Nitisinone

Nitisinone works by preventing the body from breaking down an amino acid called tyrosine and by keeping other toxic substances from building up and causing harm to your liver or kidneys.

Nitisinone is used to treat a rare genetic condition called hereditary tyrosinemia type 1 (HT-1). HT-1 is a metabolic disorder that occurs when the body does not produce enough of an enzyme that breaks down proteins from certain foods. This condition occurs most often in young babies.

Nitisinone may also be used for purposes not listed in this medication guide.

Call your doctor at once if you have vision problems, eye pain, eye redness or burning, easy bruising, unusual bleeding, itching, or jaundice (yellowing of the skin or eyes). Tell your doctor if your baby has a sudden change in behavior, ability, or development (sitting up, crawling, walking, talking, etc).

To make sure nitisinone is safe for you, tell your doctor if you have any medical conditions affecting your eyes.

FDA pregnancy category C. It is not known whether nitisinone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether nitisinone passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Your doctor may occasionally change your dose to make sure you get the best results. Do not change your medication dose or schedule without your doctor's advice.

Take nitisinone on an empty stomach, at least 1 hour before or 2 hours after a meal.

You may open the nitisinone capsule and sprinkle the medicine into a spoonful of water, baby formula, or applesauce to make swallowing easier. Use the mixture right away. Do not save for later use.

Nitisinone may be only part of a complete program of treatment that also includes a special diet. You must avoid certain foods for your treatment to be effective. Follow the diet plan created for you by your doctor or nutrition counselor.

High protein foods are high in tyrosine and phenylalanine. Since babies and children need protein to grow and develop, special foods have been developed to replace the high protein foods.

While using nitisinone, you may need frequent blood tests at your doctor's office. Your vision may also need to be checked.

Store in the refrigerator, do not freeze.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

This is not a complete list of Nitisinonedrug interactions. Ask your doctor or pharmacist for more information.

Usual Adult Dose for Hereditary Tyrosinemia Type 1:

Initial dose: 1 mg/kg/day divided into a morning and evening dose
Maintenance dose: 1 to 2 mg/kg/day divided into two daily doses
Maximum dose: 2 mg/kg/day

Comments: Requires dietary restriction of tyrosine and phenylalanine

Usual Pediatric Dose for Hereditary Tyrosinemia Type 1:

Initial dose: 1 mg/kg/day divided into a morning and evening dose
Maintenance dose: 1 to 2 mg/kg/day divided into two daily doses
Maximum dose: 2 mg/kg/day

Comments: Requires dietary restriction of tyrosine and phenylalanine

It is very important that your doctor check your progress at regular visits to make sure nitisinone is working properly. Blood and urine tests may be needed to check for unwanted effects.

Check with your doctor right away if blurred vision, difficulty seeing at night, or any other vision change occurs during or after treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Nitisinone can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. Avoid people with infections and check with your doctor if you have symptoms of an infection such as a fever or chills, a cough or hoarseness, lower back or side pain, or painful or difficult urination. Call your doctor if you have any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.

The oral suspension contains glycerol and may cause diarrhea, an upset stomach, or headaches. Let your doctor know if you have these symptoms.

• 4-Hydroxyphenylpyruvate Dioxygenase Inhibitor

Hereditary tyrosinemia type 1: Treatment of hereditary tyrosinemia type 1 (HT-1) as an adjunct to dietary restriction of tyrosine and phenylalanine

Refer to adult dosing.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), skin changes on extremities, vision changes, eye pain, severe eye irritation, confusion, chills, pharyngitis, bleeding, or bruising (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Initial dose: 1 mg/kg/day divided into a morning and evening dose
Maintenance dose: 1 to 2 mg/kg/day divided into two daily doses
Maximum dose: 2 mg/kg/day

Comments: Requires dietary restriction of tyrosine and phenylalanine

Data not available

Pregnancy

Limited data on use in pregnant women insufficiently informs a drug-associated risk of major birth defects and miscarriage

Animal data

• Reproduction studies were performed in mice at PO doses ~0.4, 4 and 20x the recommended human dose (1 mg/kg/day), nitisinone reported to cause incomplete skeletal ossification of fetal bones, increased gestational length at 4 and 20x the recommended human dose, and decreased pup survival at 0.4x the recommended human dose based on the body surface area
• Studies in rabbits at PO doses ~1.6, 4, and 8x the recommended human dose based on body surface area; nitisinone caused incomplete skeletal ossification of fetal bones

Lactation

There is are no data on the presence of enasidenib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production

Data suggest that nitisinone may be present in rat milk due ocular toxicity and lower body weight seen in drug naïve pups; consult women of the risk versus benefits for nitisinone and any potential adverse effects on breastfed infant from nitisinone

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Oral Suspension Preparation (Orfadin)

Oral suspension is dispensed with an oral syringe of appropriate size and a bottle adaptor provided by the pharmacist

Bottle without oral syringe 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 and write this date as the “Discard after” date on the bottle label
• Allow the bottle to warm to room temperature (30-60 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

Bottle with oral syringe adapter

• 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

Compounded oral suspension (Nityr)

If difficulty swallowing intact tablets, Nityr can be disintegrated in water and administered via oral syringe

Prepare only 1-2 tablets per PO syringe at one time; use 5-mL PO syringe with a cap Use only room temperature water for preparation

Remove cap and plunger from the PO syringe and place 1 whole tablet inside PO syringe

Draw 2.6 mL (1 tablet) or 5 mL (2 tablets) of room temperature water with PO syringe

Pull plunger back to 3 mL; place cap on PO syringe tip Turn PO syringe up and down for 1 minute; then leave for at least 20 minutes

After 20 minutes, turn PO syringe for 1 minute; then leave for at least 30 minutes

Repeat turning for 1 minute; inspect syringe to ensure tablet has disintegrated prior to administration Do not administer unless tablet is fully disintegrated

If not fully disintegrated, leave for at least 10 minutes; turn the PO syringe up and down for 1 minute

Administer immediately; if unable to administer immediately, store PO suspension at room temperature; protect from sunlight; discard after 2 hr

Oral Administration

Adjunct to dietary reduction of tyrosine/phenylalanine

Oral suspension (Orfadin): May take without regard to meals

Oral capsules (Orfadin)

• Take at least 1 hr before or 2 hr after a meals
• For patients who have difficulty swallowing the capsules and who are intolerant to the oral suspension, the capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use

Unable to swallow Nityr tablet

• If patients can swallow semisolid foods, Nityr tablets can be crushed and mixed with applesauce (other foods have not been studied and is not recommended)
• If difficulty swallowing intact tablets, Nityr can be disintegrated in water and administered via oral syringe (see above preparation instructions)
• Compounded Nityr suspension
  • To facilitate full administration, avoid depressing the plunger until the end of PO syringe; leave a gap between the plunger and the PO syringe
  • Rinse PO syringe with ~2 mL of water
  • Invert the PO syringe and pull the plunger to 2.6 mL; cap the PO syringe and shake well for 10 seconds to suspend any remaining particles
  • Administer the suspension into the patient’s mouth, fully depress plunger ensuring the syringe is empty

Storage

Oral capsules (Orfadin)

• Store refrigerated between 2-8°C (36-46°F)
• May store at controlled room temperature of 20-25°C (68-77°F) for up to 45 days
• The discard after date should be noted on the bottle if stored at room temperature

Oral suspension (Orfadin)

• Refrigerate at 2-8°C (36-46°F) prior to first use
• Do not freeze
• Store bottle upright
• After first opening, store the product at room temperature (up to 25°C [77°F]) for up to 60 days; if not used within 60 days, discard unused portion
• The discard after date should be noted on the bottle

Oral tablet (Nityr)

• Store at room temperature between 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
• Dispense in tight and light resistant container