ORFADIN Capsule / Oral suspension Ref.[10890] Active ingredients: Nitisinone

5.1 Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques

Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see Clinical Pharmacology (12.1)]. Therefore, treatment with ORFADIN may cause an increase in plasma tyrosine levels in patients with HT-1. Maintain concomitant reduction in dietary tyrosine and phenylalanine while on ORFADIN treatment. Do not adjust ORFADIN dosage in order to lower the plasma tyrosine concentration. Maintain plasma tyrosine levels below 500 micromol/L. 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:

• 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 (6.1)]. In a clinical study in a non HT-1 population without dietary restriction and reported tyrosine levels >500 micromol/l both symptomatic and asymptomatic keratopathies have been observed. Therefore, perform a baseline ophthalmologic examination including slit-lamp examination prior to initiating ORFADIN treatment and regularly thereafter. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes or tyrosine levels are >500 micromol/L during treatment with ORFADIN should undergo slit-lamp reexamination and immediate measurement of the plasma tyrosine concentration.
• Variable degrees of intellectual disability and developmental delay. In patients treated with ORFADIN who exhibit an abrupt change in neurologic status, perform a clinical laboratory assessment including plasma tyrosine levels.
• 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, assess dietary tyrosine and phenylalanine intake.

5.2 Leukopenia and Severe Thrombocytopenia

In clinical trials, patients treated with ORFADIN and dietary restriction developed transient 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 ORFADIN therapy.

5.3 Risk of Adverse Reactions Due to Glycerol Content of ORFADIN Oral Suspension

Oral doses of glycerol of 10 grams or more have been reported to cause headache, upset stomach and diarrhea. ORFADIN oral suspension contains 500 mg/mL of glycerol. Patients receiving more than 20 mL of ORFADIN oral suspension (10 grams glycerol) as a single dose are at increased risk of these adverse reactions. Consider switching patients who are unable to tolerate the oral suspension to ORFADIN capsules.

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.

ORFADIN was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of ORFADIN was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. The recommended starting dosage of ORFADIN is 0.5 mg/kg twice daily [see Dosage and Administration (2.1)]. Median duration of treatment was 22 months (range 0.1 to 80 months).

The most serious adverse reactions reported during ORFADIN treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions (5.1, 5.2)]. Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from 5 days to 2 years. Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL or lower. In 4 patients with thrombocytopenia, platelet counts gradually returned to normal (duration up to 47 days) without change in ORFADIN dose. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia.

Patients with HT- 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 1%).

The most common adverse reactions reported in the clinical trial are summarized in Table 1.

Table 1. Most Common Adverse Reactions in Patients with HT-1 Treated with Nitisinone*:

^* reported in at least 1% of patients

Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis.

Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3. Table 2 includes drugs with clinically important drug interactions when administered concomitantly with ORFADIN and instructions for preventing or managing them.

Table 2. Clinically Relevant Interactions Affecting Co-Administered Drugs:

Risk Summary

Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. 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 initial dose of 1 mg/kg/day. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended initial dose, and increased gestational length at doses 4 times the recommended initial dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended initial dose [see Data].

The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times the recommended initial dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8 times the recommended initial 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 initial dose, increased gestational length at 4 and 20 times the recommended initial dose, and decreased pup survival at 0.4 times the recommended initial 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 initial dose based on the body surface area.

Risk Summary

There are no data on the presence of nitisinone in human milk, the effects on the breastfed infant, or the effects on milk production. 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. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORFADIN and any potential adverse effects on the breastfed infant from ORFADIN or from the underlying maternal condition.

The safety and effectiveness of ORFADIN have been established in pediatric patients for the treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine. Use of ORFADIN in pediatric patients is supported by evidence from one open-label, uncontrolled clinical study conducted in 207 patients with HT-1 ages 0 to 22 years (median age 9 months) [see Clinical Studies (14)].

Clinical studies of nitisinone did not include any subjects aged 65 and over. No pharmacokinetic studies of nitisinone have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.