Esperavir^® (Capsules) Instructions for Use

Marketing Authorization Holder

Promomed Rus LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

Contact Information

PROMOMED RUS LLC (Russia)

ATC Code

J05AB18 (Molnupiravir)

Active Substance

Molnupiravir (Rec.INN registered by WHO)

Dosage Forms

	Esperavir®	Capsules 200 mg: 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 pcs.
		Capsules 400 mg: 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 0, white body, white cap, opaque, cylindrical in shape with hemispherical ends; capsule contents – powder or a mixture of powder and granules from white to yellowish-white; the presence of conglomerates (lumps) that disintegrate when pressed with a glass rod is allowed, may appear as a compacted mass in the shape of a cylinder.

Excipients: microcrystalline cellulose – 67 mg, croscarmellose sodium – 15 mg, povidone K30 – 15 mg, sodium stearyl fumarate – 3 mg.

Capsule body composition titanium dioxide (E171) – 2%, gelatin – up to 100%.
Capsule cap composition titanium dioxide (E171) – 2%, gelatin – up to 100%.

10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (4) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (7) – cardboard packs.
10 pcs. – contour cell packs (8) – cardboard packs.
10 pcs. – contour cell packs (9) – cardboard packs.
10 pcs. – contour cell packs (10) – cardboard packs.
40 pcs. – polymer jars (1) – cardboard packs.

Capsules hard gelatin, size No. 00, white body, blue cap, opaque, cylindrical in shape with hemispherical ends; capsule contents – powder or a mixture of powder and granules from white to yellowish-white; the presence of conglomerates (lumps) that disintegrate when pressed with a glass rod is allowed, may appear as a compacted mass in the shape of a cylinder.

Excipients: microcrystalline cellulose – 134 mg, croscarmellose sodium – 30 mg, povidone K30 – 30 mg, sodium stearyl fumarate – 6 mg.

Capsule body composition titanium dioxide (E171) – 2%, gelatin – up to 100%.
Capsule cap composition indigotine (E132) – 0.1333%, titanium dioxide (E171) – 2%, gelatin – up to 100%.

10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (4) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (7) – cardboard packs.
10 pcs. – contour cell packs (8) – cardboard packs.
10 pcs. – contour cell packs (9) – cardboard packs.
10 pcs. – contour cell packs (10) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; nucleosides and nucleotides, excluding reverse transcriptase inhibitors

Pharmacological Action

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

Mechanism of action

NHC-TP acts via a mechanism known as viral error catastrophe during the viral replication process. The incorporation of NHC-TP into viral RNA by the RNA polymerase enzyme leads to an accumulation of errors in the viral genome, resulting in the suppression of replication.

Antiviral activity

NHC demonstrated activity against SARS-CoV-2 in cell culture experiments with a 50% effective concentration (EC₅₀) ranging from 0.67 to 2.66 µmol in A-549 cells and from 0.32 to 2.03 µmol in Vero E6 cells.

NHC had similar activity against SARS-CoV-2 variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) with EC₅₀ values of 1.59, 1.77, 1.32, and 1.68 µmol, respectively.

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

Results from clinical studies have shown that a course of therapy with the drug Esperavir^® helps prevent the risks of complicated COVID-19, including in patients with risk factors for progression to severe disease. Therapy with the drug Esperavir^® led to a reduction in the time to virus elimination (72.88% of patients achieved complete virus elimination on day 6 after the start of therapy) and a reduction in the duration of disease symptoms.

Resistance

In clinical studies of molnupiravir for the treatment of COVID-19, no amino acid substitutions in the SARS-CoV-2 structure associated with resistance to NHC were identified. Studies on the selection of resistance mutations to NHC in SARS-CoV-2 in cell culture are not yet complete. In vitro resistance selection studies with SARS-CoV-2 and other coronaviruses (murine hepatitis virus and MERS-CoV) have shown a low probability of resistance development to NHC. After 30 passages in cell culture, only a 2-fold decrease in susceptibility was observed and no amino acid substitutions associated with resistance to NHC were identified. NHC retained activity in in vitro studies against SARS-CoV-2 and recombinant murine hepatitis virus with polymerase substitutions (e.g., F480L, V557L, and E802D) associated with reduced susceptibility to remdesivir, indicating a lack of cross-resistance.

Pharmacokinetics

Molnupiravir is a prodrug of the 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 after administration of 800 mg molnupiravir every 12 hours are presented in Table 1.

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

%CV: geometric coefficient of variation.

* Values obtained from population pharmacokinetic analysis.

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

Absorption

After twice-daily oral administration of 800 mg molnupiravir, the mean T_max of NHC in plasma is 1.5 h.

Distribution

The NHC metabolite does not bind to plasma proteins.

Elimination

The T_1/2 of NHC is approximately 3.3 h. The fraction of the dose excreted as NHC in urine was ≤3% in healthy volunteers.

Effect of food on oral absorption

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

Special patient groups

Sex, race, and age. Population pharmacokinetic 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.

Patients with renal impairment. Renal clearance is not a significant elimination pathway for NHC. Dose adjustment is not required for patients with any degree of renal impairment.

Population pharmacokinetic analysis showed that mild or moderate renal impairment did not significantly affect the pharmacokinetics of NHC. The pharmacokinetics of molnupiravir and NHC in patients with eGFR <30 ml/min/1.73 m² or patients on dialysis have not been studied.

Pharmacokinetics in hepatic impairment

The pharmacokinetics of molnupiravir and NHC have not been evaluated in patients with hepatic impairment. Preclinical data indicate that hepatic elimination of molnupiravir and NHC will not be a major pathway for NHC elimination; therefore, hepatic impairment is unlikely to affect NHC exposure. Dose adjustment is not required for patients with hepatic impairment.

Indications

• Treatment of the novel coronavirus infection (COVID-19), confirmed by diagnostic test results for SARS-CoV-2, of mild to moderate severity in adult patients with an increased risk of disease progression to severe course (see “Special Precautions”) and not requiring supplemental oxygen.

ICD codes

Dosage Regimen

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 (e.g., a glass of water).

The use of the drug Esperavir^® is possible only under medical supervision.

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

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

Treatment with the drug Esperavir^® should be started as soon as possible after diagnosis of the novel coronavirus infection (COVID-19) and/or within 5 days of the onset of the first symptoms of the disease.

If a dose is missed, and if it is less than 10 hours after the scheduled time, the missed dose should be taken as soon as possible and the regular dosing schedule should be resumed; if it is more than 10 hours late, 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 to make up for a missed dose.

Special patient groups

Elderly age. Dose adjustment of the drug Esperavir^® is not required based on age.

Renal impairment. Dose adjustment of the drug Esperavir^® is not required for patients with renal impairment.

Hepatic impairment. Dose adjustment of the drug Esperavir^® is not required for patients with hepatic impairment.

Children. There are no data on the safety and efficacy of the drug Esperavir^® in children and adolescents under 18 years of age.

Adverse Reactions

Summary of the safety profile

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

The ARs below are listed by organ system class and frequency of occurrence. Frequencies were defined as follows: very common (≥1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 2. Summary table of adverse reactions

A randomized clinical trial of the efficacy and safety of the drug Esperavir^® demonstrated its favorable safety profile. Common ARs reported during treatment with the drug Esperavir^® at a dose of 800 mg every 12 hours and within 23 days after the last dose of the drug were diarrhea (5.8%), nausea (3.3%), increased ALT level (4.2%), increased AST level (4.2%), and headache (1.7%). Frequent bowel movements, abdominal discomfort, dysgeusia (uncommon), upper abdominal pain, asthenia (very rare) were also recorded. The identified ARs were transient and did not require discontinuation of the drug.

Contraindications

• Hypersensitivity to molnupiravir or any other component of the drug Esperavir^®;
• Pregnancy or planning pregnancy;
• Period of breastfeeding;
• Children under 18 years of age.

With caution

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

Use in Pregnancy and Lactation

Pregnancy

Data on the use of molnupiravir in pregnant women are not available. Animal studies have shown reproductive toxicity. Oral administration of molnupiravir to pregnant rats during organogenesis led to embryo mortality and teratogenicity at NHC exposures exceeding those in humans at the recommended human clinical dose by 7.5 times and caused fetal growth retardation at NHC exposures 2.9 times higher than the recommended human clinical dose.

Oral administration of molnupiravir to pregnant rabbits during organogenesis led to fetal growth retardation at NHC exposures 18 times higher than the NHC exposure at the recommended human clinical dose.

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

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

The drug Esperavir^® is not recommended during pregnancy, as well as for women of childbearing potential not using reliable methods of contraception.

When prescribing the drug Esperavir^® to women of childbearing potential (including those with less than 2 years postmenopause), it is necessary to confirm a negative pregnancy test result before starting treatment. A repeat pregnancy test should be performed after completion of the drug.

Effective methods of contraception (condom with spermicide) must be used during drug administration and for 4 days after its completion.

Breastfeeding period

Data on the presence of molnupiravir in breast milk are not available. Data on the possible effect of molnupiravir on breast milk production or on the breastfed child are not available.

Studies on the effect of molnupiravir on lactation in animals have not been conducted. Based on the possibility of adverse reactions in the infant, breastfeeding should be discontinued during administration and for 4 days after the last dose of the drug Esperavir^®.

Fertility

At NHC exposures that exceeded those in humans at the recommended human clinical dose by approximately 2 and 6 times, respectively, no effect on fertility in male and female rats was observed.

Due to the fact that animal studies have shown reproductive toxicity of molnupiravir, the use of effective contraceptive methods in men during drug administration and for 3 months after its completion is recommended.

Use in Hepatic Impairment

Dose adjustment of the drug Esperavir^® is not required for patients with hepatic impairment.

Use in Renal Impairment

Dose adjustment of the drug Esperavir^® is not required for patients with renal impairment.

Pediatric Use

Use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Dose adjustment of the drug Esperavir^® is not required based on age.

Special Precautions

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

The use of the drug Esperavir^® is possible only under medical supervision.

If side effects occur, it is necessary to report them in the established manner for pharmacovigilance measures.

Since reproductive toxicity was observed in animal studies of molnupiravir, the drug Esperavir^® should not be prescribed to pregnant women or women suspected of being pregnant.

When prescribing the drug Esperavir^® to women of childbearing potential (including those with less than 2 years of postmenopause), it is necessary to confirm a negative pregnancy test result before starting treatment. A repeat pregnancy test must be performed after the end of the drug administration.

Women of childbearing potential must be fully informed of the risks and carefully instructed on the use of effective methods of contraception during the drug intake and for 4 days after its completion. If a possible pregnancy is suspected, the drug should be discontinued immediately and a doctor should be consulted.

There are no data on the presence of molnupiravir in breast milk. There are no data on the possible effect of molnupiravir on breast milk production or on the breastfed child. Studies on the effect of molnupiravir on lactation in animals have not been conducted. Due to the possibility of adverse reactions in breastfed infants, breastfeeding should be discontinued during the treatment and for 4 days after the last dose of the drug Esperavir^®.

Since animal studies have shown reproductive toxicity of molnupiravir, the use of effective methods of contraception is recommended in men during the drug intake and for 3 months after its completion.

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 dose consisting of 4 capsules, that is, it is essentially sodium-free.

Effect on the ability to drive vehicles and mechanisms

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

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

Overdose

There are no data on cases of overdose of medicinal products with the active substance Molnupiravir.

Treatment: in case of an overdose of the drug Esperavir^®, treatment is recommended to be carried out based on general supportive measures, including monitoring of the patient’s clinical condition. Hemodialysis is not expected to lead to effective elimination of the drug’s active substance.

Drug Interactions

No clinical drug interaction studies with molnupiravir have been conducted. Based on the limited amount of available in vitro data, no significant risks of clinically significant drug interactions have been identified when taking molnupiravir at a dose of 800 mg every 12 hours for 5 days.

Storage Conditions

The drug should be stored in the original packaging (carton), in a place inaccessible to children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.