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.

Indications

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.

Pharmacological effect

Pharmacotherapeutic group: antiviral agents of systemic action; 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 isolates 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 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.

Pharmacokinetics

The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy volunteers.

Ritonavir was administered with nirmatrelvir as a pharmacokinetic enhancer, resulting in increased systemic concentrations of nirmatrelvir. With repeated administration of nirmatrelvir/ritonavir at doses of 75 mg/100 mg, 250 mg/100 mg and 500 mg/100 mg administered twice daily, an increase in systemic exposure was observed upon reaching steady state, which, however, was not proportional to the increase in drug dose.

Steady state was reached on day 2 with approximately 2-fold accumulation with repeated administration over 10 days. Systemic exposure on day 5 was the same as on day 10 at all doses.

Suction
After a single oral dose of nirmatrelvir/ritonavir at a dose of 300 mg/100 mg, the geometric mean Cmax and AUCinf values ​​of nirmatrelvir at steady state were 2.21 μg/ml and 23.01 μg/ml, respectively. The median time to reach the maximum concentration Cmax (Tmax) was 3.00 hours. The arithmetic mean of the terminal half-life was 6.1 hours.

After a single oral dose of nirmatrelvir/ritonavir at a dose of 300 mg/100 mg, the geometric mean Cmax and AUCinf values ​​of ritonavir were 0.36 μg/ml and 3.60 μg*h/ml, respectively. The median time to reach the maximum concentration Cmax (Tmax) was 3.98 hours. The arithmetic mean of the terminal half-life was 6.1 hours.

With repeated doses of ritonavir, its accumulation is slightly less than that calculated on the basis of a single dose and depends on the duration of treatment and the dose-dependent increase in apparent clearance (Cl/F). It was found that the residual concentration of ritonavir decreased slightly over time, possibly due to enzyme induction, but stabilized at the end of two weeks. The time to reach the maximum concentration Cmax (Tmax) with increasing dose remained constant at approximately 4 hours. Renal clearance averages less than 0.1 L/h and is relatively constant across different dosages.

The maximum concentration (Cmax) of ritonavir after a single dose of 100 mg is 0.84 μg/ml, with a half-life (t½) of 5 hours. At the same time, the Cmax value of ritonavir when taken 100 mg 2 times a day is 0.89 μg/ml, with a half-life (t½) of 5 hours.

Effect of food on oral absorption

When nirmatrelvir suspension was administered with ritonavir tablets with a high-fat meal, nirmatrelvir exposure was slightly increased (approximately 15% of mean Cmax and 1.6% of mean AUClast) compared with administration on an empty stomach.

When ritonavir is administered with food, there is a slight decrease in its bioavailability.

Distribution

Protein binding of nirmatrelvir in human plasma is approximately 69%.

The apparent volume of distribution (Vs/F) of ritonavir is approximately 20-40 L after a single dose of 600 mg. The binding of ritonavir to plasma proteins in humans is about 98-99% and is constant in the concentration range of 1.0 – 100 mcg/ml. Ritonavir binds to both human alpha1-acid glycoprotein (AAG) and human serum albumin (HSA) with relatively equal affinity.

Tissue distribution studies of 14C-labeled ritonavir in rats have shown that the liver, adrenal glands, pancreas, kidneys and thyroid gland contain the highest concentrations of ritonavir. The tissue/plasma distribution ratio measured in the lymph nodes of rats is approximately 1 and suggests that ritonavir is distributed into the tissues of the lymphatic system. Ritonavir penetrates minimally into the brain.

Biotransformation

In vitro studies assessing the metabolism of nirmatrelvir without ritonavir suggest that nirmatrelvir is predominantly metabolized by CYP3A4. In in vitro studies, nirmatrelvir at clinically relevant doses has been shown to irreversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8, or CYP1A2. Nirmatrelvir is not an inducer or substrate for CYP enzymes other than CYP3A, for which nirmatrelvir/ritonavir is an inhibitor.

Administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In blood plasma, only nirmatrelvir is found unchanged. Small amounts of oxidized metabolites were detected in feces and urine.

Ritonavir is extensively metabolized by the liver cytochrome P450, mainly by the cytochrome CYP3A isoenzyme and, to a lesser extent, by CYP2D6. Animal studies as well as in vitro experiments using human liver microsomes have shown that ritonavir is primarily subject to oxidative metabolism and cytochrome P450 3A (CYP3A) is the main isoform involved in the metabolism of ritonavir, however it should be noted that CYP2D6 also contributes to the formation of the oxidized metabolite M-2. Four metabolites of ritonavir were found in humans.

The main oxidative metabolite is isopropylthiazole (M-2), the antiviral activity of which is the same as the parent compound. However, the AUC of metabolite M-2 is only 3% of the AUC of the parent compound itself. Low doses of ritonavir have a strong effect on the pharmacokinetics of other protease inhibitors (and other substances metabolized by CYP3A4), and other protease inhibitors may also affect the pharmacokinetics of ritonavir.

Removal

When nirmatrelvir and ritonavir were co-administered, the main route of elimination of nirmatrelvir was renal excretion of the intact (unmetabolized) drug. About 49.6% and 35.3% of the administered dose of nirmatrelvir 300 mg are excreted in urine and feces, respectively. In addition to unmetabolized nirmatrelvir, small amounts of metabolites resulting from hydrolysis reactions were detected in excrements. At the same time, the only quantifiable drug in the blood plasma was unchanged nirmatrelvir.

In clinical studies using isotope-labeled ritonavir, elimination of ritonavir was shown to occur primarily through the hepatobiliary system; approximately 86% of RFIDs were detected in stool, some of which were unabsorbed ritonavir. In these studies, renal elimination was not identified as the main route of elimination of ritonavir. This was consistent with observations in animal studies.

Special patient groups

The pharmacokinetic properties of nirmatrelvir/ritonavir have not been assessed in age and gender groups.

Patients with impaired renal function

Compared with healthy control volunteers, in patients with mild renal impairment, nirmatrelvir pharmacokinetics (Cmax and AUC) were 30% and 24% higher, respectively. In patients with moderate renal failure, Cmax was higher by 38%, AUC by 87%, and in patients with severe renal failure, it was higher by 48% and 204%, respectively.

The pharmacokinetic parameters of ritonavir have not been studied in patients with impaired renal function. However, since the renal clearance of ritonavir is very small, no changes in total body clearance are expected in patients with impaired renal function.

Patients with liver dysfunction

In patients with moderate hepatic impairment, there was no significant difference in the pharmacokinetic parameters of nirmatrelvir from similar parameters in the group of healthy volunteers.

The adjusted geometric mean ratio (90% CI) of nirmatrelvir AUCinf and Cmax when comparing patients with moderate hepatic impairment (test) with normal liver function (comparison) was 98.78% (CI 70.65%, 138.12%) and 101.96% (CI 74.20%, 140.11%), respectively.

The pharmacokinetic properties of nirmatrelvir/ritonavir have not been studied in patients with severe hepatic impairment.

After repeated dosing of ritonavir to healthy volunteers (500 mg twice daily) and patients with mild to moderate hepatic impairment (Child-Pugh A and B, 400 mg twice daily), ritonavir after dose normalization was not significantly different between the two groups.

Racial and ethnic groups

Systemic drug exposure among Japanese study participants was lower in magnitude, but was not clinically significantly different from exposure among Western European participants.

Pharmacokinetic interaction

CYP3A4 was a major contributor to the oxidative metabolism of nirmatrelvir when nirmatrelvir was tested alone in human liver microsomes. Ritonavir is a CYP3A inhibitor and increases plasma concentrations of nirmatrelvir and other drugs that are primarily metabolized by CYP3A. Despite concomitant use with ritonavir as a pharmacokinetic enhancer, the potential exists for strong inhibitors and inducers to alter the pharmacokinetics of nirmatrelvir.

Nirmatrelvir does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8 or CYP1A2 in vitro at clinically relevant concentrations.

Results from an in vitro study showed that nirmatrelvir may be an inducer of CYP3A4, CYP2B6, CYP2C8 and CYP2C9. Clinical significance unknown. Based on in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3, and OCT 2. Nirmatrelvir has the potential to inhibit MDR1, MATE 1, OCT 1, and OATP1B1 at clinically relevant concentrations.

Special instructions

Film-coated tablets.

Active ingredient

By prescription

Composition

For one tablet:

Active ingredients:

Nirmatrelvir – 300.0 mg
Ritonavir – 100.0 mg

Excipients:

Lactose monohydrate – 143.0 mg
Microcrystalline cellulose – 100.0 mg
Croscarmellose sodium – 54.0 mg
Povidone – 40.0 mg
Copovidone – 40.0 mg
Sodium lauryl sulfate – 19.0 mg
Sodium stearyl fumarate – 8.0 mg

Film casing:

Hypromellose – 15.625 mg (62.50%)
Titanium dioxide (E171) – 7.522 mg (30.09%)
Macrogol (Polyethylene glycol) – 1.563 mg (6.25%)
Iron oxide yellow dye (E172) – 0.290 mg (1.16%) or similar ready-made film coating – 25.0 mg.

Pregnancy

Women of childbearing age

There are no data from the use of nirmatrelvir/ritonavir in pregnant women to provide information on the risk of adverse pregnancy outcomes associated with SKYVIRA. Women of childbearing potential should avoid pregnancy during treatment and for 7 days after completion of treatment with SKYVIRA.

When prescribing the drug SKYVIRA to women capable of childbearing (including those less than 2 years postmenopausal), it is necessary to confirm a negative pregnancy test result before starting treatment. A repeat pregnancy test should be performed after stopping the medication.

The use of ritonavir may reduce the effectiveness of combined hormonal contraceptives. Patients using combined hormonal contraceptives should be advised to use an effective alternative method of contraception or an additional barrier method of contraception during treatment and until the end of one full menstrual cycle after stopping SKYVIRA.

Pregnancy

There are no data on the use of the combination of nirmatrelvir and ritonavir in pregnant women.

Preclinical studies of nirmatrelvir in combination with ritonavir have not been conducted.

Nirmatrelvir
In preclinical studies of nirmatrelvir, there was no effect of different doses of the drug on fetal morphology or embryo-fetal viability in rats and rabbits, although lower fetal body weight was observed in rabbits and there was no toxicity in females. Systemic exposure (AUC24) in rabbits at the maximum dose of the drug was approximately 3 times higher than the exposure in humans at the recommended therapeutic dose of nirmatrelvir and ritonavir, without adverse effects on fetal body weight.

Ritonavir
A large body of data on the use of ritonavir in pregnant women suggests no increase in the incidence of congenital malformations compared with rates observed in the general population.

Data from animal studies treated with ritonavir showed reproductive toxicity. Developmental toxicity (embryonic lethality, decreased fetal weight, delayed ossification, and visceral changes including delayed testicular descent) has been observed in rats, primarily at dosages toxic to the female. Developmental toxicity (embryo lethality, reduced litter size, and reduced fetal weight) has been observed in rabbits at dosages toxic to the female.

Breastfeeding period

There is no reliable data on the use of the combination of nirmatrelvir and ritonavir during breastfeeding.

It is not known whether nirmatrelvir is excreted into breast milk in women or female animals. There are also no data on the effect of nirmatrelvir on newborns/infants and the effect on milk production.

Published data indicate that ritonavir is present in breast milk. There is no information on the effect of ritonavir on newborns/infants or on the effect of the drug on milk production. A risk to neonates/infants cannot be excluded.

Breastfeeding should be discontinued during treatment with SKYVIRA and for 7 days after taking the last dose of the drug.

Fertility

There is no data on the effect of the combination of nirmatrelvir and ritonavir, or of either drug alone, on fertility in humans.

Neither nirmatrelvir nor ritonavir had any effect on fertility in rats (see section “Pregnancy”).

Contraindications

Hypersensitivity to nirmatrelvir, ritonavir or any other component of SKYVIRA
Lactose intolerance, lactase deficiency, glucose-galactose malabsorption
Severe liver failure (class C according to the Child-Pugh classification)
Severe renal failure (eGFR < 30 ml/min) Moderate renal failure (eGFR from 30 to 60 ml/min), due to the impossibility of nirmatrelvir dose adjustment Pregnancy or planning pregnancy Breastfeeding period Children under 18 years of age Medicines whose clearance is highly dependent on CYP3A and for which elevated concentrations are associated with serious and/or life-threatening reactions Medicines that are strong CYP3A inducers that significantly reduce nirmatrelvir/ritonavir plasma concentrations, which may lead to loss of virological response and possible development of resistance SKYVIRA should not be started immediately after discontinuation of therapy with any of the following CYP3A inducers due to the long half-life of the recently discontinued drug (see Interactions with Other Drugs). The medications listed below are strictly contraindicated for use together with SKYVIRA. This list is mandatory but not exhaustive: • alpha1-blockers - alfuzosin;
• analgesics – pethidine, piroxicam, propoxyphene;
• antianginal agents – ranolazine;
• antitumor agents – neratinib, venetoclax;
• antiarrhythmic drugs – amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine;
• antibiotics – fusidic acid, rifampicin;
• anticonvulsants – carbamazepine, phenobarbital, phenytoin;
• anti-gout drugs – colchicine;
• antihistamines – astemizole, terfenadine;
• antipsychotics/neuroleptics – lurasidone, pimozide, clozapine, quetiapine;
• derivatives of ergot alkaloids – dihydroergotamine, ergonovine, ergotamine, methylergonovine;
• stimulants of gastrointestinal motility – cisapride;
• herbal remedies – St. John’s wort (Hypéricum perforatum);
• lipid modifying agents:
– HMG-CoA reductase inhibitors – lovastatin, simvastatin;
– Inhibitors of microsomal triglyceride transport protein – lomitapide;
• PDE5 inhibitors: avanafil, sildenafil, vardenafil;
• Sedative/hypnotics – clorazepate, diazepam, estazolam, flurazepam, oral midazolam and triazolam.

With caution
Increased liver transaminases
Hepatitis
Moderate liver failure (class B on the Child-Pugh scale)
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 days of therapy with SKYVIRA and at a dosage of 100 mg 2 times a day)
Combined use with drugs is not recommended with drugs listed in the sections “Special instructions”, “Interaction with other drugs”, “Contraindications”.

Side Effects

Security Profile Summary

The most common adverse reactions reported during treatment with nirmatrelvir/ritonavir 300 mg/100 mg every 12 hours for 5 days and up to 34 days after the last dose were dysgeusia (5.6%), diarrhea (3.1%), headache (1.4%), and vomiting (1.1%).

Summary table of adverse reactions

Adverse reactions are listed below by class of organs and systems and frequency of development. Frequencies were defined as follows: very common (≥1/10); often (≥ 1/100, but < 1/10); uncommon (≥ 1/1,000, but < 1/100); rare (≥1/10,000, but <1/1,000); very rare (<1/10,000), including isolated reports; frequency unknown (cannot be estimated from available data).Table 1. Adverse reactions to nirmatrelvir/ritonavir

Very often

Often

Uncommon

Rarely

Very rarely

Frequency unknown

Nervous system disorders

Impaired taste perception (dysgeusia)

Headache

Gastrointestinal disorders

Diarrhea

Vomit

Adverse reactions when using ritonavir

Use of ritonavir as a pharmacokinetic enhancer
Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer depend on the co-administered specific HIV protease inhibitor, which must be taken into account in patients with HIV when treated with SKYVIRA. For information about adverse reactions, please refer to the prescribing information for the specific co-administered HIV protease inhibitor.

Adverse reactions obtained in clinical trials and in the post-registration period in adult patients.

The most frequently reported adverse reactions among patients receiving ritonavir monotherapy or ritonavir in combination with other antiretroviral drugs were gastrointestinal disorders (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), nervous system disorders (including paresthesia and paresthesia of the oral mucosa), and fatigue/asthenic syndrome.

The following moderate to severe adverse reactions have been reported, possibly or probably related to ritonavir. The listed reactions, their type, severity and frequency, corresponding to a higher dose of ritonavir and longer use in patients with this disease, may not occur when using ritonavir during 5 days of therapy with SKYVIRA and at a dosage of 100 mg 2 times a day.

Table 2. Adverse reactions when using ritonavir.

Class of organ systems

Frequency

Adverse reactions

Blood and lymphatic system disorders

Often

Decreased white blood cell count, decreased hemoglobin concentration, decreased neutrophil count, increased eosinophil count, thrombocytopenia

Uncommon

Increased neutrophil count

Immune system disorders

Often

Hypersensitivity reactions including urticaria and angioedema

Rarely

Anaphylactic reactions

Endocrine disorders

Often

Hypercholesterolemia, hypertriglyceridemia, gout, edema, including peripheral edema, dehydration (usually associated with symptoms from the digestive system)

Uncommon

Diabetes mellitus

Rarely

Hyperglycemia

Nervous system disorders

Very often

Dysgeusia, paresthesia of the oral mucosa and peripheral paresthesia, headache, dizziness, peripheral neuropathy

Often

Insomnia, agitation, confusion, impaired attention, syncope, epileptic seizures

Visual disorders

Often

Blurred vision

Heart disorders

Uncommon

Myocardial infarction

Vascular disorders

Often

Arterial hypertension, arterial hypotension, including orthostatic arterial hypotension, peripheral hypothermia

Respiratory, thoracic and mediastinal disorders

Very often

Pharyngitis, pain in the oropharynx, cough.

Gastrointestinal disorders

Very often

Abdominal pain (upper and lower), nausea, diarrhea (including severe form with electrolyte disturbances), vomiting, digestive disorders

Often

Anorexia, flatulence, oral ulcers, bleeding from the gastrointestinal tract, gastroesophageal reflux disease, pancreatitis

Disorders of the liver and biliary tract

Hepatitis (including increased activity of AST, ALT, GGT), increased concentration of bilirubin in the blood (including jaundice)

Skin and subcutaneous tissue disorders

Very often

Pruritus, rash (including erythematous and maculopapular rash)

Often

Acne

Rarely

Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)

Muscle, skeletal and connective tissue disorders

Very often

Arthralgia, back pain

Often

Myositis, rhabdomyolysis, myalgia, myopathy/increased CPK levels

Renal and urinary tract disorders

Often

Frequent urination, renal dysfunction (eg, oliguria, increased creatinine concentration)

Uncommon

Acute renal failure

Unknown

Nephrolithiasis

Disorders of the reproductive system and mammary glands

Often

Menorrhagia

General disorders and reactions at the injection site

Very often

Weakness, including asthenic syndrome, hot flashes, feeling hot

Often

Fever, weight loss

Laboratory and instrumental data

Often

Increased amylase activity, decreased concentrations of free and total thyroxine

Uncommon

Increased glucose concentration, increased magnesium concentration, increased alkaline phosphatase activity

Reactions noted as having an unknown frequency of occurrence were noted during the post-marketing period.

Selected adverse reactions

Increases in hepatic transaminase activity, five times or more above the upper limit of normal values, clinical signs of hepatitis and jaundice developed in patients receiving ritonavir as monotherapy or ritonavir in combination with other antiretroviral drugs.

Metabolism indicators

Cases of pancreatitis (some fatal) have been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. Patients with advanced HIV infection may be at risk for elevated blood triglyceride levels and the development of pancreatitis, which must be taken into account when prescribing SKYVIRA.

Cases of osteonecrosis have also been reported, particularly in patients with well-known risk factors, advanced HIV infection, or those receiving long-term combination antiretroviral therapy. Their frequency of occurrence is unknown.

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 the 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.

Table 3. Interaction of SKYVIRA with other drugs.

Drug class

Drug class representative

(Change in AUC and Cmax)

Clinical comments

Alpha1-blockers

↑Alfuzosin

Increased plasma concentrations of alfuzosin may lead to severe hypotension and are therefore contraindicated.

Amphetamine derivatives

↑Amphetamine

Ritonavir, taken as an antiretroviral agent, appears to inhibit CYP2D6, resulting in increased concentrations of amphetamine and its derivatives. When these drugs are taken together with SKYVIRA, careful monitoring for side effects is recommended.

Analgesics

↑Buprenorphine (57%, 77%),

↑Norbuprenorphine (33%, 108%)

Increases in plasma levels of buprenorphine and its active metabolite did not result in clinically significant pharmacodynamic changes in the opioid-tolerant population. Therefore, dosage adjustments of buprenorphine may not be necessary when the two are taken together.

↑Pethidine,

↑Piroxicam,

↑Propoxyphene

Increased plasma concentrations of norpethidine, piroxicam and propoxyphene can lead to serious respiratory depression or hematological disorders and are therefore contraindicated (see section “Contraindications”).

↑Fentanyl

Ritonavir, taken as a pharmacokinetic enhancer, inhibits CYP3A4, resulting in increased plasma concentrations of fentanyl. Close monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when fentanyl is coadministered with ritonavir.

↓Methadone (36%, 38%)

When coadministered with ritonavir, taken as a pharmacokinetic enhancer of nirmatrelvir, an increased dose of methadone may be required due to induction of glucuronidation. Dose adjustments should be considered based on the patient’s clinical response to methadone therapy.

↓Morphine

Morphine levels may be decreased due to induction of glucuronidation when coadministered with ritonavir, taken as a pharmacokinetic enhancer of nirmatrelvir.

Antianginal agents

↑Ranolazine

Due to the inhibition of CYP3A by ritonavir, ranolazine concentrations are expected to increase. Concomitant use with ranolazine is contraindicated (see section “Contraindications”).

Antiarrhythmic drugs

↑Amiodarone,

↑Bepridil

↑Dronedarone,

↑Enkainid

↑Flecainide,

↑Propafenone,

↑Quinidine

Coadministration with ritonavir may result in increased plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone and quinidine and is therefore contraindicated (see Contraindications section).

↑Digoxin

This interaction may be due to modification of P-gp-mediated clearance of digoxin by ritonavir taken as a pharmacokinetic enhancer

Antiasthmatic drugs

↓Theophylline (43%, 32%)

When coadministered with ritonavir, an increased dose of theophylline may be required due to induction of CYP1A2.

Antitumor agents

↑Afatinib

Serum drug concentrations may be increased due to the presence of breast cancer resistance protein (BCRP) and acute P-gp inhibition by ritonavir. The degree of increase in AUC and Cmax of drugs depends on the time of administration of ritonavir.

Caution is advised when administering afatinib with SKYVIRA (see Afatinib UTI). Monitor for afatinib-related adverse reactions.

↑Abemaciclib

Serum concentrations may be increased due to inhibition of CYP3A4 by ritonavir.

Co-administration of abemaciclib and SKYVIRA should be avoided. If coadministration is considered unavoidable, contact UTI abemaciclib for recommendations for dosage adjustments. Monitor for abemaciclib-related adverse reactions.

↑Apalutamide

Apalutamide is a moderate to strong inducer of CYP3A4, which may result in decreased exposure to SKYVIRA and potential loss of antiviral effect.

In addition, serum concentrations of apalutamide may be increased when coadministered with ritonavir, which may result in serious adverse events, including seizures. Concomitant use of SKYVIRA with apalutamide is not recommended.

↑Ceritinib

Serum concentrations of ceritinib may be increased due to inhibition of CYP3A and P-gp by ritonavir. Caution should be exercised when prescribing ceritinib with SKYVIRA. For recommendations on ceritinib dosage adjustments, see Ceritinib UTI. Monitor for ceritinib-related adverse reactions.

↑Dasatinib,

↑Nilotinib,

↑ Vincristine,

↑Vinblastine

When co-administered with ritonavir, the concentration of the drug in the blood serum may increase, which may lead to an increase in the frequency of adverse events.

↑Encorafenib

Serum concentrations of encorafenib may be increased when coadministered with ritonavir, which may increase the risk of toxicity, including the risk of serious adverse events such as QT prolongation. Co-administration of encorafenib and ritonavir should be avoided. If the benefit is considered to outweigh the risk and ritonavir must be used, patients should be closely monitored by medical personnel to monitor for possible side effects.

↑Fostamatinib

Coadministration of fostamatinib with ritonavir may increase exposure to the fostamatinib metabolite R406, resulting in dose-related adverse events such as hepatotoxicity, neutropenia, hypertension, or diarrhea. For recommendations on dose reduction if these events occur, see fostamatinib IMP.

↑Ibrutinib

Serum concentrations of ibrutinib may be increased due to CYP3A inhibition by ritonavir, resulting in an increased risk of toxicity, including the risk of tumor lysis syndrome. Co-administration of ibrutinib and ritonavir should be avoided. If the benefits are deemed to outweigh the risks and use of ritonavir is necessary, reduce the dose of ibrutinib to 140 mg and monitor the patient closely for potential adverse effects.

↑Neratinib

Serum concentrations may be increased due to ritonavir inhibition of CYP3A4.

Concomitant use of neratinib with SKYVIRA is contraindicated due to the potential for serious and/or life-threatening reactions, including hepatotoxicity (see section “Contraindications”).

↑Venetoclax

Serum concentrations may be increased due to inhibition of CYP3A by ritonavir, which leads to an increased risk of tumor lysis syndrome during initiation and during the dose-escalation phase and therefore co-administration of venetoclax and SKYVIRA is contraindicated (see section “Contraindications” and UTI for venetoclax). For patients who have completed the ramp-up phase and are taking a constant daily dose of venetoclax, reduce the venetoclax dose by at least 75% when used with strong CYP3A inhibitors (see venetoclax UTI for dosing instructions).

Anticoagulants

↑Rivaroxaban (153%, 53%)

Inhibition of CYP3A and P-gp results in increased plasma levels and pharmacodynamic effects of rivaroxaban, which may lead to an increased risk of bleeding. Therefore, the use of ritonavir is not recommended in patients taking rivaroxaban.

↑Vorapaxar

Serum concentrations may be increased due to inhibition of CYP3A by ritonavir. Co-administration of vorapaxar with SKYVIRA is not recommended (see Vorapaxar UTI).

Warfarin

↑ ↓S-warfarin (9%, 9%),

↓ ↔R-warfarin (33%)

Induction of CYP1A2 and CYP2C9 leads to a decrease in R-warfarin levels, while the pharmacokinetic effect on S-warfarin when co-administered with ritonavir is negligible.

A decrease in the level of R-warfarin may lead to a decrease in anticoagulation, therefore it is recommended to monitor anticoagulation parameters when co-administering warfarin with ritonavir.

Anticonvulsants

Carbamazepine,

Phenobarbital,

Phenytoin

Carbamazepine, phenobarbital and phenytoin are strong inducers of CYP3A4, which may result in decreased exposure to nirmatrelvir and ritonavir and potential loss of virological response. The combined use of carbamazepine, phenobarbital and phenotoin with SKYVIRA is contraindicated (see section “Contraindications”).

↓Divalproex,

Lamotrigine,

Phenytoin

Ritonavir, taken as a pharmacokinetic enhancer of nirmatrelvir, causes CYP2C9 oxidation and glucuronidation, which is expected to result in decreased plasma concentrations of anticonvulsants. When these drugs are coadministered with ritonavir, careful monitoring of serum levels or therapeutic effect is recommended. Phenytoin may decrease serum concentrations of ritonavir.

Antidepressants

↑Amitriptyline,

Fluoxetine,

Imipramine,

Nortriptyline,

Paroxetine,

Sertraline

Ritonavir, taken as an antiretroviral agent, is more likely to inhibit CYP2D6, resulting in increased concentrations of imipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine or sertraline. When these drugs are taken concomitantly with antiretroviral doses of ritonavir, careful monitoring of therapeutic and adverse effects is recommended (see section “Special Instructions”).

↑Desipramine (145%, 22%)

The AUC and Cmax of the 2-hydroxy metabolite decreased by 15% and 67%, respectively. When co-administered with ritonavir, it is recommended to reduce the dose of desipramine.

Antigout drugs

↑Colchicine

Colchicine concentrations are expected to increase when coadministered with ritonavir. Life-threatening and fatal drug interactions have been reported in patients receiving colchicine and ritonavir (inhibition of CYP3A4 and P-gp). The simultaneous use of colchicine with SKYVIRA is contraindicated (see section “Contraindications”).

Antihistamines

↑Astemizole

↑Terfenadine

Increased plasma concentrations of astemizole and terfenadine. The combined use of these drugs with SKYVIRA is contraindicated due to the increased risk of developing serious arrhythmias (see section “Contraindications”).

↑Fexofenadine

Ritonavir may indirectly alter P-gp transport of fexofenadine when taken as a pharmacokinetic enhancer, leading to increased concentrations of fexofenadine.

↑Loratadine

Ritonavir, taken as a pharmacokinetic enhancer, inhibits CYP3A, resulting in increased plasma concentrations of loratadine. When loratadine is coadministered with ritonavir, careful monitoring of therapeutic and adverse effects is recommended.

Anti-infectives

↑Fusidic acid

Coadministration of ritonavir is likely to increase plasma concentrations of both fusidic acid and ritonavir and is therefore contraindicated (see Contraindications section).

↑Rifabutin (4x, 2.5x)

↑25-O-metabolite of desacetylrifabutin (38-fold, 16-fold)

Due to the significant increase in AUC of rifabutin when coadministered with ritonavir taken as a pharmacokinetic enhancer, a dose reduction of rifabutin to 150 mg 3 times a week may be indicated.

Rifampicin

Rifampicin is a strong CYP3A4 inducer, which may result in decreased nirmatrelvir/ritonavir plasma concentrations and potential loss of virological response. The combined use of rifampicin with SKYVIRA is contraindicated (see section “Contraindications”).

↑Ketoconazole (3.4 times, 55%)

Ritonavir inhibits the CYP3A-mediated metabolism of ketoconazole. Due to the increased incidence of adverse reactions from the gastrointestinal tract and liver when used together with ritonavir, the possibility of reducing the dose of ketoconazole should be considered.

↑Itraconazole,

↑Erythromycin

Ritonavir, taken as a pharmacokinetic enhancer, inhibits CYP3A4, resulting in increased plasma concentrations of itraconazole and erythromycin. When erythromycin or itraconazole is coadministered with ritonavir, careful monitoring for side effects is recommended.

↓Voriconazole (39%, 24%)

Concomitant use of voriconazole and ritonavir (as a pharmacokinetic enhancer) should be avoided unless the benefit/risk assessment for the patient justifies the use of voriconazole.

↓Atovaquone

Ritonavir, taken as a pharmacokinetic enhancer, causes glucuronidation and, as a result, reduces the plasma concentration of atovaquone. When atovaquone is co-administered with ritonavir, careful monitoring of serum levels or therapeutic effect is recommended.

↑Bedaquiline

There are no interaction studies with ritonavir alone. Due to the risk of adverse effects associated with bedaquiline, co-administration should be avoided. If the benefit outweighs the risk, co-administration of bedaquiline with ritonavir should be done with caution. More frequent electrocardiogram monitoring and transaminase levels are recommended (see bedaquiline UTI).

Delamanid

There are no interaction studies with ritonavir alone. In a drug interaction study of delamanid 100 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily for 14 days in healthy volunteers, plasma concentrations of the delamanid metabolite DM-6705 increased by 30%.

Due to the risk of QTc prolongation associated with increased levels of DM-6705, if co-administration of delamanid with ritonavir is considered necessary, very frequent ECG monitoring is recommended throughout the treatment period with delamanid (see Precautions section).

↑Clarithromycin (77%, 31%),

↓Clarithromycin metabolite 14-OH (100%, 99%)

Due to the large therapeutic window of clarithromycin, no dose reduction is required in patients with normal renal function. Doses of clarithromycin greater than 1 g per day should not be co-administered with ritonavir as a pharmacokinetic enhancer. For patients with impaired renal function, a reduction in the dose of clarithromycin should be considered: for patients with a creatinine clearance of 30 to 60 ml/min, the dose should be reduced by 50%, for patients with a creatinine clearance of less than 30 ml/min, the dose should be reduced by 75%.

Sulfamethoxazole/ Trimethoprim

No dose adjustment of sulfamethoxazole/trimethoprim is required during concomitant therapy with ritonavir.

Antiviral [HIV] agents

↑Efavirenz (21%)

A higher incidence of adverse reactions (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes) was observed when efavirenz was co-administered with ritonavir.

↑Maraviroc (161%, 28%)

Ritonavir increases serum levels of maraviroc due to inhibition of CYP3A. Maraviroc may be taken with ritonavir to increase maraviroc exposure. For more detailed information, physicians should refer to the UTI drug maraviroc.

↓Raltegravir (16%, 1%)

Co-administration of ritonavir and raltegravir leads to a slight decrease in raltegravir levels.

↓Zidovudine (25%, ND)

Ritonavir may cause glucuronidation of zidovudine, resulting in a slight decrease in zidovudine levels. No dose change is required.

Antiviral agents for the treatment of hepatitis C virus infections

↑ Golepsum/ Pibrentasvir

Serum concentrations can increase due to inhibiting P-GP, BCRP and OATP1B ritonavir. The simultaneous intake of glucarias/ Pibrentasvira with the drug Skyvir due to increased risk of increasing the ALT associated with an increase in the effects of globaprevir is not recommended.

Antipsychotic agents

↑ closapine,

↑ Pimoside

The joint purpose of the ritonavir can lead to an increase in the concentration of closapine or pimoside in blood plasma and therefore contraindicated (see the section “contraindications”).

↑ haloperidol,

↑ risperidone,

↑ thioridase

Ritonavir probably inhibits CYP2D6, as a result of which an increase in the concentrations of haloperidol, risperidon and thioridazine is expected. With the simultaneous use of these drugs with antiretroviral doses of ritonavir, thorough monitoring of therapeutic and side effects is recommended.

↑ Lurazidon

Due to the inhibiting of CYP3A, ritonavir is expected to increase the concentration of Lurasidon. Simultaneous intake with Lurazidon is contraindicated (see the section “Contraindications”).

↑ quetiapin

Due to the inhibiting of CYP3A, ritonavir is expected to increase the concentration of quetiapine. The concomitant intake of the drug of the Cavirus and Quetiapin is contraindicated, as this can enhance the toxicity of quetiapine (see the section “Contraindications”).

β2-adrenamy (long-term)

↑ Salmeterol

Ritonavir inhibits the CYP3A4, resulting in a pronounced increase in the concentration of salmeterol in blood plasma. Therefore, simultaneous use is not recommended.

Calcium channel blockers

↑ amlodipine,

↑ diltiazem,

↑ Nifedipin

Ritonavir, taken as a pharmacokinetic amplifier or antiretroviral agent, inhibits CYP3A4, resulting in an increase in plasma concentrations of calcium channels. With the simultaneous use of these drugs with ritonavir, thorough monitoring of therapeutic and side effects is recommended.

Endothelina antagonists

↑ Bosentan

The joint purpose of Bosentan and Ritonavir can increase CMAX and AUC Bosentan.

Vasodilating agents

↑ riocygiat

Serum concentrations may increase due to the inhibiting of the CYP3A and P-GP ritonavir. The joint prescription of Riocihuat with the drug Skyvir is not recommended.

Derivatives

↑ dihydroergotamine,

↑ ergonovin,

↑ ergotamine,

↑ methylergonovin

The joint purpose of the ritonavir can lead to an increase in the concentration of derivatives of the blood spray in blood plasma and therefore contraindicated (see the section “Contraindications”).

Hypolipidemic agents (inhibitors of the GMG-Koa reductase)

↑ atorvastatin, fluvastatin,

Lovastatin,

Rightastatin, Rosuvastatin, Simvastatin

Inhibitors of the GMG-CoA reductase, which are strongly dependent on the metabolism of CYP3A, such as lovastatin and simvastatin, must have markedly increased concentrations in plasma when taking a ritonavir accepted as antiretroviral agents or as a pharmacokinetic amplifier. Since increased concentrations of lovastatin and simvastatin can lead to the development of myopathy, including rabdomyolysis, the combination of these drugs with ritonavir is contraindicated (see the section “Contraindications”). The metabolism of atorvastatin is less dependent on CYP3A. Although the excretion of rosuvastatin does not depend on the CYP3A, it was reported to increase the concentration of rosuvastatin in blood plasma when taking ritonavir joint. The mechanism of this interaction is not clear, but it may be the result of inhibiting transporters. When using a ritonavir as a pharmacokinetic amplifier, nirmatrelevir or antiretroviral agent, the minimum possible doses of atorvastatin or rosuvastatin should be prescribed. The metabolism of right -toastatine and fluvastatin does not depend on CYP3A, and interaction with the ritonavir is not expected. If the treatment with the inhibitor of the GMG-CoA reductase is shown, it is recommended that it is recommended for the right-to -tatin or fluvastatin.

Hormonal contraceptives

↓ Ethinyl Estradiol (40%, 32%)

In connection with a decrease in the concentration of ethinyl estradiol while using ritonavir as an antiretroviral agent or pharmacokinetic amplifier, the possibility of using barrier or other non -hormonal methods of contraception should be considered. Ritonavir can change the profile of uterine bleeding and reduce the effectiveness of estradiol-containing contraceptives.

Immunosuppressants

↑ cyclosporin

↑ takrolimus

↑ Everolimus

Ritonavir, taken as a pharmacokinetic amplifier of the nirmatrelevir or antiretroviral agent, inhibits CYP3A4, resulting in an increase in plasma concentrations of cyclosporine, takrolimus or everolymus. With the simultaneous use of these drugs with ritonavir, thorough monitoring of therapeutic and side effects is recommended.

Hypolipidemic

funds

↑ Lomitapid

CYP3A4 inhibitors increase the exposition of lomitapide, and strong inhibitors increase the exposure by about 27 times. Due to the inhibiting of CYP3A, ritonavir is expected to increase the concentration of lomitapide. The simultaneous use of lomitapide with the drug Skyvir is contraindicated (see the Imp Lomitapid, see the section “Contraindications”).

Phosphodesterase inhibitors (FDE5)

↑ Avanafil (13-time, 2.4-time)

The simultaneous use of avanaphil is the simultaneous use of avanafil with the drug Skyvir is contraindicated (see the section “Contraindications”).

↑ sildenafil (11-fold, 4-time)

The simultaneous use of sildenafil for the treatment of erectile dysfunction with a ritonavir taken as an antiretroviral agent or a pharmacokinetic amplifier of the nirmatrelevir should be careful, and in no case dose of siring should exceed 25 mg in 48 hours. The simultaneous use of sildenaphil with the drug Skyvir is contraindicated in patients with pulmonary arterial hypertension (see section “Contraindications”).

↑ Tadalafil (124%, ↔)

The simultaneous use of tadalafil for the treatment of erectile dysfunction with a ritonavir taken as an anti -rerovirus agent or a pharmacokinetic amplifier of the nirmaterevir should be carried out with caution in reduced doses of not more than 10 mg of tadalafil every 72 hours with increased control over the development of side -reactions.

↑ vardenafil (49-fold, 13-time)

The simultaneous use of vardenafil with the drug Skyvir is contraindicated (see the section “Contraindications”).

Sedative/ sleeping pills

↑ Closepat,

↑ diazepam,

↑ reedsols,

↑ fluorescapes

A joint reception with a ritonavir can lead to an increase in the concentration of blood plasma, diazepam, overzolam and flurasepam and therefore contraindicated (see the section “contraindications”).

↑ oral and parenteral midazolem

Midazoleums are intensively metabolized by CYP3A4. A joint purpose with the drug Skyvir can cause a significant increase in the concentration of midazolam.

It is expected that the plasma concentrations of midazolam will be much higher with the oral administration of midazolam. Therefore, the Skyvira drug should not be prescribed together with the orally taken midazolam (see the “Contraindications” section), while with the joint use of Skyvir and Parenteral Midazolam, caution should be observed. Data on the simultaneous use of parenteral midazolam with other proteases indicate a possible increase in the level of midazolam in plasma by 3-4 times.

If the Skyvira drug is prescribed together with parenteral midazolam, this should be done in the intensive care unit or similar conditions that provide careful clinical monitoring and corresponding medical
How to take, course of administration and dosage
Skyvira is taken inside, regardless of food intake.

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

The use of Skyvira is possible only under the supervision of a doctor.

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

A single dose is 300 mg of nirmaterevira + 100 mg of ritonavir. The daily dose is 600 mg of nirmaterevira + 200 mg of ritonavir. The duration of the course of treatment is 5 days.

Treatment with the drug Skywire should be started as early as possible after a diagnosis of a new coronavirus infection (Covid-19) and/or within 5 days after the first symptoms of the disease.

If the patient misses the prescribed time of taking the next dose of the drug, then the “missed dose” of the drug must be taken within 8 hours from the appointed time of administration. If the patient has not accepted the “missed dose” within 8 hours from the appointed time of administration, then it is not necessary to take a missed dose, instead it is necessary to take the next dose at the planned time. The patient should not double the dose to compensate for the missed dose.


It is recommended that the complete 5-day course of treatment is completed, even if after the start of therapy the patient needs hospitalization in connection with the progression of COVID-19 to severe treatment.


If after the start of treatment the patient needs hospitalization, then he needs to 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 (RSKF from 60 to 90 ml/min) Dose correction is not required.


Patients with the average (see the section “Special Instructions” and “Contraindications”) (RSKF from 30 to 60 ml/min) and severe renal failure (RSKF <30 ml/min, including patients with the terminal stage of renal hemodialysis) The drug is contraindicated.
Liver failure
It is not required to adjust the dose of Skyvira for patients with mild (classification of Child-pug) or medium (class B according to the classification of Child-pug) degree of liver failure.

Skyvir is contraindicated in patients with severe liver failure (see “Special Instructions” and “Pharmacokinetic properties”).


Concomitant therapy with schemes containing ritonavir or kobicistata
Dose of the drug Skyvir is not required. Patients with a diagnosis of human immunodeficiency virus (HIV) or hepatitis C virus, which receive drugs containing ritonavir or kobicistat, must continue treatment in accordance with the regime.


Children
There is no data on the safety and efficiency of using the Skyvir drug in children under 18 years of age.

Overdose

Film-coated tablets from light yellow to yellow, oval, biconvex. On a cross section, the kernel is white or yellowish.

Storage conditions

2 years.

Shelf life

Nirmatrelvir, Ritonavir

Manufacturer

Biokhimik JSC, Russia