Emtritab, 200 mg 30 pcs

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Indications

Treatment of HIV-1 infection as part of combination antiretroviral therapy

Pharmacological effect

Pharmacotherapeutic group: antiviral [HIV] agent

ATC: J.05.A.F.09 Emtricitabine
Pharmacodynamics:

Synthetic nucleoside analogue of cytidine. The mechanism of action is associated with suppression of HIV-1 reverse transcriptase activity. Emtricitabine is phosphorylated inside the cell to its active metabolite, emtricitabine 5′-triphosphate. Emtricitabine 5′-triphosphate inhibits HIV-1 reverse transcriptase through a competitive mechanism, resulting in interruption of DNA chain synthesis.

Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases a, b, e and mitochondrial DNA polymerase y.

Antiviral activity

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-I strains was assessed on lymphoblastoid cell lines (MAGI-CCR5 cell line) and peripheral blood mononuclear cells. The EC50 concentration of emtricitabine (EC50 is the concentration of the drug required to suppress 50% of viruses) ranged from 0.0013 to 0.64 μmol.

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

Resistance

Resistance to emtricitabine has been observed in vitro in some HIV-1-infected patients due to substitutions in the M184V or Ml841 reverse transcriptase codons. No other mechanisms for the development of resistance to emtricitabine have been identified.

Cross resistance

Emtricitabine-resistant strains with a substitution at codon M184V/1 showed cross-resistance to lamivudine, but remained sensitive to didanosine, stavudine, tenofovir and zidovudine. Viral strains with substitutions causing decreased sensitivity to stavudine and with mutations of resistance to zidovudine-thymidine analogues (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosella (L74V) remained sensitive to emtricitabine. HIV-1 strains containing a K 33 substitution or other substitutions associated with resistance to rilpivirine and other nucleoside reverse transcriptase inhibitors remained sensitive to emtricitabine.

Pharmacokinetics:
When taken orally, emtricitabine is rapidly absorbed from the gastrointestinal tract. Food does not have a significant effect on the bioavailability of emtricitabine. With repeated oral administration at a dose of 200 mg/day, the maximum concentration (Cmax) of emtricitabine in blood plasma is 1.8 ± 0.7 μg/ml, and the area under the concentration-time curve in the observation interval from 0 to 24 hours (AUC0-24) is 10.0 ± 3.1 μg*hour/ml. The time to reach maximum concentration in the blood (TCmax) is 1-2 hours.

The mean plasma trough concentrations of emtricitabine 24 hours after dosing at steady state are equal to or greater than the mean IC90 concentration required to inhibit the replication of 90% of viruses in vitro. When administered multiple times over a dose range of 25 to 200 mg, the pharmacokinetic parameters of emtricitabine are proportional to dose.

The binding of emtricitabine to plasma proteins in vitro is less than 4% and is independent of concentration in the range from 0.02 to 200 mcg/ml. Data from in vitro studies indicate that emtricitabine does not have an inhibitory effect on human cytochrome P450 isoenzymes. Emtricitabine is primarily excreted by the kidneys (approximately 86%) and intestinal excretion (approximately 14%). 13% of the administered dose of emtricitabine was detected in urine as three putative metabolites. The average systemic clearance of emtricitabine is 307 ml/min.

Metabolites of emtricitabine include the 3′-sulfoxin diastereomers (approximately 9% of the dose) and their conjugate with glucuronic acid in the form of 2-O-glucuronide (approximately 4% of the dose). After a single oral dose, the half-life (T1/2) of emtricitabine is approximately 10 hours. With subsequent dosing in a course regimen, the intracellular T1/2 value of emtricitabine-5′-triphosphate (the active metabolite of emtricitabine) in peripheral blood mononuclear cells is 39 hours.

Emtricitabine is eliminated by glomerular filtration and active tubular secretion.

Special patient groups

Patients with impaired renal function

In patients with impaired renal function (creatinine clearance (CC) less than 80 ml/min), the pharmacokinetics of emtricitabine changes. Systemic exposure to emtricitabine (mean ± standard deviation) increased from 11.8 ± 2.9 μg*h/ml in patients with normal renal function to 19.9 ± 1.1 μg*h/ml, 25.0 ± 5.7 μg*h/ml and 34.0 ± 2.1 μg*h/ml in patients with CK 50-80 ml/min, 30-49 ml/min and <30 ml/min, respectively.

Patients with liver dysfunction

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

Gender and race

There are no significant differences in pharmacokinetic parameters among adult men and women and among different races.

Children

In general, the pharmacokinetics of emtricitabine in children are similar to those in adults. When taking emtricitabine at a dose of 6 mg/kg per day, the average AUC0-24 values ​​in children are comparable to those in adults when taking the drug at a dose of 200 mg once a day.

Elderly patients

There are no data on the pharmacokinetics of emtricitabine in patients over 65 years of age.

Special instructions

Emtricitabine should not be co-administered with combination drugs containing emtricitabine, or with drugs that contain lamivudine (due to its similarity to emtricitabine).

Patients should be warned that treatment with antiretroviral drugs, including emtricitabine, does not prevent the risk of transmitting HIV to others through sexual contact or blood transfusion. Therefore, patients should take appropriate precautions.

Opportunistic infections

Patients receiving emtricitabine or other antiretroviral drugs may develop opportunistic infections or other complications and should be closely monitored by a physician experienced in treating HIV infection.

Renal dysfunction

In patients with renal failure (with creatinine clearance <50 ml/min) or end-stage chronic renal failure requiring dialysis, adjustment of the emtricitabine dosage regimen is recommended (see section "Dosage and Administration").

Liver dysfunction

The pharmacokinetics of emtricitabine in patients with hepatic impairment have not been studied. However, since emtricitabine is slightly metabolized in the liver, a significant effect of liver failure on the pharmacokinetics of the drug is not expected.

Lactic acidosis/severe hepatomegaly with fatty liver In HIV-infected patients (mainly women) taking nucleoside analogues as monotherapy or in combination with other antiretroviral drugs, cases of lactic acidosis have been described, which is usually accompanied by severe hepatomegaly and fatty liver, including death. Symptoms that may indicate the development of lactic acidosis include: general weakness, loss of appetite, sudden unexplained weight loss, gastrointestinal and respiratory problems (shortness of breath), and the appearance of neurological symptoms (including movement disorders). Lactic acidosis is associated with high mortality if not treated promptly and may be associated with pancreatitis, liver failure, or kidney failure. Lactic acidosis usually appears after several months of therapy. Patients with co-occurring hepatitis C receiving interferon alfa and ribavirin therapy may be at particular risk. Such patients require careful monitoring.

Treatment with emtricitabine always requires caution, and especially if the patient has risk factors for developing liver disease. If clinical or laboratory signs of lactic acidosis or liver dysfunction (including heiatomegaly and fatty liver disease, even in the absence of a marked increase in liver transaminases), emtricitabine should be discontinued. Redistribution/accumulation of subcutaneous fat

In some patients, combination antiretroviral therapy may be accompanied by redistribution/accumulation of subcutaneous fat, incl. a decrease in the amount of peripheral fatty tissue and an increase in visceral fat, weight loss of the limbs and face, enlargement of the mammary glands and fat deposition along the back of the neck and back (“buffalo hump”), as well as an increase in serum lipid concentrations and blood glucose levels. Although all drugs in the protease inhibitor and nucleoside reverse transcriptase inhibitor classes may cause one or more of the above adverse reactions associated with the common syndrome often referred to as lipodystrophy, accumulating evidence suggests that there are differences among individual members of these drug classes in the ability to cause these adverse reactions.

It should also be noted that lipodystrophy syndrome has a multifactorial etiology; for example, stage of HIV infection, advanced age, and duration of antiretroviral therapy play an important, possibly synergistic role in the development of this complication. The long-term consequences of these adverse reactions have not yet been established. Clinical examination of patients should include assessment of physical signs of fat redistribution. Serum lipid concentrations and blood glucose concentrations should also be measured. Lipid metabolism disorders must be corrected based on their clinical manifestations.

Immune reconstitution syndrome

In patients receiving combination antiretroviral therapy, including emtricitabine, the development of immune reconstitution syndrome was observed. Against the background of restoration of immune function, an exacerbation of asymptomatic or residual opportunistic infections (including those caused by Mycobacterium avium, Mycobacterium tuberculosis, Pneumocystis carinii, Cytomegalovirus) is possible, which may require additional examination and treatment. Autoimmune diseases (such as Graves’ disease, polymyositis and Guillain-Barre syndrome) have been observed in the setting of immune reconstitution, but the timing of initial manifestations varies and the disease may occur many months after the start of therapy and have an atypical course.

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

Mitochondrial dysfunction

In vitro and in vivo conditions have revealed the ability of nucleotide and nucleoside analogues to cause mitochondrial damage to varying degrees. Mitochondrial abnormalities have been reported in HIV-negative neonates exposed in utero and/or postnatally to nucleoside analogues. The main manifestations of mitochondrial dysfunction are hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These changes are often transient. Some long-term neurological disturbances (hypertension, seizures, behavioral disturbances) have been reported. All infants exposed in utero to nucleosides or nucleoside analogues, even HIV-negative neonates, should receive close clinical and laboratory monitoring and careful evaluation for the possible presence of mitochondrial disorders if they exhibit signs or symptoms.

Patients infected with both HIV and hepatitis B or C virus

The risk of hepatotoxicity from antiretroviral drugs in patients co-infected with HIV and hepatitis B or C virus is higher than in patients with HIV infection alone. Therefore, patients with chronic hepatitis B or C who are concomitantly taking antiretroviral drugs are at increased risk of adverse liver effects, possibly fatal. Such patients should be closely monitored, both clinically and laboratory.

Discontinuation of emtricitabine therapy may precipitate severe exacerbation of hepatitis in patients infected with hepatitis B virus (HBV). Therefore, before initiating antiregroviral therapy, it is recommended to screen patients for viral hepatitis B. In patients infected with HIV-1 and HBV, liver function should be carefully monitored, but at least for several months after discontinuation of emtricitabine. In some cases, resumption of therapy for viral hepatitis may be necessary. In patients with severe liver disease (cirrhosis), it is not recommended to stop treatment, since exacerbation of hepatitis that occurs after discontinuation of therapy can lead to decompensation of liver function.

Impact on the ability to drive vehicles. Wed and fur.:

There have been no specific studies of the effect of emtricitabine on the ability to drive and operate machinery. However, when assessing a patient’s ability to drive and operate machinery, his general condition should be taken into account, as well as the nature of the adverse reactions of emtricitabine. If dizziness occurs, you should refrain from performing these activities.

Active ingredient

Emtricitabine

Composition

Active ingredient:

Emtricitabine 200 mg

Excipients:

Core: pregelatinized starch – 12.0 mg, colloidal silicon dioxide (Aerosil brand A-300) – 2.0 mg, croscarmellose sodium – 12.0 mg, lactose – 118.0 mg, magnesium stearate – 4.0 mg, microcrystalline cellulose – 40.0 mg.

Film coating: hydroxypropyl methylcellulose (hypromellose) – 8.7 mg, copovidone 0.3 mg, macrogol 6000 – 1.74 mg, talc – 0.3 mg, titanium dioxide – 0.96 mg.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Emtricitabine should be used in pregnant women only when absolutely necessary, in cases where the expected benefit to the mother outweighs the possible risk to the fetus.

Emtricitabine has been shown to be excreted in breast milk. Experts do not recommend breastfeeding for HIV-infected patients to avoid transmitting HIV infection to the child. Since emtricitabine and HIV infection are excreted in breast milk, breastfeeding is contraindicated.

Contraindications

Hypersensitivity to emtricitabine and other components of the drug.

Children under 3 years of age and weighing less than 33 kg (for this dosage form).

Lactation period.

Simultaneous use with combination drugs containing emtricitabine, as well as with lamivudine, zalcitabine.

Lactase deficiency, lactose intolerance, glucose-galactose malabsorption. since the drug contains lactose.

With caution:

Renal failure, old age, pregnancy, liver disease, simultaneous use with drugs that are eliminated by active tubular secretion.

Side Effects

From the blood system and hematopoietic organs: often – neutropenia; infrequently – anemia.

From the immune system: often – allergic reactions.

From the digestive system: very often – diarrhea, nausea; often – increased amylase activity, including increased activity of pancreatic amylase; increased serum lipase activity, vomiting, abdominal pain, dyspepsia.

From the nervous system: very often – headache, often – dizziness. Mental disorders: often – insomnia, pathological dreams.

From the hepatobiliary system: often increased activity of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) in serum, hyperbilirubinemia.

From the skin: often – vesiculobullous rash, pustular rash, maculopapular rash, rash, itching, urticaria, change in skin color (increased pigmentation); infrequently – angioedema.

From the musculoskeletal and connective tissue side: very often – increased creatine kinase activity.

Other: pain, asthenia.

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridemia, hypercholesterolemia, hyperglycemia, and hyperlactatemia; redistribution/accumulation of subcutaneous fat (lipodystrophy).

Cases of lactic acidosis have been described in HIV-infected patients taking nucleoside analogs, which is usually accompanied by severe hepahomegaly and fatty liver. The frequency of development depends on many factors, including: from a specific combination of antiretroviral drugs.

Cases of osteonecrosis have been reported in patients with risk factors such as advanced HIV infection or long-term combination antiretroviral therapy.

Patients taking emtricitabine or other antiretroviral drugs may develop opportunistic infections or other complications of HIV infection.

Children

In clinical studies, the side effects of the drug in children and adult patients were similar. The development of hyperpigmentation was most often noted. An additional adverse reaction reported in clinical studies in children was anemia.

Overdose

In case of overdose, the patient should be examined to identify possible signs of intoxication. If necessary, standard supportive therapy is used.

To remove emtricitabine, hemodialysis can be used; a 3-hour hemodialysis procedure leads to the removal of approximately 30% of the drug dose taken. Interaction with other drugs

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

Emtricitabine is excreted primarily by the kidneys. Concomitant use of emtricitabine with drugs that impair renal function or compete for active tubular secretion may lead to increased serum concentrations of emtricitabine and/or other drugs that are excreted by the kidney. When emtricitabine was prescribed in combination with zidovudine, indinavir, stavudine, famciclovir and tenofovir disoproxil fumarate, no clinically significant pharmacokinetic interactions between these drugs and emtricitabine were detected.

Storage conditions

Store in the original manufacturer’s packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

2 years. Do not use after the expiration date indicated on the package.

Manufacturer

Pharmasintez JSC, Russia