rsi ad
 
drx ad
 
ad space

Baloxavir Marboxil Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Baloxavir marboxil is an antiviral PA endonuclease inhibitor. Baloxavir is supplied as white to light yellow film-coated tablets for oral administration.

Baloxavir marboxil has a partition coefficient (log P) of 2.26. It is freely soluble in dimethylsulfoxide, soluble in acetonitrile, slightly soluble in methanol and ethanol and practically insoluble in water.

The chemical name of baloxavir marboxil is ({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate. The chemical structure is shown below.

Empirical formula: C27H23F2N3O7S - Molecular weight: 571.55 g/mol

Inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, microcrystalline cellulose, povidone, sodium stearyl fumarate, talc, and titanium dioxide.

2. INDICATIONS AND USAGE

Baloxavir is indicated for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

Limitations of Use:

Influenza viruses change over time, and factors such as the virus type or subtype, emergence of resistance, or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating influenza virus strains when deciding whether to use baloxavir [see Microbiology and Clinical Studies].

3. DOSAGE AND ADMINISTRATION

Initiate treatment with baloxavir within 48 hours of influenza symptom onset. Baloxavir is taken orally as a single dose and may be taken with or without food. However, co-administration of baloxavir with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc) should be avoided [see Drug Interactions (7.1), Clinical Pharmacology].

Adults and Adolescents (12 years of age and older)

The recommended dose of baloxavir in patients 12 years of age or older with acute uncomplicated influenza is a single weight-based dose as follows:

Table 1: Recommended Baloxavir Dosage in Adults and Adolescents 12 Years and Older

4. CONTRAINDICATIONS

Baloxavir is contraindicated in patients with a history of hypersensitivity to baloxavir marboxil or any of its ingredients.

5. WARNINGS AND PRECAUTIONS

5.1 Risk of Bacterial Infections

There is no evidence of efficacy of baloxavir in any illness caused by pathogens other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms, may coexist with, or occur as a complication of influenza. Baloxavir has not been shown to prevent such complications. Prescribers should be alert to potential secondary bacterial infections and treat them as appropriate.

6. ADVERSE REACTIONS

6.1 Clinical Trials Experience

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

The safety profile of baloxavir is based on data from 2 placebo-controlled trials, in which a total of 910 subjects received baloxavir: 834 (92%) were adults (18 years and older) and 76 (8%) were adolescents (12 to less than 18 years). Of these, 710 subjects received baloxavir at the recommended dose. In Trial 1, adult subjects 20 to 64 years of age received a single oral dose of baloxavir or placebo. In Trial 2, adult subjects 20 to 64 years of age received baloxavir, placebo as a single oral dose on Day 1, or oseltamivir twice a day for 5 days, and adolescent subjects 12 to less than 20 years of age received baloxavir or placebo as a single oral dose.

Table 2 displays the most common adverse events (regardless of causality assessment) reported in at least 1% of adult and adolescent subjects who received baloxavir at the recommended dose in Trials 1 and 2.

Table 2: Incidence of Adverse Events Occurring in Greater Than or Equal to 1% of Subjects Receiving Baloxavir in the Acute Uncomplicated Influenza Trials

7. DRUG INTERACTIONS

7.1 Effect of Other Drugs on Baloxavir

Co-administration with polyvalent cation-containing products may decrease plasma concentrations of baloxavir which may reduce baloxavir efficacy. Avoid co-administration of baloxavir with polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc).

7.2 Vaccines

The concurrent use of baloxavir with intranasal live attenuated influenza vaccine (LAIV) has not been evaluated. Concurrent administration of antiviral drugs may inhibit viral replication of LAIV and thereby decrease the effectiveness of LAIV vaccination. Interactions between inactivated influenza vaccines and baloxavir have not been evaluated.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on baloxavir use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with influenza virus infection in pregnancy (see Clinical Considerations). In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits with oral administration of baloxavir marboxil at exposures approximately 5 (rats) and 7 (rabbits) times the systemic baloxavir exposure at the maximum recommended human dose (MRHD) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, stillbirth, birth defects, preterm delivery, low birth weight and small for gestational age.

Data

Animal Data

Baloxavir marboxil was administered orally to pregnant rats (20, 200, or 1,000 mg/kg/day from gestation day 6 to 17) and rabbits (30, 100, or 1,000 mg/kg/day from gestation day 7 to 19). No adverse embryo-fetal effects were observed in rats up to the highest dose of baloxavir marboxil (1,000 mg/kg/day), resulting in systemic baloxavir exposure (AUC) of approximately 5 times the exposure at the MRHD. In rabbits, fetal skeletal variations occurred at a maternally toxic dose (1,000 mg/kg/day) resulting in 2 abortions out of 19 pregnancies. No adverse maternal or embryo-fetal effects were observed in rabbits at the middle dose (100 mg/kg/day) resulting in systemic baloxavir exposure (AUC) approximately 7 times the exposure at the MRHD.

In the prenatal and postnatal development study in rats, baloxavir marboxil was administered orally at 20, 200, or 1,000 mg/kg/day from gestation day 6 to postpartum/lactation day 20. No significant effects were observed in the offspring at maternal systemic baloxavir exposure (AUC) approximately 5 times the exposure at the MRHD.

8.2 Lactation

Risk Summary

There are no data on the presence of baloxavir marboxil in human milk, the effects on the breastfed infant, or the effects on milk production. Baloxavir and its related metabolites were present in the milk of lactating rats (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for baloxavir and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Data

In a lactation study, baloxavir and its related metabolites were excreted in the milk of lactating rats administered baloxavir marboxil (1 mg/kg) on postpartum/lactation day 11, with peak milk concentration approximately 5 times that of maternal plasma concentrations occurring 2 hours post-dose. No effects of baloxavir marboxil on growth and postnatal development were observed in nursing pups at the highest oral dose tested in rats. Maternal systemic exposure was approximately 5 times the baloxavir exposure in humans at the MRHD.

8.4 Pediatric Use

The safety and effectiveness of baloxavir for the treatment of influenza have been established in pediatric patients 12 years of age and older weighing at least 40 kg [see Adverse Reactions (6.1) and Clinical Studies]. The safety and effectiveness of baloxavir have not been established in pediatric patients less than 12 years of age.

The use of baloxavir in pediatric patients 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind, controlled trial [see Clinical Studies]. In this phase 3 trial, 118 adolescents were randomized to receive either baloxavir (N=80) or placebo (N=38). The median time to alleviation of symptoms in adolescent subjects was 54 hours compared to 93 hours for subjects who received placebo. Adverse reactions reported in adolescents were similar to those reported in adults [see Adverse Reactions (6.1)].

8.5 Geriatric Use

Clinical trials of baloxavir did not include subjects 65 years of age and older to determine whether they respond differently from younger subjects.

9. OVERDOSAGE

There have been no reports of baloxavir overdoses. Treatment of an overdose of baloxavir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with baloxavir.

Baloxavir is unlikely to be significantly removed by dialysis due to high serum protein binding [see Clinical Pharmacology].

10. MECHANISM OF ACTION

Baloxavir marboxil is an antiviral drug with activity against influenza virus [see Microbiology].

Mechanism of Action

Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza virus activity. Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication. The 50% inhibitory concentration (IC50) of baloxavir was 1.4 to 3.1 nM (n=4) for influenza A viruses and 4.5 to 8.9 nM (n=3) for influenza B viruses in a PA endonuclease assay. Viruses with reduced susceptibility to baloxavir have amino acid substitutions in the PA protein.

Antiviral Activity

The antiviral activity of baloxavir against laboratory strains and clinical isolates of influenza A and B viruses was determined in an MDCK-cell-based plaque reduction assay. The median 50% effective concentration (EC50) values of baloxavir were 0.73 nM (n=19; range: 0.20-1.85 nM) for subtype A/H1N1 strains, 0.68 nM (n=19; range: 0.35-1.87 nM) for subtype A/H3N2 strains, and 5.28 nM (n=21; range: 3.33-13.00 nM) for type B strains. In an MDCK-cell-based virus titer reduction assay, the 90% effective concentration (EC90) values of baloxavir against avian subtypes A/H5N1 and A/H7N9 were 1.64 and 0.80 nM, respectively. The relationship between antiviral activity in cell culture and clinical response to treatment in humans has not been established.

Resistance

Cell culture: Influenza A virus isolates with reduced susceptibility to baloxavir were selected by serial passage of virus in cell culture in the presence of increasing concentrations of baloxavir. Reduced susceptibility of influenza A virus to baloxavir was conferred by amino acid substitutions I38T (A/H1N1 and A/H3N2) and E199G (A/H3N2) in the PA protein of the viral RNA polymerase complex.

Clinical studies: Influenza A and B viruses with treatment-emergent amino acid substitutions at positions associated with reduced susceptibility to baloxavir in cell culture were observed in clinical studies (Table 3). The overall incidence of treatment-emergent amino acid substitutions associated with reduced susceptibility to baloxavir in Trials 1 and 2 was 2.7% (5/182) and 11% (39/370), respectively.

Table 3: Treatment-Emergent Amino Acid Substitutions in PA Associated with Reduced Susceptibility to Baloxavir

None of the treatment-emergent substitutions associated with reduced susceptibility to baloxavir were identified in virus from pre-treatment respiratory specimens in the clinical studies. Strains containing substitutions known to be associated with reduced susceptibility to baloxavir were identified in approximately 0.05% of PA sequences in the National Center for Biotechnology Information/GenBank database (queried August 2018).

Prescribers should consider currently available surveillance information on influenza virus drug susceptibility patterns and treatment effects when deciding whether to use baloxavir.

Cross-Resistance

Cross-resistance between baloxavir and neuraminidase (NA) inhibitors, or between baloxavir and M2 proton pump inhibitors (adamantanes), is not expected, because these drugs target different viral proteins. Baloxavir is active against NA inhibitor-resistant strains, including A/H1N1 and A/H5N1 viruses with the NA substitution H275Y (A/H1N1 numbering), A/H3N2 virus with the NA substitution E119V, A/H7N9 virus with the NA substitution R292K (A/H3N2 numbering), and type B virus with the NA substitution D198E (A/H3N2 numbering). The NA inhibitor oseltamivir is active against viruses with reduced susceptibility to baloxavir, including A/H1N1 virus with PA substitutions E23K or I38F/T, A/H3N2 virus with PA substitutions E23G/K, A37T, I38M/T, or E199G, and type B virus with the PA substitution I38T. Influenza virus may carry amino acid substitutions in PA that reduce susceptibility to baloxavir and at the same time carry resistance-associated substitutions for NA inhibitors and M2 proton pump inhibitors. The clinical relevance of phenotypic cross-resistance evaluations has not been established.

Immune Response

Interaction studies with influenza vaccines and baloxavir marboxil have not been conducted.

11. PHARMACODYNAMICS

Cardiac Electrophysiology

At twice the expected exposure from recommended dosing, baloxavir did not prolong the QTc interval.

Exposure-Response Relationships

No change in the baloxavir exposure-response (time to alleviation of symptoms) relationship was observed at the recommended dosing.

12. PHARMACOKINETICS

Baloxavir marboxil is a prodrug that is almost completely converted to its active metabolite, baloxavir, following oral administration.

In the phase 3 trial, at the recommended dose of 40 mg for subjects weighing less than 80 kg, the mean (CV%) values of baloxavir Cmax and AUC0-inf were 96.4 ng/mL (45.9%) and 6160 ng·hr/mL (39.2%), respectively. At the recommended dose of 80 mg for subjects weighing 80 kg and more, the mean (CV%) values of baloxavir Cmax and AUC0-inf were 107 ng/mL (47.2%) and 8009 ng·hr/mL (42.4%), respectively. Refer to Table 4 for pharmacokinetic parameters of baloxavir in healthy subjects.

Table 4: Pharmacokinetic Parameters of Plasma Baloxavir

baloxavir_kin

a Median

b Meal: approximately 400 to 500 kcal including 150 kcal from fat

c in vitro

d Geometric mean (geometric CV%)

e Apparent terminal elimination half-life

f Baloxavir is primarily metabolized by UGT1A3 with minor contribution from CYP3A4

g Ratio of radioactivity to radio-labeled [14C]-baloxavir marboxil dose in mass balance study

Specific Populations

There were no clinically significant differences in the pharmacokinetics of baloxavir based on age (adolescents as compared to adults), or sex.

Patients with Renal Impairment

A population pharmacokinetic analysis did not identify a clinically meaningful effect of renal function on the pharmacokinetics of baloxavir in patients with creatinine clearance (CrCl) 50 mL/min and above. The effects of severe renal impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite, baloxavir, have not been evaluated.

Patients with Hepatic Impairment

In a clinical study comparing pharmacokinetics of baloxavir in subjects with moderate hepatic impairment (Child-Pugh class B) to subjects with normal hepatic function, no clinically meaningful differences in the pharmacokinetics of baloxavir were observed.

The pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

Body Weight

Body weight had a significant effect on the pharmacokinetics of baloxavir (as body weight increases, baloxavir exposure decreases). When dosed with the recommended weight-based dosing, no clinically significant difference in exposure was observed between body weight groups.

Race/Ethnicity

Based on a population pharmacokinetic analysis, baloxavir exposure is approximately 35% lower in non-Asians as compared to Asians; this difference is not considered clinically significant when the recommended dose was administered.

Drug Interaction Studies

Clinical Studies

No clinically significant changes in the pharmacokinetics of baloxavir marboxil and its active metabolite, baloxavir, were observed when co-administered with itraconazole (combined strong CYP3A and P-gp inhibitor), probenecid (UGT inhibitor), or oseltamivir.

No clinically significant changes in the pharmacokinetics of the following drugs were observed when co-administered with baloxavir marboxil: midazolam (CYP3A4 substrate), digoxin (P-gp substrate), rosuvastatin (BCRP substrate), or oseltamivir.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

Cytochrome P450 (CYP) Enzymes: Baloxavir marboxil and its active metabolite, baloxavir, did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Baloxavir marboxil and its active metabolite, baloxavir, did not induce CYP1A2, CYP2B6, or CYP3A4.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Baloxavir marboxil and its active metabolite, baloxavir, did not inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.

Transporter Systems: Both baloxavir marboxil and baloxavir are substrates of P-glycoprotein (P-gp). Baloxavir did not inhibit organic anion transporting polypeptides (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K.

Potential for Interactions with Polyvalent Cations: Baloxavir may form a chelate with polyvalent cations such as calcium, aluminum, or magnesium in food or medications. A significant decrease in baloxavir exposure was observed when baloxavir was co-administered with calcium, aluminum, magnesium, or iron in monkeys. No study has been conducted in humans.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

XOFLUZA Tablets:

 20 mg white to light yellow, oblong shaped film-coated tablets debossed with “logo 772” on one side and “20” on the other side available as:

o 2 x 20 mg tablets per blister card in secondary packaging: NDC 50242-828-02

o 4 x 20 mg tablets per blister card in secondary packaging: NDC 50242-828-04

 40 mg white to light yellow, oblong shaped film-coated tablets debossed with “BXM40” on one side available as:

o 1 x 40 mg tablet per blister card in secondary packaging: NDC 50242-860-01

o 2 x 40 mg tablets per blister card in secondary packaging: NDC 50242-860-02

Storage and Handling:

Store in its blister package at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Rx only

Rev 10/18