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Sapropterin Dihydrochloride

Class: Other Miscellaneous Therapeutic Agents
Chemical Name: (6R)-2-amino-6-[(1R, 2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-pteridinone dihydrochloride
Molecular Formula: C9H15N5O3 • 2HCl
CAS Number: 69056-38-8
Brands: Kuvan

Medically reviewed by Drugs.com. Last updated on Jan 13, 2020.

Introduction

Synthetic dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4); cofactor in the metabolism of phenylalanine.1 4 5 6

Uses for Sapropterin Dihydrochloride

Phenylketonuria

Used to reduce blood phenylalanine concentrations in patients with hyperphenylalaninemia associated with tetrahydrobiopterin (BH4)-responsive phenylketonuria (PKU).1 4 5 6 Use in conjunction with a phenylalanine-restricted diet.1 Designated an orphan drug by FDA for treatment of hyperphenylalaninemia.3

A therapeutic trial is necessary to determine responsiveness to the drug.1 4 5 6 9

Sapropterin Dihydrochloride Dosage and Administration

General

  • Treatment should be directed by clinicians knowledgeable in the management of patients with PKU.1

  • Response to therapy is determined by change in blood phenylalanine concentrations.1 Measure blood phenylalanine concentrations at baseline, after 1 week of treatment, and periodically for up to 1 month to evaluate response to therapy.1 Monitor blood phenylalanine concentrations periodically during therapy to ensure that concentrations are maintained in desired range.1 Frequent monitoring is recommended in pediatric patients.1 (See Hypophenylalaninemia under Cautions.)

  • A substantial decrease in blood phenylalanine concentrations usually indicates response.9 However, clinical judgment should be used to determine what constitutes a significant or beneficial decline; in clinical studies, response was generally defined as a reduction in blood phenylalanine concentrations of ≥30% from baseline.1 9

  • Dietary phenylalanine intake must not be modified while response to sapropterin therapy is being evaluated so that the drug’s effect on phenylalanine concentrations can be accurately assessed.1 (See Response to Treatment under Cautions.)

Administration

Oral Administration

Administer orally once daily as tablets or oral solution.1 Administer with meals to increase absorption, preferably at the same time each day.1

Take a missed dose as soon as possible, but avoid taking 2 doses on the same day.1

Tablets

Swallow tablets whole or dissolve in 120–240 mL of water or apple juice and consume within 15 minutes.1 It may take several minutes for the tablets to dissolve; may stir or crush them to speed up the dissolution process, but complete dissolution may not occur.1 If visible tablet fragments remain in glass, rinse with additional water or apple juice and ingest to ensure that entire dose is consumed.1

May also crush tablets and mix with a small amount of soft food such as apple sauce or pudding.1

Powder for Oral Solution

Patients weighing >10 kg: Mix contents of required number of 100- or 500-mg packets (based on prescribed dose) with 120–240 mL of water or apple juice; consume within 30 minutes of dissolution.1 Alternatively, may mix powder with a small amount of soft foods (e.g., apple sauce, pudding).1

Patients weighing ≤10 kg: Mix contents of required number of 100-mg packets (based on prescribed dose) in 5 or 10 mL of water or apple juice and administer appropriate volume with an oral dosing syringe within 30 minutes; discard remainder of mixture.1

Consult manufacturer's prescribing information for additional details on preparation of the oral solution.1

Dosage

Available as sapropterin dihydrochloride; dosage expressed in terms of the salt.1

Pediatric Patients

Phenylketonuria
Oral

Children 1 month to 6 years of age: Initially, 10 mg/kg once daily.1

Children ≥7 years of age: Initially 10–20 mg/kg once daily.1

Patients starting with a dosage of 10 mg/kg once daily: If blood phenylalanine concentrations do not decrease after 1 month, increase dosage to 20 mg/kg once daily.1 6 If blood phenylalanine concentrations do not decrease after 1 month of treatment at 20 mg/kg once daily, consider patient a nonresponder and discontinue therapy.1 6

Patients starting with a dosage of 20 mg/kg once daily: If blood phenylalanine concentrations do not decrease after 1 month, consider patient a nonresponder and discontinue therapy.1

For responders, adjust dosage within the range of 5–20 mg/kg once daily based on blood phenylalanine concentrations.1

Adults

Phenylketonuria
Oral

Initially, 10–20 mg/kg once daily.1

Patients starting with a dosage of 10 mg/kg once daily: If blood phenylalanine concentrations do not decrease after 1 month, increase dosage to 20 mg/kg once daily.1 6 If blood phenylalanine concentrations do not decrease after 1 month of treatment with 20 mg/kg once daily, consider patient a nonresponder and discontinue therapy.1 6

Patients starting with a dosage of 20 mg/kg once daily: If blood phenylalanine concentrations do not decrease after 1 month, consider patient a nonresponder and discontinue therapy.1

For responders, adjust dosage within the range of 5–20 mg/kg once daily based on blood phenylalanine concentrations.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Sapropterin Dihydrochloride

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, rash) reported.1 Discontinue drug and initiate appropriate treatment if anaphylaxis occurs.1 Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.1 Continue dietary phenylalanine restrictions in patients who experience anaphylaxis.1

Gastritis

Gastritis reported.1 Monitor patients.1

Hypophenylalaninemia

In clinical studies, some patients receiving sapropterin experienced low blood phenylalanine concentrations.1 Pediatric patients <7 years of age who are treated with a dosage of 20 mg/kg daily appear to have a higher risk.1

Patient Evaluation and Monitoring

Carefully monitor blood phenylalanine concentrations during therapy.1 All patients should follow a phenylalanine-restricted diet to ensure adequate control of phenylalanine concentrations and nutritional balance.1

Prolonged elevations of phenylalanine can lead to cognitive, behavioral, and other neurologic complications (e.g., severe mental retardation, microcephaly, delayed speech, seizures).1 6 Long-term data not available on neurocognitive outcomes in patients receiving sapropterin.1

Prolonged blood concentrations of phenylalanine that are too low have been associated with catabolism and protein breakdown.1

Response to Treatment

Response to sapropterin is variable and has ranged from 20–75% of patients with PKU depending on dosage.1 4 A therapeutic trial of the drug with close monitoring of blood phenylalanine concentrations is needed to identify responders.1 4 5 6 Response cannot be predicted based on laboratory testing (e.g., molecular testing).1 5 Discontinue treatment in patients who do not respond.1 8 (See Dosage under Dosage and Administration.)

Concomitant Use with Levodopa

Adverse neurobehavioral effects (e.g., convulsions, over-stimulation, irritability) observed in 3 patients with underlying neurological disorders who received sapropterin and levodopa concomitantly.1 (See Specific Drugs under Interactions.)

Hyperactivity

Hyperactivity reported in a few patients during postmarketing experience.1 Monitor patients for hypersensitivity.1

Specific Populations

Pregnancy

Category C.1

No adequate and well-controlled studies in pregnant women; a rare defect (holoprosencephaly) observed in the offspring of rabbits administered the drug at dosages 10 times the maximum recommended human dosage during organogenesis.1 Use during pregnancy only when benefits justify potential risks to the fetus.1

Pregnancy registry at 800-983-4587.1 7

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1 Consider known benefits of breast-feeding along with woman's clinical need for sapropterin and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in neonates.1 Clinical studies evaluating safety and efficacy of the drug have included children ≥1 month of age.1

Frequently monitor blood phenylalanine concentrations in pediatric patients.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently from younger patients.1

Common Adverse Effects

Headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, nasal congestion.1

Interactions for Sapropterin Dihydrochloride

Does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5, and does not induce CYP1A2, 2B6, or 3A4/5 in vitro.1

Does not inhibit organic anion transporter (OAT) 1 or 3, and multidrug and toxin extrusion transporter (MATE) 1 or 2K.1 Inhibits breast cancer resistance protein (BCRP) in vitro; however, clinically important interactions unlikely.1 Does not appear to affect P-glycoprotein (P-gp) substrates.1

Inhibitors of Folate Metabolism

Possible decreased tetrahydrobiopterin (BH4) concentrations with drugs that affect folate metabolism and their derivatives.1 Monitor blood phenylalanine concentrations frequently.1

Drugs Affecting Nitric Oxide-mediated Vascular Relaxation

Possible additive vascular relaxation and reduction in BP.1 Monitor BP.1

Specific Drugs

Drug

Interaction

Comments

Digoxin

Pharmacokinetics of digoxin not affected1

Levodopa

Sapropterin may increase availability of tyrosine, a precursor of levodopa1

Seizures, exacerbation of seizures, overstimulation, or irritability reported rarely in patients with neurologic disorders1

Monitor patients for changes in neurologic status1

Methotrexate

Possible decreased BH4 concentrations due to inhibition of dihydropteridine reductase1

Monitor blood phenylalanine concentrations frequently1

Phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil)

Possible hypotensive effect and additive vasorelaxation1

Monitor BP1

Sapropterin Dihydrochloride Pharmacokinetics

Absorption

Onset

Phenylalanine concentrations decrease within 24 hours following a single dose; maximal reductions occur within 1 month with daily administration.1

Duration

Phenylalanine concentrations remain stable over a 24-hour period following a single daily dose.1

Food

Absorption comparable when tablets are dissolved in water or orange juice under fasted conditions.1 Phenylalanine concentrations do not substantially increase with food intake following a single dose.1

Absorption from intact tablet is about 40% greater than from dissolved tablet under fasted conditions.1

High-fat/high-calorie meal may increase absorption of sapropterin.1 Administration of intact tablets under fed conditions increased extent of absorption by approximately 43% compared with fasting conditions.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Elimination

Metabolism

Expected to be metabolized by the same endogenous enzymes (e.g., dihydrofolate reductase and dihydropteridine reductase) and follow same metabolic pathway as endogenous BH4.1

Half-life

Approximately 6.7 hours in PKU patients (range: 3.9–17 hours).1

Special Populations

Pharmacokinetic analysis of patients 1 month to 49 years of age indicate that body weight may affect clearance.1

Stability

Storage

Oral

For Solution

20–25°C (may be exposed to 15–30°C).1 Protect from moisture.1

Tablets

Tight containers at 20–25°C (may be exposed to 15–30°C).1 Protect from moisture.1

Actions

  • Cofactor for phenylalanine hydroxylase (PAH), the enzyme that hydroxylates phenylalanine through an oxidative reaction to form tyrosine.1 4 5

  • Enhances activity of residual PAH in patients with PKU, which improves the normal oxidative metabolism of phenylalanine and thus decreases blood phenylalanine concentrations in some patients with PKU.1 4 5

Advice to Patients

  • Importance of providing patient or caregivers a copy of manufacturer’s patient information and instructions for use.1

  • Importance of informing patients that not all patients with PKU will respond to therapy with sapropterin and that response can only be determined by a therapeutic trial.1 6

  • Importance of patients following a phenylalanine-restricted diet and not modifying their existing dietary phenylalanine intake during the evaluation period in order to obtain an accurate assessment of the effect of sapropterin on blood phenylalanine concentrations.1

  • Importance of monitoring blood phenylalanine concentrations and of advising patients of the clinical consequences of excessively high or low levels.1

  • Importance of advising patients of possible adverse effects (e.g., gastritis, hyperactivity, hypersensitivity reactions).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of informing patients of the existence of a pregnancy registry for PKU patients receiving sapropterin.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant medical conditions.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Sapropterin Dihydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

For solution

100 mg per packet

Kuvan

BioMarin

500 mg per packet

Kuvan

BioMarin

Tablets, dispersible

100 mg

Kuvan

BioMarin

AHFS DI Essentials™. © Copyright 2020, Selected Revisions January 13, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. BioMarin Pharmaceutical Inc. Kuvan (sapropterin dihydrochloride) tablets prescribing information. Novato, CA; 2019 Feb.

3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2008 May 16. From FDA website. Accessed 2008 Jul 22. http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm

4. Burton BK, Grange DK, Milanowski A, et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis. 2007; 30:700-7. http://www.ncbi.nlm.nih.gov/pubmed/17846916?dopt=AbstractPlus

5. Levy HL, Milanowski A, Chakrapani A, et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet. 2007; 370:504-10. http://www.ncbi.nlm.nih.gov/pubmed/17693179?dopt=AbstractPlus

6. Anon. Sapropterin (Kuvan) for phenylketonuria. Med Lett Drugs Ther. 2008; 50:43-4. http://www.ncbi.nlm.nih.gov/pubmed/18509266?dopt=AbstractPlus

7. BioMarin Pharmaceutical Inc. The Phenylketonuria Demographics, Outcomes, and Safety (PKUDOS) registry: information for patients. From Kuvan website. Accessed 2008 Oct 9. http://www.kuvan.com

8. BioMarin, Novato, CA: Personal communication.

9. Vockley J, Andersson HC, Antshel KM et al. Phenylalanine hydroxylase deficiency: diagnosis and management guidelines. Genet Med. 2014; 16(2):188-200.

10. van Wegberg AMJ, MacDonald A, Ahring K et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017; 12:162.

11. American Academy of Pediatrics Committee on Genetics. Maternal Phenylketonuria. Pediatrics 2008; 122:445-9.