Sapropterin

KUVAN ® is indicated to reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age and older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). KUVAN is to be used in conjunction with a Phe-restricted diet. KUVAN is a phenylalanine hydroxylase activator indicated to reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age and older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin‑ (BH4‑) responsive Phenylketonuria (PKU).

KUVAN 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.

All patients with PKU who are being treated with KUVAN should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction. Starting Dosage Pediatric patients 1 month to 6 years: The recommended starting dosage of KUVAN is 10 mg/kg administered orally once daily. Patients 7 years and older: The recommended starting dosage of KUVAN is 10 to 20 mg/kg administered orally once daily. Dosage Adjustment Doses of KUVAN may be adjusted in the range of 5 to 20 mg/kg taken once daily. Monitor blood Phe regularly, especially in pediatric patients. Preparation and Administration See the full prescribing information for preparation and administration instructions.

None. None.

Hypersensitivity Reactions Including Anaphylaxis: KUVAN is not recommended in patients with a history of anaphylaxis to KUVAN, discontinue treatment in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary Phe restrictions. Upper Gastrointestinal Mucosal Inflammation: Monitor patients for signs and symptoms of these conditions including esophagitis and gastritis. Hypophenylalaninemia: Pediatric patients younger than 7 years treated with KUVAN doses of 20 mg/kg per day are at increased risk for low levels of blood Phe compared with patients 7 years and older. Monitoring Blood Phe Levels During Treatment: Ensure adequate blood Phe control and nutritional balance during treatment with KUVAN. Frequent blood monitoring is recommended, especially in pediatric patients.

Most common adverse reactions (≥4%) are: headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.

Table 4 includes drugs with clinically important drug interactions when administered with sapropterin dihydrochloride and instructions for preventing or managing them. Table 4: Clinically Relevant Drug Interactions Levodopa Clinical Impact Sapropterin dihydrochloride may increase the availability of tyrosine, a precursor of levodopa. Neurologic events were reported postmarketing in patients receiving sapropterin and levodopa concomitantly for a non-PKU indication. Intervention Monitor patients for a change in neurologic status. Inhibitors of Folate Synthesis (e.g., methotrexate, valproic acid, phenobarbital, trimethoprim) Clinical Impact In vitro and in vivo nonclinical data suggest that drugs that inhibit folate synthesis may decrease the bioavailability of endogenous BH4 by inhibiting the enzyme dihydrofolate reductase, which is involved in the recycling (regeneration) of BH4.

Storage Store KUVAN tablets at 20ºC to 25ºC (68ºF to 77ºF), excursions allowed between 15ºC to 30ºC (59ºF to 86ºF). Store KUVAN for oral solution at 20ºC to 25ºC (68ºF to 77ºF), excursions allowed between 15ºC to 30ºC (59ºF to 86ºF). Protect from moisture.