Pharmacy & Therapeutics - February 2008 - (Page 114)

Pharmaceutical Approval Update Mar vin M. Goldenberg, PhD, RPh, MS Sapropterin Dihydrochloride Tablets (Kuvan) Manufacturer: BioMarin Pharmaceutical, Inc., Novato, Calif. Indication: Kuvan is indicated for reducing blood levels of phenylalanine (an amino acid) in patients with hyperphenylalaninemia (HPA) caused by tetrahydrobiopterin (BH4)-responsive phenylketonuria (PKU). It is to be used in conjunction with a phenylalanine-restricted diet. Drug Class: This agent is a synthetic preparation of the dihydrochloride salt of naturally occurring BH4. Uniqueness of Drug: Kuvan is a cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates phenylalanine through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme, improve the normal oxidative metabolism of phenylalanine, and decrease phenylalanine levels in some patients. Warnings and Precautions: Monitoring Blood Phenylalanine Levels during Treatment: Treatment with Kuvan should be directed by physicians knowledgeable in the management of PKU. Prolonged elevations in blood phenylalanine levels in patients with PKU can result in severe neurological damage, including severe mental retardation, microcephaly, delayed speech, seizures, and behavioral abnormalities. This may occur even if patients are taking Kuvan tablets but their blood phenylalanine levels are not being adequately controlled within the recommended target range. Long-term studies of neurocognitive outcomes with Kuvan have not been conducted; conversely, prolonged levels of blood phenylalanine that are too low have been associated with catabolism and protein breakdown. Active management of dietary phenylalanine intake during Kuvan therapy is required to ensure adequate phenylalanine control and nutritional balance. Identifying Nonresponders to Kuvan: Not all patients with PKU benefit from treatment with Kuvan; in clinical trials, approximately 20% to 56% of PKU patients responded to treatment. Response cannot be predetermined by laboratory (e.g., genetic) testing; it can be determined only by a therapeutic trial of Kuvan. Treating All Patients with a Phenylalanine-Restricted Diet: Patients with PKU who are using Kuvan should also receive a phenylalanine-restricted diet. The initiation of Kuvan therapy does not eliminate the need for appropriate monitoring by trained professionals to ensure that phenylalanine levels are maintained in the context of ongoing dietary management. The author is President of Pharmaceutical and Scientific Services at Marvin M. Goldenberg, LLC, in Westfield, New Jersey. His e-mail address is MarvinMGoldenberg@verizon.net. Using Caution in Patients with Hepatic Impairment: Patients with liver impairment have not been evaluated in clinical trials with Kuvan. These patients should be carefully monitored while receiving Kuvan, because hepatic damage has been associated with impaired phenylalanine metabolism. Monitoring for Allergic Reactions: Patients with a known severe allergy to any of the components of Kuvan should not take the tablets. In clinical trials conducted with Kuvan, no severe allergic reactions were observed. The risks and benefits of continued treatment with this drug in patients with mild-to-moderate allergic reactions, such as rash, should be considered. Using Caution When Coadministering Kuvan with Agents That Inhibit Folate Metabolism: Drugs known to affect folate metabolism, such as methotrexate, and their derivatives should be used with caution during Kuvan therapy, because these drugs can decrease BH4 levels by inhibiting the enzyme dihydropteridine reductase (DHPR). Using Caution When Administering Kuvan with Agents That Affect Nitric Oxide–Mediated Vasorelaxation: Caution should be used when patients taking Kuvan are also taking drugs that affect nitric oxide–mediated vasorelaxation, for example, a phosphodiesterase-5 (PDE5) inhibitor such as sildenafil citrate (Viagra, Pfizer), vardenafil (Levitra, Bayer/ GlaxoSmithKline), or tadalafil (Cialis, Lilly), because both Kuvan and PDE5 inhibitors can induce vasorelaxation. The additive effect of coadministering Kuvan and a PDE5 inhibitor could lead to a reduction in blood pressure; however, the combined use of these medications has not been evaluated in humans. In animal studies, orally administered Kuvan in combination with a PDE5 inhibitor had no effect on blood pressure. Using Caution When Administering Kuvan with Levodopa: Caution should be used when patients taking Kuvan are also receiving levodopa. In a 10-year postmarketing safety surveillance program for a non-PKU indication using another formulation of the same active ingredient (sapropterin), three patients with underlying neurological disorders experienced convulsions or exacerbation of convulsions, overstimulation, or irritability during coadministration of levodopa and Kuvan. Dosage and Administration: The recommended starting dose for Kuvan tablets is 10 mg/kg per day taken once daily. The response to therapy is determined by change in blood phenylalanine levels following treatment with Kuvan at a dose of 10 mg/kg per day for a period of up to one month. Blood phenylalanine levels should be checked after one week of Kuvan treatment and periodically for up to a month. If blood phenylalanine concentrations do not decrease from baseline at a dose of 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. If phenylalanine levels do not decrease after one month of treatment at a dose of 20 mg/kg per day, these patients are considered nonresponders and they should stop taking Kuvan. After the patient’s responsiveness to Kuvan has been established, the dosage may be 114 P&T® • February 2008 • Vol. 33 No. 2

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Pharmacy & Therapeutics - February 2008 Contents Editorial Medication Errors Prescription: Washington The Language of (Forgive Us) Change, As P&T Enters the Digital Age New Drugs/Drug News/New Medical Devices Drug Forecast Use and Outcomes of Antifibrinolytic Therapy in Patients Undergoing Cardiothoracic Surgery at 20 Academic Medical Centers in the United States Evaluation of the Management of Acute Venous Thromboembolism and Its Outcomes: One Institution's Experience American Society of Hematology, 49th Annual Meeting Pharmaceutical Approval Update

Pharmacy & Therapeutics - February 2008

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