Xofluza^® (Tablets) Instructions for Use

ATC Code

J05AX25 (Baloxavir marboxil)

Active Substance

Baloxavir marboxil (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; other antiviral agents

Pharmacological Action

Mechanism of action

Baloxavir marboxil is a prodrug that is hydrolyzed to the active metabolite baloxavir, which is active against the influenza virus. Baloxavir acts on cap-dependent endonuclease (CEN), an influenza virus-specific enzyme in the polymerase acidic subunit of the viral RNA polymerase complex. Thereby, baloxavir inhibits the transcription of the influenza virus genome, leading to suppression of viral replication.

Pharmacodynamic effects

In vitro activity

In an enzyme inhibition assay, the 50% inhibitory concentration (IC₅₀) of baloxavir ranged from 1.4 to 3.1 nmol/L for influenza A viruses and from 4.5 to 8.9 nmol/L for influenza B viruses. In an MDCK (Madin-Darby canine kidney) cell culture assay, the median 50% effective concentration (EC₅₀) values of baloxavir were 0.73 nmol/L (n=31; range: 0.20-1.85 nmol/L) for A/H1N1 subtype strains, 0.83 nmol/L (n=33; range: 0.35-2.63 nmol/L) for A/H3N2 subtype strains, and 5.97 nmol/L (n=30; range: 2.67-14.23 nmol/L) for type B strains.

In a virus titer reduction assay in MDCK cells, the 90% effective concentration (EC₉₀) values of baloxavir ranged from 0.46 to 0.98 nmol/L for A/H1N1 and A/H3N2 subtype viruses, from 0.80 to 3.16 nmol/L for A/H5N1 and A/H7N9 subtype viruses, and from 2.21 to 6.48 nmol/L for type B viruses.

Resistance

Viruses with the PA/I38T/M/F/N/S mutation, selected in in vitro studies or in clinical studies, showed reduced susceptibility to baloxavir with changes in EC₅₀ values ranging from 11 to 57-fold for influenza A viruses and from 2 to 8-fold for influenza B viruses.

In the course of three phase III studies for the treatment of uncomplicated influenza (see below), no resistance of baseline isolates to baloxavir was detected. In two studies in adults and adolescents, treatment-emergent PA/I38T/M/N mutations were detected in 36/370 (9.7%) and 15/290 (5.2%) patients treated with baloxavir marboxil, but were not detected in patients treated with placebo.

In a phase III study in children, treatment-emergent PA/I38T/M/S mutations were detected in 11/57 (19.3%) patients treated with baloxavir marboxil.

In a phase III study on post-exposure prophylaxis (see below), PA/I38T/M mutations were detected in 10 out of 374 (2.7%) patients treated with baloxavir marboxil. PA/I38 substitutions were not detected in patients treated with placebo, except for 2 patients who received Baloxavir marboxil as a rescue medication.

Baloxavir is active in in vitro studies against viruses considered resistant to neuraminidase inhibitors, including strains with the following mutations: H274Y for A/H1N1 subtype virus, E119V and R292K for A/H3N2 subtype virus, R152K and D198E for type B virus, H274Y for A/H5N1 subtype virus, R292K for A/H7N9 subtype virus.

Clinical efficacy and safety

Treatment of uncomplicated influenza

Adults and adolescents

Study Capstone 1 (1601T0831) was a randomized, double-blind, multicenter phase III study conducted in Japan and the USA to evaluate the efficacy and safety of a single oral dose of baloxavir marboxil in tablet form compared with placebo or oseltamivir in otherwise healthy adults and adolescents (aged ≥12 years to ≤64 years) with uncomplicated influenza.

Patients were randomized to receive baloxavir marboxil (patients with body weight from 40 to <80 kg received 40 mg, and patients with body weight ≥80 kg received 80 mg), oseltamivir 75 mg twice daily for 5 days (only in patients aged ≥20 years), or placebo. The drug was taken within 48 hours of the first onset of symptoms.

A total of 1436 patients (of which 118 were aged ≥12 years to ≤17 years) were enrolled in the study during the 2016-2017 northern hemisphere influenza season. The predominant influenza virus strain in this study was subtype A/H3 (from 84.8% to 88.1%), followed by type B virus (from 8.3% to 9.0%) and subtype A/H1N1pdm (from 0.5% to 3.0%).

The primary efficacy endpoint was the time to alleviation of symptoms (cough, sore throat, headache, nasal congestion, fever or chills, muscle or joint pain, and fatigue) (TTAS). Baloxavir marboxil caused a statistically significant reduction in TTAS compared to placebo (Table 1).

Table 1. Capstone 1: Time to alleviation of symptoms (Baloxavir marboxil compared with placebo), ITTI* population

CI — confidence interval

*ITTI – Infected Intent-to-Treat population included patients who received the study drug and had a confirmed diagnosis of influenza. Confirmation of influenza was based on RT-PCR (reverse transcription polymerase chain reaction) results on Day 1.

When comparing the baloxavir marboxil group with the oseltamivir group, no statistically significant difference was found in TTAS (53.5 h compared to 53.8 h, respectively).

The median (95% CI) TTAS was 49.3 (44.0; 53.1) and 82.1 (69.5; 92.9) hours in patients with symptoms present for >0 to ≤24 hours, and 66.2 (54.4; 74.7) and 79.4 (69.0; 91.1) hours in patients with symptoms present for >24 to ≤48 hours for baloxavir marboxil and placebo, respectively.

The median time to resolution of fever in patients treated with baloxavir marboxil was 24.5 hours (95% CI: 22.6-26.6 h) compared to 42.0 hours (95% CI: 37.4-44.6 h) in patients receiving placebo. No difference in fever duration was noted in the baloxavir marboxil group compared to the oseltamivir group.

Study Capstone 2 (1602T0832) was a randomized, double-blind, multicenter phase III study to evaluate the efficacy and safety of a single oral dose of baloxavir marboxil in tablet form compared with placebo or oseltamivir in adults and adolescents (aged ≥12 years) with uncomplicated influenza and at least one factor from the body that increases the likelihood of complications. Patients were randomized to receive a single oral dose of baloxavir marboxil (according to body weight, as in the Capstone 1 study), oseltamivir 75 mg twice daily for 5 days, or placebo. The drug was taken within 48 hours of the first onset of symptoms.

Of the total 2184 patients, 59 were aged ≥12 to ≤17 years, 446 were aged ≥65 to ≤74 years, 142 were aged ≥75 to ≤84 years, and 14 were aged ≥85 years. The predominant influenza viruses in this study were subtype A/H3 (from 46.9% to 48.8%) and type B (from 38.3% to 43.5%). The primary efficacy endpoint was the time to alleviation of influenza symptoms (cough, sore throat, headache, nasal congestion, fever or chills, muscle or joint pain, and fatigue). Baloxavir marboxil caused a statistically significant reduction in TTAS compared to placebo (see Table 2).

Table 2. Capstone 2: Time to alleviation of influenza symptoms (Baloxavir marboxil compared with placebo), ITTI population

When comparing the baloxavir marboxil group with the oseltamivir group, no statistically significant difference was found in TTAS (73.2 h compared to 81.0 h, respectively).

The median (95% CI) TTAS was 68.6 (62.4; 78.8) and 99.1 (79.1; 112.6) hours in patients with symptoms present for >0 to ≤24 hours, and 79.4 (67.9; 96.3) and 106.7 (92.7; 125.4) hours in patients with symptoms present for >24 to ≤48 hours, for baloxavir marboxil and placebo, respectively.

In patients infected with type A/H3 virus, the median TTAS was shorter in the baloxavir marboxil group compared to the placebo group, but not compared to the oseltamivir group (see Table 3). In the subgroup of patients infected with type B virus, the median TTAS was shorter in the baloxavir marboxil group compared to the placebo and oseltamivir groups (see Table 3).

Table 3. Time to alleviation of symptoms by influenza virus subtype, ITTI population

The median time to resolution of fever was 30.8 hours (95% CI: 28.2-35.4 h) in the baloxavir marboxil group compared to 50.7 hours (95% CI: 44.6-58.8 h) in the placebo group. No clear differences were recorded between the baloxavir marboxil and oseltamivir groups.

The overall incidence of influenza complications (fatal outcome, hospitalization, sinusitis, otitis media, bronchitis and/or pneumonia) was 2.8% (11/388 patients) in the baloxavir marboxil group compared to 10.4% (40/386 patients) in the placebo group.

The lower overall incidence of influenza complications in the baloxavir marboxil group compared to the placebo group was mainly due to a lower incidence of bronchitis (1.8% vs. 6.0%, respectively) and sinusitis (0.3% vs. 2.1%, respectively).

Post-exposure prophylaxis of influenza

A randomized, double-blind, multicenter phase III study (1719T0834) was conducted with 749 patients in Japan to evaluate the efficacy and safety of a single oral dose of baloxavir marboxil in tablet or granule form compared with placebo for post-exposure prophylaxis of influenza. Participants lived together with index patients infected with influenza.

A total of 607 patients aged 12 years and older and 142 patients aged from 1 year to <12 years received Baloxavir marboxil at a dosage corresponding to body weight, as in the treatment studies, or placebo. The majority of participants (73%) were enrolled in the study within 24 hours of symptom onset in the index patient group. The predominant influenza virus strains in the index patients were subtype A/H3 (48.6%) and subtype A/H1N1pdm (47.5%), followed by influenza type B virus (0.7%).

The primary efficacy endpoint was the proportion of household members who were infected with the influenza virus and developed fever and at least one respiratory symptom from Day 1 to Day 10.

A statistically significant reduction in the proportion of patients with laboratory-confirmed influenza was observed, from 13.6% in the placebo group to 1.9% in the baloxavir marboxil group (see Table 4).

Table 4. Proportion of patients with influenza virus, fever, and at least one respiratory symptom (baloxavir compared with placebo)

*mITT – modified Intent-to-Treat population, the mITT population included all randomized patients who received the study drug and for whom efficacy data were available after baseline along with household members of index patients with influenza. The mITT population was analyzed as randomized.

Children

Ministone-2 (CP40563) was a randomized, double-blind, multicenter, active-controlled study designed to evaluate the safety, efficacy, and pharmacokinetics of a single oral dose of baloxavir marboxil in the form of granules for suspension compared with oseltamivir in otherwise healthy children aged 1 year to <12 years with influenza-like symptoms.

A total of 173 patients were randomized in a 2:1 ratio to receive a single oral dose of baloxavir marboxil at a dosage corresponding to body weight (2 mg/kg for patients with body weight <20 kg or 40 mg for patients with body weight ≥20 kg) or oseltamivir (at a dosage corresponding to body weight) for 5 days. Patients could receive paracetamol if necessary.

Patients with risk factors that increase the likelihood of complications (14% (25/173)) were included in the study. The predominant influenza virus strain in this study was subtype A/H3. The primary objective was to compare the safety of a single dose of baloxavir marboxil with oseltamivir, which was administered twice a day for 5 days. The secondary objective was to compare the efficacy of baloxavir marboxil with oseltamivir based on efficacy endpoints, including time to alleviation of influenza symptoms (cough and nasal symptoms, time to return to usual health and activity, and duration of fever).

The time to alleviation of influenza signs and symptoms was comparable between the baloxavir marboxil group (median 138.1 h [95% CI: 116.6, 163.2]) and the oseltamivir group (median 150 h [95% CI: 115.0, 165.7]) – see Table 5.

Table 5. Time to alleviation of influenza signs and symptoms, ITTI population

The median time to resolution of fever was comparable in the baloxavir marboxil group (41.2 h [95% CI: 24.5, 45.7]) and the oseltamivir group (46.8 h [95% CI: 30.0, 53.5]). The overall incidence of influenza complications (fatal outcome, hospitalization, pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, myositis) was 7.4% (6/81 patients) in the baloxavir marboxil group compared to 7% (3/43 patients) in the oseltamivir group. The incidence of otitis media was 3.7% (3/81 patients) in the baloxavir marboxil group compared to 4.7% (2/43 patients) in the oseltamivir group. Sinusitis, pneumonia, and bronchitis were each noted in one patient in the baloxavir marboxil group, and febrile seizures were noted in one patient in the oseltamivir group.

Preclinical safety data

In the course of preclinical studies based on the results of standard pharmacological safety studies and studies of acute toxicity and toxicity after repeated administration, no specific risk to humans was identified.

Prolongation of prothrombin time and activated partial thromboplastin time was observed in rats at exposures at least equal to human exposure based on AUC_{0-24 h}, under certain experimental conditions, i.e., fasting and when food was autoclaved or irradiated, which allowed reproduction of vitamin K restriction/deficiency conditions. These effects were not observed in studies in monkeys lasting up to 4 weeks with the maximum investigated dose equivalent to 8-fold human exposure based on AUC_{0-24 h}. They are considered to have limited clinical significance.

Carcinogenicity studies of baloxavir marboxil have not been conducted.

The prodrug Baloxavir marboxil, as well as its active form, baloxavir, are not considered genotoxic, as they showed negative results in bacterial reverse mutation tests and in mammalian cell culture micronucleus tests. Furthermore, Baloxavir marboxil also showed a negative result in an in vivo rodent micronucleus test.

Baloxavir marboxil did not affect fertility after oral administration in male and female rats at doses providing exposure equivalent to 5-fold human exposure based on AUC_{0-24 h}.

Baloxavir marboxil did not cause malformations in rats or rabbits. In an embryo-fetal development study with daily oral administration of baloxavir marboxil to rats from day 6 to day 17 of gestation at doses up to the maximum studied dose providing exposure equivalent to 5-fold human exposure based on AUC_{0-24 h}, there were no signs of toxicity to the maternal organism or the fetus.

In rabbits, a dose providing exposure equivalent to 14-fold human exposure based on the AUC_{0-24 h} value after administration of the maximum recommended dose caused maternal toxicity, leading to miscarriage and a significant increase in the frequency of minor skeletal abnormalities in the fetus (cervical ribs). These skeletal abnormalities were resorbed during the growth of adjacent cervical vertebrae. A dose providing exposure equivalent to 6-fold human exposure based on AUC_{0-24 h} did not cause adverse effects in rabbits.

A study of pre- and postnatal development in rats did not show drug-related adverse events in females and offspring when administered up to the maximum studied dose providing exposure equivalent to 5 times the human exposure based on AUC_{0-24 h}.

Pharmacokinetics

Absorption

After oral administration, Baloxavir marboxil is extensively converted to its active metabolite baloxavir. The plasma concentration of baloxavir marboxil was very low or below the limit of quantification (<0.100 ng/mL).

After a single oral administration of baloxavir marboxil at a dose of 80 mg, the maximum plasma concentration (C_max) of baloxavir under fasting conditions was reached within ~4 hours (T_max). The absolute bioavailability of baloxavir after oral administration of baloxavir marboxil has not been established.

Effect of food intake. A study of baloxavir marboxil administration in healthy volunteers under fasting conditions and after a meal (approximately 400-500 kcal, including 150 kcal from fat) revealed that after food intake, the C_max and AUC values of baloxavir decreased by 48% and 36%, respectively. In the presence of food, the T_max value did not change. In clinical studies with Xofluza^® administered on an empty stomach or after a meal in patients with influenza, no clinically significant differences in efficacy were observed.

Distribution

Under in vitro conditions, the binding of baloxavir to human plasma proteins, primarily to albumin, was 92.9-93.9%. The apparent V_d of baloxavir in the terminal elimination phase (Vz/F) after oral administration of a single dose of baloxavir marboxil was approximately 1180 liters in European patients and 647 liters in patients of Japanese origin.

Metabolism

Baloxavir is primarily metabolized by the enzyme UGT1A3 (uridine diphosphate-glucuronosyltransferase 1-3) to form a glucuronide. The isoenzyme CYP3A4 also contributes minimally to this process, forming a sulfoxide.

Drug interaction studies. Based on in vitro and in vivo drug interaction (DI) studies, Baloxavir marboxil and baloxavir are not expected to inhibit CYP or UGT family isoenzymes or cause significant induction of CYP enzymes. Based on in vitro transporter studies and in vivo DI studies, significant pharmacokinetic interaction between baloxavir marboxil or baloxavir and medicinal products that are substrates of the following transporters is not expected: OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

Excretion

After a single oral administration of isotopically labeled [¹⁴C] baloxavir marboxil at a dose of 40 mg, the proportion of total radioactivity excreted via the intestine was 80.1% of the administered dose, and for urine, this figure was 14.7% (3.3% and 48.7% of the administered dose was excreted as baloxavir by the kidneys and via the intestine, respectively). Elimination After a single oral administration of baloxavir marboxil, the apparent terminal T_1/2 of baloxavir in European adults, adolescents, and children was 79.1, 50.3, and 29.4 hours, respectively.

Linearity (non-linearity)

After a single oral administration of baloxavir marboxil in doses from 6 mg to 80 mg under fasting conditions, linear pharmacokinetics of baloxavir were observed.

Pharmacokinetics in special patient groups

Hepatic impairment. No clinically significant differences in the pharmacokinetics of baloxavir were found in patients with mild or moderate hepatic impairment (Child-Pugh class A and class B) compared to healthy volunteers with normal liver function from the control group. The pharmacokinetics in patients with severe hepatic impairment (Child-Pugh class C) have not been evaluated (see section “Dosage Regimen”).

Renal impairment . The effect of renal impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite baloxavir has not been evaluated. Renal impairment is not expected to affect the excretion of baloxavir marboxil or baloxavir.

Elderly patients. Pharmacokinetic data obtained from 181 patients ≥65 years of age showed that the exposure to baloxavir is comparable to that in patients aged ≥12 years to 64 years.

Body weight. Based on population pharmacokinetic analysis, body weight was an important covariate. Dosing recommendations for baloxavir marboxil in adults and children are based on body weight (see section “Dosage Regimen”).

Sex. Population pharmacokinetic analysis did not reveal a clinically significant effect of sex on the pharmacokinetics of baloxavir. No dose adjustment is required.

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

Age. In a population pharmacokinetic analysis using plasma concentrations of baloxavir obtained during clinical studies of baloxavir marboxil in patients aged 1 year to 64 years, age was not identified as a clinically significant covariate for the pharmacokinetics of baloxavir.

Children. Pharmacokinetic data for baloxavir marboxil collected from patients aged 1 year to <12 years showed that the body weight-adjusted dosing regimen (2 mg/kg for body weight up to 20 kg and 40 mg for body weight ≥20 kg) provides similar exposures of baloxavir marboxil across different body weight categories in children, along with similar exposures in adults and adolescents who received a 40 mg dose of baloxavir marboxil. The pharmacokinetics of baloxavir in children under 1 year of age have not been established.

Indications

Treatment of influenza

• Xofluza^® is indicated for use in adults and children with a body weight ≥20 kg for the treatment of uncomplicated influenza.

Post-exposure prophylaxis of influenza

• Xofluza^® is indicated for use in adults and children with a body weight ≥20 kg for post-exposure prophylaxis of influenza: after contact with a person ill with influenza.

ICD codes

Dosage Regimen

Tablets

Treatment of influenza

A single dose of Xofluza^® should be taken as soon as possible – within 48 hours after the onset of influenza symptoms.

Post-exposure prophylaxis of influenza

A single dose of Xofluza^® should be taken as soon as possible – within 48 hours after close contact with a person ill with influenza (see section “Pharmacological Action”).

Treatment or post-exposure prophylaxis of influenza in adults and children with body weight ≥20 kg

The recommended single dose of Xofluza^® depending on body weight is presented in Table 6.

Table 6. Dose of Xofluza^® depending on patient body weight

Special patient groups

No dose adjustment is required for elderly patients ≥65 years (see section “Pharmacokinetics”).

No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B) (see section “Pharmacokinetics”). The safety and efficacy of Xofluza^® in patients with severe hepatic impairment (Child-Pugh class C) have not been established.

No dose adjustment is required for patients with renal impairment.

Children

Data available to date are provided in the sections “Pharmacological Action”, “Pharmacokinetics”, “Adverse Reactions”. Xofluza^® should not be administered to children with body weight <20 kg due to the inability to provide a dosing regimen for this dosage form. The safety and efficacy of baloxavir marboxil in children aged <1 year have not been established. Data are lacking.

Method of administration

Orally, with water.

Patients who cannot swallow the tablet whole should not take Xofluza^® in the dosage form of film-coated tablets. The patient’s ability to swallow the tablet should be assessed before starting treatment.

Xofluza^® is used as a single dose, both with food and on an empty stomach (see section “Pharmacokinetics”).

Xofluza^® should not be taken simultaneously with laxatives or antacids containing polyvalent cations, or with dietary supplements containing iron, zinc, selenium, calcium, magnesium (see section “Drug Interactions”).

Adverse Reactions

Since clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety profile of Xofluza^® is based on data from 3 placebo-controlled clinical studies 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 diseases (N=910), as well as patients at high risk of developing influenza complications (N=730). Of all patients, 1440 received Xofluza^® at the recommended dose.

Table 7 lists the most common adverse events (regardless of relationship to the investigational product) reported in at least 1% of adult patients and adolescents who received Xofluza^® at the recommended dose during clinical studies 1518T0821, Capstone 1 (1601T0831), and Capstone 2 (1602T0832).

In a placebo-controlled clinical study of post-exposure prophylaxis of influenza involving 374 patients who received Xofluza^®, no adverse drug reactions were identified.

The most frequent adverse event in the post-exposure influenza prophylaxis study was nasopharyngitis.

During post-marketing use, hypersensitivity reactions have been reported, including reports of anaphylaxis/anaphylactic reactions and less severe forms of hypersensitivity reactions, including urticaria and angioedema.

Of these adverse reactions, only urticaria was reported in clinical studies with an established frequency category of “uncommon”.

Table 7. Frequency of adverse events reported in at least 1% of patients receiving Xofluza^® during studies 1518T0821, Capstone 1 (1601T0831), and Capstone 2 (1602T0832) for acute uncomplicated influenza.

Children

No adverse reactions were reported in patients aged from 1 year to 12 years (n=115) who received Xofluza^® in one double-blind clinical study with active control Ministone-2 (CP40563). Safety data in children aged 1 to 12 years at high risk of complications are limited.

Contraindications

• Hypersensitivity to baloxavir marboxil or to any of the excipients.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of baloxavir marboxil in pregnant women are absent or limited. Animal reproduction toxicity studies do not indicate direct or indirect harmful effects (see section “Pharmacological Action”, subsection “Preclinical safety data”). As a precautionary measure, it is preferable to avoid the use of Xofluza^® during pregnancy.

Breast-feeding period

It is unknown whether Baloxavir marboxil or baloxavir pass into human breast milk. When administered to lactating rats, Baloxavir marboxil and its metabolites were secreted into milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to abstain from Xofluza^® therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

According to animal studies, Baloxavir marboxil does not affect fertility (see section “Pharmacological Action”, subsection “Preclinical safety data”).

Use in Hepatic Impairment

The drug should be used with caution in severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

The drug should be used with caution in renal impairment.

Pediatric Use

The dosage regimen is provided for children with body weight ≥20 kg.

Geriatric Use

No dose adjustment is required for elderly patients ≥65 years.

Special Precautions

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 to use Xofluza^®, available information on the susceptibility of circulating influenza virus strains to the drug should be considered.

Excipients

Lactose. Xofluza^® contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Sodium. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effect on ability to drive and use machines

Xofluza^® has no or negligible influence on the ability to drive and use machines.

Overdose

Symptoms reports of overdose with Xofluza^® have been received in clinical studies and during post-marketing use. In most cases of overdose, no adverse events were observed. Data are insufficient to determine what symptoms can be expected as a result of overdose.

Treatment there is no known specific antidote for Xofluza^®. In case of overdose, standard supportive medical care should be provided based on the patient’s signs and symptoms of overdose. It is unlikely that baloxavir can be substantially removed by dialysis due to high serum protein binding.

Drug Interactions

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

Xofluza^® should not be taken simultaneously with laxatives or antacids containing polyvalent cations, or with dietary supplements containing iron, zinc, selenium, calcium, magnesium.

Interaction with influenza vaccines

Studies of the interaction between baloxavir marboxil and influenza vaccines have not been conducted. In studies of naturally acquired or experimentally induced influenza, treatment with Xofluza^® did not affect the humoral antibody response to influenza infection.

Children

Interaction studies have only been performed in adults.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging (blister in a carton) to protect from moisture, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life for the 40 mg dosage is 5 years, for the 80 mg dosage is 4 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.