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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

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 this use.3

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Sapropterin Dihydrochloride Dosage and Administration

General

  • Carefully monitor blood phenylalanine concentrations during therapy.1 Measure blood phenylalanine concentrations after 1 week of treatment and periodically for up to 1 month to evaluate response to therapy.1

  • 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 with food, preferably at the same time each day.1 2

Dissolve tablets in 4–8 ounces of water or apple juice and consume within 15 minutes of dissolution.1 2 Dissolution may take several minutes; stirring the mixture or crushing the tablets may increase rate of dissolution, but complete dissolution may not occur.1 2 If visible tablet fragments remain in the glass after mixture has been consumed, rinse the glass with additional water or apple juice then swallow the rinse to ensure that entire dose is consumed.1 2

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

Dosage

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

Response to therapy is determined by change in blood phenylalanine concentrations.1

Pediatric Patients

Phenylketonuria
Oral

Children ≥4 years of age: Initially, 10 mg/kg once daily.1 2 6 8 If blood phenylalanine concentrations do not decrease from baseline after 1 month of treatment, increase dose 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 the patient a nonresponder and discontinue therapy.1 6

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

Dosages >20 mg/kg once daily not studied.1

Adults

Phenylketonuria
Oral

Initially, 10 mg/kg once daily.1 2 6 8 If blood phenylalanine concentrations do not decrease from baseline after 1 month of treatment, increase dose 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 the patient a nonresponder and discontinue therapy.1 6

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

Dosages >20 mg/kg once daily have not been studied.1

Prescribing Limits

Pediatric Patients

Phenylketonuria
Oral

Safety and efficacy of dosages >20 mg/kg daily not established.1

Adults

Phenylketonuria
Oral

Safety and efficacy of dosages >20 mg/kg daily not established.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Sapropterin Dihydrochloride

Contraindications

  • Known severe hypersensitivity to sapropterin or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Consider risks and benefits of continued treatment if mild to moderate allergic reactions (e.g., rash) occur.1 However, severe allergic reactions not reported in clinical trials.1

Patient Evaluation and Monitoring

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

Carefully monitor blood phenylalanine concentrations during therapy.1 All patients should follow a phenylalanine-restricted diet; use of sapropterin does not eliminate the need for ongoing dietary management.1

Prolonged elevations of phenylalanine can lead to severe 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

Approximately 20–56% of patients with PKU respond to sapropterin.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., genetic testing).1 5 Discontinue treatment in patients who do not respond.1 8 (See Dosage under Dosage and Administration.)

Interactions

Concomitant use with certain drugs requires caution (e.g., methotrexate, PDE-5 inhibitors, levodopa).1 (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.1 Pregnant women are encouraged to enroll in manufacturer’s sapropterin pregnancy registry (The Maternal Phenylketonuria Observational Program [PKU MOMS Subregistry]), which monitors pregnant women and fetal outcomes of pregnant women exposed to sapropterin.1 7

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not evaluated in children <4 years of age in clinical studies.1 Blood phenylalanine concentrations should be frequently monitored to ensure adequate control.1

Geriatric Use

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

Hepatic Impairment

Not studied in patients with hepatic impairment.1 8 Hepatic damage has been associated with impaired phenylalanine metabolism; careful monitoring is recommended.1 8

Renal Impairment

Not studied in patients with renal impairment; monitor carefully.1 8

Common Adverse Effects

Headache, diarrhea, abdominal pain, upper respiratory tract infection, pharyngolaryngeal pain, nausea, vomiting, rhinorrhea, nasal congestion, cough, pyrexia, contusion, rash, mild to moderate neutropenia.1 2

Interactions for Sapropterin Dihydrochloride

Inhibitors of Folate Metabolism

Possible decreased tetrahydrobiopterin (BH4) concentrations with drugs that affect folate metabolism and their derivatives.1 Use with caution.1

Drugs Affecting Nitric Oxide-Mediated Vascular Relaxation

Possible additive vascular relaxation and reduction in BP.1 Use with caution.1

Specific Drugs

Drug

Interaction

Comments

Levodopa

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

Use concomitantly with caution1

Methotrexate

Possible decreased BH4 concentrations due to inhibition of dihydropteridine reductase1

Use concomitantly with caution1

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

Possible hypotensive effect and additive vasorelaxation1

Use concomitantly with caution1

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

High-fat/high-calorie meal may increase absorption of sapropterin.1

Distribution

Extent

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

Elimination

Half-life

Approximately 6.7 hours.1

Special Populations

Pharmacokinetics unaffected by age within the range of 9–49 years of age; not studied outside this range.1

Hepatic damage may impair phenylalanine metabolism.1

Stability

Storage

Oral

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.1

  • Importance of informing patients that not all patients with PKU will respond to therapy with sapropterin.1 2 6

  • Importance of patients following a phenylalanine-restricted diet.1 2

  • Importance of monitoring blood phenylalanine concentrations.1 2

  • If a dose is missed, the missed dose should be taken as soon as possible.1 2 Two doses should not be taken on the same day.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • 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 2

  • Importance of informing clinicians of concomitant medical conditions.1 2

  • 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.

Sapropterin Dihydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, dispersible

100 mg

Kuvan

BioMarin

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. BioMarin Pharmaceutical Inc. Kuvan (sapropterin dihydrochloride) tablets prescribing information. Novato, CA; 2007 Dec.

2. BioMarin Pharmaceutical Inc. Kuvan (sapropterin dihydrochloride) tablets patient information. Novato, CA; 2007 Dec.

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.

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. [PubMed 17846916]

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. [PubMed 17693179]

6. Anon. Sapropterin (Kuvan) for phenylketonuria. Med Lett Drugs Ther. 2008; 50:43-4. [PubMed 18509266]

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

8. BioMarin, Novato, CA: Personal communication.

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