In Studies1-4 (controlled and uncontrolled studies), 579 patients with PKU aged 4 to 49 years received Kuvan in doses ranging from 5 to 20 mg/kg per day for lengths of treatment ranging from 1 to 164 weeks. The patient population was evenly distributed in gender, and approximately 95% of patients were Caucasian.  The most common adverse reactions (≥4% of patients) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.

The data described in Table 3 reflect exposure of 74 patients with PKU to Kuvan at doses of 10 to 20 mg/kg per day for 6 to 10 weeks in two double-blind, placebo-controlled clinical trials (Studies 2 and 4).

Table 3 enumerates adverse reactions occurring in at least 4% of patients treated with Kuvan in the double-blind, placebo-controlled clinical trials described above.

Table 3: Summary of Adverse Reactions  Occurring in ≥4% of Patients in Placebo-Controlled Clinical Studies with Kuvan

MedDRA Preferred Term
 Treatment
 
Kuvan

(N=74)
 Placebo

(N=59)
 
 No. Patients (%)
 No. Patients (%)
 
Headache
 11 (15)
 8 (14)
 
Rhinorrhea
 8 (11)
 0
 
Pharyngolaryngeal pain
 7(10)
 1 (2)
 
Diarrhea
 6 (8)
 3 (5)
 
Vomiting
 6 (8)
 4 (7)
 
Cough
 5 (7)
 3 (5)
 
Nasal congestion
 3 (4)
 0
 
In open-label, uncontrolled clinical trials (Studies 1 and 3)  all patients received Kuvan in doses of 5 to 20 mg/kg per day, adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials [see Clinical Studies (14.1)].

In Study 5, 65 pediatric patients with PKU aged 1 month to 6 years received Kuvan 20 mg/kg per day for 6 months.  Adverse reactions in these patients were similar in frequency and type as those seen in other Kuvan clinical trials except for an increased incidence of low Phe levels. Twenty-five percent (16 out of 65) of patients developed Phe levels below normal for age [see Warnings and Precautions (5.3), Pediatric Use (8.4), and Clinical Studies (14.1)].

In Study 6, a long term, open-label, extension study of 111 patients aged 4 to 50 years, receiving Kuvan in doses ranging from 5 to 20 mg/kg per day, adverse reactions were similar in type and frequency to those reported in the previous clinical studies.  Fifty-five patients received Kuvan both as dissolved and intact tablets.  There were no notable differences in the incidence or severity of adverse reactions between the two methods of administration.  The mean (± SD) exposure to sapropterin for the entire study population was 659 ± 221 days (maximum 953 days).

Safety Experience from Clinical Studies for Non-PKU Indications

Approximately 800 healthy volunteers and patients with disorders other than PKU, some of whom had underlying neurologic disorders or cardiovascular disease, have been administered a different formulation of the same active ingredient (sapropterin) in approximately 19 controlled and uncontrolled clinical trials. In these clinical trials, subjects were administered sapropterin at doses ranging from 1 to 100 mg/kg per day for lengths of exposure from 1 day to 2 yea