Arpaxel^® (Tablets) Instructions for Use

Marketing Authorization Holder

Technology Lekarstv LLC (Russia)

Manufactured By

R-Pharm JSC (Russia)

ATC Code

J05AE (Protease inhibitors)

Active Substance

Nirmatrelvir (Rec.INN registered by WHO)

Dosage Form

Arpaxel®

Film-coated tablets, 150 mg: 20 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets oval, biconvex, light yellow with a brownish tint; on the cross-section, the tablet core is white to almost white.

Excipients: microcrystalline cellulose type 102, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, colloidal silicon dioxide.

Film coating composition Opadry II 85F220031 yellow (polyvinyl alcohol, titanium dioxide, macrogol 4000, talc, iron oxide yellow dye).

10 pcs. – blister pack (2) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

Proteolysis inhibitor with antiviral action

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; protease inhibitors

Pharmacological Action

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also called the 3C-like protease (3CLpro) or nsp5 protease.

Inhibition of SARS-CoV-2 Mpro renders it incapable of processing polyprotein precursors, leading to the prevention of viral replication.

Nirmatrelvir is co-administered with ritonavir, which acts as a pharmacokinetic enhancer.

Ritonavir inhibits CYP3A-mediated metabolism of nirmatrelvir, thereby leading to increased plasma concentrations of nirmatrelvir.

In vitro antiviral activity

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 values of 181 nM) after 3 days of exposure.

In vivo antiviral activity

Nirmatrelvir possessed antiviral activity in cell culture (with EC₅₀ values in the low nanomolar range ≤ 3-fold compared to the USAWA1/2020 isolate) against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), 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 tested variant with an approximately 3.3-fold decrease in susceptibility compared to the USAWA1/2020 isolate.

There is currently no information on nirmatrelvir antiviral resistance in the treatment of SARS-CoV-2.

Studies evaluating SARS-CoV-2 resistance to nirmatrelvir in cell culture and in clinical trials are not complete.

Data are only available from an in vitro resistance study using mouse hepatitis virus (MHV)-Mpro.

The study showed a 4.4-5 fold decrease in nirmatrelvir susceptibility 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.

Pharmacokinetics

Since Nirmatrelvir is not indicated for use without ritonavir, the pharmacokinetics of the Nirmatrelvir+ritonavir combination were studied in healthy volunteers.

Ritonavir was combined with nirmatrelvir as a pharmacokinetic enhancer, leading to increased systemic concentrations of nirmatrelvir.

Upon repeated administration of nirmatrelvir+ritonavir at doses of 75+100 mg, 250+100 mg, and 500+100 mg twice daily, at steady state, an increase in systemic exposure was observed, which, however, was not proportional to the increase in the drug dose.

Steady state was achieved on day 2 with approximately 2-fold accumulation upon multiple administration over 10 days.

Systemic exposure on day 5 was the same as on day 10 at all doses.

After a single oral dose of nirmatrelvir+ritonavir 300+100 mg, the geometric mean values for C_max and AUC from drug administration to infinity (AUC_inf) of nirmatrelvir at steady state were 2.21 µg/ml and 23.01 µg×h/ml, respectively.

The median T_max was 3.00 h.

The arithmetic mean terminal T_1/2 was 6.1 h.

After a single oral dose of the Nirmatrelvir+ritonavir combination 300+100 mg, the geometric mean values for C_max and AUC_inf of ritonavir were 0.36 µg/ml and 3.60 µg×h/ml, respectively.

The median T_max was 3.98 h.

The arithmetic mean terminal T_1/2 was 6.1 h.

When taking a nirmatrelvir suspension together with ritonavir tablets, along with a high-fat meal, nirmatrelvir exposure slightly increased (by approximately 15% for the mean C_max value and by 1.6% for the mean AUC_last value) compared to taking the drug on an empty stomach.

The binding of nirmatrelvir to proteins in human plasma is approximately 69%.

In vitro studies evaluating the metabolism of nirmatrelvir without ritonavir suggest that Nirmatrelvir is predominantly metabolized by CYP3A4.

In vitro studies have shown that Nirmatrelvir at clinically significant doses irreversibly inhibits CYP2D6, CYP2C9, CYP2C19, CYP2C8 or CYP1A2.

Nirmatrelvir is not an inducer or substrate for other CYP enzymes except CYP3A, for which Nirmatrelvir/ritonavir is an inhibitor.

The use of nirmatrelvir with ritonavir suppresses the metabolism of nirmatrelvir.

In plasma, only Nirmatrelvir is detected unchanged.

Small amounts of oxidized metabolites were found in feces and urine.

When nirmatrelvir and ritonavir are taken together, the main route of elimination of nirmatrelvir was renal excretion of unchanged nirmatrelvir.

Approximately 49.6% and 35.3% of the administered nirmatrelvir 300 mg dose is excreted in urine and feces, respectively.

Along with unmetabolized nirmatrelvir, small amounts of metabolites resulting from hydrolysis reactions were found in excreta.

At the same time, the only quantifiable drug substance in plasma was unchanged Nirmatrelvir.

Indications

Treatment of mild to moderate novel coronavirus infection (COVID-19) in adults, including those at increased risk of disease progression to severe course and not requiring supplemental oxygen therapy (in combination with a low dose of ritonavir).

ICD codes

Dosage Regimen

Take orally.

Nirmatrelvir should be used simultaneously with ritonavir 2 times/day every 12 hours.

Incorrect co-administration of nirmatrelvir with ritonavir may result in plasma concentrations of nirmatrelvir being insufficient to achieve the desired therapeutic effect.

The daily dose is 600 mg nirmatrelvir + 200 mg ritonavir.

The course of treatment is 5 days.

The 5-day course of treatment with this combination should be started as soon as possible after the diagnosis of COVID-19 is established and/or within 5 days after the onset of the first symptoms of the disease.

Adverse Reactions

Nervous system disorders common – dysgeusia, headache.

Digestive system disorders: common – diarrhea, vomiting.

The possibility of developing adverse reactions due to the action of ritonavir used as a booster in combination with nirmatrelvir should be taken into account.

Contraindications

Hypersensitivity to nirmatrelvir; severe hepatic impairment (Child-Pugh class C); severe renal impairment (eGFR <30 ml/min); pregnancy or planning pregnancy, breastfeeding period; children under 18 years of age; use of drugs whose clearance is largely dependent on CYP3A isoenzymes and for which increased concentrations are associated with serious and/or life-threatening reactions; drugs that are strong inducers of CYP3A, which significantly reduce plasma concentrations of nirmatrelvir, which may lead to loss of virologic response and possible development of resistance; administration of this combination should not be started immediately after discontinuation of therapy with any of the following CYP3A inducers due to the long T_1/2 of the recently discontinued drug.

The drugs listed below are strictly contraindicated for co-administration with this combination (the list provided is mandatory but not exhaustive): alpha₁-adrenergic blockers (alfuzosin), analgesics (pethidine, piroxicam, propoxyphene), antianginal agents (ranolazine), anticancer agents (venetoclax, neratinib), antiarrhythmic agents (amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine), antimicrobial agents (fusidic acid, rifampicin), anticonvulsants (carbamazepine, phenobarbital, phenytoin), antigout agents (colchicine), antihistamines (astemizole, terfenadine), antipsychotics/neuroleptics (lurasidone, pimozide, clozapine, quetiapine), ergot alkaloid derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility stimulants (cisapride), herbal medicines (St. John’s wort); hypolipidemic agents (HMG-CoA reductase inhibitors – lovastatin, simvastatin; microsomal triglyceride transfer protein inhibitors – lomitapide); PDE5 inhibitors (avanafil, sildenafil, vardenafil), sedatives/hypnotics (clorazepate, diazepam, estazolam, flurazepam, oral midazolam and triazolam).

With caution

Increased activity of hepatic transaminases; hepatitis; moderate hepatic impairment (Child-Pugh class B); moderate renal impairment (eGFR from 30 to 60 ml/min); patients with organic heart disease and pre-existing cardiac conduction system disorders or patients taking drugs that prolong the PR interval (such as verapamil or atazanavir, when using ritonavir as a pharmacokinetic enhancer during 5-day therapy with the Nirmatrelvir + ritonavir combination at a dose of 100 mg ritonavir twice daily).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Women of childbearing potential should avoid pregnancy during treatment and for 7 days after completion of nirmatrelvir use.

Breastfeeding should be discontinued during the use of the nirmatrelvir with ritonavir combination and for 7 days after the last dose.

Use in Hepatic Impairment

Contraindication: severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

Contraindication: severe renal impairment (eGFR <30 ml/min).

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

The use of nirmatrelvir in combination with ritonavir is possible only as prescribed and under the supervision of a physician.

If adverse effects occur, they must be reported in the prescribed manner for pharmacovigilance measures.

The use of nirmatrelvir in combination with ritonavir in patients with severe renal impairment may lead to excessive exposure with potential toxicity, therefore Nirmatrelvir should not be used in patients with severe renal impairment (eGFR <30 ml/min, including patients with end-stage renal disease on hemodialysis).

Patients receiving ritonavir have experienced elevated liver transaminases, clinical hepatitis, and jaundice.

Therefore, caution should be exercised when prescribing nirmatrelvir in combination with ritonavir to patients with pre-existing liver disease, liver enzyme abnormalities, or hepatitis.

This combination should not be used in patients with severe hepatic impairment.

Since Nirmatrelvir is prescribed simultaneously with ritonavir, there may be a risk of developing HIV-1 resistance to human immunodeficiency virus protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

Effect on ability to drive vehicles and operate machinery

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.

Drug Interactions

Nirmatrelvir is a substrate of CYP3A isoenzymes, therefore initiating drugs that inhibit or induce CYP3A may also increase or decrease nirmatrelvir concentrations.

Co-administration of ritonavir, which is a CYP3A inhibitor, with nirmatrelvir in patients receiving drugs metabolized by CYP3A, or initiating drugs metabolized by CYP3A in patients already receiving Nirmatrelvir, may increase the plasma concentrations of drugs metabolized by CYP3A.

Such an interaction may lead to clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal outcomes due to increased exposure to concomitant drugs; clinically significant adverse reactions caused by increased exposure to nirmatrelvir; loss of therapeutic effect of nirmatrelvir and possible development of viral resistance.

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.