KUVAN SIDE EFFECTS

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction 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

The safety of Kuvan was evaluated in 7 clinical studies in patients with PKU (aged 1 month to 50 years).

In Studies 1-4 (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 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

In open-label, uncontrolled clinical trials (Studies 1 and 3) all patients received Kuvan in doses of 5 to 20 mg/kg per day, and adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials.

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.

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).

In Study 7, 27 pediatric patients with PKU aged 0 to 4 years received Kuvan 10 mg/kg per day or 20 mg/kg per day. Adverse reactions were similar in type and frequency to those observed in other clinical trials, with the addition of rhinitis, which was reported in 2 subjects (7.4%).

Safety Experience From Clinical Studies For Non-PKU Indications

Approximately 800 healthy subjects 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 years. Serious and severe adverse reactions (regardless of causality) during sapropterin administration were seizures, exacerbation of seizures, 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.

Postmarketing Experience

The following adverse reactions have been reported 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 a causal relationship to drug exposure.

Hypersensitivity reactions including anaphylaxis and rash: Most hypersensitivity reactions occurred within several days of initiating treatment.

Gastrointestinal reactions: esophagitis, gastritis, oropharyngeal pain, pharyngitis, esophageal pain, abdominal pain, dyspepsia, nausea, and vomiting.

Hyperactivity: Two cases have been reported. In one case, the patient received an accidental overdosage of Kuvan.