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Overview
Nitisinone is a Gastrointestinal Agent that is FDA approved for the treatment of hereditary tyrosinemia type 1 (HT-1). Common adverse reactions include hepatic neoplasm, liver failure, thrombocytopenia, leucopenia, visual system complaints including conjunctivitis, corneal opacity, keratitis, and photophobia.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
Orfadin(R) capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1
Dosage
The recommended dose of Orfadin is 1 to 2 mg/kg divided into two daily doses. The initial dose is 1 mg/kg/day divided for morning and evening administration. Treatment with Orfadin should be initiated by a physician experienced in the treatment of HT-1.
The dose of Orfadin may be adjusted in each patient. In patients whose erythrocyte PBG-synthase activity and urine 5-ALA and urine succinylacetone are not normalized within one month after the start of Orfadin treatment, the Orfadin dose may be increased to 1.5 mg/kg/day. In patients receiving 1.5 mg/kg/day, whose erythrocyte PBG-synthase activity and urine 5-ALA and urine succinylacetone remain elevated and whose plasma succinylacetone is not normalized after three months, the dose may be increased to up a maximum dose of 2 mg/kg/day.
If plasma nitisinone concentration, plasma succinylacetone, urine 5-ALA and erythrocyte PBG-synthase activity are not available, clinical laboratory assessments should include urine succinyl acetone, liver function tests, alpha fetoprotein, and serum tyrosine and phenylalanine level. During initiation of therapy and during acute exacerbations, it may be necessary to follow more closely all available biochemical parameters
3 DOSAGE FORMS AND STRENGTHS
Orfadin capsules (nitisinone) are available as white capsules imprinted with ”NTBC” followed by "2 mg", "5 mg", or "10 mg", indicating the actual amount of nitisinone in each capsule.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nitisinone in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitisinone in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Indications
Orfadin(R) capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1)
Dosage
The recommended dose of Orfadin is 1 to 2 mg/kg divided into two daily doses. The initial dose is 1 mg/kg/day divided for morning and evening administration. Treatment with Orfadin should be initiated by a physician experienced in the treatment of HT-1.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nitisinone in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitisinone in pediatric patients.
Contraindications
None
Warnings
High Plasma Tyrosine Levels
Orfadin is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see CLINICAL PHARMACOLOGY (12)]. 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 (6)]. 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.
5.2 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 (6)]. 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 thromobocytopenia. Platelet and white blood cell counts should be monitored regularly during nitisinone therapy.
Adverse Reactions
Clinical Trials Experience
The following serious adverse reactions are described below and elsewhere in the labeling:
High Plasma Tyrosine Levels[see WARNINGS AND PRECAUTIONS (5.1)].
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 clinical practice.
6.1 CLINICAL TRIALS EXPERIENCE
Orfadin was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 21.7 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinyl-acetone in the urine or plasma. The starting dose of Orfadin was 0.6 to 1 mg/kg/day, and the dose was increased in some patients to 2 mg/kg/day based on weight, biochemical, and enzyme markers. Median duration of treatment was 22.2 months (range 0.1 to 80 months).
The most serious adverse reactions reported during Orfadin treatment were thrombocytopenia, leucopenia, porphyria, and ocular/visual complaints [see WARNINGS AND PRECAUTIONS (5)]. Most patients with ocular/visual events had transient symptoms lasting less than one week, while 6 patients had symptoms lasting 16 to 672 days. Six patients had thrombocytopenia, with platelet counts 30,000/uL or lower in 3 patients. In 4 patients with thrombocytopenia, platelet counts returned to normal without change in Orfadin dose. In 2 patients platelet count returned to normal 2 weeks to 5 months after Orfadin treatment was discontinued. No patients developed infections or bleeding as a result of the episodes of leucopenia and thrombocytopenia.
Other serious adverse events reported during Orfadin treatment were hepatic neoplasm, liver failure, and porphyric crises. Patients with hereditary tyrosinemia type 1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure 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 monitoring for these complications by hepatic imaging (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended. Patients with increasing alpha-fetoprotein levels or development of liver nodules during treatment with nitisinone should be evaluated for hepatic malignancy.
The most common adverse reactions reported in the clinical trial are summarized in Table 1.
Adverse reactions reported in less than 1% of the patients, regardless of causality assessment, included death, seizure, brain tumor, encephalopathy, headache, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, tooth discoloration, hepatic function disorder, elevated hepatic enzymes, liver enlargement, dehydration, hypoglycemia, thirst, infection, septicemia, otitis, infection (not otherwise specified), bronchitis, respiratory insufficiency, pathologic fracture, amenorrhea, nervousness, and somnolence.
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nitisinone in the drug label.
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.
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitisinone in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Nitisinone during labor and delivery.
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 Orfadin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Orfadin is administered to a nursing woman.
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 (14.1)]. Monitoring of blood and urine succinyl acetone levels are recommended in the children to ensure adequate control [see DOSAGE AND ADMINISTRATION (2)]. 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.
Geriatic 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.
Gender
The effect of gender on the pharmacokinetics of Orfadin has not been studied.
Race
The effect of race on the pharmacokinetics of Orfadin has not been studied.
Renal Impairment
The effect of renal insufficiency on the pharmacokinetics of Orfadin has not been studied.
Hepatic Impairment
The effect of hepatic dysfunction on the pharmacokinetics of nitisinone has not been studied.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nitisinone in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Nitisinone in patients who are immunocompromised.
Administration and Monitoring
Administration
Orfadin should be taken at least one hour before or at least two hours after a meal, since food effect is unknown. For young children, Orfadin capsules may be opened and the contents suspended in a small amount of water immediately before use.
Physicians should counsel patients and their parents or caregivers of the need to maintain dietary restriction of tyrosine and phenylalanine when taking Orfadin to treat hereditary tyrosinemia type 1.
Monitoring
There is limited information regarding Monitoring of Nitisinone in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Nitisinone in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Nitisinone in the drug label.
Pharmacology
There is limited information regarding Nitisinone Pharmacology in the drug label.
