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.

AMPYRA (NDA-022250)

(DALFAMPRIDINE)

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

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11/18/2021 (SUPPL-19)

Approved Drug Label (PDF)

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

17 PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Risk of Seizures

Inform patients that AMPYRA can cause seizures, and that they must discontinue use of AMPYRA if they experience a seizure [see Warnings and Precautions (5.1)].

AMPYRA dosing

Instruct patients to take AMPYRA exactly as prescribed. Instruct patients not to take a double dose after they miss a dose, as this would increase their risk of seizure. Instruct patients not to take more than 2 tablets in a 24- hour period and to make sure that there is an approximate 12-hour interval between doses [see Dosage and Administration (2.1, 2.2)].

Anaphylaxis

Advise patients to discontinue AMPYRA and seek medical care if they develop signs and symptoms of anaphylaxis [see Warnings and Precautions (5.4)].

Effects on Driving or Using Machinery

Counsel patients that central nervous system-related adverse reactions, such as vertigo and dizziness, associated with the use of AMPYRA might impair their ability to drive or use machinery should they develop these symptoms.

MEDICATION GUIDE

Additions and/or revisions underlined

What should I avoid while taking AMPYRA?

AMPYRA may cause dizziness or vertigo. If you have these symptoms, do not drive, operate machinery, or do other dangerous activities.

02/24/2021 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use with dalfampridine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: vomiting, vertigo.

12/19/2019 (SUPPL-17)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

Risk Summary

There are no adequate data on the developmental risk associated with use of AMPYRA in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at clinically relevant doses. In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of dalfampridine to pregnant rats and rabbits throughout organogenesis resulted in no evidence of developmental toxicity in either species. The highest doses tested (10 mg/kg/day in rats, 5 mg/kg/day in rabbits), which were associated with maternal toxicity, are approximately 5 times the MRHD on a body surface area (mg/m2) basis.

Oral administration of dalfampridine (0, 1, 3, and 9 to 6 mg/kg/day; high dose reduced during the second week of dosing) to female rats throughout pregnancy and lactation resulted in decreased offspring viability at the highest dose tested and decreased body weight in offspring at the mid and high doses. The no-effect dose for pre- and postnatal developmental toxicity in rats (1 mg/kg/day) is less than the MRHD on a mg/m2 basis.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

Risk Summary

There are no data on the presence of dalfampridine in human milk, the effects of dalfampridine on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AMPYRA and any potential adverse effects on the breastfed infant from AMPYRA or from the underlying maternal condition.

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

MEDICATION GUIDE

(Additions and/or revisions underlined)

Before you take AMPYRA, tell your doctor if you:

have any other medical conditions

are taking compounded 4-aminopyridine (fampridine, 4-AP)

are taking any other medicines, including over-the-counter medicines such as cimetidine

are pregnant or plan to become pregnant. It is not known if AMPYRA will harm your unborn baby.

are breast-feeding or plan to breast-feed. It is not known if AMPYRA passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you take AMPYRA.

09/29/2017 (SUPPL-15)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

The use of AMPYRA is contraindicated in the following conditions:

History of seizure
Moderate or severe renal impairment (CrCl less than or equal to 50 mL/min)
History of hypersensitivity to AMPYRA or 4-aminopyridine; reactions have included anaphylaxis

5 Warnings and Precautions

5.1 Seizures

(additions underlined)

AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily (2 times the maximum recommended dosage) in controlled clinical studies of 9–14 weeks duration with dalfampridine in patients with MS. In open-label extension trials in MS patients, the incidence of seizures during treatment with dalfampridine 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY). In the post-marketing period seizures have been reported. The majority of seizures occurred at the recommended dose and in patients without a history of seizures, and generally within days to weeks of starting therapy.

…

5.4 Anaphylaxis

(additions underlined)

AMPYRA can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. AMPYRA is contraindicated in patients with a history of hypersensitivity to AMPYRA or 4- aminopyridine. Inform patients of the signs and symptoms of anaphylaxis and instruct them to discontinue AMPYRA and seek immediate medical care should these signs and symptoms occur.

7 Drug Interactions

7.1 OCT2 Inhibitors

(new subsection added)

Concurrent treatment with OCT2 inhibitors, such as cimetidine, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking OCT2 inhibitors concurrently with AMPYRA should be considered against the risk of seizures in these patients.

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

MEDICATION GUIDE

(additions underlined)

…

What should I tell my doctor before taking AMPYRA? Before you take AMPYRA, tell your doctor if you:

have any other medical conditions
are taking compounded 4-aminopyridine (fampridine, 4-AP)
are taking any other medicines, including over-the-counter medicines such as cimetidine
are pregnant or plan to become pregnant. It is not known if AMPYRA will harm your unborn baby. You and your doctor will decide if you should take AMPYRA while you are pregnant
are breast-feeding or plan to breast-feed. It is not known if AMPYRA passes into your breast milk. You and your doctor should decide if you will take AMPYRA or breast-feed. You should not do both.

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Drug Interactions

Instruct patients to notify their healthcare provider prior to starting any new medication, including over-the-counter drugs.

10/13/2016 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Controlled Clinical Trials Experience (addition underlined)

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

6.3 Postmarketing Experience (subsection added)

The following adverse event has been identified during postmarketing experience with dalfampridine. Because adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: vomiting.

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

17 PATIENT COUNSELING INFORMATION (additions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).