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Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

PKU Clinical Studies

In clinical studies, Kuvan was administered to 579 patients with PKU in doses ranging from 5 to 20 mg/kg/day for lengths of treatment ranging from 1 to 164 weeks. Patients were aged 4 to 50 years old. The patient population was nearly evenly distributed in gender, and approximately 95% of patients were Caucasian.

The most common adverse reactions ( ≥ 4% of patients) across all investigational studies (n=579) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.

The data described in Table 1 reflect exposure of 74 patients with PKU to Kuvan at doses of 10 to 20 mg/kg/day for 6 to 10 weeks in 2 double-blind, placebo-controlled clinical trials. The overall incidence of adverse reactions in patients receiving Kuvan was similar to that reported with patients receiving placebo.

Table 1 enumerates adverse reactions occurring in at least 4% of patients treated with Kuvan in the double-blind, placebo-controlled clinical trials described above.

Table 1: Summary of Adverse Reactions Occurring in ≥ 4% of Patients in Placebo-Controlled Clinical Studies with Kuvan

MedDRA Preferred Term Treatment
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 in which all patients received Kuvan in doses of 5 to 20 mg/kg/day, adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials [see Clinical Studies].

In a long term, open-label, extension study of 111 patients receiving Kuvan in doses of ranging from 5 to 20 mg/kg/day [see Clinical Studies], 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.

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/day for lengths of exposure from 1 day to 2 years. Serious and severe adverse reactions (regardless of causality) during sapropterin administration were convulsions, exacerbation of convulsions [see WARNINGS AND PRECAUTIONS], 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.

Post-Marketing Experience

The 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].