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Sapropterin

Medically reviewed by Drugs.com. Last updated on Jun 8, 2019.

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

~6.7 hours (range: 3.9 to 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: 10 to 20 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

Phenylalanine hydroxylase (PAH) deficiency disorders (eg, hyperphenylalaninemia, phenylketonuria [PKU]), adjunct treatment: Oral:

Infants and Children ≤6 years:

Initial: 10 mg/kg/dose once daily; adjust dose after 1 month based on phenylalanine levels; if phenylalanine levels have not decreased from baseline after 1 month of therapy, increase dose to 20 mg/kg/dose once daily; if still no response after 1 month of therapy at the higher dose (20 mg/kg/day) then discontinue sapropterin (nonresponder)

Usual maintenance range: 5 to 20 mg/kg/dose once daily, dosage should be individualized based on patient response. Note: In clinical trials of patients ≥7 months, doses were rounded to the nearest 100 mg increment so dosages up to 24 mg/kg/day were used (Burton 2011)

Children ≥7 years and Adolescents:

Initial: 10 to 20 mg/kg/dose once daily; adjust dose after 1 month based on phenylalanine levels:

Initial dose 10 mg/kg/dose: If phenylalanine levels have not decreased from baseline after 1 month of therapy, increase dose to 20 mg/kg/dose once daily; if still no response after 1 month of therapy at the higher dose (20 mg/kg/day) then discontinue sapropterin (nonresponder)

Initial dose 20 mg/kg/dose: If no response after 1 month of therapy, discontinue sapropterin (nonresponder)

Usual maintenance range: 5 to 20 mg/kg/dose once daily; dosage should be individualized based on patient response. Note: In clinical trials of patients ≥7 months, doses were rounded to the nearest 100 mg increment so dosages up to 24 mg/kg/day were used (Burton 2011)

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.

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-Containing Products: Sapropterin may enhance the adverse/toxic effect of Levodopa-Containing Products. 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%, postmarketing, case reports, and/or frequency not defined: Abdominal pain, agitation, anaphylaxis, arthralgia, dizziness, dyspepsia, esophageal pain, gastritis, gastrointestinal hemorrhage, hemorrhage (postprocedural), hyperactivity, hypersensitivity, hypophenylalaninemia, irritability, myocardial infarction, nausea, oropharyngeal pain, overstimulation, peripheral edema, pharyngitis, polyuria, respiratory failure, seizure (including seizure exacerbation), skin rash, upper abdominal pain, 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 of age treated at 20 mg/kg daily are at increased risk for hypophenylalaninemia as compared to patients ≥7 years of age.

Disease-related concerns:

• Phenylketonuria: 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).

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 <7 years of age 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); 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 Considerations

Outcome information following maternal use of sapropterin during pregnancy is limited (Aldámiz-Echevarría 2014; Feillet 2014; Grange 2014; Sakamoto 2018).

High levels of maternal phenylalanine are associated with adverse fetal outcomes, including congenital heart disease, developmental delay, facial dysmorphism, growth retardation, learning difficulties, and microcephaly. Phenylalanine (PHE) concentrations should be normalized prior to conception. Pregnancy outcomes are comparable to the general population when appropriate maternal PHE concentrations are maintained (van Wegberg 2017). Fetal development is optimal when maternal PHE concentrations <360 micromol/L are achieved prior to conception (Vockley 2014).

Dietary control with proper supplementation is recommended prior to and during pregnancy. Although pregnancy outcome data are limited, sapropterin may be used in pregnant females with tetrahydrobiopterin (BH4)-responsive phenylketonuria (PKU) in conjunction with a PHE-restricted diet when appropriate (ACOG 636 2015; Vockley 2014).

Data collection to monitor pregnancy and infant outcomes following exposure to sapropterin is ongoing. Patients may enroll themselves in the registry by calling (800) 983-4587.

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, nausea, vomiting, abdominal pain, common cold symptoms, diarrhea, or joint pain. Have patient report immediately to prescriber dizziness; black, tarry, or bloody stools; vomiting blood; flushing; cough; shortness of breath; fidgeting; movement disorder; excessive talking; chest pain; passing out; polyuria; seizures; agitation; 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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