Orfadin® capsules (Nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.

Treatment with Nitisinone should be initiated by a physician experienced in the treatment of hereditary tyrosinemia type 1.

The dose of Nitisinone should be adjusted in each patient. The recommended initial dose is 1 mg/kg/day divided for morning and evening administration. Since an effect of food is unknown, Nitisinone should be taken at least one hour before a meal. Because of the long half-life of Nitisinone, the total dose may be split unevenly as convenient in order to limit the total number of capsules given at each 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. For young children, capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use.

Dose Adjustment

Nitisinone treatment should block the flux through the tyrosine degradation pathway at the level of 4-hydroxy-phenylpyruvate dioxygenase. Treatment should lead to normalized porphyrin metabolism (i.e., normal erythrocyte PBG- synthase activity and urine 5-ALA). Succinylacetone should not be detectable in urine or plasma. If the biochemical parameters (except plasma succinylacetone) are not normalized within one month after start of Nitisinone treatment, the dose should be increased to 1.5 mg/kg/day. For plasma succinylacetone, it may take up to three months before the level is normalized after the start of Nitisinone treatment. Since plasma Nitisinone concentration, plasma succinylacetone, urine 5-ALA, and erythtocyte PBG-synthase activity are not routinely available, it is appropriate during regular monitoring to follow urine succinylacetone, liver function tests, alpha-fetoprotein, and serum tyrosine, and phenylalanine levels. However, during the initiation of therapy and during acute exacerbations, it may be necessary to follow more closely all available biochemical parameters (see Laboratory Tests). A dose of 2 mg/kg/day may be needed, especially in infants, once liver function has improved. This dose should be considered as a maximal dose for all patients.

Orfadin® capsules are white and marked in black with "NTBC" and identified as 2mg, 5mg or 10mg strengths of Nitisinone. The capsules are packaged in a high density (HD) polyethylene container with a tamper-resistant low density (LD) polyethylene snap-on cap. Each bottle contains 60 capsules.

Orfadin® is available as:

2 mg white capsules imprinted "NTBC 2 mg" in black ink. NDC 66607-10026. 5 mg white capsules imprinted "NTBC 5 mg" in black ink. NDC 66607-10056. 10 mg white capsules imprinted "NTBC 10 mg" in black ink. NDC 66607-10106.

Storage

Store refrigerated, 2 - 8°C (36 - 46°F).

Caution: ^Rx only

Manufactured by: Apoteket AB, Sweden; for SWEDISH ORPHAN INTERNATIONAL AB, Sweden.

Distributed by: Rare Disease Therapeutics, Inc. 1101 Kermit Drive Nashville, TN 37217 Phone number: 615-399-0700

Revised January 2002

Orfadin® owned by SWEDISH ORPHAN INTERNATIONAL AB, Sweden.

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