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.

TAMIFLU (NDA-021087)

(OSELTAMIVIR PHOSPHATE)

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

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08/02/2019 (SUPPL-71)

Approved Drug Label (PDF)

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

PATIENT INFORMATION

(additions underlined)

…

How should I store TAMIFLU?

…

Store TAMIFLU for oral suspension in the refrigerator for up to 17 days between 36ºF to 46ºF (2ºC to 8ºC). Do not freeze.

…

12/12/2018 (SUPPL-70)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion; extensive changes. Please refer to label for complete information.

04/04/2018 (SUPPL-69)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.8 Use in Patients with Chronic Conditions

(Additions and/or revisions are underlined)

Efficacy of TAMIFLU in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease was evaluated in one randomized, placebo-controlled clinical trial. Efficacy in this population, as measured by time to alleviation of all symptoms, was not established, but no new safety signals were identified.

06/20/2016 (SUPPL-68)

Approved Drug Label (PDF)

5 Warnings and Precautions

Fructose Intolerance in Patients with Hereditary Fructose Intolerance (additional subsection)

Fructose can be harmful to patients with hereditary fructose intolerance. One dose of 75 mg TAMIFLU for oral suspension delivers 2 grams of sorbitol. This is above the daily maximum limit of sorbitol for patients with hereditary fructose intolerance, and may cause dyspepsia and diarrhea.

Neuropsychiatric Events

(Addition of sentences to section) Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. Closely monitor TAMIFLU-treated patients with influenza for signs of abnormal behavior.

Risk of Bacterial Infections

(addition of sentences to section) There is no evidence for efficacy of TAMIFLU in any illness caused by pathogens other than influenza viruses.
Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.

Serious Skin/Hypersensitivity Reactions

(Addition of sentence to section)The use of TAMIFLU is contraindicated in patients with known serious hypersensitivity to TAMIFLU.

6 Adverse Reactions

(throughout section, converting safety information from Adverse Events to Adverse Drug Reactions)

Clinical Trials Experience (following are new sub-sections)

Adverse Reactions from Treatment and Prophylaxis Trials in Adult and Adolescent Subjects (13 years of age and older)

The overall safety profile of TAMIFLU is based on data from 2,646 adult and adolescent subjects that received the recommended dosage of 75 mg orally twice daily for 5 days for treatment of influenza and 1,943 adult and adolescent subjects that received the recommended dosage of 75 mg orally once daily for up to 6 weeks for prophylaxis of influenza in clinical trials.
The most common adverse reactions in the pooled treatment and pooled prophylaxis trials in adults and adolescents are displayed in Table 5. The majority of these adverse reactions were reported on a single occasion, occurred on either the first or second treatment day and resolved spontaneously within 1-2 days. This summary includes otherwise healthy adults/adolescents and subjects “at risk” (subjects at higher risk of developing complications associated with influenza, e.g., elderly patients and patients with chronic cardiac or respiratory disease). In general, the safety profile in the subjects “at risk” was qualitatively similar to that in otherwise healthy adults/adolescents.
Table 5 Adverse Reactions Occurring in =1% of Adults and Adolescents (13 years of age and older) in Treatment and Prophylaxis Trials*
- New table added. Please see label for full table.

Adverse Reactions from Treatment and Prophylaxis Trials in Pediatric Subjects (1 year to 12 years of age)

A total of 1,481 pediatric subjects (including otherwise healthy pediatric subjects aged 1 year to 12 years and asthmatic pediatric subjects aged 6 to 12 years) participated in clinical trials of TAMIFLU for the treatment of influenza. A total of 859 pediatric subjects received treatment with TAMIFLU for oral suspension either at a 2 mg per kg twice daily for 5 days or weight-band dosing. Vomiting was the only adverse reaction reported at a frequency of >1% in subjects receiving TAMIFLU (16%) compared to placebo (8%).
Amongst the 148 pediatric subjects aged 1 year to 12 years who received TAMIFLU at doses of 30 to 60 mg once daily for 10 days in a post-exposure prophylaxis study in household contacts (n = 99), and in a separate 6–week seasonal influenza prophylaxis safety study (n = 49), vomiting was the most frequent adverse reaction (8% on TAMIFLU versus 2% in the no prophylaxis group).

Adverse Reactions from Treatment Trials in Pediatric Subjects (2 weeks to less than 1 year of age) (updated sub-section)

Assessment of adverse reactions in pediatric subjects 2 weeks to less than 1 year of age was based on two open label studies that included safety data on 135 influenza-infected subjects 2 weeks to less than 1 year of age (including premature infants at least 36 weeks post conceptional age) exposed to TAMIFLU at doses ranging from 2 to 3.5 mg per kg of the formulation for oral suspension twice daily orally for 5 days. The safety profile of TAMIFLU was similar across the age range studied, with vomiting (9%), diarrhea (7%) and diaper rash (7%) being the most frequently reported adverse reactions, and was generally comparable to that observed in older pediatric and adult subjects.

Adverse Reactions from the Prophylaxis Trial in Immunocompromised Subjects (renamed sub-section)

Postmarketing Experience

(section has undergone numerous changes as listed below)

General disorders and administration site conditions: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia
Skin and subcutaneous tissue disorders: Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme
Gastrointestinal Disorders: Gastrointestinal bleeding, hemorrhagic colitis
Cardiac Disorders: Arrhythmia
Hepatobiliary Disorders: Hepatitis, abnormal liver function tests
Nervous System Disorders: Seizure
Metabolism and Nutrition Disorders: Aggravation of diabetes
Psychiatric Disorders: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions

7 Drug Interactions

Drugs Without Clinically Significant Drug Interaction with TAMIFLU (addition)

No dose adjustments are needed for either oseltamivir or the concomitant drug when coadministering oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), rimantadine, amantadine, or warfarin.

Influenza Vaccines (updated section)

Live Attenuated Influenza Vaccine

The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for TAMIFLU to inhibit replication of live vaccine virus and possibly reduce the efficacy of LAIV, avoid administration of LAIV within 2 weeks before or 48 hours after TAMIFLU administration, unless medically indicated.

Inactivated Influenza Vaccine

Inactivated influenza vaccine can be administered at any time relative to use of TAMIFLU.

8 Use in Specific Populations

Geriatric Use (section updated)

Treatment of Influenza

Of the 4,765 adults in clinical trials of TAMIFLU for the treatment of influenza, 948 (20%) were 65 years and older, while 329 (7%) were 75 years and older. In three double-blind, placebo-controlled trials in the treatment of influenza in patients at least 65 years old, that enrolled 741 subjects (374 received placebo and 362 received TAMIFLU), no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

Prophylaxis of Influenza

Of the 4,603 adults in clinical trials of TAMIFLU for the prophylaxis of influenza, 1,046 (23%) were 65 years and older, while 719 (16%) were 75 years and older. In a randomized, placebo-controlled trial in elderly residents of nursing homes who took TAMIFLU for up to 42 days for the prophylaxis of influenza (TAMIFLU n=276, placebo n=272), no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

Renal Impairment (updated section)

Patients with renal impairment had higher blood levels of oseltamivir carboxylate compared to patients with normal renal function which may increase the risk of TAMIFLU-associated adverse reactions. Therefore, dosage adjustment is recommended for patients with a serum creatinine clearance between 10 and 60 mL/minute and for patients with end-stage renal disease (ESRD) undergoing routine hemodialysis or continuous peritoneal dialysis treatment. TAMIFLU is not recommended for patients with ESRD not undergoing dialysis.

Use in Patients with Chronic Conditions (additional section)

Efficacy of TAMIFLU in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease was evaluated in one randomized, placebo-controlled clinical trial. Efficacy in this population, as measured by time to alleviation of all symptoms, was not established but no new safety signals were identified.
No clinical trial data are available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization.

Immunocompromised Patients (additional section)

Efficacy of TAMIFLU for the treatment or prophylaxis of influenza has not been established in immunocompromised patients. Safety of TAMIFLU for prophylaxis of influenza has been demonstrated for up to 12 weeks in immunocompromised patients.

Pediatric Use (section updated)

Treatment of Influenza

The safety and efficacy of TAMIFLU for the treatment of influenza in pediatric patients 2 weeks old to 17 years of age has been established and is based on:

13 to 17 years of age: Safety and efficacy in adolescent patients 13 to 17 years of age was supported by adequate and well-controlled trials in adults and adolescents and younger pediatric patients and safety data in adolescents treated with TAMIFLU in a study of treatment and prophylaxis.
1 year to 12 years of age: Safety and efficacy in pediatric patients 1 year to 12 years of age was supported by results of one double-blind, placebo-controlled trial in 452 pediatric patients with influenza in whom TAMIFLU 2 mg per kg twice daily or placebo was administered within 48 hours of symptom onset. Additional safety information was provided in a double-blind, placebo-controlled trial in pediatric patients 6 to 12 years of age with known asthma. Efficacy could not be established in pediatric patients with asthma.
2 weeks to less than 1 year of age: Safety and efficacy in pediatric patients 2 weeks to less than 1 year of age is supported by adequate and well-controlled trials in adults and older pediatric patients and two open-label trials of TAMIFLU (2 to 3.5 mg per kg twice daily for 5 days) in 136 pediatric subjects 2 weeks to less than 1 year of age. In these two trials, the oseltamivir plasma concentrations in these subjects were similar to or higher than the oseltamivir plasma concentrations observed in older pediatric subjects and adults.

The safety and efficacy of TAMIFLU for treatment of influenza in pediatric patients less than 2 weeks of age have not been established.

Prophylaxis of Influenza

The safety and efficacy of TAMIFLU for the prophylaxis of influenza in pediatric patients 1 year to 17 years old has been established and is based on:

13 to 17 years of age: Prophylaxis in adolescent patients 13 to 17 years of age is supported by one randomized, placebo-controlled post-exposure household prophylaxis trial of TAMIFLU 75 mg taken orally once daily for 7 days in household contacts including 207 adolescents.
1 year to 12 years of age: TAMIFLU for prophylaxis in pediatric patients 1 year to 12 years of age is supported by one randomized, open-label, post-exposure household prophylaxis trial including pediatric subjects 1 year to 12 years of age who received 30 to 60 mg of TAMIFLU for oral suspension (supplied as powder) taken orally once daily for 10 days. Additional safety information was provided in a 6-week seasonal prophylaxis (community outbreak) safety study in 49 patients 1 year to 12 years of age.

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

PCI - Extensive changes; please refer to label.

PI - Entire section has been reformatted; please refer to label.

PI - What are the possible side effects of TAMIFLU?

Addition of headache to The most common side effects of TAMIFLU when used for treatment of the flu.
Addition of headache to The most common side effects of TAMIFLU when used for the prophylaxis of the flu.