rs. Serious and severe adverse reactions (regardless of causality) during sapropterin administration were convulsions, exacerbation of convulsions [see Warnings and Precautions (5.10)], dizziness, gastrointestinal bleeding, post-procedural bleeding, headache, irritability, myocardial infarction, overstimulation, and respiratory failure. Common adverse reactions were headache, peripheral edema, arthralgia, polyuria, agitation, dizziness, nausea, pharyngitis, abdominal pain, upper abdominal pain, and upper respiratory tract infection.
6.2 Post-Marketing ExperienceThe following adverse reactions have been identified during post-approval use of Kuvan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.
In worldwide marketing experience, the most common adverse reactions due to Kuvan are oropharyngeal pain, pharyngitis, esophageal pain, gastritis, dyspepsia, abdominal pain, nausea and vomiting. Hypersensitivity reactions including anaphylaxis and rash have been reported. Most hypersensitivity reactions occurred within several days of initiating treatment. Two cases of hyperactivity have been reported, including one case in a patient who received an accidental overdose of Kuvan [see Warnings and Precautions (5.1, 5.11)].
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7. DRUG INTERACTIONS
No drug interaction studies were performed.
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8. USE IN SPECIFIC POPULATIONS
8.1 PregnancyPregnancy Category C
A patient registry has been established that collects data on women who are treated with Kuvan during pregnancy. For more information regarding the registry program call 1-866-906-6100.
Risk Summary
There are no adequate and well-controlled studies with Kuvan in pregnant women. An embryo-fetal development study with sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended human dose (MRHD) given during the period of organogenesis showed no effects. In a rabbit study using oral administration of sapropterin dihydrochloride during the period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD. Kuvan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Disease-associated maternal and/or embryofetal risk
Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in PKU‑affected women demonstrated that uncontrolled Phe levels above 600 µmol/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 the incidence of Phe-induced teratogenic effects.
Animal Data
No effects on embryo-fetal development were observed in a reproduction study in rats using oral doses of up to 400 mg/kg per day sapropterin dihydrochloride (about 3 times the MRHD of 20 mg/kg per day, based on body surface area) administered during the period of organogenesis. However, in a rabbit reproduction study, oral administration of a maximum dose of 600 mg/kg per day (about 10 times the MRHD, based on body surface area) during the period of organogenesis was associated with a non-statistically significant inc
