Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

XOFLUZA (NDA-210854)

(BALOXAVIR MARBOXIL)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/01/2024 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

In an active-controlled, double-blind trial Trial CP40563 in pediatric subjects, a total of 79 subjects 5 to less than 12 years of age, received the recommended weight-based dosage of XOFLUZA, and 39 subjects received oseltamivir. Of the 118 subjects 5 to less than 12 years of age in Trial CP40563, 15 subjects in the XOFLUZA arm and 4 subjects in the oseltamivir arm were at high risk of developing influenza complications. The most frequently reported AEs (greater than or equal to 5%) in all subjects in the XOFLUZA treatment arm were vomiting (5%) and diarrhea (5%). Vomiting was reported in 18% of subjects in the oseltamivir arm [see Clinical Studies (14.1)]. There are limited safety data in patients 5 to <12 years at high risk of developing influenza complications.

…

08/11/2022 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Increased Incidence of Treatment-Emergent Resistance in Patients Less Than 5 Years of Age

Newly added subsection:

XOFLUZA is not indicated in patients less than 5 years of age due to increased incidence of treatment- emergent resistance in this age group. In clinical trials, the incidence of virus with treatment-emergent substitutions associated with reduced susceptibility to baloxavir (resistance) was higher in pediatric subjects younger than 5 years of age (43%, 36/83) than in pediatric subjects ? 5 years to < 12 years of age (16%, 19/117) or subjects ? 12 years of age (7%, 60/842). The potential for transmission of resistant strains in the community has not been determined [see Indications and Usage (1), Use in Specific Populations (8.4), and Microbiology (12.4)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Treatment of Acute Uncomplicated Influenza in Adolescent Subjects (? 12 Years of Age)

The safety and effectiveness of XOFLUZA for the treatment of acute uncomplicated influenza in adolescent subjects 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind, controlled trial in otherwise healthy subjects Trial T0831 and one trial in subjects at high risk of developing influenza-related complications Trial T0832 [see Clinical Studies (14.1)]. A total of 117 otherwise healthy adolescents 12 to17 years of age were randomized and received either XOFLUZA (N=76) or placebo (N=41) in Trial T0831; 38 adolescents 12 to 17 years of age at high risk for influenza complications were randomized and received either XOFLUZA (N=21) or placebo (N=17) in Trial T0832. The median time to alleviation of symptoms in influenza-infected adolescent subjects aged 12 to 17 years in Trial T0831 was comparable to that observed in adults. In Trial T0832, the median time to improvement of symptoms in the limited number of influenza-infected adolescent subjects aged 12 to 17 years was similar in the XOFLUZA and placebo arms [see Clinical Studies (14.1)]. Adverse events reported in adolescents in both trials were similar to those reported in adults [see Adverse Reactions (6.1)].

Treatment of Acute Uncomplicated Influenza in Pediatric Subjects (5 to < 12 Years of Age)

The safety and effectiveness of XOFLUZA in otherwise healthy pediatric subjects 5 to less than 12 years of age is supported by one randomized, double-blind, controlled trial Trial CP40563 with a primary endpoint of safety. In this trial, 118 otherwise healthy pediatric subjects were randomized and treated in a 2:1 ratio and received either XOFLUZA (N=79) or oseltamivir (N=39). Efficacy was extrapolated from adults and adolescents based on comparable PK exposures in adults, adolescents and pediatric subjects 5 to less than 12 years of age. The median time to alleviation of signs and symptoms in influenza-infected subjects was comparable in the XOFLUZA and oseltamivir arms. Adverse events reported with XOFLUZA in pediatric subjects were similar to those observed in adults and adolescents except for vomiting and diarrhea, which were both more commonly reported in pediatric subjects [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

Post-Exposure Prophylaxis of Influenza in Pediatric and Adolescent Subjects (5 to < 18 Years of Age)

The safety and effectiveness of XOFLUZA for post-exposure prophylaxis in pediatric and adolescent subjects 5 to less than 18 years of age is supported by one randomized, double-blind, controlled trial conducted in Japan Trial T0834 [see Clinical Studies (14.3)]. Subjects in this trial were randomized in a 1:1 ratio to receive XOFLUZA or placebo. A total of 69 subjects from 5 to <18 years of age in Trial T0834 received XOFLUZA. The incidence of RT-PCR-confirmed symptomatic influenza in pediatric subjects 5 to <18 years of age was similar to that observed in adult subjects [see Clinical Pharmacology (12.3), and Clinical Studies (14.3)]. Efficacy was extrapolated from adults based on comparable PK exposures in adults, adolescents and pediatric subjects 5 to <18 years of age.

Adverse events reported in pediatric and adolescent subjects were similar to those reported in adults in the same trial [see Adverse Reactions (6.1)].

Pediatric Subjects (< 5 Years of Age)

The safety and effectiveness of XOFLUZA for treatment and post-exposure prophylaxis of influenza in pediatric subjects less than 5 years of age have not been established [see Warnings and Precautions (5.2) and Microbiology (12.4)].

8.5 Geriatric Use

Additions and/or revisions underlined:

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 T0832, 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Tablets: Provided as a blister card containing either one tablet of 40 mg, or one tablet of 80 mg as a single dose [see Dosage and Administration (2.2)].

For oral suspension: Provided in a bottle containing 40 mg/20 mL (2 mg/mL) after constitution by the healthcare provider [see How Supplied/Storage and Handling (16)]. Advise the patients and/or caregiver to use a measuring device (oral syringe) to measure their prescribed dose. Counsel patients and/or caregivers how to use the measuring device (oral syringe) provided and inform patients that they may need to draw up XOFLUZA for oral suspension multiple times using the oral syringe to receive the full dosage. The suspension should be taken as soon as possible but no later than 10 hours after constitution by the healthcare provider because the product does not contain a preservative [see Dosage and Administration (2.2, 2.3)].

…

PATIENT INFORMATION

Extensive changes; please refer to label

11/23/2020 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

The overall safety profile of XOFLUZA is based on data from 1,943 subjects 12 years of age and older in 4 controlled clinical trials who received XOFLUZA [see Clinical Studies (14)].

Treatment of Acute Uncomplicated Influenza

Adult and Adolescent Subjects:

The safety of XOFLUZA in adult and adolescent subjects is based on data from 3 placebo-controlled trials in which a total of 1,640 subjects received XOFLUZA: 1,334 (81%) subjects were 18 to 64 years of age, 209 (13%) subjects were adults 65 years of age or older, and 97 (6%) subjects were adolescents 12 to 17 years ofage. 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 (14.1, 14.2)]. Trial 1 was a phase 2 dose-finding placebo- controlled trial where otherwise received weight-based XOFLUZA or placebo as a single oral dose on Day 1 or oseltamivir twice a day for 5 days. Trial 3 was a randomized, double-blind, placebo- and active- controlled trial where adults and adolescents at high risk of influenza complications 12 years of age and older received either XOFLUZA, placebo or oseltamivir.healthy adult subjects 20 to 64 years of age received single oral dose of XOFLUZA or placebo. Trial 2 was a placebo- and active-controlled trial in otherwise healthy adults and adolescents 12 to 64 years of age; subjects received weight-based XOFLUZA or placebo as a single oral dose on Day 1 or oseltamivir twice a day for 5 days. Trial 3 was a randomized, double-blind, placebo- and active- controlled trial where adults and adolescents at high risk of influenza complications 12 years of age and older received either XOFLUZA, placebo or oseltamivir.

…

Post-Exposure Prophylaxis of Influenza

The safety of XOFLUZA in adult and adolescent subjects is based on data from one placebo-controlled clinical trial in which 374 subjects, of which 303 were adult and adolescent subjects ? 12 years, received XOFLUZA: eight (3%) subjects were adults 65 years of age or older, and 12 (4%) subjects were adolescents 12 to 17 years of age. The most frequently reported AE in the total study population was nasopharyngitis which occurred in 6% of subjects who received XOFLUZA and 7% on placebo [see Clinical Studies (14.3)].

6.2 Postmarketing Experience

Additions underlined

…

Immune System Disorders: Anaphylactic reactions, anaphylactic shock, anaphylactoid reactions, hypersensitivity reactions, angioedema (swelling of face, eyelids, tongue and lips)

…

7 Drug Interactions

7.1 Effect of Other Drugs on XOFLUZA

Additions underlined

Baloxavir may form a chelate with polyvalent cations such as calcium, aluminum, or magnesium. Coadministration with polyvalent cation-containing products may decrease plasma concentrations of baloxavir [see Clinical Pharmacology (12.3)], which may reduce XOFLUZA efficacy. Avoid coadministration of XOFLUZA with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc).

8 Use in Specific Populations

8.4 Pediatric Use

Additions underlined

Treatment of Acute Uncomplicated Influenza in Pediatric Subjects

The safety and effectiveness of XOFLUZA for the treatment of acute uncomplicated influenza in pediatric subjects 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind, controlled trial in otherwise healthy subjects (Trial 2) and one trial in subjects at high risk of developing influenza-related complications (Trial 3) [see Clinical Studies (14.1)]. A total of 117 otherwise healthy adolescents 12-17 years old were randomized and received either XOFLUZA (N=76) or placebo (N=41) in Trial 2; 38 adolescents aged 12 to 17 years at high risk for influenza complications were randomized and received either XOFLUZA (N=21) or placebo (N=17) in Trial 3. The median time to alleviation of symptoms in influenza-infected adolescent subjects aged 12 to 17 years in Trial 2 was comparable to that observed in adults. In Trial 3, the median time to improvement of symptoms in the limited number of influenza-infected adolescent subjects aged 12 to 17 years was similar in the XOFLUZA and placebo arms [see Clinical Studies (14.1)].

Adverse events reported in adolescents in both trials were similar to those reported in adults [see Adverse Reactions (6.1)].

The safety and efficacy of XOFLUZA in pediatric subjects less than 12 years of age have not been established for the treatment of acute uncomplicated influenza. For information on baloxavir resistance in subjects less than 12 years of age [see Microbiology (12.4)].

Post-Exposure Prophylaxis of Influenza in Pediatric Subjects

The safety and effectiveness of XOFLUZA for post-exposure prophylaxis in adolescents (12 years to < 18 years) is supported by one randomized, double-blind, controlled trial conducted in Japan (Trial 4) [see Clinical Studies (14.3)]. Subjects in this trial were randomized in a 1:1 ratio to receive XOFLUZA or placebo. A total of 12 subjects from greater than or equal to 12 to < 18 years of age received XOFLUZA. The incidence of RT-PCR-confirmed symptomatic influenza was similar in the XOFLUZA and placebo arms in the limited number of adolescent subjects aged 12 to 17 years of age [see Clinical Studies (14.3)]. Adverse events reported in adolescent subjects were similar to those reported in adults in the same trial [see Adverse Reactions (6.1)].

The safety and efficacy of XOFLUZA for post-exposure prophylaxis of influenza in pediatric subjects less than 12 years of age have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions underlined

…

Important Dosing Information

Instruct patients to begin treatment with XOFLUZA as soon as possible at the first appearance of influenza symptoms, within 48 hours of onset of symptoms. Instruct patients to start taking XOFLUZA for prevention as soon as possible after exposure [see Dosage and Administration (2)].

…

Advise patients to follow the healthcare provider’s dosing recommendation for a single, one-time dose of XOFLUZA. XOFLUZA is dosed based on weight and is available in tablet form or as for oral suspension for oral or enteral use.

Tablets: Provided as blister cards containing either two tablets of 20 mg to be taken together as a single 40 mg dose or blister cards containing two tablets of 40 mg to be taken together as a single 80 mg dose [see Dosage and Administration (2.2)].

For oral suspension: Provided in a bottle containing 40 mg/20 mL (2 mg/mL) after constitution by the healthcare provider [see How Supplied/Storage and Handling (16)]. The total prescribed dose of XOFLUZA for oral suspension may require more than one bottle. The suspension should be taken as soon as possible but no later than 10 hours after constitution by the healthcare provider because the product does not contain a preservative [see Dosage and Administration (2.3)].

…

PATIENT INFORMATION

Extensive additions please refer to label for complete information.

11/23/2020 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

The overall safety profile of XOFLUZA is based on data from 1,943 subjects 12 years of age and older in 4 controlled clinical trials who received XOFLUZA [see Clinical Studies (14)].

Treatment of Acute Uncomplicated Influenza

Adult and Adolescent Subjects:

…

Post-Exposure Prophylaxis of Influenza

6.2 Postmarketing Experience

Additions underlined

…

Immune System Disorders: Anaphylactic reactions, anaphylactic shock, anaphylactoid reactions, hypersensitivity reactions, angioedema (swelling of face, eyelids, tongue and lips)

…

7 Drug Interactions

7.1 Effect of Other Drugs on XOFLUZA

Additions underlined

8 Use in Specific Populations

8.4 Pediatric Use

Additions underlined

Treatment of Acute Uncomplicated Influenza in Pediatric Subjects

Adverse events reported in adolescents in both trials were similar to those reported in adults [see Adverse Reactions (6.1)].

Post-Exposure Prophylaxis of Influenza in Pediatric Subjects

The safety and efficacy of XOFLUZA for post-exposure prophylaxis of influenza in pediatric subjects less than 12 years of age have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions underlined

…

Important Dosing Information

…

PATIENT INFORMATION

Extensive additions please refer to label for complete information.

10/16/2019 (SUPPL-1)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

XOFLUZA is contraindicated in patients with a history of hypersensitivity to baloxavir marboxil or any of its ingredients. Serious allergic reactions have included anaphylaxis, angioedema, urticaria and erythema multiforme.

5 Warnings and Precautions

Newly added subsection:

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.

6 Adverse Reactions

Clinical Trials Experience

Additions and/or revisions underlined:

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.

Table 2 is updated with data from an additional trial. Please see label for complete information.

Newly added subsection:

Postmarketing Experience

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

8 Use in Specific Populations

Geriatric Use

Newly added information:

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. 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.

Pediatric Use

Additions and/or revisions underlined:

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. 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). 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. Adverse events reported in adolescents were similar to those reported in adults.

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). Adverse events reported in adolescents were similar to those reported in adults.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Newly added information:

· Your healthcare provider will prescribe 2 tablets of XOFLUZA you will take at the same time as a single dose.

Additions and/or revisions underlined:

What are the possible side effects of XOFLUZA? XOFLUZA may cause serious side effects, including:

· Allergic reactions. Get emergency medical help right away if you develop any of these signs and symptoms of an allergic reaction:

o trouble breathing o swelling of your face, throat or mouth

o skin rash, hives or blisters o dizziness or lightheadedness

The most common side effects of XOFLUZA in adults and adolescents include:

· diarrhea · headache

· bronchitis · nausea

· sinusitis