sapropterin (Rx)

>10%

Rhinorrhea (11%)

Headache (15%)

1-10%

Diarrhea (8%)

Pharyngolaryngeal pain (10%)

Cough (7%)

Nasal congestion (4%)

Vomiting (8%)

Nausea (8%)

<1%

Gastritis

Gastrointestinal bleeding

Thrombocytopenia

Spinal cord injury

Abdominal pain

Decreased appetite

Respiratory tract infection

Peripheral edema

Contraindications

None listed in the manufacturer's label

Cautions

Do not eliminate ongoing Phe-restricted diet: treat all patients with a Phe-restricted diet

Children < 7 years treated with 20 mg/kg/day are at increased risk for low levels of blood Phe compared with patients 7 years and older

Treatment should be directed by physicians knowledgeable in management of PKU;. prolonged elevations in blood Phe levels in patients with PKU can result in severe neurologic damage, including severe mental retardation, microcephaly, delayed speech, seizures, and behavioral abnormalities; prolonged levels of blood Phe that are too low are associated with catabolism and protein breakdown; active management of dietary Phe intake while receiving therapy is required to ensure adequate Phe control and nutritional balance; monitor blood Phe levels during treatment to ensure adequate blood Phe level control; frequent blood monitoring is recommended in pediatric population

Hypersensitivity reactions including anaphylaxis and rash have occurred

Gastritis reported; monitor patients for signs and symptoms of gastritis

Use caution in renal and hepatic impairment

Patients that show no improvement after treating at 20 mg/kg/day for 1 month are considered nonresponders; response to treatment cannot be pre-determined by laboratory testing (e.g., molecular testing), and can only be determined by therapeutic trial

Caution in coadministration of medications known to inhibit folate metabolism (eg, methotrexate), PDE-5 inhibitors, or levodopa

Hyperactivity behavior reported (rare)

Monitor patients for hypotension when co-administering drug with medications known to affect nitric oxide-mediated vasorelaxation

Pregnancy

A patient registry has been established that collects data on women who are treated during pregnancy; for information regarding registry program call 1-800-983-4587

There are no adequate and well-controlled studies in pregnant women; therapy should be administered during pregnancy only if potential benefit justifies potential risk to fetus

Available data from maternal Phenylketonuria Collaborative Study in PKU-affected women demonstrated that uncontrolled Phe levels above 600 micromol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies; good dietary control of Phe levels during pregnancy is essential to reduce incidence of Phe-induced teratogenic effects

Animal data

• An embryo-fetal development study in rats using oral doses up to 3 times maximum recommended human dose (MRHD) given during period of organogenesis showed no effects; in a rabbit study using oral administration of sapropterin dihydrochloride during period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD

Lactation

Not known whether drug is present in human milk; it is present in milk of intravenously, but not orally, treated lactating rats; consider developmental and health benefits of human milk feeding along with mother’s clinical need for therapy and any potential adverse effects on human milk-fed child from drug or from underlying maternal condition; exercise caution when drug is administered to a nursing woman

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Synthetic tetrahydrobiopterin (BH4), for phenylalanine hydroxylase (PAH); PAH hydroxylates Phe to form tyrosine; BH4 activates residual PAH enzyme, improving oxidative metabolism of Phe & thereby decreasing Phe blood levels

Pharmacokinetics

Half-Life: 7 hr; range: 3.9-17 hr

Onset: 24 hr; up to 2 month (maximum effect)

Peak Plasma Time: stable over 24-hr period

Duration: 24 hr