Xofluza

Xofluza

baloxavir marboxil

Manufacturer:

Roche

Distributor:

DKSH
Full Prescribing Info
Contents
Baloxavir marboxil.
Description
XOFLUZA 20 mg film-coated tablets: Each film-coated tablet contains 20 mg baloxavir marboxil.
XOFLUZA 40 mg film-coated tablets: Each film-coated tablet contains 40 mg baloxavir marboxil.
Excipients/Inactive Ingredients: Lactose monohydrate, croscarmellose sodium, povidone, microcrystalline cellulose, sodium stearyl fumarate, hypromellose, talc, titanium dioxide.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Baloxavir marboxil is a prodrug that is converted by hydrolysis to its active metabolite, baloxavir, the active form that exerts anti-influenza activity. Baloxavir acts on the cap-dependent endonuclease (CEN), an influenza virus-specific enzyme in the polymerase acidic (PA) subunit of the viral RNA polymerase complex and thereby inhibits the transcription of influenza virus genomes resulting in inhibition of influenza virus replication. The 50% inhibition concentration (IC50) of baloxavir was 1.4 to 3.1 nmol/L for influenza A viruses and 4.5 to 8.9 nmol/L for influenza B viruses in an enzyme inhibition assay.
Nonclinical studies demonstrate potent antiviral activity of baloxavir against influenza A and B virus in vitro and in vivo. The antiviral activity of baloxavir against laboratory strains and clinical isolates of influenza A and B viruses was determined in the MDCK 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 subtype A/H1N1 strains, 0.83 nmol/L (n=33; range: 0.35-2.63 nmol/L) for subtype A/H3N2 strains, and 5.97 nmol/L (n=30; range: 2.67-14.23 nmol/L) for type B strains. In a MDCK cell-based virus titer reduction assay, the 90% effective concentration (EC90) values of baloxavir were in the range of 0.46 to 0.98 nmol/L for subtype A/H1N1 and A/H3N2 viruses, 0.80 to 3.16 nmol/L for avian subtype A/H5N1 and A/H7N9 viruses, and 2.21 to 6.48 nmol/L for type B viruses.
Viruses bearing the PA/I38T/M/F/N mutation selected in vitro or in clinical studies show reduced susceptibility to baloxavir. Baloxavir is active against neuraminidase inhibitor resistant strains including H274Y in A/H1N1, E119V and R292K in A/H3N2, and R152K and D198E in type B virus, H274Y in A/H5N1, R292K in A/H7N9.
The relationship between antiviral activity in cell culture and inhibition of influenza virus replication in humans has not been established.
At twice the expected exposure from recommended dosing, XOFLUZA did not prolong the QTc interval.
Clinical/Efficacy Studies: Otherwise healthy patients: Study 1601T0831: Study 1601T0831 is a randomized, double-blind, multicenter, placebo- and active-controlled study designed to evaluate the efficacy and safety of single oral dose of XOFLUZA compared with placebo or oseltamivir in otherwise healthy adult and adolescent patients (aged ≥12 years to ≤64 years) with influenza.
A total of 1436 patients were randomized to receive treatment in the 2016-2017 Northern Hemisphere influenza season. Patients were randomized to receive 40 mg or 80 mg of XOFLUZA according to weight (<80kg or ≥80kg respectively), oseltamivir 75 mg twice daily for 5 days (if aged >20 years) or placebo. The predominant influenza virus strain in this study was the A/H3 subtype (84.8% to 88.1%) followed by the B type (8.3% to 9.0%) and the A/H1N1pdm subtype (0.5% to 3.0%). The primary efficacy endpoint was time to alleviation of symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue). A statistically significant and clinically meaningful improvement in the primary endpoint was seen for XOFLUZA when compared with placebo, see Table 1.

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When the XOFLUZA group was compared to the oseltamivir group, there was no statistically significant difference in time to alleviation of symptoms (53.5 h vs 53.8 h respectively), see Table 2.

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Secondary endpoints included time to resolution of fever and culture-based assessment of time to cessation of viral shedding (by virus titer).
Resolution of Fever: Following study drug administration there was faster resolution of fever in the XOFLUZA group compared with the placebo group. The median time to resolution of fever in patients treated with XOFLUZA was 24.5 hours (95% CI: 22.6, 26.6) compared with 42.0 hours (95% CI: 37.4, 44.6) in those receiving placebo. No difference was noted in duration of fever in the Xofluza group compared with the oseltamivir group.
Antiviral Activity: Patients treated with XOFLUZA showed a rapid reduction in virus titer. The median time to cessation of viral shedding determined by virus titer was 24.0 hours (95% CI: 24.0, 48.0) in the XOFLUZA group compared with 72.0 hours (95% CI: 72.0, 96.0) in the oseltamivir group and 96.0 hours (95% CI: 96.0, 96.0) in the placebo group.
Study 1518T0821: The phase 2 study was designed to evaluate the efficacy and safety of a single oral dose of XOFLUZA compared with placebo in otherwise healthy adult patients (aged ≥20 years to ≤64 years) with influenza. A total of 400 patients were randomized to one of three dose groups of XOFLUZA (10, 20 or 40 mg) or placebo in the 2015-2016 Northern Hemisphere influenza season in Japan. The predominant influenza virus strain was A/H1N1pdm subtype (61% to 71%) followed by B subtype (21% to 24%) and A/H3N2 subtype (5% to 13%).
The median time to alleviation of symptoms was significantly shorter (p<0.05) compared with placebo in all dose groups . At 40 mg the median time to alleviation of symptoms was 49.5 hours (95% CI: 44.5, 64.4) in the group versus 77.7 hours (95% CI: 67.6, 88.7) in the placebo group.
Resolution of Fever: The median time to resolution of fever was significantly reduced in all dose groups compared with placebo. At 40 mg the median time was 28.9 hours (95% CI: 24.5, 34.7) versus 45.3 hours (95% CI: 35.6, 54.0) in the placebo group. Viral endpoint results were consistent with those in study 1601T0831.
High risk patients: Study 1602T0832: Study 1602T0832 is a randomized, double-blind, multicenter, placebo- and active-controlled study designed to evaluate the efficacy and safety of single oral dose of XOFLUZA compared with placebo or oseltamivir in adult and adolescent patients (aged ≥12 years) with influenza at high risk of influenza complications (e.g. asthma or chronic lung disease, endocrine disorders, heart disease, age ≥ 65 years, metabolic disorders, morbid obesity).
A total of 2184 patients were randomized to receive a single oral dose of 40 mg or 80 mg of XOFLUZA according to body weight (patients who weighed 40 to < 80 kg received 40 mg and patients who weighed ≥ 80 kg received 80 mg), oseltamivir 75 mg twice daily for 5 days, or placebo. The predominant influenza viruses in this study were the A/H3 subtype (46.9% to 48.8%) and influenza B (38.3% to 43.5%). The primary efficacy endpoint was time to improvement of influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue). A statistically significant improvement in the primary endpoint was observed for XOFLUZA when compared with placebo, see Table 3.

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When the XOFLUZA group was compared to the oseltamivir group, there was no statistically significant difference in time to improvement of influenza symptoms (73.2 h vs 81.0 h respectively), see Table 4.

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Virus Subtype: For patients infected with type A/H3 virus (predominant strain), the median time to improvement of influenza symptoms was shorter in the XOFLUZA group compared with the placebo group but not when compared with the oseltamivir group (see Table 5). In the subgroup of patients infected with type B virus, the median time to improvement of influenza symptoms was shorter in the XOFLUZA group compared with both the placebo and oseltamivir group. (See Table 5.)

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Resolution of Fever: The proportion of patients who had fever was reduced more rapidly in the XOFLUZA group than in the placebo group following study drug administration. The median time to resolution of fever was 30.8 hours (95% CI: 28.2, 35.4) in the XOFLUZA group compared with 50.7 hours (95% CI: 44.6, 58.8) in the placebo group. No clear differences between the XOFLUZA group and the oseltamivir group were observed.
Incidence of Influenza-Related Complications: The overall incidence of influenza-related complications (death, hospitalization, sinusitis, otitis media, bronchitis, and/or pneumonia) was 2.8% (11/388 patients) in the XOFLUZA group compared with 10.4% (40/386 patients) in the placebo group and 4.6% (18/389 patients) in the oseltamivir group. The lower overall incidence of influenza-related complications in the baloxavir marboxil group compared with the placebo group was mainly driven by lower incidences of bronchitis (1.8% vs. 6.0%, respectively) and sinusitis (0.3% vs. 2.1%, respectively).
The proportion of patients requiring systemic antibiotics for infections secondary to influenza infection was lower in the XOFLUZA group (3.4%) compared with the placebo group (7.5%), and the difference between these 2 groups was statistically significant (p=0.0112). The proportion of patients requiring systemic antibiotics in the XOFLUZA group was comparable with the proportion in the oseltamivir group (3.9%).
Antiviral Activity: Patients at high risk of influenza complications, treated with XOFLUZA, showed a rapid reduction in virus titer and a significantly shortened time to cessation of viral shedding. The median time to cessation of viral shedding determined by virus titer was 48 hours in the XOFLUZA group compared with 96 hours in the placebo group and the oseltamivir group.
Resistance Monitoring during Clinical Development: Influenza A virus isolates with treatment-emergent amino acid substitutions in the PA protein at position I38T/F/M/N associated with > 10 fold reduced susceptibility to baloxavir and influenza B virus isolates with treatment-emergent amino acid substitutions in the PA protein at position I38T associated with > 5 fold reduced susceptibility to baloxavir were observed in clinical studies. The clinical impact of this reduced susceptibility is unknown.
No pre-treatment isolates, with amino acid substitutions associated with reduced susceptibility to baloxavir, were found in the clinical studies.Prescribers should consider available information from the CDC on influenza virus drug susceptibility patterns and treatment effects when deciding whether to use XOFLUZA.
In the phase 3 study in otherwise healthy patients (1601T0831), PA/I38T/M were detected in 36 of 370 patients (9.7%) in the XOFLUZA treatment group. In the phase 3 study in high risk patients (1602T0832), PA/I38T/M/N were detected in 15 of 290 patients (5.2%) in the XOFLUZA treatment group.
Cross Resistance: No single amino acid substitution has been identified that could confer cross-resistance between baloxavir and neuraminidase inhibitors (e.g., peramivir, oseltamivir, zanamivir). However, a virus may carry amino acid substitutions associated with reduced susceptibility to baloxavir in the PA protein and to neuraminidase inhibitors in the neuraminidase and may therefore exhibit reduced susceptibility to both classes of inhibitors. The clinical relevance of phenotypic cross resistance evaluations has not been established.
Immunogenicity: Immune Response: Interaction studies with influenza vaccines and baloxavir marboxil have not been conducted. In studies of naturally acquired and experimental influenza, treatment with XOFLUZA did not impair normal humoral antibody response to infection.
Pharmacokinetics: After oral administration baloxavir marboxil is extensively converted to its active metabolite, baloxavir, predominantly by arylacetamide deacetylase in the gastrointestinal lumen, intestinal epithelium, and liver. The plasma concentration of baloxavir marboxil was very low or below the limit of quantitation (<0.100 ng/mL).
The pharmacokinetic parameters of baloxavir in Japanese healthy adult subjects after a single oral administration of 40 mg baloxavir marboxil in the fasted and fed states are summarized in Table 6. The pharmacokinetic parameters of baloxavir in Caucasian healthy adult subjects after a single oral administration of 80 mg baloxavir marboxil in the fasted state are summarized in Table 7. (See Tables 6 and 7.)

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Absorption: Following a single oral administration of 80 mg of baloxavir marboxil, the time to achieve peak plasma concentration (Tmax) of baloxavir was reached at approximately 4 hours in the fasted state. The absolute bioavailability of baloxavir marboxil has not been established.
Food effect: A food-effect study involving administration of baloxavir marboxil to healthy volunteers under fasting conditions and with a meal (approximately 400 to 500 kcal including 150 kcal from fat) indicated that the Cmax and AUC of baloxavir were decreased by 48% and 36%, respectively, under fed conditions. Tmax was unchanged in the presence of food. In clinical studies with influenza patients where XOFLUZA was administered with or without food, no clinically relevant differences in efficacy were observed.
Distribution: In an in vitro study, the binding of baloxavir to human serum proteins, primarily albumin, is 92.9% to 93.9%. The apparent volume of distribution of baloxavir following a single oral administration of 80 mg of baloxavir marboxil is approximately 1180 liters in Caucasian patients and 647 liters in Japanese subjects.
Metabolism: In vitro studies revealed that arylacetamide deacetylase in the gastrointestinal lumen, intestinal epithelium, and the liver mainly contributes to the conversion from baloxavir marboxil to baloxavir and baloxavir is primarily metabolized by UGT1A3 with minor contribution from CYP3A4.
In the human mass balance study, after administration of a single oral dose of 40 mg of [14C]-labeled baloxavir marboxil, baloxavir accounted for 82.2% of the plasma AUC for total radioactivity. Baloxavir glucuronide (16.4% of the plasma AUC for total radioactivity) and (12aR,5R,11S) sulfoxide of baloxavir (1.5% of the plasma AUC for total radioactivity) were also detected in plasma, confirming that the in vivo metabolism of baloxavir marboxil occurs via ester hydrolysis to form baloxavir with subsequent metabolism of baloxavir to form sulfoxides, and a glucuronide.
Excretion: Baloxavir marboxil and baloxavir were excreted mainly via fecal route in humans. Following a single oral administration of 40 mg of [14C]-labeled baloxavir marboxil, the amount of total radioactivity excreted were 80.1% of the administered dose in the feces and 14.7% in urine. The amount of baloxavir excreted in the urine was 3.3% of the administered dose.
Elimination: The apparent terminal elimination half-life (t½,z) of baloxavir after a single oral administration of baloxavir marboxil is 79.1 hours in Caucasian patients, and 93.9 hours in Japanese subjects, see Tables 6 and 7.
Linearity/non-linearity: Following single oral administration of baloxavir marboxil, baloxavir exhibits linear pharmacokinetics in the fasted state within the dose range of 6 mg to 80 mg.
Pharmacokinetics in Special Populations: Body weight: Body weight is identified as the significant covariate based on the population pharmacokinetic analysis. The dose proposed in adults is 40 mg for patients with body weight 40 kg to <80 kg, and 80 mg for patients with body weight ≥80 kg.
Gender: A population pharmacokinetic analysis did not identify a clinically meaningful effect of gender on the pharmacokinetics of baloxavir. No dose adjustment based on gender is required.
Race: Based on a population pharmacokinetic analysis, race is a covariate on CL/F of baloxavir in addition to body weight, however, no dose adjustment of baloxavir marboxil based on race is required.
Age: A population pharmacokinetic analysis using plasma baloxavir concentrations from clinical studies with baloxavir marboxil for subjects aged 12 to 64 years did not identify a clinically meaningful effect of age on the pharmacokinetics of baloxavir.
Pediatric Population: The pharmacokinetics of XOFLUZA in pediatric patients (<12 years of age) has not been established.
Geriatric Population: Pharmacokinetic data collected in patients ≥65 years show that drug exposure to baloxavir was similar to patients aged ≥12 to 64 years.
Renal impairment: The effects of renal impairment on the pharmacokinetics of baloxavir marboxil or baloxavir have not been evaluated. Renal impairment is not expected to alter the elimination of baloxavir marboxil or baloxavir. Renal excretion represents a minor pathway of elimination for baloxavir marboxil or baloxavir. A population pharmacokinetic analysis did not identify a clinically meaningful effect of renal function on the pharmacokinetics of baloxavir. No dose adjustment is required in patients with renal impairment.
Baloxavir is unlikely to be significantly removed by dialysis.
Hepatic impairment: Geometric mean ratios (90% confidence interval) of Cmax and AUC of baloxavir in patients with moderate hepatic impairment (Child-Pugh class B) compared to healthy controls were 0.80 (0.50-1.28) and 1.12 (0.78-1.61), respectively. Since no clinically meaningful differences in the pharmacokinetics of baloxavir were observed in patients with moderate hepatic impairment (Child-Pugh class B) compared with healthy controls with normal hepatic function, no dose adjustment is required in patients with mild or moderate hepatic impairment.
The pharmacokinetics in patients with severe hepatic impairment has not been evaluated.
Toxicology: Preclinical safety data: Nonclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity.
Carcinogenicity: Carcinogenicity studies have not been performed with baloxavir marboxil.
Genotoxicity: The pro-drug baloxavir marboxil, and its active form, baloxavir, were negative in bacterial reverse mutation tests, micronucleus tests with cultured mammalian cells, and baloxavir marboxil was negative in an in vivo rodent micronucleus test.
Impairment of Fertility: Baloxavir marboxil had no effects on fertility when given orally to male and female rats at doses up to 1000 mg/kg/day, which is equivalent to 5-times the human exposure based on AUC0-24hr.
Reproductive toxicity: Baloxavir marboxil did not cause malformations in rats or rabbits. The oral embryo-fetal development study of baloxavir marboxil in rats with daily doses from gestation day 6 to 17 revealed no signs of maternal or fetal toxicity up to the highest tested dose of 1000 mg/kg/day, which is equivalent to 5-times the human exposure based on AUC0-24hr.
In rabbits, a dose level of 1000 mg/kg/day (equivalent to 12-times the human exposure based on AUC0-24hr following the MHRD) caused maternal toxicity resulting in 2 miscarriages out of 19 and an increased incidence of fetuses with a skeletal variation (cervical rib), but no malformations. This minor skeletal variation is reabsorbed during the growing process of adjacent cervical vertebra. A dose of 100 mg/kg/day (equivalent to 7-times the human exposure based on AUC0-24hr) in rabbits was without adverse effects.
The pre- and postnatal study in rats did not show drug-related adverse findings in dams and pups up to the highest tested dose of 1000 mg/kg/day, which is equivalent to 5-times the human exposure based on AUC0-24hr.
Other: Not applicable.
Indications/Uses
XOFLUZA is indicated for the treatment of influenza in patients aged 12 and above who have been symptomatic for no more than 48 hours (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
XOFLUZA is indicated for treatment of influenza in patients aged 12 and above who have been symptomatic for no more than 48 hours, and are at high risk of developing influenza complications.
Limitations of Use: Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use XOFLUZA (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies: Resistance Monitoring during Clinical Development under Actions).
Dosage/Direction for Use
General: A single dose of XOFLUZA should be initiated within 48 hours of symptom onset.
XOFLUZA may be taken with or without food. Do not take XOFLUZA with dairy products, calcium-fortified beverages, laxatives, antacids, or oral supplements containing iron, zinc, selenium, calcium, or magnesium (see Pharmacology: Pharmacokinetics under Actions).
Adults and Adolescents (≥12 years of age): The recommended dose of XOFLUZA depending on body weight is shown in Table 8. (See Table 8.)

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Dose Modifications: No dose reductions of XOFLUZA are recommended.
Special Dosage Instructions: Pediatric use: The safety and efficacy of XOFLUZA in patients <12 years of age has not been established. For patients ≥12 years see previous text.
Geriatric use: No dosage adjustment is recommended (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations: Geriatric Population under Actions).
Renal Impairment: The safety and efficacy of XOFLUZA has not been studied in patients with renal impairment. A change in dose is not required for patients with renal impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations: Renal impairment under Actions).
Hepatic Impairment: No dose adjustment is required in patients with mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations: Hepatic impairment under Actions). XOFLUZA has not been studied in patients with severe hepatic impairment.
Overdosage
Clinical experience: No case of overdose has been reported.
Management:
No known specific antidote exists for XOFLUZA. In the event of overdose, standard supportive medical care should be initiated based on the patient's signs and symptoms.
Baloxavir is unlikely to be significantly removed by dialysis due to high serum protein binding.
Contraindications
XOFLUZA is contraindicated in patients with a known hypersensitivity to baloxavir marboxil or any of the excipients (see Postmarketing Experience under Adverse Reactions).
Special Precautions
General: No warnings and precautions based on the available data.
Drug Abuse and Dependence: Not applicable.
Effects on ability to drive and use machine effects: No studies on the effects on the ability to drive and to use machines have been performed.
Renal Impairment: The safety and efficacy of XOFLUZA in patients with renal impairment has not been studied. See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Hepatic Impairment: The safety and efficacy of XOFLUZA in patients with severe hepatic impairment has not been studied. See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use in Children: The safety and efficacy in pediatric patients (<12 years of age) has not been established.
Use in Elderly: The safety and efficacy of XOFLUZA for the treatment of influenza in geriatric patients age ≥ 65 years and weighing at least 40 kg have been established. See Special Dosage Instructions under Actions, Clinical Trials under Adverse Reactions and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use In Pregnancy & Lactation
Females and Males of Reproductive Potential: Fertility: No effects on fertility were observed in animal studies performed with baloxavir marboxil (see Pharmacology: Toxicology: Preclinical safety data: Impairment of Fertility under Actions).
Pregnancy: There are no adequate and well-controlled studies with XOFLUZA in pregnant women. The potential risk of XOFLUZA in pregnant women is unknown. XOFLUZA should be avoided during pregnancy unless the potential benefit justifies the potential risk to the fetus.
Baloxavir marboxil did not cause malformations in rats or rabbits. High dose levels of baloxavir marboxil given to pregnant rabbits caused maternal toxicity resulting in miscarriages and an increase in the incidence rates of minor skeletal abnormalities in rabbits but no malformations. Such effects were not seen in rats (see Pharmacology: Toxicology: Preclinical safety data: Reproductive toxicity under Actions.)
Labor and Delivery: The safe use of XOFLUZA during labor and delivery has not been established.
Lactation: It is not known whether baloxavir marboxil and the active metabolite, baloxavir, are excreted in human breast milk. When dosed at 1 mg/kg baloxavir marboxil or its metabolites are secreted in the milk of lactating rats.
Therefore, a decision should be made whether to discontinue nursing or to initiate treatment with XOFLUZA, taking into consideration the potential benefit of XOFLUZA to the nursing mother and the potential risk to the infant.
Adverse Reactions
Clinical Trials: The overall safety profile of XOFLUZA is based on data from 2109 subjects in 17 clinical trials receiving XOFLUZA. No adverse drug reactions have been identified based on pooled data from 3 placebo-controlled clinical studies (Studies 1518T0821, 1601T0831 and 1602T0832) in adult and adolescent patients, in which a total of 1640 patients have received XOFLUZA. This includes otherwise healthy adults, and adolescents and patients at high risk of developing complications associated with influenza, e.g. elderly patients and patients with chronic cardiac or respiratory disease. 1334 patients (81.3%) were adults ≥18 years to ≤64 years, 209 patients (12.7%) were adults ≥65 years and 97 patients (5.9%) were adolescents (≥12 years to <18 years). Of these, 1440 patients received XOFLUZA at 40 mg and 80 mg doses and 100 patients each received 10 mg or 20 mg doses. The safety profile in patients at high risk was similar to that in otherwise healthy adults and adolescents.
Postmarketing Experience: The following adverse drug reactions have been identified from postmarketing experience with baloxavir marboxil (Table 9) based on spontaneous case reports and cases from non-interventional study programs. Adverse drug reactions are listed according to system organ classes in MedDRA and the corresponding frequency category estimation for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 9.)

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Description of selected adverse drug reactions from postmarketing experience: Hypersensitivity reactions have been observed in the postmarketing setting which include reports of anaphylaxis/anaphylactic reactions and less severe forms of hypersensitivity reactions including urticaria and angioedema.
Drug Interactions
No clinically significant drug-drug interactions are anticipated between baloxavir marboxil or its active metabolite baloxavir and substrates, inhibitors, or inducers of cytochrome P450 (CYP enzymes), inhibitors of UDP-glucuronosyltransferase (UGT) enzyme, or gut, renal, or hepatic transporters.
Polyvalent cation containing products may decrease plasma concentrations of baloxavir. XOFLUZA should not be taken with polyvalent cation containing laxatives or antacids, or oral supplements containing iron, zinc, selenium, calcium, magnesium.
Effects of Other Drugs on Baloxavir Marboxil or its Active Metabolite Baloxavir: Itraconazole, an inhibitor of P gp, increased the Cmax and AUC0-inf of baloxavir 1.33 fold and 1.23 fold, respectively. These increases are not considered to be clinically meaningful.
Probenecid, an inhibitor of UGT enzyme, decreased the Cmax and AUC0-inf of baloxavir by 21% and 25%, respectively. These decreases are not considered to be clinically meaningful.
Effects of Baloxavir Marboxil or its Active Metabolite Baloxavir on Other Drugs: In in vitro studies at clinically relevant concentrations, baloxavir marboxil and its active metabolite, baloxavir did not inhibit any of the following isozymes of CYP or UGT family: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1,UGT1A3,UGT1A4,UGT1A6,UGT1A9,UGT2B7, and UGT2B15 isozymes). In in vitro studies at clinically relevant concentrations, baloxavir marboxil and baloxavir did not cause significant induction of CYP1A2, CYP2B6, and CYP3A4 . In in vitro transporter studies at clinically relevant concentrations, baloxavir marboxil and baloxavir inhibited the efflux transporter (P-gp). Baloxavir but not baloxavir marboxil inhibited BCRP.
Based on in vitro transporter studies, despite a weak in vitro inhibitory potential, baloxavir is not expected to be an in vivo inhibitor of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K, hence no relevant pharmacokinetic interaction is anticipated between baloxavir and medicines which are substrates of these transporters.
A single 40 mg dose of baloxavir marboxil did not affect the pharmacokinetics of midazolam, a substrate of CYP3A4, suggesting that baloxavir marboxil or baloxavir is not expected to affect the pharmacokinetics of co-administered drugs that are substrates of CYP3A.
A single 80 mg dose of baloxavir marboxil did not affect the pharmacokinetics of digoxin, a substrate of P-gp, suggesting that baloxavir marboxil or baloxavir is not expected to affect the pharmacokinetics of co-administered drugs that are substrates of P-gp.
A single 80 mg dose of baloxavir marboxil decreased Cmax and AUC0-inf of rosuvastatin, a substrate of BCRP, by 18% and 17%, respectively. These decreases are not considered to be clinically meaningful and indicate that baloxavir marboxil or baloxavir is not expected to affect the pharmacokinetics of co-administered drugs that are substrates of BCRP.
Caution For Usage
Incompatibilities: Not applicable.
Special Instructions for Use, Handling and Disposal: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Storage
Do not store above 30°C, store in the original package in order to protect from moisture.
Shelf-Life: 2 years.
MIMS Class
ATC Classification
J05AX25 - baloxavir marboxil ; Belongs to the class of other antivirals. Used as a direct acting antiviral in the systemic treatment of viral infections.
Presentation/Packing
FC tab 20 mg (white to light yellow, oblong shaped, debossed with "
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" on one side and "20" on the other side) x 2's. 40 mg (white to light yellow, oblong shaped, debossed on one side with "BXM40") x 2's.
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