8.3  Nursing MotherIt is not known whether Kuvan is present in human milk. Sapropterin is present in the milk of intravenously, but not orally, treated lactating rats. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for Kuvan and any potential adverse effects on the human milk-fed child from the drug or from the underlying maternal condition. Exercise caution when Kuvan is administered to a nursing woman.

8.4  Pediatric UsePediatric patients with PKU, ages 1 month to 16 years, have been treated with Kuvan in clinical trials [see Clinical Studies (14.1)]. 

The efficacy and safety of Kuvan have not been established in neonates.  The safety of Kuvan has been established in children younger than 4 years in trials of 6 months duration and in children 4 years and older in trials of up to 3 years in length [see Adverse Reactions (6.1)].

In children aged 1 month and older, the efficacy of Kuvan has been demonstrated in trials of 6 weeks or less in duration [see Clinical Studies (14.1)]. 

In a multicenter, open-label, single arm study, 57 patients aged 1 month to 6 years who were defined as Kuvan responders after 4 weeks of Kuvan treatment and Phe dietary restriction were treated for 6 months with Kuvan at 20 mg/kg per day.  The effectiveness of Kuvan alone on reduction of blood Phe levels beyond 4 weeks could not be determined due to concurrent changes in dietary Phe intake during the study.  Mean (±SD) blood Phe values over time for patients aged 1 month to <2 years and 2 to <7 years are shown in Figure 1.

8.5  Geriatric UseClinical studies of Kuvan in patients with PKU did not include patients aged 65 years and older. It is not known whether these patients respond differently than younger patients.

8.6  Patients with Renal ImpairmentPatients with renal impairment have not been eva luated in clinical trials. Monitor patients who have renal impairment carefully when they are receiving Kuvan.

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10.  OVERDOSAGE

Two unintentional overdosages with Kuvan have been reported. One adult patient in a Kuvan clinical trial received a single Kuvan dose of 4,500 mg (36 mg/kg) instead of 2,600 mg (20 mg/kg). The patient reported mild headache and mild dizziness immediately after taking the dose; both symptoms resolved within 1 hour with no treatment intervention. There were no associated laboratory test abnormalities. The patient suspended therapy for 24 hours and then restarted Kuvan with no reports of abnormal signs or symptoms. In postmarketing, one pediatric patient received Kuvan doses of 45 mg/kg per day instead of 20 mg/kg per day. The patient reported hyperactivity that began at an unspecified time after overdose and resolved after the Kuvan dose was reduced to 20 mg/kg per day. 

In a clinical study to eva luate the effects of Kuvan on cardiac repolarization, a single supra-therapeutic dose of 100 mg/kg (5 times the maximum recommended dose) was administered to 54 healthy adults. No serious adverse reactions were reported during the study. The only adverse reactions reported in more than 1 subject who received the supra-therapeutic dose were upper abdominal pain (6%) and dizziness (4%). A dose-dependent shortening of the QT interval was observ