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Orfadin

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Orfadin

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

High Plasma Tyrosine Levels

ORFADIN is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see CLINICAL PHARMACOLOGY]. Therefore, treatment with ORFADIN 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 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 treatment. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes during treatment with ORFADIN 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 who exhibit an 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 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 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 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

Category C.

Risk Summary

There are no adequate and well-controlled studies with ORFADIN in pregnant women. However, 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 20 and 8 times respectively, the recommended human dose. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended human dose, and increased gestational length at doses 4 times the recommended human dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended human dose. ORFADIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data

Animal Data

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

It is not known whether ORFADIN is present in human milk. 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. Because of the potential for serious adverse reactions in nursing infants from ORFADIN, a decision should be made to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

Pediatric patients with HT-1, ages birth to 17 years have been treated with ORFADIN 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 has not been studied.

Gender Effect

The effect of gender on the pharmacokinetics of ORFADIN has not been studied.

Race Effect

The effect of race on the pharmacokinetics of ORFADIN has not been studied.

Last reviewed on RxList: 7/15/2014
This monograph has been modified to include the generic and brand name in many instances.

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