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.

HARLIKU (NDA-209449)

(NITISINONE)

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

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06/10/2025 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Ocular Symptoms and Hyperkeratotic Plaques Due to Elevated Plasma Tyrosine Levels

Additions and/or revisions underlined:

Treatment with HARLIKU may cause elevated plasma tyrosine levels in patients with AKU. Tyrosine levels greater than 500 micromol/L may lead to the following:

Ocular signs and symptoms including keratitis, corneal opacities, corneal irritation, corneal ulcers, conjunctivitis, eye pain, and photophobia. These ocular adverse reactions have been reported in patients treated with nitisinone [see Adverse Reactions (6.1)]. In a clinical trial in the AKU population, without dietary restriction and reported tyrosine levels > 500 micromol/L, both symptomatic and asymptomatic keratopathies have been observed. Perform a baseline ophthalmologic examination including slit-lamp examination prior to initiating HARLIKU 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 HARLIKU should undergo slit-lamp re- examination and immediate measurement of the plasma tyrosine concentration.
Painful hyperkeratotic plaques on the soles and palms.

There is no routine dietary restriction requirement for AKU patients taking HARLIKU. However, in patients who develop keratopathies, monitor plasma tyrosine levels, and implement a diet restricted in tyrosine and phenylalanine to keep the plasma tyrosine level below 500 micromol/L. Consider temporarily interrupting HARLIKU until resolution of symptoms.

5.2 Leukopenia and Severe Thrombocytopenia

Additions and/or revisions underlined:

In clinical trials, patients with hereditary tyrosinemia type 1 (HT-1) treated with another oral formulation of nitisinone and dietary restriction developed reversible leukopenia (3%), thrombocytopenia (3%), or both (1.5%). Ten percent of patients in Trial 1 developed thrombocytopenia [see Adverse Reactions (6.1)]. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia.

Monitor platelet and white blood cell counts during HARLIKU therapy.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

The safety of HARLIKU was evaluated in Trial 1, a three-year, open-label, randomized, no-treatment controlled trial in 40 patients with AKU. Patients were between 38 and 68 years of age (27 male, 13 female) [see Clinical Studies (14)]. Patients received either HARLIKU 2 mg orally once daily or no treatment [see Dosage and Administration (2)].

The serious adverse reactions reported with HARLIKU were ocular/visual complaints associated with elevated tyrosine levels (keratitis) [see Warnings and Precautions (5.1)]. Keratitis led to permanent treatment discontinuation in 1 (5%) treated patient.

The most common adverse reactions (>1%) reported in Trial 1 are summarized in TABLE 1.

TABLE 1. Most Common Adverse Reactions* in Patients with AKU Treated with Nitisinone**

Extensive changes to table, please refer to label for complete information.

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Effects of HARLIKU on Other Drugs

Sensitive CYP2C9 Substrates

Reduce the dosage of the co-administered drug metabolized by CYP2C9 by half. Additional dosage adjustments may be needed to maintain therapeutic drug concentrations where minimal concentration changes may lead to serious adverse reactions. See prescribing information for those drugs.

Nitisinone is a moderate CYP2C9 inhibitor. Nitisinone may increase exposure of co-administered drugs metabolized by CYP2C9 [see Clinical Pharmacology (12.3)].

OAT1/OAT3 Substrates

The concomitant use of HARLIKU with OAT1/OAT3 substrates may increase the risk of adverse reactions related to the co-administered drug. See prescribing information for those drugs.

Nitisinone is an OAT1/OAT3 inhibitor which can lead to increased exposure of the co-administered drug. [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Available data from published case reports with nitisinone use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal 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 600 and 240 times respectively, the maximum recommended human daily dose (MRHDD) of 2 mg/day. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 12 times the MRHDD, and increased gestational length at doses 120 times the MRHDD. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 48 times the MRHDD (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Data

Animal Data

In an embryo-fetal development study in mice, nitisinone was administered via oral gavage to pregnant mice at dose levels of 12, 120 and 600 times the maximum recommended human daily dose (MRHDD) of 2 mg/day.

Nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 12 times the MRHDD and increased gestational length at doses 120 times the MRHDD.

In an embryo-fetal development study in rabbits, nitisinone was administered via oral gavage to pregnant rabbits at dose levels of 48, 120 and 240 times the MRHDD of 2 mg/day. Nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 48 times the MRHDD.

In a single dose-group study in rats given 100 mg/kg (486 times the MRHDD of 2 mg/day), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There are no data on the presence of nitisinone in human milk, the effects on the breastfed infant, or the effects on milk production. Data suggest that nitisinone is present in rat milk due to findings of ocular toxicity and lower body weight seen in drug naive nursing rat pups. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HARLIKU and any potential adverse effects on the breastfed infant from HARLIKU or from the underlying maternal condition.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of HARLIKU have not been established in pediatric patients with AKU.

8.6 Geriatric Use

Additions and/or revisions underlined:

There was 1 patient 65 years of age and older in the clinical studies for AKU [see Clinical Studies (14)]. Of the total number of HARLIKU-treated patients in these studies, 1 (2.5 %) were 65 years of age and older, while 0 (0%) were 75 years of age and older.

Clinical studies of HARLIKU did not include sufficient number of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Ocular Symptoms and Hyperkeratotic Plaques Due to Elevated Plasma Tyrosine Levels

Advise the patient or caregiver to report any unexplained ocular or other symptoms promptly to their healthcare provider [see Warnings and Precautions (5.1)].

How Supplied/Storage and Handling

Advise the patient or caregiver to store HARLIKU in the container that it is dispensed in and keep the container tightly closed [see How Supplied/Storage and Handling (16)].