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KUVAN (sapropterin dihydrochloride) tablets(九)
2015-08-13 10:31:57 来源: 作者: 【 】 浏览:7556次 评论:0
ed [see Clinical Pharmacology (12.2)].

Patients should be advised to notify their physicians in cases of overdose.

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11.  DESCRIPTION

Kuvan (sapropterin dihydrochloride) is an orally administered Phenylalanine Hydroxylase activator (or PAH activator). Sapropterin dihydrochloride, the active pharmaceutical ingredient in Kuvan, is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Sapropterin dihydrochloride is an off-white to light yellow crystals or crystalline powder.

The chemical name of sapropterin dihydrochloride is (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-pteridinone dihydrochloride and the molecular formula is C9H15N5O3·2HCl with a molecular weight of 314.17.

Sapropterin dihydrochloride has the following structural formula:

 
Kuvan is supplied as tablets and powder for oral solution containing 100 mg of sapropterin dihydrochloride (equivalent to 76.8 mg of sapropterin base). Kuvan is also supplied as powder for oral solution containing 500 mg of sapropterin dihydrochloride (equivalent to 384 mg of sapropterin base).

Tablets are round, off-white to light yellow, mottled, and debossed with “177”. Each tablet contains the following inactive ingredients: ascorbic acid (USP), crospovidone (NF), dibasic calcium phosphate (USP), D-mannitol (USP), riboflavin (USP), and sodium stearyl fumarate (NF).

Kuvan powder for oral solution is off-white to yellow in color. Each unit dose packet contains the following inactive ingredients: ascorbic acid (USP), D-mannitol (USP), potassium citrate (USP), and sucralose (NF).%3

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12.  CLINICAL PHARMACOLOGY


12.1 Mechanism of ActionKuvan is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme activity, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.


12.2 PharmacodynamicsIn PKU patients who are responsive to BH4 treatment, blood Phe levels decrease within 24 hours after a single administration of sapropterin dihydrochloride, although maximal effect on Phe level may take up to a month, depending on the patient. A single daily dose of Kuvan is adequate to maintain stable blood Phe levels over a 24-hour period. Twelve patients with blood Phe levels ranging from 516 to 986 μmol/L (mean 747 ± 153 μmol/L) were assessed with 24‑hour blood Phe level monitoring following a daily morning dose of 10 mg/kg per day. The blood Phe level remained stable during a 24‑hour observation period. No substantial increases in blood Phe levels were observed following food intake throughout the 24-hour period.

Kuvan dose-response relationship was studied in an open-label, forced titration study at doses of 5 mg/kg per day, then 20 mg/kg per day, and then 10 mg/kg per day (Study 3) [see Clinical Studies (14.1)]. Individual blood Phe levels were highly variable among patients. The mean blood Phe level observed at the end of each 2-week dosing period decreased as the dose of sapropterin dihydrochloride increased, demonstrating an inverse relationship between the dose of sapropterin dihydrochloride and mean blood Phe levels. 

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