MDK-NITISONE

Nitisinone is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase.

It is used in the treatment of hereditary tyrosinemia type and Alkaptonuria.

It is sold under the brand names Orfadin and Harliku. 1, 2.

Nitisinone under the brand name

ORFADIN is indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.

Under the name

HARLIKU, nitisinone is indicated for the reduction of urine homogentisic acid (HGA) in adult patients

Hereditary tyrosinemia type 1 occurs due to a deficiency in fumarylacetoacetase (FAH), the final enzyme in the tyrosine catabolic pathway.

Nitisinone inhibits catabolism of tyrosine by preventing the catabolic intermediates.

In patients with

HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity.

Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1.

4-hydroxyphenylpyruvate dioxygenase Inhibitor.

The capsule and liquid formulations are bioequivalent in both the plasma concentration-time curve and maximum plasma concentration (Cmax).

The arithmetic mean (SD) apparent volume of distribution of nitisinone is 8.2 L in healthy subjects.

The arithmetic mean (SD) terminal half-life of nitisinone is 59.3 (±8.9) hours in healthy subjects.

The estimated mean (CV%) renal clearance of nitisinone is 0.003 L/h (25%).

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Side effects include elevated plasma levels of this amino acid, hepatic and liver failure.

The recommended starting dosage is 0.5 mg/kg orally twice daily.

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 may be given once daily.

Titrate the dosage based on biochemical and/or clinical response, as described in the full prescribing information.

The maximum total daily dosage is 2 mg/kg orally.

For instructions on preparing, measuring and administering the oral suspension, see the full prescribing information.

Maintain dietary restriction of tyrosine and phenylalanine Take ORFADIN capsules at least one hour before, or two hours after a meal For patients who have difficulties swallowing 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.

ORFADIN oral suspension without regard to meals. 2.1 Dosage Starting Dosage The recommended starting dosage of ORFADIN is 0.5 mg/kg administered orally twice daily.

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) .

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.

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. 2.2 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.

Once the bottle is prepared with the adapter: Use the oral syringe to measure the dose.

Keep the bottle upright and insert the oral syringe into the adapter.

Carefully turn the bottle upside down with the oral syringe in place.

Wait for the foam to rise to the top of the bottle.

Pull back on the syringe plunger to withdraw the dose.

Leave the syringe in the adapter and turn the bottle upright.

Remove the syringe from the adapter by gently twisting it out of the bottle.

Dispense the dose into the patient's mouth.

Do not remove the bottle adapter.

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.

Take at least one hour before, or two hours after a meal.

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.

Oral suspension

Take without regard to meals.

White capsules marked in black with "NTBC" and identified as 2 mg, 5 mg, 10 mg or 20 mg strengths of nitisinone.

The capsules are packed in a high density (HD) polyethylene container with a tamper-resistant low density (LD) polyethylene snap-on cap.

Each bottle contains 60 capsules. 2 mg white capsules imprinted "NTBC 2 mg" in black ink, NDC 66658-102-60 5 mg white capsules imprinted "NTBC 5 mg" in black ink, NDC 66658-105-60 10 mg white capsules imprinted "NTBC 10 mg" in black ink, NDC 66658-110-60 20 mg white capsules imprinted "NTBC 20 mg" in black ink, NDC 66658-120-60 Store refrigerated at 2° to 8°C (36° to 46°F).

Alternatively, patients/caregivers may store ORFADIN capsules at room temperature up to 25°C (77°F) for up to 45 days.

If not used within 45 days, discard ORFADIN capsules.

Oral suspension

White, slightly viscous opaque suspension. 1 mL contains 4 mg of nitisinone.

The suspension is provided in a 100 mL brown bottle (type III glass) with a white child resistant HDPE screw cap with sealing and tamper evidence.

Each bottle contains 90 mL oral suspension.

Oral suspension 4 mg/mL, NDC 66658-204-90 Store refrigerated at 2°C to 8°C (36°F to 46°F) prior to first use.

Do not freeze.

Store 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.

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 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.

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 to 4% and to 20%, respectively.

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 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.

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 to 22 years (median age 9 months) .

Clinical studies of nitisinone did not include any subjects aged 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.