Enter drug's generic or brand name below. Results will appear here. Note: all drug related information obtained on this page is provided by RX List.
Using the RX LIST database:
(1) Enter the drug name in the search box below and hit ENTER
(2) The rx list web site will open here with the drug search completed. Next, scroll down the page to locate the link to the drug you are searching for and then click on the link.
HARLIKU (nitisinone) is a hydroxyphenyl-pyruvate dioxygenase inhibitor.
Nitisinone occurs as a white to yellowish-white, crystalline powder. It is practically insoluble in water, soluble in 2M sodium hydroxide and in methanol, and sparingly soluble in alcohol.
The chemical name of nitisinone is 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione. The molecular formula is C14H10F3NO5 and the molecular weight is 329.23. The structural formula is:
 |
Each HARLIKU (nitisinone) tablet contains 2 mg of nitisinone to be administered orally. The inactive ingredients are glyceryl dibehenate and lactose monohydrate.
HARLIKU is indicated for the reduction of urine homogentisic acid (HGA) in adult patients with alkaptonuria (AKU).
The recommended dosage of HARLIKU is 2 mg administered orally, once daily.
Administer HARLIKU with or without food [see Clinical Pharmacology (12.3)].
Maintain dietary restriction of tyrosine and phenylalanine when administering NITYR.
The recommended maintenance dosage of NITYR in patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, is 1 to 2 mg/kg once daily [see Clinical Pharmacology (12.2)].
A maximum total daily dosage of 2 mg/kg may be needed based on the evaluation of all biochemical parameters.
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.
Tablets: 2 mg white to beige, round, flat tablets, which may display light yellow to brown speckles, debossed with “2â€Â mg on one side and “Lâ€Â on the other side.
HARLIKU (nitisinone) tablet is white to beige, round, flat which may display light yellow to brown speckles, debossed with the “strengthâ€Â in mg on one side and “Lâ€Â on the other side. Each tablet contains 2 mg nitisinone. HARLIKU is supplied in a high-density polyethylene (HDPE) square bottle with a child-resistant tamper-evident polypropylene (PP) screw cap. Each bottle contains 60 tablets. 2 mg tablets: NDC 70709-112-60
NITYR is supplied in a high-density polyethylene (HDPE) square bottle with a child-resistant tamper-evident polypropylene (PP) screw cap. Each bottle contains 60 tablets.
2 mg tablets: NDC 70709-002-60
5 mg tablets: NDC 70709-005-60
10 mg tablets: NDC 70709-000-60
Store HARLIKU tablets at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
Pharmacist: Dispense in tight and light resistant container as defined in USP.
Manufactured by: PCI Pharma Services 23-24 Tafarnaubach Industrial Estate Tredegar, Gwent NP22 3AA, United Kingdom
Rivopharm SA Centro Insema 6928 Manno, Switzerland
Marketed by: Cycle Pharmaceuticals Ltd The Broers Building 21 JJ Thomson Ave Cambridge, CB3 0FA, United Kingdom
Included as part of the PRECAUTIONS section.
Treatment with NITYR may cause elevated plasma tyrosine levels in patients with HT-1. Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine levels and levels greater than 500 micromol/L may lead to the following:
Maintain concomitant reduction in dietary tyrosine and phenylalanine while on NITYR treatment. In patients with HT-1 who are treated with NITYR and dietary restriction and develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake. Do not adjust NITYR dosage in order to lower the plasma tyrosine concentration. Maintain plasma tyrosine levels below 500 micromol/L.
In clinical trials, patients treated with another oral formulation of nitisinone and dietary restriction developed reversible leukopenia (3%), thrombocytopenia (3%), or both (1.5%) [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 NITYR therapy.
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.
No information provided
No information provided
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.
Nitisinone time to Cmax (Tmax) is 3.5 hours (median, ranging from 1 to 4 hours) following single oral administration of 10 mg (5 times the recommended dosage) nitisinone under fasting conditions.
Effect of Food: In a food effect study, a high-fat and high-calorie breakfast (973.6 cal distributed in carbohydrate 250.1 cal, proteins 157 cal, fat 566.5 cal) did not significantly affect the total exposure (AUC0-120h) and Cmax of nitisinone following single oral administration of 10 mg NITYR. The median Tmax was delayed to 6 hours under fed conditions [see Dosage and Administration (2.2)].
The arithmetic mean (SD) apparent volume of distribution of nitisinone is 8.2 (1.6) L in healthy subjects (n=23).
In vitro binding of nitisinone to human plasma proteins is greater than 95% at 50 micromolar concentration.
The arithmetic mean (SD) terminal half-life of nitisinone is 59.3 (8.9) hours in healthy subjects (n=23). The mean (CV%) apparent plasma clearance in 18 healthy adults following multiple once daily doses of nitisinone Reference ID: 5604690 80 mg (40 times the recommended dosage) is 113 (16) mL/hr. The mean of the fraction of dose excreted renally as unchanged nitisinone in the urine (fe(%)) was 3% (n=3) following multiple oral doses of 80 mg (40 times the recommended dosage) daily in healthy subjects.
Metabolism
In vitro studies have shown that nitisinone is relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme.
Excretion
The estimated mean (CV%) renal clearance of nitisinone was 0.003 L/h (25%).
TABLE 2. Percent Change in AUC0-inf and Cmax for Co-administered Drugs in the Presence of Nitisinone in 18 Healthy Subjects
| Co-administered Drug a | Dose of Coadministered Drug (Route of Administration) |
|
|||||
|---|---|---|---|---|---|---|---|
| CYP2C9 Substrate Tolbutamide c | 500 mg (oral) | 131% ↑ | 16% ↑ | ||||
| CYP2E1 Substrate Chlorzoxazone | 500 mg (oral) | 27% ↑ | 18% ↑ | ||||
| OAT1/3 Substrate Furosemide | 20 mg (intravenous) | 72% ↑ | 12% ↑ | ||||
|
↑ = Increased; ↓ = Decreased |
|||||||
In Vitro Studies
CYP450 Enzymes: Nitisinone does not inhibit CYP1A2, 2C19, or 3A4. Nitisinone does not induce CYP1A2, 2B6 or 3A4/5.
Transporter Systems: Nitisinone does not inhibit P-gp, BCRP, OATP1B1, OATP1B3 and OCT2.
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Advise the patient or caregiver to:
Advise the patient or caregiver to store NITYR in the container that it is dispensed in and keep the container tightly closed [see How Supplied/Storage and Handling (16)].
Advise the patient or caregiver that inadequate dietary restriction may be associated with ocular signs and symptoms, intellectual disability and developmental delay, and painful hyperkeratotic plaques on the soles and palms. Additionally, advise the patient or caregiver of the need to maintain dietary restriction of tyrosine and phenylalanine and to report any unexplained ocular, neurologic, or other symptoms promptly to their healthcare provider [see Warnings and Precautions (5.1)].
