5.5 Identify Non-Responders to Kuvan TreatmentNot all patients with PKU respond to treatment with Kuvan. In two clinical trials at a dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients responded to treatment with Kuvan, and in one clinical trial at a dose of 10 mg/kg per day, 20% of adult and pediatric PKU patients responded to treatment with Kuvan [see Clinical Studies (14.1)]. 

Response to treatment cannot be pre-determined by laboratory testing (e.g., molecular testing), and can only be determined by a therapeutic trial of Kuvan [see Dosage and Administration (2.1)].

5.6 Treat All Patients with  a Phe-restricted DietAll patients with PKU who are being treated with Kuvan should also be treated with a Phe-restricted diet.

5.7 Monitor Patients with Hepatic ImpairmentPatients with liver impairment have not been eva luated in clinical trials with Kuvan. Monitor liver function tests in patients with liver impairment who are receiving Kuvan because hepatic damage has been associated with impaired Phe metabolism.

5.8 Monitor Patients when Co-administering Kuvan and Medications Known to Inhibit Folate MetabolismCo-administering Kuvan with drugs known to affect folate metabolism (e.g., methotrexate) and their derivatives may require more frequent monitoring of blood Phe levels because these drugs can decrease endogenous BH4 levels by inhibiting the enzyme dihydropteridine reductase (DHPR).

5.9 Monitor Patients for Hypotension when Co-administering Kuvan and Drugs Known to Affect Nitric Oxide-Mediated VasorelaxationMonitor blood pressure when administering Kuvan with drugs that affect nitric oxide‑mediated vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil), because both sapropterin dihydrochloride and PDE-5 inhibitors may induce vasorelaxation. The additive effect of sapropterin and PDE-5 inhibitor co-administration could lead to a reduction in blood pressure; however, the combined use of these medications has not been eva luated in humans. In animal studies, orally administered Kuvan in combination with a PDE-5 inhibitor had no effect on blood pressure.

5.10 Monitor Patients when Co-administering Kuvan and LevodopaCaution should be used with the administration of Kuvan to patients who are receiving levodopa. In a 10-year post-marketing safety surveillance program for a non-PKU indication using another formulation of the same active ingredient (sapropterin), 3 patients with underlying neurologic disorders experienced convulsions, exacerbation of convulsions, over-stimulation, or irritability during co-administration of levodopa and sapropterin. Monitor for change in neurologic status.

5.11 Monitor Patients for HyperactivityIn the post-marketing safety surveillance program for PKU, 2 patients experienced hyperactivity with administration of Kuvan. Monitor patients for hyperactivity.

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6.  ADVERSE REACTIONS

6.1 Clinical Trials ExperienceBecause 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

The safety of Kuvan was eva luated in 6 clinical studies in patients with PKU (aged 1 month to 5