August 30, 2016
Recommended Topic Related To:

Orfadin

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Orfadin




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay And Hyperkeratotic Plaques

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 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]. 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 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.

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]. One patient who developed both leucopenia leukopenia and thrombocytopenia improved after the dose of ORFADIN was decreased from 1 mg/kg to 1 0.5 mg/kg twice daily. 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.

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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

Preparation And Administration Instructions

[see DOSAGE AND ADMINISTRATION]

Preparation of the Oral Suspension

The oral suspension will be dispensed with an oral syringe of appropriate size and a bottle adaptor provided by a pharmacist or other healthcare provider.

Preparing a Bottle Without the Adapter Already Inserted:

  • Store the bottle in the refrigerator prior to first use.
  • Remove the bottle from the refrigerator. Calculate 60 days from when the bottle is removed from the refrigerator. Write this date as the “Discard after” date on the bottle label.
  • Allow the bottle to warm to room temperature (30 to 60 minutes).
  • Shake the bottle vigorously for at least 20 seconds until the solid cake at the bottom of the bottle is completely dispersed. Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle.
  • Insert the bottle adapter.

Preparing a Bottle With the Adapter Inserted:

  • Shake the bottle vigorously for at least 5 seconds. Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle.
Measuring and Administering the Dose

Once the bottle is prepared with the adapter:

  1. Use the oral syringe to measure the dose.
  2. Keep the bottle upright and insert the oral syringe into the adapter.
  3. Carefully turn the bottle upside down with the oral syringe in place. Wait for the foam to rise to the top of the bottle.
  4. Pull back on the syringe plunger to withdraw the dose.
  5. Leave the syringe in the adapter and turn the bottle upright.
  6. Remove the syring efrom the adapter by gently twisting it out of the bottle.
  7. Dispense the dose into the patient's mouth.
  8. Do not remove the bottle adapter.
  9. Store the bottle at room temperature (not above 25°C).
Administration of ORFADIN Capsules and Oral Suspension
  • Maintain dietary restriction of tyrosine and phenylalanine when taking ORFADIN.
  • Capsules: Take at least one hour before, or two hours after a meal. For patients who have difficulty swallowing the capsules and for which the oral suspension is not suitable [see WARNINGS AND PRECAUTIONS]), the capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use. Or, the oral suspension may be used instead.
  • Oral suspension: Take without regard to meals.
Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques
  • Inform patients that inadequate restriction may be associated with ocular signs and symptoms, intellectual disability and developmental delay, and painful hyperkeratotic plaques on the soles and palms. Advise patients and caregivers of the need to maintain dietary restriction of tyrosine and phenylalanine and to report any unexplained ocular, neurologic, or other symptoms promptly to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Risk Of Adverse Reactions Due To Glycerol Content Of ORFADIN Oral Suspension

Advise patients receiving doses of greater than 20 mL of ORFADIN oral suspension that they may experience headache, upset stomach and diarrhea due to the glycerol component of the formulation and if they develop symptoms to report these to their healthcare provider [see WARNINGS AND PRECAUTIONS].

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 initial clinical dose 1 mg/kg per day 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

Risk Summary

Limited data on nitisinone use in pregnant women are not sufficient to inform any drug associated risk. 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 [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 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.

Lactation

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.

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 plasma and urine succinylacetone levels are recommended in the pediatric patients 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. 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.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 6/21/2016

Warnings
Precautions

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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