Expiration date: 01/2024
Release form
Capsules, 200 mg - 40 pcs per pack.
Dosage form
Solid gelatin capsules No. 0, the body is white, the lid is white, opaque, cylindrical in shape with hemispherical ends.
Composition
Composition for 1 capsule:
Active substance:
Molnupiravir 200.0 mg
Auxiliary substances:
Microcrystalline cellulose 67.0 mg
Croscarmellose sodium 15.0 mg
Povidone K30 15.0 mg
Sodium stearyl fumarate 3.0 mg
Capsule body:
Titanium dioxide (E171) 2.0 %
Gelatin up to 100.0 %
Capsule lid:
Titanium dioxide (E171) 2.0 %
Gelatin up to 100.0 %
Pharmacotherapeutic group
antiviral agent
Pharmacodynamics
Molnupiravir is a prodrug metabolized to an analog of the ribonucleoside N-hydroxycytidine (NHC). NHC is distributed into cells and phosphorylated to form pharmacologically active ribonucleoside triphosphate (NHC-TP).
Mechanism of action
NHC-TP operates through a mechanism known as an error crash during the virus replication process. Embedding NHC-TP into viral RNA with the help of the RNA polymerase enzyme leads to the accumulation of errors in the virus genome, resulting in suppression of replication.
Antiviral activity
NHC in the cell culture experiment showed activity against SARS-CoV-2 with a 50% effective concentration (EC50) in the range from 0.67 to 2.66 mmol in A-549 cells and from 0.32 to 2.03 mmol 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 EC50 values of 1.59, 1.77 and 1.32 and 1.68 mmol, respectively.
When NHC was tested in combination with other antiviral drugs (abacavir, emtricitabine, hydroxychloroquine, lamivudine, nelfinavir, remdevir, ribavirin, sofosbuvir, tenofovir), no effect was observed on the antiviral activity of NHC against SARS-CoV-2 in vitro.
The results of clinical studies have shown that taking ESPERAVIR® on the 6-7 day of therapy leads to the elimination of the virus from the body.
Resistance
In clinical studies of molnupiravir in the treatment of COVID-19, no amino acid substitutions in the structure of SARS-CoV-2 were identified that would be associated with resistance to NHC. Studies on the selection of NHC resistance mutations in SARS-CoV-2 in cell culture have not been completed. In vitro studies on the selection of resistance of SARS-CoV-2 with other coronaviruses (mouse hepatitis virus and MERS-CoV) showed a low probability of developing resistance to NHC. After 30 passages, only a 2-fold decrease in susceptibility was observed in cell culture 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 (for example, F480L, V557L and E802D) associated with decreased sensitivity to remdesivir, indicating the absence 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 people and patients with COVID-19.
Suction
After twice oral administration of 800 mg of molnupiravir, the average time to reach the peak concentration of NHC (Tmax) in plasma is 1.5 hours.
Distribution
The NHC metabolite does not bind to plasma proteins.
Withdrawal
The half-life of NHC is approximately 3.3 hours. The proportion of the dose excreted as NHC in urine was ?3% in healthy volunteers
Effect of food on oral absorption
In healthy volunteers, a single administration of 200 mg of molnupiravir against the background of a high-fat meal led to a decrease in peak NHC concentrations by 35% (Cmax), while the food did not significantly affect the AUC parameter.
Other special populations
Gender, race and age
Population FC analysis showed that age, gender, race and ethnicity did not have a significant effect on the pharmacokinetics of NHC.
Children's patients
Molnupiravir has not been studied in pediatric patients.
Pharmacokinetics in renal insufficiency
Renal clearance is not a significant elimination pathway for NHC. Dose adjustment in patients with any degree of renal insufficiency is not required.
In a pharmacokinetic population analysis, it was shown that mild or moderate renal impairment had no significant effect on the pharmacokinetics of NHC. The pharmacokinetics of molnupiravir and NHC in patients with eGFR less than 30 ml/min/1.73 m2 or patients on dialysis have not been studied.
Pharmacokinetics in hepatic insufficiency
The pharmacokinetics of molnupiravir and NHC have not been evaluated in patients with hepatic insufficiency. Preclinical data indicate that excretion of molnupiravir and NHC by the liver will not be the main route of elimination of NHC, therefore liver failure is unlikely to affect the effects of NHC. Dose adjustment in patients with hepatic insufficiency is not required.
Indications
This medicinal product is registered according to the procedure of registration of drugs intended for use in conditions of threat of occurrence, occurrence and liquidation of emergency situations. The instruction has been prepared on the basis of a limited amount of clinical data on the use of the drug and will be supplemented as new data become available. The use of the drug is possible only under the supervision of a doctor.
Treatment of a new coronavirus infection (COVID-19) of mild or moderate severity in adults, including those with an increased risk of disease progression to severe (see "Special instructions") and not requiring additional oxygen therapy.
Contraindications
- Hypersensitivity to molnupiravir or any other component of the drug ESPERAVIR®
- Pregnancy or pregnancy planning
- Breastfeeding period
- Children under 18 years of age
With caution
In patients with severe renal insufficiency (GFR less than 30 ml/min / 1.73 m2) and in patients with impaired liver function, monitoring of blood biochemical parameters is necessary.
Use during pregnancy and during breastfeeding
Pregnancy
There are no data on the use of molnupiravir in pregnant women. Animal studies have shown the presence of reproductive toxicity. Oral administration of molnupiravir to pregnant rats during organogenesis led to embryo mortality and teratogenicity at NHC concentrations exceeding those in humans when using the recommended clinical dose in humans by 7.5 times and caused fetal growth retardation when exposed to NHC 2.9 times higher than the recommended clinical dose in humans.
Oral administration of molnupiravir to pregnant rabbits during organogenesis resulted in fetal growth retardation at NHC exposure 18 times higher than NHC exposure at the recommended clinical dose in humans.
NHC exposure in humans differs from rats and rabbits by 0.8 and 6.5 times, respectively, in terms of the dose level that does not have the observed undesirable effect (NOAEL), in relation 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, the effect of molnupiravir on maternal toxicity indicators cannot be excluded.
ESPERAVIR® is not recommended during pregnancy, as well as for women capable of childbirth who do not use reliable methods of contraception.
When prescribing the drug ESPERAVIR® to women capable of childbearing (including postmenopausal women less than 2 years old), it is necessary to confirm a negative pregnancy test result before starting treatment. A repeat pregnancy test should be performed after the end of taking the drug.
It is necessary to use effective methods of contraception (a condom with spermicide) during and after taking the drug for 4 days.
Breastfeeding period
There are no data on the presence of molnupiravir in breast milk. There are no data on the possible effect of molnupiravir on the production of breast milk or the effect on a breastfed 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 at the time of administration and within 4 days after the last dose of the drug ESPERAVIR®.
Fertility
Against the background of NHC concentrations that exceeded those in humans when using the recommended clinical dose for humans by about 2 and 6 times, respectively, no effect on male and female fertility was observed in rats.
Due to the fact that animal studies have shown the reproductive toxicity of molnupiravir, it is recommended to use effective methods of contraception in men during the administration of the drug and for 3 months after its termination.
Method of administration and dosage
The drug ESPERAVIR® is taken orally regardless of food intake.
Capsules should be swallowed whole, without opening, crushing or chewing them, washed down with a sufficient amount of liquid (for example, a glass of water).
The use of ESPERAVIR® is possible only under the supervision of a doctor.
Dosage regimen
For the treatment of a new coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus, the following dosage regimen is recommended in adults:
- 4 capsules 200 mg or 2 capsules 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 the course of treatment is 5 days.
Treatment with ESPERAVIR® should be initiated as early 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.
In case of missing the next dose of the drug, if the delay in admission was less than 10 hours from the scheduled time of admission, then the missed dose should be taken as soon as possible and the usual dosing regimen should be resumed; if the delay in admission was more than 10 hours, then the missed dose should not be taken, and the next dose is taken at the usual time. The patient should not take a double dose of the drug to compensate for the missed dose.
Special patient groups
Old age
Dose adjustment of ESPERAVIR® is not required depending on age.
Kidney failure
Dose adjustment of ESPERAVIR® is not required for patients with renal insufficiency.
Liver failure
Dose adjustment of ESPERAVIR® is not required for patients with hepatic insufficiency.
Children
There is no data on the safety and efficacy of ESPERAVIR® in children under 18 years of age.
Side effects
Brief description of the security profile
The most frequent adverse reactions reported during treatment with molnupiravir at a dose of 800 mg every 12 hours for 5 days and for 14 days after taking the last dose of the drug were diarrhea (3%), nausea (2%), dizziness (1%) and headache (1%), which had mild or moderate severity.
Summary table of undesirable reactions
Adverse reactions are listed below by organ and system classes and frequency of development. The frequencies were determined as follows: very often (?1/10); often (? 1/100, but <1/10); infrequently (? 1/1 000, but <1/100); rare (?1/10000, but <1/1 000); very rare (<1/10 000).
Overdose
There are no data on cases of overdose of drugs with the active substance molnupiravir.
Treatment
In case of overdose with ESPERAVIR®, treatment is recommended on the basis of general supportive measures, including monitoring of the patient's clinical condition. It is expected that hemodialysis will not lead to effective elimination of the active substance of the drug.
Drug interaction
Clinical studies of drug interactions with molnupiravir have not been conducted. Based on the limited amount of available in vitro data, there were no significant risks of clinically significant drug interactions when taking molnupiravir at a dose of 800 mg every 12 hours for 5 days.
Special instructions
Risk factors for the progression of COVID-19 to severe course.
A number of concomitant diseases increase the risk of progression of COVID-19 to a severe course: age ? 60 years old, 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 doctor.
With the development of a side effect, it is necessary to report this in accordance with the established procedure for the implementation of pharmacovigilance measures.
Since reproductive toxicity has been observed in animal studies of molnupiravir, ESPERAVIR® should not be prescribed to pregnant and presumably pregnant women.
When prescribing the drug ESPERAVIR® to women capable of childbearing (including postmenopausal women less than 2 years old), it is necessary to confirm a negative pregnancy test result before starting treatment. A repeat pregnancy test should be performed after the end of taking the drug.
Women who are capable of childbearing need to fully explain the risks and carefully instruct them on the use of effective methods of contraception during the administration of the drug and within 4 days after its termination. Under the assumption of a possible pregnancy, it is necessary to immediately cancel taking the drug and consult a doctor.
There are no data on the presence of molnupiravir in breast milk. There are no data on the possible effect of molnupiravir on the production of breast milk or the effect on a breastfed baby. Studies of the effect of molnupiravir on lactation in animals have not been conducted. Based on the possibility of adverse reactions in infants, it is necessary to stop breastfeeding at the time of administration and within 4 days after the last dose of ESPERAVIR®.
Due to the fact that animal studies have shown the reproductive toxicity of molnupiravir, it is recommended to use effective methods of contraception in men during the administration of the drug and for 3 months after its termination.
Patients with impaired liver and kidney function
Patients with severe renal insufficiency were excluded from clinical trials. The experience of using molnupiravir in patients with any degree of hepatic insufficiency is limited.
Sodium
This drug contains less than 1 mmol of sodium (23 mg) per dose consisting of 4 capsules, that is, in fact, it does not contain sodium.
Influence on the ability to drive vehicles, mechanisms
Studies of the effect of the drug ESPERAVIR® on the ability to drive a car have not been conducted.
During treatment, you should refrain from driving a car, as well as engaging in potentially dangerous activities that require increased concentration and speed of psychomotor reactions.
Storage temperature
from 2℃ to 25℃
