XOFLUZA Film-coated tablet Ref.[9938] Active ingredients: Baloxavir marboxil

5.1 Hypersensitivity

Cases of anaphylaxis, urticaria, angioedema, and erythema multiforme have been reported in post-marketing experience with XOFLUZA. Appropriate treatment should be instituted if an allergic-like reaction occurs or is suspected. The use of XOFLUZA is contraindicated in patients with known hypersensitivity to XOFLUZA [see Contraindications (4) and Adverse Reactions (6.2)].

5.2 Risk of Bacterial Infections

There is no evidence of efficacy of XOFLUZA 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. XOFLUZA has not been shown to prevent such complications. Prescribers should be alert to potential secondary bacterial infections and treat them as appropriate.

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 XOFLUZA is based on data from 3 placebo-controlled trials in which a total of 1,640 subjects received XOFLUZA: 1,334 subjects (81%) were 18 to 64 years of age, 209 subjects (13%) were adults 65 years of age or older and 97 subjects (6%) were adolescents 12 to 17 years of age. These trials included otherwise healthy adults and adolescents (N=910) and subjects at high risk of developing complications associated with influenza (N=730). Of these, 1,440 subjects received XOFLUZA at the recommended dose [see Clinical Studies (14)].

Table 2 displays the most common adverse events (regardless of causality assessment) reported in at least 1% of adult and adolescent subjects who received XOFLUZA at the recommended dose in Trials 1, 2 and 3.

Table 2. Incidence of Adverse Events Occurring in At Least 1% of Subjects Receiving XOFLUZA in the Acute Uncomplicated Influenza Trials 1, 2, and 3:

The following adverse reactions have been identified during postmarketing use of XOFLUZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to XOFLUZA exposure.

Body as a Whole: Swelling of the face, eyelids or tongue, dysphonia, angioedema, anaphylactic reactions, anaphylactic shock, anaphylactoid reactions

Skin and Subcutaneous Tissue Disorders: Rash, urticaria, erythema multiforme

Gastrointestinal disorders: Vomiting, bloody diarrhea, melena, colitis

Psychiatric: Delirium, abnormal behavior, and hallucinations

7.1 Effect of Other Drugs on XOFLUZA

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

7.2 Vaccines

The concurrent use of XOFLUZA 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 XOFLUZA have not been evaluated.

Risk Summary

There are no available data on XOFLUZA 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.

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 XOFLUZA 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.

The safety and effectiveness of XOFLUZA for the treatment of acute uncomplicated 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 (14)]. The safety and effectiveness of XOFLUZA have not been established in pediatric patients less than 12 years of age.

Treatment of Acute Uncomplicated Influenza in Otherwise Healthy Pediatric Patients

The safety and effectiveness of XOFLUZA in otherwise healthy pediatric patients 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind, controlled trial (Trial 2) [see Clinical Studies (14.1)]. In this phase 3 trial, 117 adolescents 12-17 years old were randomized and received either XOFLUZA (N=76) or placebo (N=41). The median time to alleviation of symptoms in influenza-infected adolescent subjects aged 12 to 17 years was 54 hours and 93 hours for subjects who received XOFLUZA (N=63) or placebo (N=27), respectively, and was comparable to that observed in the overall trial population [see Clinical Studies (14.1)]. Adverse events reported in adolescents were similar to those reported in adults [see Adverse Reactions (6.1)].

Treatment of Acute Uncomplicated Influenza in Pediatric Patients at High Risk for Influenza Complications

The safety and effectiveness of XOFLUZA in pediatric patients 12 years of age and older weighing at least 40 kg who are at high risk of developing influenza-related complications is supported by extrapolation from a clinical trial in otherwise healthy adults and adolescents with acute uncomplicated influenza (Trial 2), and from one randomized, double-blind, phase 3 controlled trial in patients at high risk for influenza complications (Trial 3) in which 38 adolescents aged 12 to 17 years were randomized and received either XOFLUZA (N=21) or placebo (N=17). The median time to improvement of influenza symptoms in the limited number of adolescent subjects aged 12 to 17 years who were infected with influenza was similar for subjects who received XOFLUZA (188 hours) or placebo (191 hours) (N=13 and N=12, respectively) [see Clinical Studies (14.2)]. Adverse events reported in adolescents were similar to those reported in adults [see Adverse Reactions (6.1)].

The safety and effectiveness of XOFLUZA in subjects 65 years of age and older has been established and is supported by one randomized, double-blind, controlled trial [see Clinical Studies (14.2)]. In Trial 3, of 730 XOFLUZA-treated subjects at high risk of influenza-related complications, 209 (29%) subjects were 65 years of age and older. The median time to improvement of influenza symptoms in subjects 65 years of age and older was 70 hours in subjects who received XOFLUZA (N=112) and 88 hours in those who received placebo (N=102). The safety profile observed for this population was similar to that reported in the overall trial population except for nausea, which was reported in 6% of elderly subjects compared to 1% of subjects from 18 to 64 years of age.