HARLIKU

1 INDICATIONS AND USAGE HARLIKU TM is indicated for the reduction of urine homogentisic acid (HGA) in adult patients with alkaptonuria (AKU). HARLIKU is a hydroxyphenyl-pyruvate dioxygenase inhibitor indicated for the reduction of urine homogentisic acid (HGA) in adult patients with alkaptonuria (AKU). ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of HARLIKU is 2 mg administered orally, once daily. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of HARLIKU is 2 mg administered orally, once daily. Administer HARLIKU with or without food [see Clinical Pharmacology ( 12.3 )] . Missed Dose If a dose of HARLIKU is missed, do not administer two doses at once to make up for a missed dose. Take the next dose at the scheduled time.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Ocular Symptoms and Hyperkeratotic Plaques Due To Elevated Plasma Tyrosine Levels : Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine and levels above 500 micromol/L may lead to ocular signs and symptoms or painful hyperkeratotic plaques on the soles and palms. ( 5.1 ) Assess plasma tyrosine levels in patients presenting with ocular signs and symptoms. ( 5.1 ) Obtain slit-lamp examination prior to treatment and regularly thereafter. ( 5.1 ) Implement diet restriction and/or treatment interruption as appropriate. ( 5.1 ) Leukopenia and Severe Thrombocytopenia: Monitor platelet and white blood cell counts. ( 5.2 ) 5.1 Ocular Symptoms and Hyperkeratotic Plaques Due to Elevated Plasma Tyrosine Levels 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 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.

7 DRUG INTERACTIONS Sensitive CYP2C9 Substrates: Reduce dosage of co-administered drug metabolized by CYP2C9 by half. ( 7.1 ) OAT1/OAT3 Substrates : Avoid concomitant use of HARLIKU with OAT1/OAT3 substrates. Concomitant use with OAT1/OAT3 substrates may increase the risk of adverse reactions related to the co-administered drug. ( 7.1 ) 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 )] .

6 ADVERSE REACTIONS Most common adverse reactions (>1%) are elevated tyrosine levels, keratitis and thrombocytopenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cycle Pharmaceuticals Ltd at 1-855-831-5413 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Serious and/or clinically significant adverse reactions described elsewhere in labeling include: Ocular Symptoms and Hyperkeratotic Plaques Due to Elevated Plasma Tyrosine Levels [see Warnings and Precautions ( 5.1 )] Leukopenia and Severe Thrombocytopenia [see Warnings and Precautions ( 5.2 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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** Adverse Reactions Nitisinone (N=20) n (%) No Treatment (N=20) n (%) Elevated tyrosine levels 19 (95) 0 (0) Keratitis*** 3 (15) 0 (0) Thrombocytopenia 2 (10) 0 (0) * reported in at least 1% of patients; ** another oral formulation of nitisinone; *** keratitis also includes eye irritation, eye pain and photophobia.

8.1 Pregnancy 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.