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
Mechanism of Action
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 is enhanced when administered with food (high fat/high calorie); absorption via intact tablet administration is greater than dissolved tablet administration.
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
~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.
There are no contraindications listed in the manufacturer’s labeling.
Canadian labeling: Hypersensitivity to sapropterin or any component of the formulation
Dosage and Administration
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.
Refer to adult dosing.
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)
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.
Maintain adherence to a phenylalanine-restricted diet.
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.
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
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
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.
- 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 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
- 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).
- 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.
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.
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.
- 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; passing a lot of urine; 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.