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

Postmarketing Reports

Gastrointestinal reactions: Esophagitis, oropharyngeal pain, pharyngitis, esophageal pain, and dyspepsia

Contraindications

None

Cautions

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

Children aged <7 yr treated with 20 mg/kg/day are at increased risk for low levels of blood Phe compared with patients aged ≥7 yr

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

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 (eg, molecular testing), and can only be determined by therapeutic trial

Some patients with PKU do not show biochemical response (reduction in blood Phe) with treatment; in two clinical trials at a dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients showed a biochemical response to therapy, and in one clinical trial at a dose of 10 mg/kg per day, 20% of adult and pediatric PKU patients showed a biochemical response to drug

Hyperactivity behavior reported (rare)

Gastrointestinal (GI) adverse reactions suggestive of upper GI mucosal inflammation reported with therapy; serious adverse reactions included esophagitis and gastritis; if left untreated, these could lead to severe sequelae including esophageal stricture, esophageal ulcer, gastric ulcer, and bleeding and such complications have been reported in patients receiving therapy; monitor patients for signs and symptoms of upper GI mucosal inflammation

Drug interaction overview

• Caution in coadministration of medications known to inhibit folate metabolism (eg, methotrexate), PDE-5 inhibitors, or levodopa
• Monitor patients for hypotension when coadministering 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; blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during 3 months before conception 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 and 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

Oral Preparation

Tablet

• Tablets may be swallowed either as whole tablets or dissolved
• Dissolve in 4-8 oz (120-240 mL) water or apple juice and take within 15 minutes of dissolution
• To make the tablets dissolve faster, stir or crush them
• Tablets may not dissolve completely; small tablet pieces may float on top of the water or apple juice, this is normal and safe to swallow
• If after drinking the medicine, add more water or apple juice to glass and drink to ensure the entire dose is taken

Powder for oral solution

• Weight >10 kg

  • Dissolve powder in 4-8 oz (120-240 mL) of water or apple juice and drink within 30 minutes of dissolution
  • Alternatively, powder may be stirred in a small amount of soft foods (eg, apple sauce, pudding)

• Infants weighing <10 kg

  • Can be dissolved in as little as 5 mL of water or apple juice and a portion of this solution corresponding to a 10 mg/kg dose may be administered PO via an oral dosing syringe
  • Administer within 30 minutes of dissolution

Oral Administration

Take with food

Missed dose: Take missed dose as soon as possible, but do not take 2 doses on the same day

Storage

Tablets

• Store at 20-25ºC (68-77ºF); excursions allowed between 15-30ºC (59-86ºF)
• Keep container tightly closed
• Protect from moisture

Powder for oral solution

• Store at 20-25ºC (68-77ºF); excursions allowed between 15-30ºC (59-86ºF)
• Keep container tightly closed