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Sapropterin

Pronunciation

(sap roe TER in)

Index Terms

  • 6R-BH4
  • Phenoptin
  • Sapropterin Dihydrochloride
  • Tetrahydrobiopterin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Packet, Oral, as dihydrochloride:

Kuvan: 100 mg (1 ea, 30 ea); 500 mg (1 ea, 30 ea)

Tablet Soluble, Oral, as dihydrochloride:

Kuvan: 100 mg

Brand Names: U.S.

  • Kuvan

Pharmacologic Category

  • Enzyme Cofactor

Pharmacology

Sapropterin is a synthetic form of the cofactor BH4 (tetrahydrobiopterin) for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates phenylalanine to form tyrosine. BH4 activates residual PAH enzyme, improving normal phenylalanine metabolism and decreasing phenylalanine levels in sapropterin responders. Approximately 25% to 50% of patients with PAH deficiency are responsive to sapropterin (Vockley, 2014).

Absorption

Absorption is enhanced when administered with food (high fat/high calorie); absorption via intact tablet administration is greater than dissolved tablet administration.

Metabolism

The enzymes dihydrofolate reductase and dihydropteridine reductase are responsible for the metabolism and recycling of BH4.

Onset of Action

Within 24 hours; maximum effect: up to 1 month

Duration of Action

24 hours

Half-Life Elimination

~7 hours (range: 4-17 hours)

Use: Labeled Indications

Hyperphenylalaninemia: To reduce blood phenylalanine (PHE) levels in patients with hyperphenylalaninemia caused by tetrahydrobiopterin (BH4)-responsive phenylketonuria in conjunction with a PHE-restricted diet.

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to sapropterin or any component of the formulation

Dosing: Adult

Hyperphenylalaninemia: Oral:

Initial:

US labeling: 10 to 20 mg/kg once daily

Canadian labeling: 10 mg/kg once daily

Maintenance: Adjust dose after 1 month based on blood phenylalanine levels (if phenylalanine levels do not decrease from baseline after initiating 10 mg/kg, increase dose to 20 mg/kg once daily); discontinue if phenylalanine levels do not decrease after 1 month of treatment at 20 mg/kg/day (nonresponder). Maintenance range: 5 to 20 mg/kg once daily

Missed dose: A missed dose should be taken as soon as possible, but 2 doses should not be taken on the same day.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hyperphenylalaninemia:

US labeling:

Infants and Children ≥1 month to 6 years: Initial: 10 mg/kg once daily; adjust after 1 month based on blood phenylalanine levels (if phenylalanine levels do not decrease from baseline after initiating 10 mg/kg, increase dose to 20 mg/kg once daily); discontinue if phenylalanine levels do not decrease after 1 month of treatment at 20 mg/kg/day (nonresponder). Maintenance range: 5 to 20 mg/kg once daily

Children ≥7 years and Adolescents: Refer to adult dosing.

Canadian labeling: Children ≥4 years and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in manufacturer’s labeling (has not been studied). Use with caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in manufacturer’s labeling (has not been studied). Use with caution.

Administration

Powder for oral solution: Administer with food, preferably at the same time each day. Dissolve powder for oral solution in 120 to 240 mL (4 to 8 oz) water or apple juice or in a small amount of soft foods such as apple sauce or pudding and mix thoroughly. Take within 30 minutes of dissolution.

Infants weighing 10 kg or less: Powder for oral solution can be dissolved in as little as 5 mL of water or apple juice; the appropriate dose may be administered orally via an oral dosing syringe (refer to prescribing information for dilution and administration volumes).

Tablets: Administer with food, preferably at the same time each day. Swallow tablets whole or dissolve tablets in 120 to 240 mL (4 to 8 oz) water or apple juice. May crush or stir to aid in dissolution. Take within 15 minutes of dissolution. Tablets may not dissolve completely; rinse remaining tablet residue (with more water or apple juice) and drink. Tablets may also be crushed and then mixed in a small amount of soft food such as apple sauce or pudding.

Dietary Considerations

Maintain adherence to a phenylalanine-restricted diet.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions to 15°C to 30°C (59°F to 86°F) permitted. Protect from moisture.

Drug Interactions

Levodopa: Sapropterin may enhance the adverse/toxic effect of Levodopa. Monitor therapy

Methotrexate: May decrease the serum concentration of Sapropterin. Specifically, methotrexate may decrease tissue concentrations of tetrahydrobiopterin. Monitor therapy

Phosphodiesterase 5 Inhibitors: Sapropterin may enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Monitor therapy

PRALAtrexate: May decrease the serum concentration of Sapropterin. Specifically, pralatrexate may decrease tissue concentrations of tetrahydrobiopterin. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Headache (15%)

Respiratory: Rhinorrhea (11%)

1% to 10%:

Gastrointestinal: Diarrhea (8%), vomiting (8%)

Respiratory: Pharyngolaryngeal pain (10%), cough (7%), rhinitis (infants and children: 7%), nasal congestion (4%)

<1% (Limited to important or life-threatening): Anaphylaxis, gastritis, gastrointestinal hemorrhage, hemorrhage (postprocedural), hyperactivity, myocardial infarction, peripheral edema, seizure (including seizure exacerbation), upper respiratory tract infection

Warnings/Precautions

Concerns related to adverse effects:

• Gastritis: Gastritis has been reported; monitor patients for gastritis.

• Hyperactivity: Hyperactivity has been observed; monitor patients for hyperactivity.

• Hypersensitivity: Hypersensitivity reactions, including anaphylaxis and rash, have occurred; not recommended for use in patients with a history of anaphylaxis to sapropterin. Discontinue use and initiate appropriate medical treatment in patients who experience anaphylaxis. Dietary phenylalanine (PHE) restrictions should be continued in patients who experience anaphylaxis.

• Hypophenylalaninemia: Some patients my experience low blood phenylalanine levels. Patients <7 years treated at 20 mg/kg daily are at increased risk for hypophenylalaninemia as compared to patients ≥7 years.

Disease-related concerns:

• Hepatic impairment: Has not been studied in patients with hepatic impairment. Monitor carefully; hepatic damage has been associated with impaired phenylalanine metabolism.

• Phenylketonuria: Phenylalanine (PHE) levels should be monitored and maintained within the target range during sapropterin treatment. Upon diagnosis, blood PHE levels should be lowered into the desired treatment range (120 to 360 micromol/L) as quickly as possible; infants with levels >600 micromol/L require treatment, although treatment may be initiated at ≥360 micromol/L; if testing is done in early infancy, it is recommended to initially lower blood PHE to 480 to 600 micromol/L (Vockley, 2014). Prolonged high levels of phenylalanine can result in severe neurologic damage, including behavioral abnormalities, delayed speech, microcephaly, seizures, and severe mental retardation. Low levels of phenylalanine are associated with catabolism and protein breakdown. Dietary management of phenylalanine intake is required to ensure nutritional balance and adequate phenylalanine control. Monitor blood PHE levels during treatment (frequently in children). PHE blood level testing at doses <20 mg/kg may underestimate response rate (Vockley, 2014).

• Renal impairment: Has not been studied in patients with renal impairment; use with caution.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information

Special populations:

• Pediatric: Children younger than 7 years treated with doses of 20 mg/kg/day are at increased risk for low levels of blood phenylalanine (hypophenylalaninemia).

• Nonresponders: Response to sapropterin treatment is established through treatment (cannot be predetermined by lab testing). Patients whose phenylalanine levels do not decrease after treatment at 20 mg/kg/day for 1 month are considered nonresponders.

Monitoring Parameters

Blood phenylalanine levels (baseline, after 1 week of treatment, periodically for first month, regularly thereafter); children may require more frequent monitoring; blood pressure in patients taking concomitant PDE-5 inhibitors (eg, sildenafil, vardenafil, tadalafil); patients with renal or hepatic impairment; change in neurologic status in patients taking concurrent levodopa; signs and symptoms of gastritis; hyperactivity

Guideline recommended monitoring for patients with phenylalanine hydroxylase deficiency (Vockley, 2014):

Newly diagnosed infants: Monitor phenylalanine (PHE) and tyrosine (TYR) frequently until the PHE concentrations stabilize, then monitor PHE weekly until age 1 (increase frequency during rapid growth or dietary transitions)

Children 1 to 12 years of age: Monitor PHE every 2 to 4 weeks

Adolescents and Adults who are stable: Monitor PHE monthly

If formal nutritional assessment suggests suboptimal dietary intake or for over reliance on nutritionally incomplete medical foods: Consider monitoring plasma amino acids (full panel), transthyretin, albumin, CBC, ferritin, 25-OH vitamin D, vitamin B12, red blood cell essential fatty acids, trace minerals (copper, selenium, zinc), vitamin A, comprehensive metabolic panel, and folic acid.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. High levels of maternal phenylalanine are associated with congenital heart disease, developmental delay, facial dysmorphism, learning difficulties, and microcephaly. Phenylalanine (PHE) concentrations should be normalized prior to conception. Fetal development is optimal when PHE concentrations <360 micromol/L are achieved prior to conception (Vockley, 2014). Dietary control with proper supplementation is recommended during pregnancy. Maternal PHE requirements may change throughout pregnancy; frequent testing and dietary modifications may be necessary (Vockley, 2014). Some clinicians recommend that dietary control be achieved for at least 4 weeks prior to conception; however, studies suggest that as long as control is achieved by 10 weeks of pregnancy, teratogenic effects of untreated maternal phenylketonuria can be decreased (Koch, 2003; Maillot, 2007). In addition to standard fetal monitoring, fetal echocardiography is recommended at 18-22 weeks gestation (Vockley, 2014). Pregnant women exposed to sapropterin are encouraged to enroll in the Kuvan pregnancy registry (866-906-6100).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, diarrhea, rhinorrhea, rhinitis, pharyngitis, or vomiting. Have patient report immediately to prescriber dizziness; black, tarry, or bloody stools; vomiting blood; severe abdominal pain; flushing; wheezing; cough; shortness of breath; severe nausea; severe vomiting; fidgeting; movement disorder; excessive talking; angina; passing out; polyuria; seizures; or swelling of arms or legs (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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