NIOCH-14 (Capsules) Instructions for Use

Marketing Authorization Holder

Vector VB State Research Center Federal State Institution of Rospotrebnadzor (Russia)

Manufactured By

Siberian Center of Pharmacology and Biotechnology, JSC (Russia)

ATC Code

J05AX (Other antiviral drugs)

Dosage Form

NIOCH-14

Capsules 200 mg: 45 pcs.

Dosage Form, Packaging, and Composition

Capsules are hard gelatin, size No. 0, with a white body and a red cap; the capsule contents are a white powder.

Excipients: microcrystalline cellulose – 96 mg, lactose monohydrate – 48 mg, magnesium stearate – 2 mg, colloidal silicon dioxide (aerosil) – 2 mg, potato starch – 9 mg, sodium chloride – 35 mg, purified water – 8 mg.

Composition of the gelatin capsule body: titanium dioxide (E171) – 2%, medical gelatin – up to 100%.
Composition of the gelatin capsule cap: azorubine (E122) – 0.19%; quinoline yellow (E104) – 0.37% titanium dioxide (E171) – 1%, medical gelatin – up to 100%.

45 pcs. – polymer jars (1) – cardboard packs.

Pharmacotherapeutic Group

Systemic antiviral agent

Pharmacological Action

This medicinal product is registered under the procedure for the registration of drugs intended for use in the context of the threat of occurrence, occurrence and liquidation of emergencies. The instructions are prepared based on a limited amount of clinical data on the use of the drug and will be supplemented as new data becomes available. The use of the drug is possible only in the conditions of inpatient medical care.

Mechanism of action

The drug NIOCH-14 is a prodrug, the active metabolite of which is ST-246 (tecovirimat), which has activity against orthopoxviruses, including the smallpox virus, in vitro and in vivo. Tecovirimat is an inhibitor of the highly conserved envelope protein p37 of orthopoxviruses, present in all representatives of orthopoxviruses. Thus, the target of ST-246 is the p37 protein, a highly conserved product of homologous genes of orthopoxviruses. The drug NIOCH-14 in the form of its active metabolite ST-246 blocks the interaction of p37 with cellular GTPase Rab₉ and TIP₄₇ and thereby prevents the formation and release of enveloped virions from the cell, through which the virus spreads in cell culture and in the body.

Resistance to the drug NIOCH-14

When studying the antiviral activity of the drug NIOCH-14 against strains of orthopoxviruses (vaccinia virus, cowpox, mousepox, monkeypox and smallpox) from the State Collection of Viral Infections and Rickettsiae Pathogens of the FBUN SRC VB “Vector” of Rospotrebnadzor, no strains resistant to this drug were identified in cell culture and in animal experiments.

Specific activity of the drug NIOCH-14

In experiments on cell culture, the drug NIOCH-14 exhibits activity against vaccinia virus, cowpox, mousepox, monkeypox and smallpox virus with a 50% effective (virus-inhibiting) concentration (EC50) in the range of 0.01-0.05 µM. When administered orally to laboratory animals, the drug NIOCH-14 has a protective effect against orthopoxvirus infections. The antiviral effect of the drugs NIOCH-14 and ST-246 (tecovirimat) was the same against the smallpox virus and other orthopoxviruses in in vitro and in vivo experiments.

Pharmacokinetics

Absorption and bioavailability

In a clinical study with a single oral application of the drug NIOCH-14 at a dose of 200 mg, the C_max of the active metabolite ST-246 in blood plasma reached 215 ng/ml after 6 hours (T_max), T_1/2 was 17.8 hours; single dose of 600 mg: C_max=375 ng/ml, T_max=6 hours, T_1/2=19.8 hours; single dose of 1200 mg: C_max=1212 ng/ml, T_max=6 hours, T_1/2=29 hours. When using NIOCH-14 for 6 days at 200 mg per day, the following pharmacokinetic parameters of the active metabolite ST-246 in blood plasma were: C_max=189 ng/ml, T_max=6 hours, T_1/2=26 hours; for 6 days at 600 mg per day: C_max=740 ng/ml, T_max=6 hours, T_1/2=29 hours; for 6 days at 1200 mg per day: C_max=607 ng/ml, T_max=96 hours, T_1/2=18 hours.

After a single oral application of the drug tecovirimat at a dose of 600 mg, the pharmacokinetic parameters in human blood plasma were as follows: C_max=1070 ng/ml, T_max=4 hours, T_1/2=24.4 hours. In addition, 1 day after its application at a dose of 250 mg, C_max in the blood was 985 (±346) ng/ml, and after application for 6 days, C_max reached 1212 (±350) ng/ml. At the same time, 1 day after the application of tecovirimat at a dose of 400 mg, C_max was 1392 (±411) ng/ml, and an increase in the time of its administration at this dose to 6 days was not accompanied by an increase in C_max and was 1298 (±277) ng/ml.

The pharmacokinetic parameters of the drug NIOCH-14 obtained in experiments on mice indicate its high bioavailability. After a single oral administration at a dose of 50 µg/g of mouse body weight, the tissue availability of the drug NIOCH-14, calculated based on the parameters of its active metabolite ST-246, for the lungs was 7.2%, for the liver – 9.8%, for the spleen – 3.2%, and the absolute bioavailability of the drug NIOCH-14 was 61.1%.

The absolute bioavailability of the drug tecovirimat when administered orally at doses from 30 to 2000 mg/kg was 4-45% in mice, 8-29% in rabbits and 28-50% in monkeys. In addition, experiments on mice have shown that tecovirimat spread in the body within 4 hours, reaching the highest concentrations in the blood, liver, lungs and bone marrow.

Tecovirimat reaches C_max in blood plasma 4 – 6 hours after oral administration with food. Taking tecovirimat with food of moderate fat and calorie content (~600 kcal and ~25 grams of fat), compared with tecovirimat taken on an empty stomach, increased drug exposure (AUC) by 39%.

Distribution

In clinical studies, it was found that the apparent V_d of the drug NIOCH-14, i.e., the hypothetical volume of fluid in which the total amount of the administered substance could be distributed to create its concentration, such as in the blood, with a single oral administration at doses of 200, 600 and 1200 mg was 950, 1400 and 1760 liters, respectively.

With a single oral application of tecovirimat in healthy volunteers at doses of 200 and 600 mg, its V_d was 986 and 1356 liters, respectively.

Tecovirimat is 77.3-82.2% bound to human plasma proteins. After a single dose of 600 mg of [¹⁴C]-tecovirimat in healthy subjects, total radioactivity concentrations at all time points were lower in whole blood compared to plasma, with the whole blood to plasma ratio ranging from 0.62-0.90 at all time points. Tecovirimat has a large V_d (1356 liters).

Metabolism

During preclinical studies of the drug NIOCH-14, it was found that in solvents used for mass spectrometry, in the body, blood serum and organ homogenates of animals, NIOCH-14 is converted into the active metabolite ST-246 and the inactive metabolite K.

Based on human studies, tecovirimat is metabolized to form pharmacologically inactive metabolites. Tecovirimat is a substrate of UGT1A1 and UGT1A4. However, none of the glucuronide conjugates were detected as a major metabolite in plasma.

Excretion

No own studies on the excretion of the drug NIOCH-14 in urine and feces have been conducted. After oral application of the drug NIOCH-14 at a dose of 200 mg, the T_1/2 of its active metabolite ST-246 from the blood was 17.8 hours.

After a single dose of tecovirimat, approximately 95% of healthy subjects had the isotope [¹⁴C] detected in urine and feces during the 192-hour period after dose administration. At the same time, approximately 73% of the isotope [¹⁴C] was detected in the urine, and 23% was detected in the feces, indicating that the renal pathway is the main route of excretion. Renal excretion of the parent compound was minimal and amounted to less than 0.02%. Most of the drug excreted by the kidneys is in glucuronidated form. Unchanged tecovirimat was mainly excreted in the feces. The final T_1/2 of tecovirimat was 19.3 hours.

Indications

For adults from 18 years of age for the treatment of infections caused by

• Smallpox virus;
• Monkeypox virus;
• Cowpox virus.

ICD codes

Dosage Regimen

The drug NIOCH-14 is taken orally, within 30 minutes after a meal (fat-rich food, dairy products).

The use of the drug NIOCH-14 is possible only in the conditions of inpatient medical care.

The recommended dose of the drug is 600 mg 2 times/day (every 12 hours). The maximum daily dose is 1200 mg.

The duration of treatment is 14 days.

Dose adjustment in elderly patients, in patients with impaired liver or kidney function is not required.

Adverse Reactions

Contraindications

Hypersensitivity to the active substance; pregnancy and breastfeeding period (due to lack of data on efficacy and safety); children under 18 years of age (due to lack of data on efficacy and safety).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Dose adjustment in patients with impaired liver function is not required.

Use in Renal Impairment

Dose adjustment in patients with impaired renal function is not required.

Caution should be exercised when prescribing the drug in the elderly. The drug has not been studied in this group of patients.

In patients with impaired renal and/or liver function, NIOCH-14 should be used with caution, since clinical data are lacking.

Geriatric Use

Dose adjustment in elderly patients is not required.

Special Precautions

The use of the drug NIOCH-14 is possible only in the conditions of inpatient medical care.

Use with caution in elderly patients. The drug has not been studied in this group of patients.

In patients with impaired renal and/or liver function, NIOCH-14 should be used with caution, since clinical data are lacking.

The safety and efficacy of the drug NIOCH-14 has not been evaluated in immunocompromised people.

Effect on ability to drive vehicles and mechanisms

Studies on the effect of the drug NIOCH-14 on the ability to drive cars and other mechanisms have not been conducted.

Tecovirimat has a minor influence on the ability to drive and use machines. Patients should be informed about the possible occurrence of dizziness and the need to exercise caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions during the treatment period; they should be cautioned about driving or operating machinery.

Drug Interactions

No studies of the interaction of the drug NIOCH-14 with other drugs have been conducted.

Tecovirimat and its metabolites are inducers of the CYP3A, CYP2B6 and CYP3A4 isoenzymes, as well as a weak inhibitor of CYP2C8 and CYP2C19. Concomitant use of tecovirimat with other drugs may lead to a change in the effects of the prescribed drugs. Monitoring is recommended during concomitant use of tecovirimat with CYP2C8 and CYP2C19 substrates that have a narrow therapeutic index.

Caution should be exercised when co-administering with tecovirimat such drugs as voriconazole, rilpivirine, maraviroc, atorvastatin, tacrolimus, methadone, sildenafil, tadalafil, vardenafil, darunavir, rabeprazole, lansoprazole. These drug interactions have not been studied. Concomitant use of tecovirimat with midazolam, omeprazole, bupropion may affect the effectiveness of the latter. Combination of these drugs requires caution.

Concomitant use of repaglinide and tecovirimat may lead to hypoglycemia. Blood glucose monitoring is recommended.

Some animal studies have shown that concomitant use of tecovirimat and a live smallpox vaccine may lead to a decrease in the immune response to the vaccine. The clinical impact of this interaction on vaccine efficacy is unknown.

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.