Xoflusa, 20 mg 2 pcs

Pharmacotherapeutic group

Antiviral agent.

ATX code: J05AX25

Pharmacological properties

.Pharmacodynamics

Mechanism of action

p> Baloxavir marboxyl is a prodrug that is converted by hydrolysis to the active metabolite baloxavir, which has action against the influenza virus. Baloxavir affects the 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 in vitro studies or in clinical trials have shown 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 influenza virus replication in humans has not been established.

Other

Ksoflusa^® does not cause an increase in the QTc interval.

Doclinical safety data

Preclinical studies based on results of standard pharmacological safety studies and acute toxicity and repeated administration toxicity studies have not shown any particular risk to humans.

Carcinogenicity

Carcinogenicity studies of baloxavir marboxil have not been conducted.

Resistance

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

In clinical trials, no virus isolates with baseline (non-therapy-related) amino acid substitutions were found to be associated with reduced sensitivity to baloxavir. In controlled clinical trials, influenza virus with the RA/I38T/M mutation was detected in 9.7% of patients without comorbidities; influenza virus with the RA/I38T/M/N mutation was detected in 5.2% of patients at high risk for complications receiving Xoflusa^®.

Cross Resistance

. Amino acid substitutions that could provide cross-resistance between baloxavir and neuraminidase inhibitors (e.g., peramivir, oseltamivir, zanamivir) have not been detected. However, the virus may carry amino acid substitutions in 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 exhibit reduced sensitivity to both classes of inhibitors. The clinical significance of assessing phenotypic cross-resistance has not been established.

immunogenicity

There have been no interaction studies of influenza vaccines and baloxavir marboxil. Xoflusa^® had no effect on the normal humoral antibody response in studies following infection of patients by natural and experimental routes.

Pharmacokinetics

. After oral administration, baloxavir marboxil is extensively converted to its active metabolite baloxavir, primarily under the action of arilacetamide deacetylase in the GI tract, intestinal epithelium and liver. Plasma concentrations of baloxavir marboxyl were very low or below the limit of quantification (<0.100 ng/ml).

absorption

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

Effects of food intake

A study of baloxavir marboxil administration in healthy volunteers on an empty stomach and after a meal (approximately 400-500 kcal, including 150 kcal as fat) found that after a meal, C_max and AUC of baloxavir were reduced by 48% and 36%, respectively. The T_max did not change in the presence of food. In clinical trials, no clinically significant differences in efficacy were observed in patients with influenza when Xoflusa^® was administered on an empty stomach or after a meal.

Distribution

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

Metabolism

In in vitro conditions it has been shown that the conversion of baloxavir marboxyl to the metabolite baloxavir is predominantly performed by arylacetamide deacetylase, which is found in the GI lumen, intestinal epithelium and liver. Baloxavir is primarily metabolized by the enzyme UGT1A3 (uridine diphosphate-glucuronosyltransferase 1-3). The CYP3A4 isoenzyme also provides a minimal contribution to this process.

In a mass balance study in humans after a single oral administration 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 for total plasma radioactivity) and (12aR,5R,11S) baloxavir sulfoxide (1.5% of the AUC for total plasma radioactivity) were also detected in plasma. This confirms the realization of the metabolism of baloxavir marboxyl under in vivo conditions through ester hydrolysis to form baloxavir. The latter undergoes subsequent metabolism with the formation of sulfoxides and glucuronide.

Elimation

Baloxavir marboxyl and its metabolite baloxavir are excreted in humans mainly by the intestine. After a single oral administration of [¹⁴C-labeled baloxavir marboxil at a dose of 40 mg, the proportion of total intestinal radioactivity excreted was 80.1% of the administered dose, and for urine the figure was 14.7%. The amount of baloxavir excreted with the kidneys was 3.3% of the administered dose.

After a single oral administration of baloxavir marboxil, the apparent terminal elimination half-life (t_1/2,z) of baloxavir in European patients was 79.1 hours (see Table 1).

After a single oral administration of baloxavir marboxil at doses ranging from 6 mg to 80 mg in the fasting state, linear pharmacokinetics of baloxavir were observed.

Pharmacokinetics in special patient groups

Body weight

Body weight has been identified as an important covariate based on population pharmacokinetic analysis. The recommended dose in adult patients is 40 mg (if body weight is 40 to <80 kg) and 80 mg (if body weight is ≥80 kg).

Gender

Population pharmacokinetics analysis showed no clinically significant effect of gender on baloxavir pharmacokinetics. No dose adjustment is required.

Race

Based on population pharmacokinetics analysis, it was concluded that in addition to body weight, race was also a covariate of the CL/F (apparent total clearance) of baloxavir. Nevertheless, there is no need to adjust the dose of baloxavir marboxil according to race.

Age

. A population pharmacokinetics analysis using plasma concentrations of baloxavir from clinical studies of baloxavir marboxil in patients aged 12 years to 64 years showed no clinically significant effect of age on baloxavir pharmacokinetics.

Patients of pediatric age

The pharmacokinetics of Xoflusa^® in pediatric patients (˂12 years) have not been established.

Elderly patients

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

Patients with impaired renal function

Population pharmacokinetics analysis showed no clinically significant effect of renal function on baloxavir pharmacokinetics in patients with a creatinine clearance (CrCl) ≥50 ml/min. The effect of severe renal function impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite baloxavir has not been studied.

Patients with impaired liver function

The ratios of geometric mean (90% confidence interval) of C_max and AUC 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. Because there were no clinically significant differences in baloxavir pharmacokinetics between patients with mild to moderate hepatic impairment (Child-Pugh class B) and healthy volunteers with normal hepatic function, it can be concluded that no dose adjustment is necessary in patients with mild to moderate hepatic impairment.

In patients with severe hepatic impairment, pharmacokinetics has not been studied.

Indications

Treatment of influenza in patients 12 years of age and older who have influenza symptoms for 48 hours or less and who have no additional medical conditions.

The treatment of influenza in patients 12 years of age and older who have influenza symptoms for up to 48 hours and who are at high risk for influenza complications.

Limitations of Use

Influenza viruses change over time, and factors such as virus type or subtype, emergence of resistance, or changes in viral virulence may reduce the clinical benefit of antiviral drugs. When deciding whether to use Xoflusa®, the available information about the susceptibility of circulating strains of influenza virus to the drug should be reviewed.

Active ingredient

Composition

One film-coated tablet, 20 mg contains:

active ingredient: baloxavir marboxil – 20 mg;

excipients: lactose monohydrate – 77.9 mg, croscarmellose sodium – 5.5 mg, povidone K25 – 5.5 mg, microcrystalline cellulose – 11.4 mg, sodium stearyl fumarate – 1.7 mg;

coating: Opadry White 03A48081 (hypromellose, talc, titanium dioxide (E171)) – 4.8 mg, talc – 0.2 mg.

How to take, the dosage

General Guidelines

Therapy with Xoflusa® should be started within 48 hours after the onset of flu symptoms.

Adults and children over 12 years of age

The drug Xoflusa® is used once, either with food or on an empty stomach (see Pharmacological properties).

The recommended daily dose of Xofluzam® as a function of body weight is shown in Table 2.

Table 2. Dose of Xoflusa® as a function of a patient’s body weight.

Patient body weight(kg) Recommended dose to take
40 kg to <80 kg 40 mg
≥80 kg 80 mg

Dosage in special cases

Patients in children

The safety and effectiveness of Xofluz® in children and adolescents ˂12 years of age have not been established. For recommendations on the use of Xoflusa® in adolescents ≥12 years of age, see the “General Recommendations” subsection above.

Elderly patients

Dose adjustment in elderly patients ≥65 years of age is not necessary (see Pharmacological properties, subsection “Pharmacokinetics in special patient groups”, section “Elderly patients”).

Patients with impaired renal function

Population pharmacokinetics analysis showed no clinically significant effect of renal function on baloxavir pharmacokinetics in patients with a creatinine clearance (CrCl) ≥50 mL/min. The effect of severe renal function impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite baloxavir has not been studied.

Patients with hepatic impairment

Dose adjustment in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment is not required (see “Pharmacological properties of baloxivir. See “Pharmacological properties”, subsection “Pharmacokinetics in special patient groups”, section “Patients with impaired hepatic function”). The use of Xoflusa® in patients with severe hepatic impairment has not been studied.

Interaction

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

Polyvalent cation-containing drugs can decrease the plasma concentration of baloxavir. Xoflusa® should not be taken with laxatives or antacids containing polyvalent cations or supplements containing iron, zinc, selenium, calcium, magnesium.

Interaction with vaccines

The interaction of the drug Xoflusa

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

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

Itraconazole, a P-glycoprotein inhibitor (P-gp), increased the Cmax and AUC0-∞ of baloxavir by 1.33-fold and 1.23-fold, respectively. The increase in these values was not considered clinically significant.

The UST enzyme inhibitor probenecid reduced the Cmax and AUC0-∞ of baloxavir by 21% and 25%, respectively. The decrease in these values was not considered clinically significant.

The effect of baloxavir marboxil or its active metabolite baloxavir on other drugs

In in vitro

Special Instructions

Hypersensitivity reactions

In the post-registration use of Xoflusa

sup>® cases of anaphylaxis, urticaria, angioedema and erythema multiforme have been reported. In case of allergic-like reactions or suspected allergic reactions, appropriate treatment should be started. The use of Xoflusa® is contraindicated in patients with a history of hypersensitivity to Xoflusa® (see sections “Contraindications” and “Side effects”).

Risk of bacterial infections

The evidence of efficacy of Xofluzsup>® for any disease caused by any pathogen other than influenza viruses is not available. Serious bacterial infections may start with flu-like symptoms, may accompany influenza, or may occur as a complication of influenza. Xoflusa® does not prevent such complications. When prescribing Xoflusa®, the potential occurrence of secondary bacterial infections should be considered and appropriate treatment prescribed.

Instructions for disposal of unused or expired medication

The release of the medication into the environment should be minimized. The drug should not be disposed of in wastewater or with household waste.

Disposal of unused medication or consumables should be done according to local requirements.

Influence on driving and operating ability

There have been no studies of the effect of Xoflusa® on driving and operating ability.

Synopsis

Contraindications

He has a history of hypersensitivity to baloxavir marboxil or other excipients of the drug (see section “Adverse effects”, subsection “Post-registration use”).

Simultaneous use with laxatives or antacids containing polyvalent cations, as well as supplements containing iron, zinc, selenium, calcium, magnesium (decrease in plasma concentration of baloxavir).

Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Children under 12 years of age.

With caution

Kidney function impairment.

Serious impairment of liver function.

Side effects

Because clinical studies have been conducted under different conditions, the frequency of adverse drug reactions observed in clinical studies of a drug cannot be directly compared to the frequency of adverse reactions observed in clinical studies of another drug. The frequency of adverse drug reactions observed in clinical studies may not reflect the frequency of adverse reactions in actual practice.

The safety profile of Xofluz® is based on data from 3 placebo-controlled clinical trials in which 1640 patients received the drug: 1334 patients (81%) aged 18 to 64 years, 209 patients (13%) aged ≥65 years, and 97 patients (6%) aged 12 to 17 years. These studies included adult patients and adolescents without additional medical conditions (N=910) as well as patients at high risk for influenza complications (N=730). Of all patients, 1,440 received Xoflusa® at the recommended dose.

Post-registration use

. The following adverse drug reactions were identified during post-registration use of Xofluz®. Because these adverse reactions were reported voluntarily in a patient population of unknown size, it is not possible to reliably estimate the frequency of their development or whether they are associated with Xoflusa®.

Psychiatric disorders: delirium, abnormal behavior, and hallucinations.

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

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

General disorders and disorders at the site of administration:Facial, eyelid or tongue edema, dysphonia, angioedema, anaphylactic reactions, anaphylactic shock, anaphylactoid reactions.

Overdose

No cases of overdose have been reported.

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

Pregnancy use

Fertility

Baloxavir marboxil has no effect on fertility according to studies in animals.

Pregnancy

There have been no separate controlled studies of Xoflusa® in pregnant women. The potential risk of Xoflusa® in pregnant women is unknown. Xoflusa® should not be administered during pregnancy unless the potential benefit exceeds the possible risk to the fetus.

Doclinical data

Baloxavir marboxil has not caused malformations in rats or rabbits. High-dose levels of baloxavir marboxil used in pregnant rabbits had maternal toxicity, leading to the development of miscarriage and an increased incidence of minor skeletal abnormalities in rabbits, but there were no malformations. These effects were not noted in rats.

partum and delivery

The safety of Xofluz® during labor has not been established.

Breastfeeding period

It is currently unknown whether baloxavir marboxil and its active metabolite baloxavir can penetrate human breast milk. When administered at a dose of 1 mg/kg in lactating rats, baloxavir marboxil or its metabolites were secreted into milk.

Hence, the decision to discontinue breastfeeding or to initiate treatment with Xoflusa® should be based on the potential benefit of the drug to the nursing mother as well as the potential risk to the baby.