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.

FYCOMPA (NDA-208277)

(PERAMPANEL)

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

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05/31/2019 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Neurologic Effects

(additions underlined)

…

Risk Ameliorat ion

Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known. Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when FYCOMPA is used with other drugs with sedative properties because of potential additive effects.

09/27/2018 (SUPPL-2)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Partial-Onset Seizures

Adult and Adolescent Patients (12 years of age and older)

Table 2. Adverse Reactions in Pooled Placebo-Controlled Trials in Adult and Adolescent Patients with Partial- Onset Seizures (Studies 1, 2, and 3) (Reactions ? 2% of Patients in Highest FYCOMPA Dose (12 mg) Group and More Frequent than Placebo)

Addition of the following:

Pediatric Patients (4 to <12 years of age)

In two studies in pediatric patients 4 to <12 years of age with epilepsy, a total of 225 patients received FYCOMPA, with 110 patients exposed for at least 6 months, and 21 patients for at least 1 year. Adverse reactions in pediatric patients 4 to <12 years of age were similar to those seen in patients 12 years of age and older.

Additions and/or revisions underlined:

… Similar increases in weight were also observed in adult and adolescent patients …

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Safety and effectiveness of FYCOMP A for the treatment of partial-onset seizures have been established in pediatric patients 4 years of age and older.

The safety and effectiveness of FYCOMP A in patients 12 years of age and older was established by three randomized double-blind, placebo-controlled, multicenter studies, which included 72 pediatric patients between 12 and 16 years of age exposed to FYCOMPA. Use of FYCOMPA for the treatment of partial-onset seizures in pediatric patients 4 years to less than 12 years of age is supported by evidence from adequate and well-controlled studies of FYCOMP A in patients 12 years of age and older with partial onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in 225 pediatric patients 4 years to less than 12 years of age treated with FYCOMPA.

… The safety and effectiveness of FYCOMPA for the treatment of partial-onset seizures in pediatric patients less than 4 years of age or for the treatment of primary generalized tonic-clonic seizures in pediatric patients less than 12 years of age have not been established.

07/26/2017 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

(new subsection added)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including FYCOMPA. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. FYCOMPA should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

6 Adverse Reactions

(additions underlined)

The following serious adverse reactions are described below and elsewhere in the labeling:

Serious Psychiatric and Behavioral Reactions
Suicidal Behavior and Ideation
Neurologic Effects
Falls
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

7 Drug Interactions

7.2 Moderate and Strong CYP3A4 Inducers

(additions underlined)

The concomitant use of known moderate and strong CYP3A4 inducers including carbamazepine, phenytoin, or oxcarbazepine with FYCOMPA decreased the plasma levels of perampanel by approximately 50-67%. The starting doses for FYCOMPA should be increased in the presence of moderate or strong CYP3A4 inducers.

When these moderate or strong CYP3A4 inducers are introduced or withdrawn from a patient’s treatment regimen, the patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary.

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

MEDICATION GUIDE

(additions underlined)

…

What is FYCOMPA?
FYCOMPA is a prescription medicine used:
treat partial-onset seizures with or without secondarily generalized seizures in people with epilepsy who are 12 years of age and older

with other medicines to treat primary generalized tonic-clonic seizures in people with epilepsy who are 12 years of age and older

FYCOMPA is a controlled substance (CIII) because it can be abused or lead to drug dependence. Keep your FYCOMPA in a safe place to protect it from theft. Never give your FYCOMPA to anyone else because it may harm them. Selling or giving away this medicine is against the law.
It is not known if FYCOMPA is safe and effective in children under 12 years of age.
...
What are the possible side effects of FYCOMPA?
See “What is the most important information I should know about FYCOMPA?” FYCOMPA may cause other serious side effects, including:

Dizziness, vertigo (sense of spinning), and problems walking normally. You may have problems walking normally if you are unsteady because you feel dizzy. These symptoms can increase when your dose of FYCOMPA is increased. Your risk of feeling dizzy and having problems walking normally may be higher if you are elderly.
Sleepiness and tiredness. See “What should I avoid while taking FYCOMPA?”
Increased risk of falls. Taking FYCOMPA can increase your chance of falling. These falls can cause serious injuries. Your risk of falling may be higher if you are elderly.
A serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death. Call your healthcare provider right away if you have:
- a skin rash, hives
- fever or swollen glands that do not go away
- swelling of your face
- shortness of breath, swelling of the legs, yellowing of the skin or whites of the eyes, or dark urine.
  …

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Suicidal Thinking and Behavior

Counsel patients, their caregivers, and families that AEDs, including FYCOMPA, may increase the risk of suicidal thinking and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers.

…

DRESS/Multi-organ Hypersensitivity

Instruct patients that a fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately.