In clinical studies, sapropterin was administered to 579 patients with phenylketonuria in doses ranging from 5 to 20 mg/kg/day for lengths of treatment ranging from 1 to 164 weeks in patients ranging from 4 to 50 years of age. Among the most common adverse events reported in this trial and similar placebo-controlled trials were headache (15% vs. 14%), rhinorrhea (11% vs. 0%), pharyngolaryngeal pain (10% vs. 2%), cough (7% vs. 5%), and nasal congestion (4% vs. 0%). Rhinitis was infrequently reported, with 2 patients (7.4%) reporting this side effect in a study of 27 pediatric patients 0 to 4 years (n = 27). Post-marketing, oropharyngeal pain and pharyngitis were also reported.[33635]

In clinical evaluation of sapropterin, gastrointestinal related adverse events reported relative to placebo include diarrhea (8% vs. 5%) and vomiting (8% vs. 7%). Postmarketing, esophagitis, oropharyngeal pain, pharyngitis, esophageal pain, gastritis, dyspepsia, abdominal pain, nausea, and vomiting have been reported. If left untreated, esophageal stricture, esophageal ulcer, gastric ulcer, and bleeding have occurred. Monitor patients for signs and symptoms of upper GI mucosal inflammation.[33635]

Severe hypersensitivity reactions, including anaphylactoid reactions and rash (unspecified) have occurred during sapropterin administration. Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Discontinue sapropterin immediately and initiate appropriate medical treatment if anaphylaxis is suspected. Continue dietary Phe restrictions in patients who experience anaphylaxis. Post-marketing, most reported hypersensitivity reactions occurred within several days of initiating treatment.[33635]

In the post-marketing safety surveillance program for phenylketonuria (PKU), 2 patients experienced hyperactivity with administration of sapropterin. One case occurred in a patient who received an accidental overdose of the drug. Monitor patients for hyperactivity.[33635] In other safety evaluation among 800 healthy volunteers and patients with disorders other than PKU (some with underlaying neurological or cardiovascular disorders), sapropterin was administered as different formulations at doses ranging from 1—100 mg/kg/day for lengths of exposure from 1 day to 2 years. Serious and severe adverse nervous system reactions (regardless of causality) during sapropterin administration included seizures, exacerbation of convulsions, dizziness, headache, irritability, and overstimulation. Common adverse reactions reported were headache, agitation, and dizziness.[33635]

In other safety evaluation among 800 healthy volunteers and patients with disorders other than phenylketonuria (some with underlaying neurological or cardiovascular disorders), sapropterin was administered as different formulations at doses ranging from 1 to 100 mg/kg/day for lengths of exposure from 1 day to 2 years. Serious and severe adverse reactions (regardless of causality) during sapropterin administration included post-procedural bleeding, GI bleeding, myocardial infarction, and respiratory failure. Common adverse reactions were peripheral edema, arthralgia, polyuria, nausea, pharyngitis, abdominal pain, upper abdominal pain, and upper respiratory tract infection.[33635]

Fever and infection may cause blood phenylalanine (Phe) concentrations to increase.[33635] Patients with a fever or an infection may need an adjustment in their sapropterin dose or dietary management to keep blood Phe concentrations within the desired range.

Blood phenylalanine (Phe) concentrations should be closely monitored in patients with anorexia nervosa or bulimia nervosa. Adequate dietary intake of Phe is required to prevent blood Phe concentrations from being too low. Prolonged blood Phe concentrations that are too low may result in catabolism and protein breakdown. Sapropterin should be used with caution in these patients.

During clinical trials, severe gastritis has been associated with sapropterin use. Monitor all patients, especially those with GI disease, for signs and symptoms of gastritis.[33635]

Patients with renal impairment have not been evaluated in clinical trials. Renally impaired patients should be closely monitored when receiving sapropterin.[33635]

Sapropterin has not been evaluated in patients with hepatic disease. In clinical trials, patients with elevations in alanine transaminase > 5 times the upper-limit of normal were excluded. Patients with hepatic disease should be closely monitored when receiving sapropterin, as hepatic damage has been associated with impaired phenylalanine (Phe) metabolism.

In clinical trials, infants and children less than 7 years who received sapropterin doses of 20 mg/kg/day were at increased risk for developing low blood phenylalanine (Phe) concentrations compared to patients >= 7 years of age. Prolonged periods of low Phe concentrations have been associated with catabolism and protein breakdown, which could be particularly detrimental to infants and young children. Initiate sapropterin therapy at the lower end of the initial dosage range (i.e., 10 mg/kg/day) in children < 7 years, and monitor blood phenylalanine concentrations carefully. Sapropterin is not FDA-approved for use in neonates.[33635]

There are insufficient data to assess the presence of sapropterin in human milk and no data on the effects on milk production. In postmarketing pregnancy registries, a total of 16 women from both registries were identified as breast-feeding for a mean of 3.5 months. No lactation-related safety concerns were reported in infants of mothers nursing during maternal treatment with sapropterin. Sapropterin is present in the milk of lactating rats following intravenous administration, but not following oral administration. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.[33635]

There is a pregnancy exposure registry that has been established that monitors pregnancy outcomes in women who are exposed to sapropterin (Kuvan) during pregnancy. For more information regarding the registry program call 1-800-983-4587. Available pregnancy registry data have not reported an association with sapropterin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when the drug was used during pregnancy. 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. Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception. 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 micromol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies. Control of blood phenylalanine during pregnancy is essential to reduce the incidence of Phe-induced teratogenic effects. Pregnancy Registry Data from 62 live births reported 3 abnormalities at birth (one case each of microcephaly, cleft palate, and tongue tie). These outcomes were associated with Phe levels greater than 360 micromol/L during pregnancy.[33635]