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.

ORFADIN (NDA-206356)

(NITISINONE)

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

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05/17/2019 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkertoic Plaques

Additions and/or revisions underlined:

Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia have been reported in patients treated with ORFADIN. In a clinical study in a non HT-1 population without dietary restriction and reported tyrosine levels >500 micromol/l both symptomatic and asymptomatic keratopathies have been observed. Therefore, perform a baseline ophthalmologic examination including slit-lamp examination prior to initiating ORFADIN treatment and regularly thereafter. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes or tyrosine levels are > 500 micromol/L during treatment with ORFADIN …

7 Drug Interactions

Additions and/or revisions underlined:

Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3. Table 2 includes drugs with clinically important drug interactions when administered concomitantly with ORFADIN and instructions for preventing or managing them.

Table 2: Clinically Relevant Interactions Affecting Co-Administered Drugs Newly added table; please refer to label for complete information.

09/01/2017 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratopitc Plaques

Additions and/or revisions underlined:

· Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia have been reported in patients treated with ORFADIN. Therefore, a baseline ophthalmologic examination including slit-lamp examination should be considered prior to initiating ORFADIN treatment. Patients who develop photophobia, eye pain …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

ORFADIN was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma … The recommended starting dosage of ORFADIN is 0.5 mg/kg twice daily. Median duration of treatment was 22 months (range 0.1 to 80 months).

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. Animal reproduction studies have been conducted for nitisinone. In these studies, nitisinone was administered to mice and rabbits during organogenesis with oral doses of nitisinone up to 20 and 8 times respectively, the recommended initial dose of 1 mg/kg/day. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended initial dose, and increased gestational length at doses 4 times the recommended initial dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended initial dose.

Data

Animal Data

Initial replaces human in all instances in this subsection.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of ORFADIN have been established in pediatric patients for the treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine. Use of ORFADIN in pediatric patients is supported by evidence from one open-label, uncontrolled clinical study conducted in 207 patients with HT-1 ages 0 to 22 years (median age 9 months).