HARLIKU

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.

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. 

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.

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)]

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**

* reported in at least 1% of patients; ** another oral formulation of nitisinone;
*** keratitis also includes eye irritation, eye pain and photophobia.

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)] .

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

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 numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Nitisinone is a competitive inhibitor of hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of homogentisate 1,2-dioxygenase (HGD) in the tyrosine catabolic pathway.

In patients with AKU, HGA accumulates in various tissues and urine. In an open-label, single center, randomized, no-treatment controlled trial nitisinone treatment resulted in reduction of urinary HGA concentrations in patients with AKU [see Clinical Studies (14)].

Nitisinone exposure-response relationship and time course of pharmacodynamic response for the effectiveness have not been fully characterized.

Nitisinone inhibits catabolism of the amino acid tyrosine and can result in elevated plasma levels of tyrosine in patients with AKU. Treatment with nitisinone does not require routine dietary restriction in patients with AKU; however, patients who develop keratopathies should be monitored and dietary restriction of tyrosine and phenylalanine should be implemented [see Warnings and Precautions (5.1)].

The single-dose pharmacokinetics of nitisinone tablets have been studied in healthy adult subjects. Nitisinone pharmacokinetic parameters are presented as geometric mean [range] unless otherwise specified. Nitisinone maximum concentration (Cmax) and area under the curve from time 0 to 120 hours (AUC0-120h) were 1278 [780 to 1649] ng/mL and 77874 [42335 to 104211] ng•h/mL following oral administration of 10 mg (5 times the recommended dosage) nitisinone under fasting conditions.

The carcinogenic potential of nitisinone was assessed in a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice. There were no drug-related neoplastic findings in male or female Tg.rasH2 mice at doses up to 100 mg/kg/day nitisinone (approximately 243 times the maximum recommended human daily dose of 2 mg/day).

Nitisinone was not genotoxic in the Ames test and the in vivo mouse liver unscheduled DNA synthesis (UDS) test. Nitisinone was mutagenic in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in an in vivo mouse bone marrow micronucleus test.

The effectiveness of HARLIKU was evaluated in an open-label, single center, randomized, no-treatment controlled trial in 40 adult patients diagnosed with AKU (NCT00107783). Patients received either HARLIKU at 2 mg orally once daily or no treatment for three years.

One patient in the HARLIKU group died after experiencing atrial fibrillation and had discontinued treatment one month prior to death, and 2 patients in the no treatment control group discontinued the study early. Among the 40 patients enrolled in the trial, 27 (67.5%) were male and 13 (32.5%) were female, ranging in age from 38 to 68 with a mean age of 51.7 years. Thirty-seven (92.5%) patients were White, 2 (5%) were Asian, and 1 (2.5%) was American Indian or Alaska Native. Thirty-nine (97.5%) patients were not Hispanic or Latino and 1 (2.5%) patient was Hispanic or Latino.

HARLIKU was effective at reducing levels of urinary HGA. The HARLIKU group had an average percent reduction from baseline of 88% (95% CI: 79, 97%) after 1 year of treatment, which was sustained through three years of treatment with an average percent reduction from baseline of 91% at year 3 (95% CI: 85, 97%). In contrast, the untreated controls had an average increase of 107% from baseline to year 1 (95% CI: 0, 216%) and 108% from baseline to year 3 (95% CI: 19, 198%).