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Included as part of the PRECAUTIONS section.

High Plasma Tyrosine Levels

Orfadin (nitisinone) is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see CLINICAL PHARMACOLOGY]. Therefore, treatment with Orfadin (nitisinone) may cause an increase in blood tyrosine in patients with HT-1, and patients should maintain concomitant reduction in dietary tyrosine and phenylalanine while on Orfadin (nitisinone) treatment. Plasma tyrosine levels should be maintained below 500 µmol/L. Inadequate restriction of tyrosine and phenylalanine intake may increase blood tyrosine levels and may be associated with blood tyrosine levels greater than 500 µmol/L leading to the following:

• Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia have been reported in patients treated with Orfadin [see ADVERSE REACTIONS]. Therefore, ophthalmologic examination including slit-lamp examination should be performed prior to initiating Orfadin (nitisinone) treatment. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes during treatment with Orfadin (nitisinone) should undergo slit-lamp reexamination and immediate measurement of the plasma tyrosine concentration.
• Variable degrees of mental retardation and developmental delay. In patients treated with Orfadin (nitisinone) who exhibit and abrupt change in neurologic status, a clinical laboratory assessment including plasma tyrosine levels should be performed.
• Painful hyperkeratotic plaques on the soles and palms.

In patients with HT-1 treated with dietary restrictions and Orfadin (nitisinone) who develop elevated plasma tyrosine levels, an assessment of dietary tyrosine intake should be performed.

Leucopenia and Severe Thrombocytopenia

In clinical trials, patients treated with Orfadin (nitisinone) and dietary restriction developed transient leucopenia (3%), thrombocytopenia (3%), or both (1.5%) [see ADVERSE REACTIONS]. One patient who developed both leucopenia and thrombocytopenia improved after the dose of Orfadin (nitisinone) was decreased from 2 mg/kg to 1 mg/kg. No patients developed infections or bleeding as a result of the episodes of leucopenia and thrombocytopenia. Platelet and white blood cell counts should be monitored regularly during nitisinone therapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of nitisinone. 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.

In a single dose-group study in rats given 100 mg/kg (12 times the recommended clinical dose based on relative body surface area), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.

Use In Specific Populations

Pregnancy

Teratogenic effects: Pregnancy Category C.

Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times the recommended human dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8 times the recommended human dose based on the body surface area. In mice, nitisinone has been shown to cause incomplete skeletal ossification of fetal bones at 0.4, 4 and 20 times the recommended human dose, increased gestational length at 4 and 20 times the recommended human dose, and decreased pup survival at 0.4 times the recommended human dose based on the body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetal bones at 1.6, 4 and 8 times the recommended human dose based on the body surface area. However, there are no adequate and well controlled studies in pregnant women. Nitisinone should be used during pregnancy only if the potential benefit justified the potential risk to the fetus.

Nursing Mothers

Although the exposure was not quantified naïve pups that were exposed to Orfadin (nitisinone) via breast milk showed signs of ocular toxicity and lower body weight. This suggests that Orfadin (nitisinone) is excreted via breast milk in rats. It is not known whether Orfadin (nitisinone) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Orfadin (nitisinone) is administered to a nursing woman.

Pediatric Use

Pediatric patients with HT-1, ages birth to 17 years have been treated with Orfadin (nitisinone) in one open-label, uncontrolled clinical study [see Clinical Studies]. Monitoring of blood and urine succinylacetone levels are recommended in the children to ensure adequate control [see DOSAGE AND ADMINISTRATION]. A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine.

Geriatric Use

Clinical studies of nitisinone did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. HT-1 is presently a disease of the pediatric population. No pharmacokinetic studies of nitisinone have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.

Hepatic or Renal Impairment

The effect of hepatic dysfunction on the pharmacokinetics of nitisinone has not been studied. The effect of renal insufficiency on the pharmacokinetics of Orfadin (nitisinone) has not been studied.

Gender Effect

The effect of gender on the pharmacokinetics of Orfadin (nitisinone) has not been studied.

Race Effect

The effect of race on the pharmacokinetics of Orfadin (nitisinone) has not been studied.

Last reviewed on RxList: 2/18/2010
This monograph has been modified to include the generic and brand name in many instances.