Company:

BioMarin

Enzyme cofactor (BH4)

Sapropterin dihydrochloride 100mg; tabs.

In conjunction with a phenylalanine (Phe)-restricted diet: To reduce blood Phe levels in hyperphenylalaninemia (HPA) in responsive phenylketonuria (PKU).

Phenylketonuria is an inborn error of metabolism that causes an accumulation of the amino acid Phe to harmful levels, causing neurological injury. In normal patients, Phe is converted to tyrosine by the enzyme phenylalanine hydroxylase. In patients with PKU, the activity of this enzyme is deficient or absent. BH4 (tetrahydrobiopterin) is a cofactor for this enzyme that is necessary for its efficient functioning; sapropterin is a synthetic version of this cofactor. Treatment with BH4 can activate residual phenylalanine hydroxylase (PAH), improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.

The responsiveness of an individual patient to treatment with sapropterin cannot be predicted based on lab testing; only a therapeutic trial can determine if the drug is effective and appropriate for each patient. In clinical trials, about 20% to 56% of patients responded to treatment. All patients treated with sapropterin should be placed on a Phe-restricted diet, and treatment should be directed by physicians knowledgeable in the management of PKU. Neurologic damage may occur despite treatment, and both elevated and low blood levels of Phe must be avoided. In patients who are responsive to sapropterin, blood levels of Phe drop within 24 hours after a single dose, while peak effects may take up to a month.

Four clinical trials were conducted to assess the safety and efficacy of sapropterin in the treatment of PKU. Study 1 was a multicenter, open-label, uncontrolled trial of 489 patients with PKU who had baseline Phe levels ≥450micromoles/L and who were not on Phe-restricted diets. All patients were treated with sapropterin 10mg/kg per day; at day 8, 20% of patients had at least a 30% reduction in blood Phe levels. Study 2 was a multicenter, double-blind, placebo-controlled trial of 88 patients with PKU who had been responders in Study 1. After a washout period, patients were given either sapropterin 10mg/kg or placebo daily for 6 weeks. At 6 weeks, the patients treated with sapropterin had mean changes in blood Phe of -239micromoles/L compared to 6micromoles/L for placebo. Changes in blood Phe were seen in week 1 and were sustained through week 6. Study 3 was a multicenter, open-label extension study in which 80 patients who had responded in Study 1 and who completed Study 2 underwent 6 weeks of dose titration with three doses of sapropterin, with a 2-week course for each dose. At doses of 5, 10, and 20mg/kg per day, mean changes in blood Phe were -100, -204, and -263micromoles/L, respectively. Study 4 was an open-label multicenter study that enrolled 90 children ages 4 to 12 years with PKU who were on Phe-restricted diets and had blood Phe levels ≤480micromoles/L. At day 8, 56% of patients had a ≥30% reduction in blood Phe levels.

<4 years: consult manufacturer. ≥4 years: Take with food. Dissolve tablet in 4–8oz water or apple juice (may crush tab) and drink within 15 minutes (tablet may not completely dissolve). Initially 10mg/kg once daily; if inadequate response may increase to 20mg/kg once daily; if inadequate response after 1 month, discontinue. Usual range 5–20mg/kg per day; adjust based on blood Phe levels.

Monitor blood levels of Phe after 1 week to assess effect, then periodically. Maintain Phe-restricted diet. Hepatic or renal impairment. Pregnancy (Cat.C). Nursing mothers: not recommended.

Caution with drugs that can inhibit folate metabolism (eg, methotrexate), PDE-5 inhibitors (eg, sildenafil, tadalafil, vardenafil), other nitric oxide donors, levodopa.

Headache, GI upset, upper respiratory infection/symptoms, throat pain, cough, fever, contusion, abdominal pain, rash; others (see literature).

Register pregnant patients exposed to sapropterin by calling (866) 906-6100.

Tabs—120

1/10/08