Inadequate restriction of tyrosine and phenylalanine intake can result in elevations in plasma tyrosine. Plasma tyrosine levels should be kept below 500 µmol/L in order to avoid toxic effects to the eyes (corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia), skin (painful hyperkeratotic plaques on the soles and palms), and nervous system (variable degrees of mental retardation and developmental delay). In most patients, eye symptoms were transient, lasting less than one week. Six patients had prolonged episodes lasting 16 to 672 days (see PRECAUTIONS, General).

Transient Thrombocytopenia and Leucopenia

Patients treated with Nitisinone and dietary restriction in clinical trials were observed to develop transient thrombocytopenia (3%), leucopenia (3%) or both (1.5%). One patient, who developed both leucopenia and thrombocytopenia, improved after the dose of Nitisinone was decreased from 2 mg/kg to 1 mg/kg. Another patient, who developed thrombocytopenia, had Nitisinone stopped for 2 weeks, but platelet values continued to be low for 3 months and slowly returned to normal after 5 months. In all other patients, platelet values and white blood cell counts normalized gradually without documented change in Nitisinone dose. 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.

General

Ophthalmologic Care of Patients Treated with Nitisinone (see WARNINGS)

· Slit-lamp examination of the eyes should be performed before initiation of Nitisinone treatment.

· Patients who develop photophobia, eye pain or signs of inflammation such as redness, swelling, or burning of the eyes during treatment with Nitisinone should undergo slit-lamp reexamination and immediate measurement of the plasma tyrosine concentration.

· A more restricted diet should be implemented if the plasma tyrosine level is above 500 µmol/L.

· Nitisinone dosage should not be adjusted in order to lower the plasma tyrosine concentration, since the HT-1 metabolic defect may result in deterioration of the patient's clinical condition.

Risk of Porphyric Crises, Liver Failure, and Hepatic Neoplasms

Patients with hereditary tyrosinemia type 1 are at increased risk of developing porphyric crises, liver failure, or hepatic neoplasms requiring liver transplantation. These complications of HT-1 were observed in patients treated with Nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 0.5%). Regular liver monitoring by imaging (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended. An increase in serum alpha-fetoprotein concentration may be a sign of inadequate treatment, but patients with increasing alpha-fetoprotein or signs of nodules of the liver during treatment with Nitisinone should always be evaluated for hepatic malignancy.

Information for Patients

See PATIENT INFORMATION section.

Laboratory Tests

· Plasma Nitisinone concentration, urine and plasma succinylacetone levels, urine 5-ALA levels, and erythrocyte PBG-synthase activity were used during clinical trials to guide drug dosage. The probability of recurrence of abnormal values of urine succinylacetone was 1% at a Nitisinone concentration of 37 µmol/L (95% confidence interval: 23-51 µmol/L). Assays for plasma Nitisinone concentration, plasma succinyl acetone, urine 5-ALA, and erythrocyte PBG-synthase activity are not routinely available in the U.S. However, urine succinylacetone levels can be used to guide drug dose adjustment (see DOSAGE and ADMINISTRATION).

· Serum alpha-fetoprotein concentrations are generally markedly elevated at the time of diagnosis, and gradually decrease during the course of Nitisinone treatment. Increases during therapy may be a sign of inadequate treatment. An exponential increase in serum alpha-fetoprotein concentration should be promptly evaluated for potential liver neoplasia. Platelet and white blood cell counts should be monitored regularly because of the risk of transient thrombocytopenia and leukopenia (see WARNINGS).

· Serum phosphate should be measured as a screening test for patients with renal involvement at risk of secondary hypophosphatemia and rickets. · Plasma tyrosine levels should be kept below 500 µmol/L in order to avoid toxic effects (see WARNINGS).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate the carcinogenic potential of Nitisinone. Nitisinone was not mutagenic in the Ames test. In a single dose-group study in rats given 100 mg/kg/day (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.

Pregnancy Category C:

Adequate reproductive toxicity studies have not been conducted with Nitisinone. It is not known if Nitisinone can produce harm to the fetus if administered to pregnant women. Nitisinone should be given to a pregnant woman only if clearly needed.

Nursing Mothers

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

Pediatric Use

Nitisinone has been studied in patients ranging in age from birth to 21.7 years. The median age of enrolment in a study of 207 patients with HT-1 was 9 months.

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. 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 of concomitant disease or other drug therapy in this patient population.

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