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Sapropterin

Medically reviewed by Drugs.com. Last updated on May 21, 2020.

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)

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

Tablet Soluble, Oral, as dihydrochloride:

Kuvan: 100 mg

Generic: 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 adult and pediatric patients ≥1 month of age with hyperphenylalaninemia caused by 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: Note: Existing dietary protein and PHE intake should not be modified during the initial evaluation period.

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:

Note: During the initial evaluation period, existing dietary protein and phenylalanine intake should not be modified.

Infants and Children ≤6 years:

Initial: Oral: 10 mg/kg/dose once daily; check phenylalanine level 1 week after starting and periodically during the first month; 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: Oral: 5 to 20 mg/kg/dose once daily, dosage should be individualized based on patient response.

Children ≥7 years and Adolescents:

Initial: Oral: 10 to 20 mg/kg/dose once daily; check phenylalanine level 1 week after starting and periodically during the first month; adjust dose after 1 month based on phenylalanine levels:

For 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).

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

Usual maintenance range: Oral: 5 to 20 mg/kg/dose once daily; dosage should be individualized based on patient response.

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

PHENobarbital: May decrease the serum concentration of Sapropterin. Specifically, phenobarbital 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

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

Valproate Products: May decrease the serum concentration of Sapropterin. Specifically, valproate products may decrease tissue concentrations of tetrahydrobiopterin. Monitor therapy

Adverse Reactions

>10%:

Nervous system: Headache (15%)

Respiratory: Rhinorrhea (11%)

1% to 10%:

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

Respiratory: Pharyngolaryngeal pain (10%), cough (7%), nasal congestion (4%)

<1%, postmarketing, and/or case reports: Abdominal pain, anaphylaxis, dyspepsia, esophageal pain, esophagitis, gastritis, gastrointestinal inflammation, hyperactive behavior, hypersensitivity reaction, nausea, oropharyngeal pain, pharyngitis, skin rash

Warnings/Precautions

Concerns related to adverse effects:

• GI effects: GI adverse reactions suggestive of upper GI mucosal inflammation have been reported, including esophagitis and gastritis. If left untreated, severe sequelae may occur, including esophageal stricture, esophageal ulcer, gastric ulcer, and bleeding; monitor patients for signs and symptoms of upper GI mucosal inflammation.

• Hyperactivity: Hyperactivity has been observed (rarely); 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 protein and phenylalanine (PHE) restrictions should be continued in patients who experience anaphylaxis.

• Hypophenylalaninemia: Some patients may experience low blood PHE 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 PHE can result in severe neurologic damage, including intellectual disability, developmental delay, behavioral abnormalities, delayed speech, microcephaly, and seizures. Low levels (<120 micromol/L) of PHE are associated with catabolism and endogenous protein breakdown. Dietary management of PHE intake is required to ensure nutritional balance and adequate PHE 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 PHE (hypophenylalaninemia).

Other warnings/precautions:

• Biochemical response: Response to sapropterin treatment is established through treatment (generally cannot be predetermined by lab testing). Discontinue treatment in patients who do not show a biochemical response (blood PHE does not decrease) after 1 month of treatment at 20 mg/kg/day.

Monitoring Parameters

Blood phenylalanine (PHE) 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 upper GI mucosal inflammation; hyperactivity.

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

Newly diagnosed infants: Monitor PHE and tyrosine 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.

Reproductive Considerations

Family planning is recommended for females with phenylalanine hydroxylase deficiency (ACOG 802 2020). Testing for response to sapropterin prior to conception is recommended when possible (Muntau 2019). Phenylalanine concentrations should be normalized 3 months prior to conception (ACOG 802 2020; Vockley 2014).

Pregnancy Considerations

Outcome information following maternal use of sapropterin during pregnancy is limited (Aldámiz-Echevarría 2014; Feillet 2014; Grange 2014; Nyuzuki 2019; Sakamoto 2018).

High levels of maternal phenylalanine (PHE) are associated with adverse fetal outcomes, including congenital heart disease, developmental delay, facial dysmorphism, growth retardation, learning difficulties, and microcephaly. 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 (6 mg/dL) are achieved prior to conception (ACOG 802 2020; 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 802 2020; Vockley 2014). Treatment with sapropterin should be considered in pregnant women when appropriate PHE concentrations cannot be maintained by diet alone. Pre-pregnancy body weight should be used for determining the dose when the sapropterin test is conducted during pregnancy. Testing should not be conducted in pregnant patients with forms of PKU unlikely to respond to sapropterin treatment. Sapropterin can be continued in women taking it prior to pregnancy and who wish to continue. Close monitoring is required during pregnancy; decreased doses may be needed during the third trimester as PHE tolerance increases due to fetal growth (Muntau 2019). Maternal plasma concentrations of PHE 120 to 360 micromol/L (2 to 6 mg/dL) are recommended throughout pregnancy (ACOG 802 2020).

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

What is this drug used for?

• It is used to treat phenylketonuria (PKU).

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Common cold symptoms

• Diarrhea

• Joint pain

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Dizziness

• Throat pain

• Abdominal pain

• Severe nausea

• Vomiting

• Trouble swallowing

• Lack of appetite

• Black, tarry, or bloody stools

• Vomiting blood

• Flushing

• Cough

• Shortness of breath

• Fidgeting

• Movement disorder

• Excessive talking

• Chest pain

• Passing out

• Passing a lot of urine

• Seizures

• Agitation

• Swelling of arms or legs

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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