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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in manufacturer's labeling (has not been studied). Use with caution.
There are no dosage adjustments provided in manufacturer's labeling (has not been studied). Use with caution.
(For additional information see "Sapropterin: Drug information")
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in manufacturer's labeling.
There are no dosage adjustments provided in manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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
There are no contraindications listed in the manufacturer’s labeling.
Canadian labeling: Hypersensitivity to sapropterin or any component of the formulation
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).
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Packet, Oral, as dihydrochloride:
Javygtor: 100 mg (1 ea, 30 ea); 500 mg (1 ea, 30 ea)
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, Oral, as dihydrochloride:
Javygtor: 100 mg
Kuvan: 100 mg
Generic: 100 mg
Yes
Pack (Javygtor Oral)
100 mg (per each): $50.40
500 mg (per each): $252.00
Pack (Kuvan Oral)
100 mg (per each): $50.40
500 mg (per each): $252.00
Pack (Sapropterin Dihydrochloride Oral)
100 mg (per each): $43.52 - $45.35
500 mg (per each): $217.61 - $226.77
Tablets (Javygtor Oral)
100 mg (per each): $50.40
Tablets (Kuvan Oral)
100 mg (per each): $50.40
Tablets (Sapropterin Dihydrochloride Oral)
100 mg (per each): $43.04 - $45.36
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Packet, Oral, as dihydrochloride:
Kuvan: 100 mg (30 ea); 500 mg (30 ea)
Generic: 100 mg (30 ea); 500 mg (30 ea)
Tablet, Oral, as dihydrochloride:
Kuvan: 100 mg
Oral: Administer with food, preferably at the same time each day; a missed dose should be taken as soon as possible, but 2 doses should not be taken on the same day.
Powder for oral solution: Dissolve powder for oral solution in water or apple juice or mix in a small amount of soft foods, such as apple sauce or pudding, prior administration. Take within 30 minutes of dissolution. Note: For use in infants and young children, sapropterin has shown similar stability when mixed with phenylalanine-free formula, applesauce, and pudding (Ref).
Tablets: Swallow tablets whole or dissolve tablets in water or apple juice. Dose should be consumed within 15 minutes of dissolution; may 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.
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.
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.
Reduction of blood phenylalanine (PHE) levels in patients with hyperphenylalaninemia caused by tetrahydrobiopterin (BH4)-responsive phenylketonuria (PKU) in conjunction with a PHE-restricted diet (FDA approved in ages ≥1 month and adults).
Sapropterin may be confused with cyproterone
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Levodopa-Foslevodopa: Sapropterin may enhance the adverse/toxic effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Methotrexate: May decrease the serum concentration of Sapropterin. Specifically, methotrexate may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor therapy
PHENobarbital: May decrease the serum concentration of Sapropterin. Specifically, phenobarbital may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: Sapropterin may enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
PRALAtrexate: May decrease the serum concentration of Sapropterin. Specifically, pralatrexate may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor therapy
Primidone: May decrease the serum concentration of Sapropterin. Risk C: Monitor therapy
Trimethoprim: May decrease the serum concentration of Sapropterin. Specifically, trimethoprim may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor therapy
Valproate Products: May decrease the serum concentration of Sapropterin. Specifically, valproate products may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor therapy
Maintain adherence to a phenylalanine-restricted diet.
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).
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.
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)
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.
Phenylalanine hydroxylase deficiency, blood phenylalanine goal range: 2 to 5.9 mg/dL (SI: 120 to 360 micromol/L) (Vockley 2014).
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).
Onset of action: Within 24 hours; maximum effect: up to 1 month
Duration: 24 hours
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.
Half-life elimination: ~6.7 hours (range: 3.9 to 17 hours)
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