Esperavir capsules 200mg 40 pcs

Pharmacotherapeutic group: antiviral agent

Code ATH: J05AX27

Pharmacological properties

Pharmacodynamics
Molnupiravir is a prodrug that is metabolized to the ribonucleoside analogue N-hydroxycytidine (NHC). NHC is distributed into cells and phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP).

Mechanism of action

NHC-TP operates through a mechanism known as error catastrophe during the viral replication process. Incorporation of NHC-TP into viral RNA by the enzyme RNA polymerase leads to the accumulation of errors in the viral genome, resulting in suppression of replication.

Antiviral activity

NHC in a cell culture experiment showed activity against SARS-CoV-2 with a 50% effective concentration (EK₅₀) in the range from 0.67 to 2 .66 µM in A-549 cells and 0.32 to 2.03 µM in Vero E6 cells.

NHC had similar activity against SARS-CoV-2 variants B.1.1.7 (Alpha), B.1351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) with EC< values a i=1>50 1.59, 1.77 and 1.32 and 1.68 µmol, respectively.

When NHC was tested in combination with other antiviral drugs (abacavir, emtricitabine, hydroxychloroquine, lamivudine, nelfinavir, remdevir, ribavirin, sofosbuvir, tenofovir), no effect on the antiviral activity of NHC against SARS-CoV-2 in vitro was observed.

The results of clinical studies have shown that taking the drug ESPERAVIR^® on the 6-7th day of therapy leads to the elimination of the virus from the body.

Resistance

Clinical trials studying molnupiravir for the treatment of COVID-19 did not identify any amino acid substitutions in the structure of SARS-CoV-2 that would be associated with NHC resistance. Studies examining the selection of NHC resistance mutations in SARS-CoV-2 in cell culture have not been completed. In vitro resistance selection studies of SARS-CoV-2 with other coronaviruses (mouse hepatitis virus and MERS-CoV) have shown a low likelihood of developing resistance to NHC. After 30 passages in cell culture, only a 2-fold decrease in susceptibility was observed and no amino acid substitutions were identified that would be associated with resistance to NHC. NHC remained active in in vitro studies against SARS-CoV-2 and recombinant mouse hepatitis virus with polymerase substitutions (e.g., F480L, V557L, and E802D) associated with decreased susceptibility to remdesivir, indicating lack of cross-resistance.

Pharmacokinetics

Molnupiravir is a prodrug of 5′-isobutyrate, which is hydrolyzed to NHC before entering the systemic circulation. The pharmacokinetics of NHC are similar in healthy individuals and patients with COVID-19.

The steady-state pharmacokinetics of NHC following molnupiravir 800 mg every 12 hours are shown in Table 1.

Table 1: Pharmacokinetics NHC after administration of 800 mg of molnupiravir every 12 hours.

%CV: geometric coefficient of variation.

*Values ​​derived from population pharmacokinetic analysis.

**Values ​​were obtained from a phase 1 study in healthy volunteers.

Suction

After two oral doses of molnupiravir 800 mg, the mean time to peak plasma NHC concentration (T_max) in plasma is   1.5 hours.

Distribution

The NHC metabolite does not bind to plasma proteins.

Removal

The half-life of NHC is approximately 3.3 hours. The proportion of dose excreted as NHC in urine was ≤3% in healthy volunteers

Effect of food on oral absorption

In healthy volunteers, a single dose of 200 mg molnupiravir administered with a high-fat meal resulted in a 35% reduction in peak NHC concentrations (C_max), with food did not significantly affect the AUC parameter.

Other special populations

Gender, race and age

Population PK analysis showed that age, sex, race and ethnicity did not have a significant effect on the pharmacokinetics of NHC.

Pediatric patients

Molnupiravir has not been studied in pediatric patients.

Pharmacokinetics in renal failure

Renal clearance is not a significant elimination route for NHC. No dose adjustment is required in patients with any degree of renal impairment.

In a population pharmacokinetic analysis, it was shown that mild to moderate renal impairment did not have a significant effect on the pharmacokinetics of NHC. The pharmacokinetics of molnupiravir and NHC in patients with eGFR less than 30 ml/min/1.73 m²or patients on dialysis have not been studied.

Pharmacokinetics in liver failure

The pharmacokinetics of molnupiravir and NHC have not been evaluated in patients with hepatic impairment. Preclinical data indicate that hepatic clearance of molnupiravir and NHC will not be the primary route of NHC elimination, so hepatic impairment is unlikely to affect NHC exposure. No dose adjustment is required in patients with hepatic impairment.

Pregnancy

There are no data on the use of molnupiravir in pregnant women. Animal studies have shown reproductive toxicity. Oral administration of molnupiravir to pregnant rats during organogenesis resulted in fetal lethality and teratogenicity at NHC concentrations exceeding those in humans at 7.5 times the recommended human clinical dose and caused fetal growth restriction at 2.9 times the recommended clinical NHC exposure. doses in humans.

Oral administration of molnupiravir to pregnant rabbits during the period of organogenesis resulted in fetal growth retardation with NHC exposure 18 times higher than NHC exposure at the recommended clinical dose in humans.

NHC exposure in humans at the no observed adverse effect dose level (NOAEL) differs from rats and rabbits by 0.8 and 6.5 times, respectively, relative to the recommended clinical dose in humans.

Since maternal toxicity was observed in both rats and rabbits at all doses at which embryotoxic effects were observed, an influence of molnupiravir on maternal toxicity rates cannot be ruled out.

ESPERAVIR^® is not recommended during pregnancy, as well as in women of childbearing potential who do not use reliable methods of contraception.

When prescribing the drug ESPERAVIR^® to women capable of childbearing (including those less than 2 years postmenopausal), it is necessary to confirmonegative test resultsta for pregnancy before the start of treatment . A repeat pregnancy test should be performed after stopping the drug.

It is necessary to use effective methods of contraception (condom with spermicide) while taking the drug and after its completion for 4 days.

Breastfeeding period

There are no data on the presence of molnupiravir in breast milk. There are no data on the possible effects of molnupiravir on breast milk production or on the breast-fed baby.

Studies of the effect of molnupiravir on lactation in animals have not been conducted. Based on the possibility of adverse reactions in the infant, it is necessary to stop breastfeeding during administration and for 4 days after the last dose of the drug ESPERAVIR^®.

Fertility

At NHC concentrations that were approximately 2 and 6 times the recommended human clinical dose, respectively, in rats, no effects on male or female fertility were observed.

Due to the fact that animal studies have shown reproductive toxicity of molnupiravir, the use of effective methods of contraception in men is recommended while taking the drug and for 3 months after its termination.

• Hypersensitivity to molnupiravir or any other component of the drug ESPERAVIR^®
• Pregnancy or planning pregnancy
• Breastfeeding period
• Children under 18 years of age

Carefully

In patients with severe renal failure (GFR less than 30 ml/min/1.73 m²) and in patients with impaired liver function, monitoring of biochemical parameters is necessary blood.

Brief description of the security profile

The most common adverse reactions reported during treatment with molnupiravir 800 mg every 12 hours for 5 days and up to 14 days after the last dose were diarrhea (3%), nausea (2%), dizziness (1%). and headache (1%), which were of  mild or moderate severity.

Summary table of adverse reactions

Adverse reactions are listed below by class of organs and systems and frequency of development. Frequencies were defined as follows: very common (≥1/10); often (≥ 1/100, but <1/10); uncommon (≥ 1/1,000, but <1/100); rare (≥1/10000, but <1/1,000); very rare (< 1/10,000).

Table 2: Summary table of adverse reactions

According to a clinical study of the drug ESPERAVIR^®no adverse events associated with taking the drug were recorded.

The drug ESPERAVIR^®is taken orally, regardless of meals.

Capsules should be swallowed whole, without opening, crushing or chewing them, with a sufficient amount of liquid (for example, a glass of water).

The use of ESPERAVIR^® is possible only under the supervision of a physician.

Dosage regimen

For the treatment of novel coronavirus infection (COVID-19), caused by the SARS-CoV-2 virus, the following dosage regimen is recommended in adults:

– 4 capsules of 200 mg or 2 capsules of 400 mg orally 2 times a day (every 12 hours). A single dose is 800 mg. The daily dose is 1600 mg. The duration of treatment is 5 days.

Treatment with ESPERAVIR®️ should be started as soon as possible after the diagnosis of a new coronavirus infection (COVID-19) and/or within 5 days after the first symptoms of the disease appear.

 If you miss the next dose of the drug, if the delay in taking it was less than 10 hours from the scheduled time of administration, then the missed dose should be taken as soon as possible and the usual dosage regimen should be resumed; If the delay in taking is more than 10 hours, then the missed dose should not be taken, and the next dose should be taken at the usual time. The patient should not take a double dose of the drug to make up for a missed dose.

Special patient groups

Elderly age

Dose adjustment of ESPERAVIR^®is not required depending on age.

Kidney failure

Dose adjustment of ESPERAVIR^®is not required for patients with renal failure.

Liver failure

Dose adjustment of ESPERAVIR^®is not required for patients with liver failure.

Children

There are no data on the safety and effectiveness of ESPERAVIR^® in children under 18 years of age.

There are no data on cases of overdose of drugs containing the active substance molnupiravir.

Treatment

In case of overdose with ESPERAVIR^®, treatment is recommended on the basis of general supportive measures, including monitoring the patient’s clinical condition. It is expected that hemodialysis will not lead to effective elimination of the active substance of the drug.

Risk factors for progression ofCOVID-19 to severe disease.

A number of concomitant diseases increase the risk of progression of COVID-19 to severe disease:age ≥ 60 years,obesity (BMI > 30kg/m²), diabetes mellitus, chronic kidney disease, severe diseases of the cardiovascular system, chronic obstructive pulmonary disease, active malignant neoplasms.

The use of ESPERAVIR^® is possible only under the supervision of a physician.

If a side effect develops, it is necessary to report this in the prescribed manner for the implementation of pharmacovigilance activities.

Because reproductive toxicity was observed in animal studies with molnupiravir, ESPERAVIR^®cannot be administered to pregnant or suspected pregnant women.

When prescribing the drug ESPERAVIR^® to women capable of childbearing (including those less than 2 years postmenopausal), it is necessary to confirmonegative test resultsta for pregnancy before the start of treatment . A repeat pregnancy test should be performed after stopping the drug.

Women of childbearing potential should be fully explained the risks and carefully instructed to use effective contraceptive methods while taking the drug and for 4 days after stopping it. If you suspect a possible pregnancy, you should immediately stop taking the drug and consult your doctor.

There are no data on the presence of molnupiravir in breast milk. There are no data on the possible effects of molnupiravir on breast milk production or on the breast-fed baby. Studies of the effect of molnupiravir on lactation in animals have not been conducted. Based on the possibility of developing adverse reactions in infants, it is necessary to stop breastfeeding during administration and for 4 days after the last dose of ESPERAVIR^®.

Due to the fact that animal studies have shown reproductive toxicity of molnupiravir, the use of effective methods of contraception in men is recommended while taking the drug and for 3 months after its termination.

Patients with impaired liver and kidney function

Patients with severe renal impairment were excluded from clinical studies. Experience with molnupiravir in patients with any degree of hepatic impairment is limited.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 4-capsule dose, which means it is essentially sodium-free.

Impact on the ability to drive vehicles and machinery

No studies have been conducted on the effect of the drug ESPERAVIR^® on the ability to drive a car.

During treatment, you should refrain from driving a car, as well as engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.