Skyvira 300 mg+100 mg 10 pcs

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 disease (see “Special Instructions”) and who do not require additional oxygen therapy.

Composition

Pharmachologic effect

Pharmacotherapeutic group: systemic antiviral agents; direct acting antivirals; protease inhibitors.  ATX code: J05AE. Pharmacodynamics  Mechanism of Action Nirmatrelvir is a peptidomimetic inhibitor of SARS-CoV-2 major protease (Mpro), also called 3C-like protease (3CLpro) or nsp5 protease. Inhibition of Mpro by SARS-CoV-2 renders it unable to process polyprotein precursors, resulting in prevention of viral replication.  The action of ritonavir as a pharmacokinetic enhancer is based on the activity of ritonavir as a potent inhibitor of metabolism mediated by the cytochrome CYP3A isoenzyme.  In the combination medicinal product SKYVIRA, ritonavir, acting as a pharmacokinetic enhancer, inhibits the CYP3A-mediated metabolism of nirmatrelvir, thereby leading to an increase in plasma concentrations of nirmatrelvir. Antiviral activity Antiviral activity in vitro  Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 viral infection in dNHBE cell culture, a primary human lung alveolar epithelial cell line (with EC50 values ​​of 61.8 nM and EC90 of 181 nM) after 3 days of exposure to the drug.  Antiviral activity in vivo  Nirmatrelvir had antiviral activity in cell culture (with EC50 values ​​in the low nanomolar range ≤ 3-fold compared to isolate USA-WA1/2020) against SARS-CoV-2 Alpha (B.1.1.7) isolates ), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621) and Omicron (B.1.1.529) variants. The beta (B.1.351) variant was the least susceptible variant tested, with an approximately 3.3-fold reduction in susceptibility compared to isolate USA-WA1/2020. Resistance There is currently no information on antiviral resistance of nirmatrelvir in the treatment of SARS-CoV-2. Studies assessing the resistance of SARS-CoV-2 to nirmatrelvir in cell culture and clinical trials have not been completed. Data are only available from an in vitro resistance study using mouse hepatitis virus (MHV)-M pro. The study showed a 4.4- to 5-fold decrease in the sensitivity of nirmatrelvir to mutant viruses with 5 mutations (Pro55Leu, Ser144Ala, Thr129Met, Thr50Lys, Pro15Ala) in MHV-Mpro after 10 passages in cell culture. The significance of this for SARS-CoV-2 is unknown.

Ritonavir-resistant HIV-1 isolates have been isolated from patients receiving therapeutic doses of ritonavir. The decrease in antiretroviral activity of ritonavir is primarily associated with protease mutations V82A/F/T/S and I84V. The accumulation of other mutations in the protease gene (including positions 20, 33, 36, 46, 54, 71, and 90) may also contribute to ritonavir resistance. As mutations associated with ritonavir resistance accumulate, susceptibility to other protease inhibitors may decrease due to cross-resistance.

Use during pregnancy and breastfeeding

Contraindications

Interaction

SKYVIRA is an inhibitor of the CYP3A enzyme and may increase the concentrations of drugs whose main route of metabolism depends on the cytochrome CYP3A.

Drugs that are extensively metabolized by CYP3A and have high first-pass metabolism are most susceptible to significant increases in exposure when coadministered with nirmatrelvir/ritonavir.

Therefore, concomitant use of nirmatrelvir/ritonavir with drugs whose clearance is highly dependent on cytochrome CYP3A and whose elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (see Table 3).

Ritonavir has high affinity for several cytochrome P450 (CYP) isoforms and can inhibit oxidation in the following order: CYP3A4 → CYP2D6. 

Ritonavir also has high affinity for P-glycoprotein (P-gp) and can inhibit this transporter.

Ritonavir may induce cytochromes CYP1A2, CYP2C8, CYP2C9 CYP2C19, thereby increasing the biotransformation via glucuronidation and oxidation of some drugs that are metabolized in these ways, which may lead to a decrease in the systemic exposure of these drugs and reduce or reduce their therapeutic effect.

Concomitant administration of other CYP3A4 substrates that may result in potentially significant interactions with it (see Table 3) should only be considered if the benefits outweigh the risks. 

Nirmatrelvir and ritonavir are substrates of CYP3A, therefore drugs that induce CYP3A may reduce plasma concentrations of nirmatrelvir and ritonavir and the therapeutic effect of SKYVIRA.

How to take, course of administration and dosage

The drug SKYVIRA is taken orally regardless of meals.

The tablets should be swallowed whole, without chewing, breaking or crushing, and with a sufficient amount of liquid.

The use of SKYVIRA is possible only under the supervision of a physician.

Dosage regimen 
For the treatment of new coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus, the following dosage regimen is recommended in adults:
– 1 tablet orally (orally) twice a day (every 12 hours).

A single dose is 300 mg nirmatrelvir + 100 mg ritonavir. The daily dose is 600 mg nirmatrelvir + 200 mg ritonavir. The duration of the course of treatment is 5 days.  Treatment with SKYVIRA 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 the patient misses the scheduled time for taking the next dose of the drug, then the “missed dose” of the drug must be taken within 8 hours of the scheduled time of administration. If the patient has not taken the “missed dose” within 8 hours of the scheduled dosing time, then the missed dose does not need to be taken, but instead the next dose must be taken at the scheduled time. The patient should not double the dose to make up for a missed dose. Completion of the full 5-day course of treatment is recommended, even if after initiation of therapy the patient requires hospitalization due to progression of COVID-19 disease to severe treatment. If, after starting treatment, the patient requires hospitalization, he should consult with his attending physician about the need to complete the 5-day course of treatment. Special groups of patients Renal failure Patients with mild renal failure (eGFR 60 to 90 ml/min) do not require dose adjustment. Patients with moderate (see section “Special instructions” and “Contraindications”) (eGFR from 30 to 60 ml/min) and severe renal failure (eGFR < 30 ml/min, including patients with end-stage renal failure on hemodialysis ) taking the drug is contraindicated. Hepatic impairment No dosage adjustment of SKYVIRA is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. SKYVIRA is contraindicated in patients with severe hepatic impairment (see “Special Instructions” and “Pharmacokinetic Properties”). Concomitant therapy with regimens containing ritonavir or cobicistat
No dose adjustment of SKYVIRA is required. Patients diagnosed with human immunodeficiency virus (HIV) or hepatitis C virus who are receiving medications containing ritonavir or cobicistat should continue treatment as prescribed.

Children
There are no data on the safety and effectiveness of the drug SKYVIRA in children under 18 years of age.