Kuvan® A Case Presentation Stefanie L. Drahuschak PharmD Candidate Class of 2014 University of Pittsburgh School of Pharmacy Walgreens Specialty Pharmacy March 5, 2014

Objectives 1) Understand the basics of phenylketonuria 2) Understand the dosing, administration, and counseling points of Kuvan® 3) Apply the understanding of PKU and Kuvan® to a patient case.

Patient Case: RS 29 yo male No known drug allergies Diagnosis: Phenylketonuria – PKU ICD9 code: 270.1 Current medications and PMHx unknown

Phenylketonuria (PKU) A condition in which the body cannot process phenylalanine (Phe), an amino acid common in many foods. Person with disease lacks a single enzyme: phenylalanine hydroxylase (PAH) Phenylalanine hydroxylase usually converts phenylalanine to tyrosine PAH enzyme is deficient or absent Phe cannot be converted to tyrosine Phe accumulates and leads to mental and behavioral issues

Diagnosing PKU All 50 states and US territories require newborns to be screened for PKU Many other countries also routinely screen After birth, a few drops of blood are taken from the newborn’s heel to determine if Phe levels are already elevated Some mothers who have already given birth to a child with PKU can have future children screened for PKU before birth

PKU Classification There are >500 known mutations of the PAH gene, which leads to different presentations of PKU Varies from mild to severe Phe levels Classic PKU > 1200 umol/L (20 mg/dL) Moderate PKU = 900-1200 umol/L (15-20 mg/dL) Mild PKU = 600-900 umol/L (10-15 mg/dL) Mild Hyperphenylalaninemia (HPA) = 300-600 umol/L (5-10 mg/dL) Can also be classified based on maximum daily Phe tolerance

PKU Epidemiology Countries with the highest incidence of PKU Turkey 1:2600 Ireland 1:4500 Estonia 1:6000 Latvia 1:8700 Hungary 1:9000 Countries with lowest incidence of PKU Finland 1:100,000 Japan 1:108,000 Thailand 1:212,000 United States incidence: ~1:10,000; estimated that > 350 children are diagnosed with PKU per year

Importance of Control Outcomes in PKU are related to Phe levels, especially in the first 6 years of a child’s life Elevated Phe levels can cause issues other than mental retardation Lower intelligence (↓ IQ) Depression Anxiety Irritability Slower thought processing and response time Inability to focus or pay attention Strictly controlling Phe and PKU from early on leads to optimal adult outcomes

Dietary Management of PKU A dietician is available for counsel for all patients with PKU or patients taking PKU drug therapy A Phe-restricted diet is essential Low-protein foods Phe-free medical products (“formula”) containing required protein amounts, minerals, and vitamins Avoid aspartame in food and drugs

Kuvan ® Sapropterin dihydrochloride A biologically active synthetic form of tetrahydrobiopterin (BH4) Indication Kuvan® is indicated in conjunction with a Phe-restricted diet to reduce blood phenylalanine (Phe) levels in PKU patients with BH4-responsive disease

Kuvan® Availability Supplied in 100 mg off-white to light-yellow mottled tablets debossed with “177” Powder is available as a unit dose packet of off-white to yellow powder containing 100 mg sapropterin Dissolvable tablets Powder for oral solution 120 count bottles

Mechanism of Action Reduces blood Phe levels by activating residual phenylalanine hydroxylase (the deficient enzyme) and improving the normal oxidative metabolism of phenylalanine  tyrosine Treatment with sapropterin can therefore promote the normal metabolism of Phe and lower blood levels in some patients

Kuvan® Dosing Initial dose: Maintenance dose: 10 mg/kg PO once daily with food Increase dose to 20 mg/kg/day if Phe levels do not decrease after one month Medication should be discontinued if Phe levels do not decrease after one month of treatment with maximum dose of 20 mg/kg/day Maintenance dose: 5 to 20 mg/kg PO once daily depending on response

Kuvan® Administration Should be taken with food Dissolvable tablets Dissolve in 4 to 8 ounces (120-240 mL) of water or apple juice and take within 15 minutes of dissolving into the liquid May crush or stir to facilitate dissolution Not all particles may dissolve into the liquid If after drinking the medicine patients still see pieces of tablets remaining they can add more water/juice to make sure all medication is taken

Kuvan® Adverse Events Common (≥ 4%) Headache Diarrhea Nausea/Vomiting Abdominal pain Upper respiratory tract infections Pain in throat Nasal discharge Hyperactivity Serious Neutropenia Gastritis Spinal cord injury Streptococcal infection Testicular carcinoma Urinary tract infection Gastritis: can be severe; should contact MD right away if have severe upper stomach area discomfort/pain, N/V, black/tarry stools, blood in vomit or stool

Kuvan® Pharmacokinetics Absorption: Should be taken with food PO administration with food increases the AUC by 87% and Cmax by 84% Elimination half-life Approximately 6.7 hours

Kuvan® Effectiveness

Drug-Drug Interactions Monitoring or modification of treatment should be implemented if concomitantly taking folate antagonists Combination of Kuvan® and folate antagonists may decrease the efficacy of sapropterin Folate antagonists: Methotrexate Premetrexed Pyrimethamine Sulfadoxine/pyrimethamine Trimethoprim Trimethoprim/sulfamethoxazole

Drug-Drug Interactions Monitor for hypotension when co-administering drugs known to affect NO-mediated vasodilation Sildenafil Vardenafil Tadalafil Monitor for patients taking Kuvan® with levodopa In a post-marketing study, 3 patients with underlying neurologic disorders experienced convulsions, exacerbation of convulsions, over-stimulation, or irritability during co-administration Monitor for changes in mental status

Pregnancy Considerations Pregnancy Category C No adequate or well-controlled studies with Kuvan® in pregnant women A patient registry exists to collect data from pregnant women who take Kuvan® Nursing mothers It is not known whether Kuvan® is present in human milk

Special Populations Pediatric use Geriatric use Renal impairment Use in pediatric patients less than 4 yo has not been studied Geriatric use Clinical studies of Kuvan® in patients with PKU did not include patients aged 65 years and older – unknown how elderly patients respond Renal impairment Patients with renal impairment have not been evaluated – extra monitoring should be implemented in patients taking Kuvan®

Kuvan® Non-Responders Not all patients with PKU respond to treatment with Kuvan® In clinical trials, approximately 20% to 56% of PKU patients responded to treatment Response to treatment cannot be pre-determined with laboratory testing Can only be determined via therapeutic trial of Kuvan® If patient does not respond after one month at maximum dose of Kuvan®, medication should be d/c’ed

Patient Case: RS Patient was started on Kuvan® to lower Phe levels First fill with WSP in July 2012, but unknown if on medication prior to 2012 Dose Dissolve 18 – 100 mg tablets in water or orange juice once daily Patient’s weight unknown; ~20 mg/kg dosing Patient has been continuing on same medication at the same dose through last fill at WSP on 2/14/2014 No adverse reactions or changes in medical conditions were reported Kuvan was FDA approved for use in PKU in 2007

RS: Assessment and Plan Patient appears to be well managed on current Kuvan® dose Plan Continue on Kuvan® 100 mg – 18 tablets daily for Phe level control Continue on a restricted phenylalanine diet Continue with regular MD visits and obtain regular blood Phe levels

References 1) Pey AL, Martinez A. The Phenylalanine Hydroxylase System. In: Blau N. PKU and BH4–Advances in Phenylketonuria and Tetrahydrobiopterin. 1st ed. SPS Publications;2006: 67-91. 2) Singh R, Jurecki E, Rohr, F. Recommendations for personalized dietary adjustments based on patient response to tetrahydrobiopterin (BH4) in phenylketonuria. Top Clin Nutr. 2008:149-157. 3) Mitchell J, Scriver C. Phenylalanine hydroxylase deficiency. In: GeneReviews at GeneTests: Medical Genetics Information Resource. Copyright, University of Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Accessed February 3, 2009. 4) Waisbren SE, Noel K, Fahrbach K, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007;92(1-2):63-70

References 5) Levy H, Burton B, Cederbaum S, Scriver C. Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria and its use in treatment. Mol Genet Metab.2007;92:287-291 6) Kuvan® [package insert]. Novato, CA: BioMarin Pharmaceuticals, Inc; 2013.

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