Orfadin

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

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some side effects may result from not properly following your diet plan and consuming restricted foods or beverages.

Call your doctor at once if you have:

• a sudden change in behavior, ability, or development (sitting up, crawling, walking, talking, etc);
• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
• nausea, diarrhea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• vision problems,
• eye pain, redness or swelling, burning, white or yellow patches on your eyes; or
• calluses, peeling, or hardened skin on the palms of your hands or the soles of your feet.

Common side effects may include:

• increased sensitivity of your eyes to light;
• dry skin; or
• mild rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Rare Disease Therapeutics, Inc.

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.

While you are taking nitisinone, you must not eat foods that are high in tyrosine or phenylalanine, including:

• chicken, beef, pork, liver, fish, processed meats (bologna, hot dogs, pepperoni, hard sausages), meat tenderizer, herring or other dried fish;

• cheese, milk, sour cream, yogurt;

• beer, wine, distilled liquor;

• avocados, bananas, carrots, potatoes, spinach, tomatoes, raisins, red plums,

• oatmeal, brown rice,

• soy sauce, soy protein, tofu, bean curd, garbanzo beans, soy beans, and certain nuts or seeds; or

• foods that contain an artificial sweetener called aspartame (NutraSweet)--diet soda, some foods labeled as "sugar-free" or "zero calorie."

There are other foods that may contain tyrosine or phenylalanine. Get familiar with the list of foods you must avoid to help control your condition.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Black, tarry stools
• bleeding gums
• blindness
• blood in the urine or stools
• bloody nose
• blurred vision
• burning, dry, or itching eyes
• change in color vision
• chest pain or discomfort
• chills
• cough
• decreased vision
• difficulty seeing at night
• excessive eye tearing
• eye redness, irritation, or pain
• fever
• increased sensitivity of the eyes to sunlight
• painful or difficult urination
• pinpoint red spots on the skin
• redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swollen or painful glands
• unusual bleeding or bruising
• unusual tiredness or weakness

• Agitation
• back pain
• bluish color of the fingernails, lips, skin, palms, or nail beds
• confusion
• cough with mucus
• difficulty with breathing
• dizziness
• drowsiness
• hallucinations
• headache
• irritability
• seizures
• stiff neck
• tightness in the chest
• vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Dry skin
• hair loss or thinning
• itching or skin rash
• red, swollen skin
• scaly skin

• Abdominal or stomach pain
• cold sweats
• cool, pale skin
• depression
• fast heartbeat
• headache
• increased hunger
• nausea
• nightmares
• seizures
• shakiness
• slurred speech

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Dosage

Starting Dosage

The recommended starting dosage of Orfadin is 0.5 mg/kg administered orally twice daily

Maintenance Regimen

In patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, the total daily dose of Orfadin may be given once daily (e.g., 1 to 2 mg/kg once daily) [see Clinical Pharmacology (12.2)].

Dosage Titration

Titrate the dosage in each individual patient based on biochemical and/or clinical response.

• Monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alpha-fetoprotein levels.
• If succinylacetone is still detectable in blood or urine 4 weeks after the start of nitisinone treatment, increase the nitisinone dosage to 0.75 mg/kg twice daily. A maximum total daily dosage of 2 mg/kg may be needed based on the evaluation of all biochemical parameters.
• If the biochemical response is satisfactory (undetectable blood and/or urine succinylacetone), the dosage should be adjusted only according to body weight gain and not according to plasma tyrosine levels.
• During initiation of therapy, when switching from twice daily to once daily dosing, or if there is a deterioration in the patient's condition, it may be necessary to follow all available biochemical parameters more closely (i.e. plasma and/or urine succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity).
• Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction of tyrosine and phenylalanine intake [see Warnings and Precautions (5.1)]. In patients who develop plasma tyrosine levels above 500 micromol/L, assess dietary tyrosine and phenylalanine intake. Do not adjust the Orfadin dosage in order to lower the plasma tyrosine concentration.

Preparation and Administration Instructions

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 syringe from 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 [see Clinical Pharmacology (12.3)]. For patients who have difficulty swallowing the capsules and who are intolerant to the oral suspension [see Warnings and Precautions (5.3)], the capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use.
• Oral suspension: Take without regard to meals [see Clinical Pharmacology (12.3)].

• Capsules: 2 mg, 5 mg, 10 mg and 20 mg white capsules imprinted with “NTBC” followed by “2 mg”, “5 mg”, “10 mg” or ”20 mg”, indicating the actual amount of nitisinone in each capsule.
• Oral suspension: 4 mg/mL, a white, slightly viscous opaque suspension.

None.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of nitisinone was assessed in a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice. There were no drug-related neoplastic findings in male or female Tg.rasH2 mice at doses up to 100 mg/kg/ day nitisinone (approximately 8.1 times the recommended initial dose of 1 mg/kg/day on a body surface area basis).

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 (16.2 times the recommended initial dose of 1 mg/kg/day on a body surface area basis), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.