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

2. 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.

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

4. 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

5. 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

6. 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 = umol/L (15-20 mg/dL)
Mild PKU = umol/L (10-15 mg/dL)
Mild Hyperphenylalaninemia (HPA) = umol/L (5-10 mg/dL)
Can also be classified based on maximum daily Phe tolerance

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. Kuvan® Administration
Should be taken with food
Dissolvable tablets
Dissolve in 4 to 8 ounces ( 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

15. 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

16. 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

17. Kuvan® Effectiveness

18. 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

19. 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

20. 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

21. 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®

22. 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

23. 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

24. 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

25. 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:
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:
3) Mitchell J, Scriver C. Phenylalanine hydroxylase deficiency. In: GeneReviews at GeneTests: Medical Genetics Information Resource. Copyright, University of Washington, Seattle Available at 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

26. 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:
6) Kuvan® [package insert]. Novato, CA: BioMarin Pharmaceuticals, Inc; 2013.

27. Questions?