ was 0.007-1.5 µmol).

Resistance to emtricitabine was observed in vitro in some HIV-1 infected patients due to substitutions at codons M184V or M184I of reverse transcriptase.

Emtricitabine-resistant strains with the M184V/I codon substitution demonstrated cross-resistance to lamivudine but remained sensitive to didanosine, stavudine, tenofovir and zidovudine.

Virus strains with substitutions conferring reduced sensitivity to stavudine and with thymidine analogue resistance mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74Y) remained sensitive to emtricitabine. HIV-1 strains containing the K103N substitution or other substitutions associated with resistance to rilpivirine and other non-nucleoside reverse transcriptase inhibitors remained sensitive to emtricitabine.

Pharmacokinetics

After oral administration, emtricitabine is rapidly absorbed, reaching C_max within 1-2 hours. After multiple oral administration of emtricitabine at a dose of 200 mg in twenty HIV-infected patients, the steady-state C_max of emtricitabine was 1.8±0.7 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 taken orally 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 to the dose increase. When emtricitabine was co-administered with a high-fat meal, the systemic exposure (AUC) of emtricitabine did not change, while C_max decreased by 29%.

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

Data from in vitro studies indicate that emtricitabine does not have an inhibitory effect on the cytochrome P450 isoenzyme system. After administration of ¹⁴C-labeled emtricitabine, approximately 86% of it is excreted in the urine and about 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).

The systemic clearance of emtricitabine averages 307 ml/min. 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.

In 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 increased interval between doses of the drug in such patients.

When emtricitabine was administered at a dose of 6 mg/kg/day, the mean AUC_0-24 values in children were comparable to those in adults when the drug was administered at a dose of 200 mg once daily.

Indications

Treatment of HIV-1 infection as part of combined antiretroviral therapy.

ICD codes

Dosage Regimen

Orally.

Adults and children aged up to 18 years and weighing more than 33 kg are prescribed Emtricitabine 200 mg once daily.

In renal impairment, the following dosing regimen for emtricitabine is recommended: for CrCl >50 ml/min – 200 mg every 24 hours; for CrCl 30-49 ml/min – 200 mg every 48 hours; for CrCl 15-29 ml/min – 200 mg every 72 hours. For CrCl <15 ml/min or patients on hemodialysis, Emtricitabine is prescribed 200 mg every 96 hours. If the drug intake falls on a dialysis day, Emtricitabine should be taken after the hemodialysis session or dialysis should be performed at least 12 hours after the last dose of emtricitabine.

In children with renal impairment, the same scheme for adjusting the drug dosing regimen as in adults is recommended, depending on the CrCl value.

Adverse Reactions

From the hematopoietic system neutropenia, anemia.

From the immune system allergic reactions (including urticaria, angioedema).

From the nervous system headache, dizziness, neuropathy, peripheral neuritis.

Psychiatric disorders insomnia, abnormal dreams, depressive disorders.

From the respiratory system increased cough, rhinitis.

From the digestive system diarrhea, dyspepsia, nausea, vomiting, abdominal pain; increased activity of AST, ALT, pancreatic amylase, serum lipase; hyperbilirubinemia.

From the skin rash, pruritus, skin discoloration (increased pigmentation).

From the musculoskeletal system increased creatine kinase activity, arthralgia, myalgia.

Other asthenia.

In clinical studies, the side effects of the drug in children and adults were similar. The most frequently noted was the development of hyperpigmentation. An additional adverse reaction identified in clinical studies in children was anemia.

Contraindications

Hypersensitivity to emtricitabine; children under 3 years of age and body weight less than 33 kg; lactation period; simultaneous use with combined preparations containing Emtricitabine, as well as with lamivudine, zalcitabine.

Use in Pregnancy and Lactation

Emtricitabine should be used in pregnant women only in cases of extreme necessity, when the expected benefit to the mother outweighs the potential risk to the fetus.

It has been shown that Emtricitabine is excreted in breast milk. Experts do not recommend breastfeeding for HIV-infected patients to avoid transmission of HIV infection to the child. Since Emtricitabine and HIV pass into breast milk, breastfeeding is contraindicated.

Use in Hepatic Impairment

Emtricitabine should be used with caution in liver diseases.

Use in Renal Impairment

Emtricitabine should be used with caution in renal failure.

Pediatric Use

Contraindicated for use in children under 3 years of age and in children weighing less than 33 kg.

Geriatric Use

Emtricitabine should be used with caution in elderly patients.

Special Precautions

Emtricitabine should be used with caution in renal failure, liver diseases, simultaneously with drugs whose elimination is carried out by active tubular secretion, in elderly patients, during pregnancy.

Emtricitabine should not be prescribed simultaneously with combined preparations containing Emtricitabine, as well as with drugs that contain lamivudine (due to its similarity to emtricitabine).

Patients receiving Emtricitabine or other antiretroviral drugs may develop opportunistic infections or other complications, so they should be under the close supervision of a physician experienced in the treatment of HIV infection.

When using nucleoside analogues, including emtricitabine, as monotherapy or in combination with other antiretroviral drugs, there have been reports of the occurrence of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Most of these cases were observed in women. Obesity and the use of long-acting nucleosides may be risk factors. Nucleoside analogues should be used with particular caution in patients with known risk factors for liver disease; however, such cases have been reported in patients without known risk factors. If a patient develops clinical or laboratory signs of lactic acidosis or overt hepatotoxicity (which may include hepatomegaly and steatosis, even in the absence of a marked increase in transaminase levels), treatment with the drug should be discontinued.

In some patients, combined antiretroviral therapy may be accompanied by redistribution/accumulation of subcutaneous adipose tissue, including a decrease in peripheral adipose tissue and an increase in visceral fat, a decrease in adipose tissue on the limbs and face, breast enlargement and dorsocervical fat deposition (“buffalo hump”), as well as an increase in serum lipid concentrations and blood glucose levels. Clinical examination of patients should include an assessment of physical signs of fat redistribution. Serum lipid concentrations and blood glucose concentrations should also be measured. Lipid metabolism disorders should be corrected based on their clinical manifestations.

In patients receiving combined antiretroviral therapy, including with the use of emtricitabine, the development of immune reconstitution syndrome has been observed. Against the background of immune function recovery, an exacerbation of asymptomatic or residual opportunistic infections (including those caused by Mycobacterium avium, Mycobacterium tuberculosis, Pneumocystis carinii, Cytomegalovirus) may occur, which may require additional examination and treatment. Autoimmune diseases (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have been observed against the background of immune reconstitution, however, the time of primary manifestations varied, and the disease could occur many months after the start of therapy and have an atypical course.

Although the etiology of osteonecrosis is considered multifactorial (including the use of corticosteroids, alcohol consumption, severe immunosuppression, high BMI), cases of osteonecrosis have been reported, in particular, in patients with advanced HIV infection and/or with long-term combined antiretroviral therapy. Patients should be advised to consult a doctor if they experience joint pain, joint stiffness, or difficulty moving.

In vitro and in vivo conditions have revealed the ability of nucleotide and nucleoside analogues to cause mitochondrial damage of varying degrees. The development of mitochondrial disorders has been reported in HIV-negative newborns exposed to nucleoside analogues in utero and/or postnatally. The main manifestations of mitochondrial dysfunction are hematological (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These changes are often transient. Some long-term neurological disorders (hypertension, convulsions, behavioral disorders) have been recorded. All children exposed to nucleosides or nucleoside analogues in utero, even HIV-negative newborns, in case of relevant signs or symptoms, should be under careful clinical and laboratory supervision and undergo a thorough examination for the possible presence of mitochondrial disorders.

All HIV-infected patients are recommended to be tested for chronic hepatitis B before starting 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 hepatitis B virus and HIV. Severe acute exacerbation of hepatitis B has been reported in patients co-infected with HIV and HBV who discontinued Emtricitabine. In some patients receiving emtricitabine treatment, exacerbation of hepatitis B was accompanied by hepatic decompensation and liver damage. In patients co-infected with HIV and HBV who discontinue emtricitabine, liver function should be monitored clinically and by laboratory methods for at least several months. If necessary, treatment for hepatitis B should be initiated.

The risk of hepatotoxic effects of antiretroviral drugs in patients with co-infection of HIV and hepatitis B or C virus is higher than with HIV infection alone. Therefore, patients with chronic hepatitis B or C who are simultaneously taking antiretroviral drugs are at increased risk of adverse effects on the liver with a possible fatal outcome. Such patients should be closely monitored, both clinically and by laboratory methods.

Discontinuation of emtricitabine therapy may provoke severe exacerbation of hepatitis in patients infected with hepatitis B virus (HBV). Therefore, it is recommended to examine patients for viral hepatitis B before starting antiretroviral therapy. In patients infected with HIV-1 and HBV, liver function should be carefully monitored for at least several months after discontinuation of emtricitabine. In some cases, it may be necessary to resume therapy for viral hepatitis. In patients with severe liver disease (cirrhosis), discontinuation of treatment is not recommended, as the exacerbation of hepatitis that occurs after discontinuation of therapy can lead to decompensation of liver function.

Effect on ability to drive vehicles and mechanisms

When assessing a patient’s ability to drive a car and moving mechanisms, his general condition, as well as the nature of the adverse reactions of emtricitabine, should be taken into account. If dizziness occurs, you should refrain from performing these activities.

Drug Interactions

The likelihood of pharmacokinetic interaction with drugs metabolized by CYP450 isoenzymes is low, since Emtricitabine is not an inhibitor of these isoenzymes.

Emtricitabine is excreted primarily by the kidneys. Simultaneous use of emtricitabine with drugs that impair renal function or compete for active tubular secretion may lead to an increase in the serum concentration of emtricitabine and/or other drugs that are excreted by the kidneys.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx 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.