Xofluza pills 20mg, 2pcs

Composition

One film-coated tablet of 20 mg contains:

Active ingredient: baloxavir marboxil-20 mg;

excipients: lactose monohydrate-77.9 mg, sodium croscarmellose-5.5 mg, povidone K 25-5.5 mg, microcrystalline cellulose-11.4 mg, sodium stearyl fumarate-1.7 mg;

shell: Opadry White 03 A 48081 (hypromellose, talc, titanium dioxide (E 171)) – 4.8 mg, talc-0.2 mg

Pharmacological action

Pharmacotherapy group

Antiviral agent.

ATX code:  J05AX25

Pharmacological properties

Pharmacodynamics

Mechanism of action

Baloxavir marboxil is a prodrug that is converted during hydrolysis to the active metabolite of baloxavir, which has an effect on the influenza virus. Baloxavir acts on cap-dependent endonuclease – CEN), an influenza virus-specific enzyme in the polymerase acid subunit of the viral RNA polymerase complex. Thus, baloxavir inhibits the transcription of the influenza virus genome, leading to suppression of viral replication.

Viruses with the PA/I38T/M/F/N mutation selected in vitro or in clinical studies showed reduced sensitivity to baloxavir. Baloxavir has activity against strains resistant to the neuraminidase inhibitor, including the following mutations: H274Y for subtype A/H1N1 virus; E119V and R292K for subtype A/H3N2 virus; R152K and D198E for type B virus; H274Y for subtype A/H5N1 virus and R292K for subtype A/H7N9 virus.

The relationship between antiviral activity in cell culture and inhibition of human influenza virus replication has not been established.

Other things

Xofluza® does not cause an increase in the QTc interval.

Preclinical safety data sheet

Preclinical studies based on the results of standard pharmacological safety studies and acute and repeated-dose toxicity studies have not identified a particular risk to humans.

Carcinogenicity

Studies on the carcinogenicity of baloxavir marboxil have not been conducted.

Resistance

Influenza A virus isolates with amino acid substitutions of the RA protein (an enzyme in the polymerase acid subunit of the viral RNA polymerase complex) at position I38 T/F/M/N developed during therapy were associated with a more than 10-fold decrease in sensitivity to baloxavir. Influenza B virus isolates with amino acid substitutions at position I38T were associated with a more than 5-fold decrease in sensitivity to baloxavir. The clinical significance of this reduced sensitivity is unknown.

No virus isolates with initial (non-therapy-related) amino acid substitutions that were associated with reduced sensitivity to baloxavir were detected in clinical trials. In controlled clinical trials, influenza virus with the RA/I38 T/M mutation was detected in 9.7% of patients without comorbidities; influenza virus with the RA/I38 T/M/N mutation was detected in 5.2% of patients at high risk of complications receiving Xofluza®.

Cross-resistance

Substitutions of amino acids that can provide cross-resistance of baloxavir and neuraminidase inhibitors (for example, peramivir, oseltamivir, zanamivir) were not detected. However, the virus may carry amino acid substitutions in the PA protein associated with reduced sensitivity to baloxavir, as well as amino acid substitutions in neuraminidase associated with reduced sensitivity to neuraminidase inhibitors. Thus, the virus may show reduced sensitivity to both classes of inhibitors. The clinical significance of assessing phenotypic cross-resistance has not been established.

Immunogenicity

No interaction studies have been conducted between influenza vaccines and baloxavir marboxil. Xofluza® did not affect the normal response of humoral antibodies in studies after patients were infected naturally and experimentally.

Pharmacokinetics

After oral use of baloxavir, marboxil is extensively converted to its active metabolite baloxavir, mainly by arylacetamide deacetylase in the gastrointestinal tract lumen, intestinal epithelium, and liver. The plasma concentration of baloxavir marboxil was very low or below the limit of quantification (

Suction

After a single oral use of baloxavir marboxil at a dose of 80 mg, the time to reach the maximum plasma concentration (tmax) of baloxavir in the fasting state was ~4 hours. The absolute bioavailability of baloxavir marboxil has not been established.

Effect of food intake

A study of the use of baloxavir marboxil in healthy volunteers on an empty stomach and after eating (approximately 400-500 kcal, including 150 kcal in fat form) revealed that after eating, the_cmax and AUC values of baloxavir decreased by 48% and 36%, respectively. In the presence of food, the Tmax index did not change. In clinical trials, no clinically significant differences in efficacy were observed when Xofluza® was administered on an empty stomach or after meals in patients with influenza.

Distribution

In vitro binding of baloxavir to human plasma proteins, mainly albumin, was 92.9-93.9%. After oral use of baloxavir marboxil at a dose of 80 mg, the volume of distribution of baloxavir in Caucasian patients was ~1180 liters.

Metabolism

In vitro studies have shown that the conversion of baloxavir marboxil to the metabolite baloxavir is mainly carried out by arylacetamide deacetylase, which is contained in the gastrointestinal tract lumen, intestinal epithelium, and liver. Baloxavir is primarily metabolized by the enzyme UGT1A3 (uridine diphosphate-glucuronosyltransferase 1-3). The CYP3A4 isoenzyme also makes a minimal contribution to this process.

In a study of human weight balance after a single oral use of [14C] isotope-labeled baloxavir marboxil at a dose of 40 mg, baloxavir accounted for 82.2% of the AUC for total plasma radioactivity. Baloxavir glucuronide (16.4% of the AUC value for total plasma radioactivity) and (12aR,5R,11S) baloxavir sulfoxide (1.5% of the AUC value for total plasma radioactivity) were also detected in plasma. This confirms the realization of the metabolism of baloxavir marboxil in vivo by hydrolysis of the ester to form baloxavir. The latter undergoes subsequent metabolism with the formation of sulfoxides and glucuronide.

Deduction

Baloxavir marboxil and its metabolite baloxavir are mainly excreted in humans by the intestines. After a single oral use of [14C] isotope-labeled baloxavir marboxil at a dose of 40 mg, the proportion of total intestinal radioactivity was 80.1% of the administered dose, and for urine this indicator was 14.7%. The amount of renal excretion of baloxavir was 3.3% of the administered dose.

After a single oral use of baloxavir marboxil, the apparent terminal half-life (t_{1/2, z}) of baloxavir in European patients was 79.1 hours (see table 1).

After a single oral use of baloxavir marboxil in doses from 6 mg to 80 mg in an empty stomach, linear pharmacokinetics of baloxavir were observed.

Pharmacokinetics in special patient groups

Body weight

Based on the analysis of population pharmacokinetics, body weight was determined as an important covariate. The recommended dose in adult patients is 40 mg (with a body weight of 40 to

Gender

Analysis of population pharmacokinetics did not reveal a clinically significant effect of gender on the pharmacokinetics of baloxavir. No dose adjustment is required.

Race

Based on the analysis of population pharmacokinetics, it was concluded that in addition to body weight, race is also a covariate of the CL/F (apparent total clearance) indicator of baloxavir. However, no race-specific dose adjustment of baloxavir marboxil is required.

Age group

Analysis of population pharmacokinetics using plasma concentrations of baloxavir obtained during clinical trials of baloxavir marboxil in patients aged 12 to 64 years did not reveal a clinically significant effect of age on the pharmacokinetics of baloxavir.

Paediatric patients

Pharmacokinetics of Xofluza® in paediatric patients (12 years of age) not installed.

Elderly patients

Pharmacokinetic data obtained in patients ≥65 years of age showed that the exposure of baloxavir is comparable to that in patients aged 12 years (inclusive) to 64 years.

Patients with impaired renal function

Analysis of population pharmacokinetics did not reveal a clinically significant effect of renal function on the pharmacokinetics of baloxavir in patients with creatinine clearance (CrCl) ≥50 ml/min. The effect of severe renal impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite baloxavir has not been studied.

Patients with impaired liver function

Geometric mean ratios (90% confidence interval) of C indicators_{The max} and AUC values of baloxavir in patients with moderate hepatic impairment (Child-Pugh class B) and healthy volunteers were 0.80 (0.50-1.28) and 1.12 (0.78-1.61), respectively. Since there were no clinically significant differences in the pharmacokinetics of baloxavir in patients with moderate hepatic impairment (Child-Pugh class B) and in healthy volunteers with normal liver function, it can be concluded that no dose adjustment is required in patients with mild or moderate hepatic impairment.

Pharmacokinetics have not been studied in patients with severe hepatic impairment.

Indications

Treatment of influenza in patients aged 12 years and older who have flu-like symptoms for no more than 48 hours and who have no additional medical conditions.

Treatment of influenza in patients aged 12 years and older who have flu symptoms for no more than 48 hours and who are at high risk of developing flu complications.

Application Restriction

Influenza viruses change over time, and factors such as the type or subtype of virus, the emergence of resistance, or changes in viral virulence may reduce the clinical benefit of antiviral medications. When making a decision on the use of Xofluza®, it is necessary to study the available information on the susceptibility of circulating strains of influenza virus to the drug.

Use during pregnancy and lactation

Fertility

According to the results of animal studies, baloxavir marboxil has no effect on fertility.

Pregnancy

Separate controlled studies of Xofluza® in pregnant women have not been conducted. The potential risk of using Xofluza in pregnant women is unknown. Xofluza should not be used during pregnancy unless the potential benefit outweighs the potential risk to the fetus.

Preclinical data

Baloxavir marboxil did not cause malformations in rats or rabbits. High-dose levels of baloxavir marboxil used in pregnant rabbits were toxic to the maternal body, leading to the development of miscarriage and an increase in the frequency of minor disorders on the part of the rabbit skeleton, but there were no malformations. These effects were not observed in rats.

Childbirth and delivery

The safety of using Xofluza during labor has not been established.

Breast-feeding period

Currently, it is not known whether baloxavir marboxil and its active metabolite baloxavir can enter human breast milk. When administered at a dose of 1 mg/kg in nursing rats, baloxavir marboxil or its metabolites were secreted into milk.

Therefore, the decision to stop breastfeeding or to start treatment with Xofluza® should be made taking into account the potential benefits of this drug for the nursing mother, as well as taking into account the potential risk to the child.

Contraindications

Hypersensitivity to baloxavir marboxil or to other excipients of the drug in the anamnesis (see the section “Side effects”, subsection “Post-marketing use”).

Simultaneous use with laxatives or antacids containing polyvalent cations, as well as with food additives containing iron, zinc, selenium, calcium, magnesium (reducing the concentration of baloxavir in blood plasma).

Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Children under 12 years of age.

With caution

Impaired renal function.

Severe liver dysfunction.

Side effects

Since clinical trials have been conducted under different conditions, the frequency of adverse drug reactions observed in clinical trials of a drug cannot be directly compared with the frequency of adverse reactions observed in clinical trials of another drug. The frequency of adverse drug reactions observed in clinical trials may not reflect the frequency of adverse drug reactions in real practice.

The safety profile of Xofluza is based on data from 3 placebo-controlled clinical trials in which 1,640 patients received the drug: 1,334 patients (81%) aged 18-64 years,209 patients (13%) aged ≥65 years, and 97 patients (6%) aged 12-17 years. These studies included adult patients and adolescents without additional diseases (N=910), as well as patients with a high risk of developing flu complications (N=730). Of all patients,1440 people received Xofluza® at the recommended dose.

Post-registration application

The following adverse drug reactions were identified during post-marketing use of Xofluza®. Since these adverse reactions were reported voluntarily in a population of patients of unknown size, it is not possible to reliably assess the frequency of their development or the presence of an association with Xofluza®.

Mental disorders: delirium, abnormal behavior, and hallucinations.

Gastrointestinal disorders: vomiting, bloody diarrhea, melena, colitis.

Skin and subcutaneous tissue disorders: rash, urticaria, erythema multiforme.

General disorders and disorders at the injection site: swelling of the face, eyelids or tongue, dysphonia, angioedema, anaphylactic reactions, anaphylactic shock, anaphylactoid reactions.

Interaction

No clinically significant drug interactions are expected between baloxavir marboxil or its active metabolite baloxavir and substrates, inhibitors or inducers of cytochrome P450 (CYP isoenzymes), inhibitors of the uridine-5-diphosphate glucuronyltransferase (UGT), or transporters in the intestine, kidney, or liver.

Polyvalent cation-containing drugs may reduce the plasma concentration of baloxavir. Xofluza® should not be taken with laxatives or antacids containing polyvalent cations, or with food additives containing iron, zinc, selenium, calcium, or magnesium.

Interaction with vaccines

The interaction of Xofluza with intranasal live attenuated influenza vaccine (LAIV) has not been studied. Concomitant use of antiviral drugs may inhibit LAIV viral replication and thus reduce the effectiveness of LAIV vaccination. The interaction of Xofluza with inactivated influenza vaccine has not been studied.

Effect of other drugs on baloxavir marboxil or its active metabolite baloxavir

Itraconazole, a P-glycoprotein (P-gp) inhibitor, increased the_cmax and AUC_{of 0 – ∞} baloxavir by 1.33-fold and 1.23-fold, respectively. The increase in these parameters was not considered clinically significant.

The UGT enzyme inhibitor probenecid reduced the_cmax and AUC_{0 – ∞} values of baloxavir by 21% and 25%, respectively. The decrease in these indicators was not considered clinically significant.

Effect of baloxavir marboxil or its active metabolite baloxavir on other drugs

In conditions in vitro poloxamer karboksil and its active metabolite balaclavas (when used in clinically relevant concentrations) is not inhibited none of these isoenzymes CYP or UGT: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT 1A1,1A3 UGT, UGT 1A4,1A6 UGT, UGT 1A9, UGT UGT 2B7 and 2B15. Under in vitro conditions, baloxavir marboxil and baloxavir (when used at clinically significant concentrations) did not cause significant induction of cytochromes CYP1A2, CYP2B6 and CYP3A4. In vitro vector studies, baloxavir marboxil and baloxavir inhibited the efflux transporter (P-gp) at clinically significant concentrations. Baloxavir caused inhibition of BCRP (breast cancer resistance protein), although this effect was not observed in baloxavir marboxil.

Based on in vitro vector studies, baloxavir is not expected to be an inhibitor of the OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K vectors in vivo (even though baloxavir has a weak inhibitory potential in vitro). Therefore, no significant pharmacokinetic interaction is expected between baloxavir and the substrates of these carriers.

A single 40 mg dose of baloxavir marboxil did not affect the pharmacokinetics of midazolam, a substrate of the CYP3A4 isoenzyme. It is assumed that baloxavir marboxil or baloxavir do not affect the pharmacokinetics of concomitantly used drugs-substrates of the CYP3A isoenzyme.

A single 80 mg dose of baloxavir marboxil did not affect the pharmacokinetics of digoxin, a P-gp substrate. It is assumed that baloxavir marboxil or baloxavir do not affect the pharmacokinetics of concomitantly used P-gp substrates.

A single 80 mg dose of baloxavir marboxil resulted in an 18% and 17% reduction in cmax and AUC_{0-∞ of} rosuvastatin, a BCRP substrate, respectively. This decrease is not clinically significant and indicates that the effect of baloxavir marboxil or baloxavir on the pharmacokinetics of concomitantly used BCRP substrate drugs is not expected.

How to take it, course of use and dosage

General recommendations

Xofluza therapy should be initiated within 48 hours of the onset of flu symptoms.

Adults and children over 12 years of age

The drug Xofluza® is used once, both with food and on an empty stomach (see the section “Pharmacological properties”).

The recommended single dose of Xofluza®, depending on body weight, is shown in table 2.

Table 2. The dose of Xofluza ® depends on the patient’s body weight.

Patient’s body weight (kg) Recommended dose: 40 kg to <80 kg 40 mg≥80 kg 80 mg

Dosage in special cases

Children’s patients

The safety and efficacy of Xofluza in children and adolescents aged 12 years have not been established. For recommendations on the use of Xofluza® in adolescents ≥12 years of age, see the section “General recommendations” above.

Elderly patients

No dose adjustment is required in elderly patients ≥65 years of age (see section “Pharmacological properties”, subsection “Pharmacokinetics in special patient groups”, section”Elderly patients”).

Patients with impaired renal function

Analysis of population pharmacokinetics did not reveal a clinically significant effect of renal function on the pharmacokinetics of baloxavir in patients with creatinine clearance (CrCl) ≥50 ml/min. The effect of severe renal impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite baloxavir has not been studied.

Patients with impaired liver function

No dose adjustment is required in patients with mild (Child-Pugh class A) or moderate (Child-Pugh Class B) hepatic impairment (see section “Pharmacological properties”, subsection “Pharmacokinetics in special patient groups”, section”Patients with hepatic impairment”). The use of Xofluza in patients with severe hepatic impairment has not been studied.

Overdose

No cases of overdose were reported.

Therapy: There is no known specific antidote for Xofluza®. In case of overdose, standard supportive medical care should be provided based on the patient’s existing signs and symptoms of overdose. It is unlikely that a significant amount of baloxavir can be removed by dialysis due to its high binding to serum proteins.

Description

Dosage 20 mg: oval biconvex film-coated tablets, white to light yellow in color. On one side of the tablet are engraved the trademark of the manufacturer and “772”, on the other side of the tablet – “20”.

Special instructions

Hypersensitivity reactions

Cases of anaphylaxis, urticaria, angioedema, and erythema multiforme have been reported during post-marketing use of Xofluza. If a reaction similar to an allergic reaction occurs or is suspected, appropriate treatment should be initiated. The use of Xofluza® is contraindicated in patients with a history of hypersensitivity to Xofluza® (see sections “Contraindications” and “Side effects”).

Risk of developing bacterial infections

There is no evidence for the effectiveness of Xofluza® in any diseases caused by any pathogens other than influenza viruses. Serious bacterial infections may start with flu-like symptoms, may accompany the flu, or may occur as a complication of the flu. Xofluza® does not prevent such complications. When prescribing Xofluza®, the potential occurrence of secondary bacterial infections should be taken into account and appropriate treatment should be prescribed.

Instructions for disposing of an unused or expired product

The release of the medicinal product into the environment should be kept to a minimum. Do not dispose of the product in wastewater or together with household waste.

Disposal of unused medicines or consumables should be carried out in accordance with local requirements.

Influence on the ability to drive vehicles and mechanisms

Studies of the effect of Xofluza® on the ability to drive vehicles and mechanisms have not been conducted.

Form of production

Film-coated tablets,20 mg and 40 mg

1 or 2 tablets (40 mg dosage) or 2 or 4 tablets (20 mg dosage) in a contour cell package (blister) made of cold-formed laminate consisting of oriented polyamide (OPA)/aluminum foil (AL)/polyvinyl chloride (PVC) with a protective foil with a heat-sealable PVC-based layer.

1 blister together with the instructions for use is placed in a cardboard box.

In order to control the first opening, a protective holographic sticker is applied to the pack.

Storage conditions

Store at a temperature not exceeding 30 °C in the original packaging (blister pack) to protect against moisture. Keep out of reach of children.

Shelf

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

Active ingredient

Baloxavir marboxil

Conditions of release from pharmacies

By prescription

Dosage form

Tablets