Sapropterin Dihydrochloride
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Sapropterin Dihydrochloride Prescribing Information
Sapropterin dihydrochloride tablets are indicated to reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age and older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin-(BH4-) responsive Phenylketonuria (PKU). Sapropterin dihydrochloride tablets are to be used in conjunction with a Phe-restricted diet.
All patients with PKU who are being treated with sapropterin dihydrochloride tablets should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction. (
Treatment with sapropterin dihydrochloride tablets should be directed by physicians knowledgeable in the management of PKU.
All patients with PKU who are being treated with sapropterin dihydrochloride tablets should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction.
Starting Dosage
•
Pediatric patients 1 month to 6 years:
The recommended starting dosage of sapropterin dihydrochloride tablets is 10 mg/kg administered orally once daily. (The recommended starting dosage of sapropterin dihydrochloride tablets is:
Pediatric Patients 1 month to 6 years:
10 mg/kg (actual body weight) administered orally once daily.Patients 7 years and older:
10 to 20 mg/kg (actual body weight) administered orally once daily.Administer sapropterin dihydrochloride tablets with a meal, preferably at the same time each day
[see Clinical Pharmacology (12.3)].
A missed dose should be administered as soon as possible, but two doses should not be administered on the same day.
Evaluation Period
Existing dietary protein and Phe intake should not be modified during the evaluation period.
If a 10 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day do not show a biochemical response and treatment with sapropterin dihydrochloride tablets should be discontinued in these patients.
If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically during the first month. Treatment should be discontinued in patients who do not show a biochemical response (blood Phe does not decrease) after 1 month of treatment at 20 mg/kg per day
[see Warnings and Precautions (5.4)].
Dosage Adjustment
Once responsiveness to sapropterin dihydrochloride tablets has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to biochemical response to therapy (blood Phe). Periodic blood Phe monitoring is recommended to assess blood Phe control, especially in pediatric patients
[see Warnings and Precautions (5.3)].
•
Patients 7 years and older:
The recommended starting dosage of sapropterin dihydrochloride tablets is 10 to 20 mg/kg administered orally once daily. (The recommended starting dosage of sapropterin dihydrochloride tablets is:
Pediatric Patients 1 month to 6 years:
10 mg/kg (actual body weight) administered orally once daily.Patients 7 years and older:
10 to 20 mg/kg (actual body weight) administered orally once daily.Administer sapropterin dihydrochloride tablets with a meal, preferably at the same time each day
[see Clinical Pharmacology (12.3)].
A missed dose should be administered as soon as possible, but two doses should not be administered on the same day.
Evaluation Period
Existing dietary protein and Phe intake should not be modified during the evaluation period.
If a 10 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day do not show a biochemical response and treatment with sapropterin dihydrochloride tablets should be discontinued in these patients.
If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically during the first month. Treatment should be discontinued in patients who do not show a biochemical response (blood Phe does not decrease) after 1 month of treatment at 20 mg/kg per day
[see Warnings and Precautions (5.4)].
Dosage Adjustment
Once responsiveness to sapropterin dihydrochloride tablets has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to biochemical response to therapy (blood Phe). Periodic blood Phe monitoring is recommended to assess blood Phe control, especially in pediatric patients
[see Warnings and Precautions (5.3)].
Dosage Adjustment
• Doses of sapropterin dihydrochloride tablets may be adjusted in the range of 5 to 20 mg/kg taken once daily. (
The recommended starting dosage of sapropterin dihydrochloride tablets is:
Pediatric Patients 1 month to 6 years:
10 mg/kg (actual body weight) administered orally once daily.Patients 7 years and older:
10 to 20 mg/kg (actual body weight) administered orally once daily.Administer sapropterin dihydrochloride tablets with a meal, preferably at the same time each day
[see Clinical Pharmacology (12.3)].
A missed dose should be administered as soon as possible, but two doses should not be administered on the same day.
Evaluation Period
Existing dietary protein and Phe intake should not be modified during the evaluation period.
If a 10 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day do not show a biochemical response and treatment with sapropterin dihydrochloride tablets should be discontinued in these patients.
If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically during the first month. Treatment should be discontinued in patients who do not show a biochemical response (blood Phe does not decrease) after 1 month of treatment at 20 mg/kg per day
[see Warnings and Precautions (5.4)].
Dosage Adjustment
Once responsiveness to sapropterin dihydrochloride tablets has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to biochemical response to therapy (blood Phe). Periodic blood Phe monitoring is recommended to assess blood Phe control, especially in pediatric patients
[see Warnings and Precautions (5.3)].
• Monitor blood Phe regularly, especially in pediatric patients. (
The recommended starting dosage of sapropterin dihydrochloride tablets is:
Pediatric Patients 1 month to 6 years:
10 mg/kg (actual body weight) administered orally once daily.Patients 7 years and older:
10 to 20 mg/kg (actual body weight) administered orally once daily.Administer sapropterin dihydrochloride tablets with a meal, preferably at the same time each day
[see Clinical Pharmacology (12.3)].
A missed dose should be administered as soon as possible, but two doses should not be administered on the same day.
Evaluation Period
Existing dietary protein and Phe intake should not be modified during the evaluation period.
If a 10 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day do not show a biochemical response and treatment with sapropterin dihydrochloride tablets should be discontinued in these patients.
If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically during the first month. Treatment should be discontinued in patients who do not show a biochemical response (blood Phe does not decrease) after 1 month of treatment at 20 mg/kg per day
[see Warnings and Precautions (5.4)].
Dosage Adjustment
Once responsiveness to sapropterin dihydrochloride tablets has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to biochemical response to therapy (blood Phe). Periodic blood Phe monitoring is recommended to assess blood Phe control, especially in pediatric patients
[see Warnings and Precautions (5.3)].
In clinical trials of sapropterin dihydrochloride tablets, some PKU patients experienced hypophenylalaninemia (low blood Phe) during treatment with sapropterin dihydrochloride tablets. In a clinical study of pediatric patients younger than 7 years old treated with sapropterin dihydrochloride tablets 20 mg/kg per day, the incidence of hypophenylalaninemia was higher than in clinical trials of older patients
[see Adverse Reactions (6.1)].
Preparation and Administration
• See the full prescribing information for preparation and administration instructions. (
Sapropterin Dihydrochloride Tablets
● Sapropterin dihydrochloride tablets may be swallowed either as whole tablets or dissolved in 120 to 240 mL of water or apple juice and taken orally within 15 minutes of dissolution.
● It may take a few minutes for the tablets to dissolve.
● To make the tablets dissolve faster, tablets may be stirred or crushed.
● The tablets may not dissolve completely. Patients may see small pieces floating on top of the water or apple juice. This is normal and safe for patients to swallow.
● If after drinking the medicine, patients still see pieces of the tablet in the container, more water or apple juice can be added to make sure all of the medicine is consumed.
● Sapropterin dihydrochloride tablets may also be crushed and then mixed in a small amount of soft foods such as apple sauce or pudding.
Sapropterin dihydrochloride tablets are for oral use. Each tablet contains 100 mg of sapropterin dihydrochloride. Tablets are off-white to light yellow mottled round, tablets debossed with “I 1” on one side and plain on other side.
Risk Summary
Available data from pregnancy safety studies, pharmacovigilance, and published case reports with sapropterin dihydrochloride use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
(see Data)
. Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects(see Clinical Considerations)
. An embryo-fetal development study with sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended human dose (MRHD) given during the period of organogenesis showed no effects. In a rabbit study using oral administration of sapropterin dihydrochloride during the period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD.
All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU.
Clinical Considerations
Disease-Associated Maternal and/or Embryo-Fetal Risk
Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception
[see
Administer sapropterin dihydrochloride tablets with a meal, preferably at the same time each day
A missed dose should be administered as soon as possible, but two doses should not be administered on the same day.
Existing dietary protein and Phe intake should not be modified during the evaluation period.
If a 10 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day do not show a biochemical response and treatment with sapropterin dihydrochloride tablets should be discontinued in these patients.
If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically during the first month. Treatment should be discontinued in patients who do not show a biochemical response (blood Phe does not decrease) after 1 month of treatment at 20 mg/kg per day
Once responsiveness to sapropterin dihydrochloride tablets has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to biochemical response to therapy (blood Phe). Periodic blood Phe monitoring is recommended to assess blood Phe control, especially in pediatric patients].
The recommended starting dosage of sapropterin dihydrochloride tablets is:
Pediatric Patients 1 month to 6 years:
10 mg/kg (actual body weight) administered orally once daily.Patients 7 years and older:
10 to 20 mg/kg (actual body weight) administered orally once daily.Administer sapropterin dihydrochloride tablets with a meal, preferably at the same time each day
[see Clinical Pharmacology (12.3)].
A missed dose should be administered as soon as possible, but two doses should not be administered on the same day.
Evaluation Period
Existing dietary protein and Phe intake should not be modified during the evaluation period.
If a 10 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day do not show a biochemical response and treatment with sapropterin dihydrochloride tablets should be discontinued in these patients.
If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically during the first month. Treatment should be discontinued in patients who do not show a biochemical response (blood Phe does not decrease) after 1 month of treatment at 20 mg/kg per day
[see Warnings and Precautions (5.4)].
Dosage Adjustment
Once responsiveness to sapropterin dihydrochloride tablets has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to biochemical response to therapy (blood Phe). Periodic blood Phe monitoring is recommended to assess blood Phe control, especially in pediatric patients
[see Warnings and Precautions (5.3)].
Data
Human Data
Uncontrolled Maternal PKU
Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in PKU-affected women demonstrated that uncontrolled Phe levels above 600 micromol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies. Control of blood phenylalanine during pregnancy is essential to reduce the incidence of Phe-induced teratogenic effects.
Pregnancy Registry Data
Available data from pregnancy sub-registries within the Phenylketonuria Developmental Outcomes and Safety (PKUDOS) Registry and the sapropterin dihydrochloride Adult Maternal Pediatric European Registry (KAMPER) have identified 72 live births (79 pregnancies) in women with PKU exposed to sapropterin during pregnancy. Three birth defects were reported, including one case each of microcephaly, cleft palate, and tongue tie. The two major birth defects (microcephaly and cleft palate) were associated with Phe levels greater than 360 micromol/L during pregnancy.
Animal Data
No effects on embryo-fetal development were observed in a reproduction study in rats using oral doses of up to 400 mg/kg per day sapropterin dihydrochloride (about 3 times the MRHD of 20 mg/kg per day, based on body surface area) administered during the period of organogenesis. However, in a rabbit reproduction study, oral administration of a maximum dose of 600 mg/kg per day (about 10 times the MRHD, based on body surface area) during the period of organogenesis was associated with a non-statistically significant increase in the incidence of holoprosencephaly in two high dose-treated litters (4 fetuses), compared to one control-treated litter (1 fetus).
None.
•
Hypersensitivity Reactions Including Anaphylaxis:
Sapropterin dihydrochloride tablets are not recommended in patients with a history of anaphylaxis to sapropterin dihydrochloride tablets; discontinue treatment in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary Phe restrictions. (Sapropterin dihydrochloride is not recommended in patients with a history of anaphylaxis to sapropterin dihydrochloride. Hypersensitivity reactions, including anaphylaxis and rash, have occurred
[see Adverse Reactions (6.2)]
. Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.Discontinue treatment with sapropterin dihydrochloride in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary protein and Phe restriction in patients who experience anaphylaxis.
•
Upper Gastrointestinal Mucosal Inflammation:
Monitor patients for signs and symptoms of these conditions including esophagitis and gastritis. (Gastrointestinal (GI) adverse reactions suggestive of upper GI mucosal inflammation have been reported with sapropterin dihydrochloride tablets. Serious adverse reactions included esophagitis and gastritis
[see Adverse Reactions (6.2)]
. If left untreated, these could lead to severe sequelae including esophageal stricture, esophageal ulcer, gastric ulcer, and bleeding and such complications have been reported in patients receiving sapropterin dihydrochloride tablets. Monitor patients for signs and symptoms of upper GI mucosal inflammation.•
Hypophenylalaninemia:
Pediatric patients younger than 7 years treated with sapropterin dihydrochloride tablets doses of 20 mg/kg per day are at increased risk for low levels of blood Phe compared with patients 7 years and older. (In clinical trials of sapropterin dihydrochloride tablets, some PKU patients experienced hypophenylalaninemia (low blood Phe) during treatment with sapropterin dihydrochloride tablets. In a clinical study of pediatric patients younger than 7 years old treated with sapropterin dihydrochloride tablets 20 mg/kg per day, the incidence of hypophenylalaninemia was higher than in clinical trials of older patients
[see Adverse Reactions (6.1)].
•
Monitoring Blood Phe Levels During Treatment:
Ensure adequate blood Phe control and nutritional balance during treatment with sapropterin dihydrochloride tablets. Frequent blood monitoring is recommended, especially in pediatric patients. (Prolonged elevations of blood Phe levels in patients with PKU can result in severe neurologic damage, including severe intellectual disability, developmental delay, microcephaly, delayed speech, seizures, and behavioral abnormalities. Conversely, prolonged levels of blood Phe that are too low have been associated with catabolism and endogenous protein breakdown, which has been associated with adverse developmental outcomes. Active management of dietary Phe intake while taking sapropterin dihydrochloride tablets is required to ensure adequate Phe control and nutritional balance. Monitor blood Phe levels during treatment to ensure adequate blood Phe level control. Frequent blood monitoring is recommended in the pediatric population
[see Dosage and Administration (2.2)].
Treatment with sapropterin dihydrochloride tablets should be directed by physicians knowledgeable in the management of PKU.
All patients with PKU who are being treated with sapropterin dihydrochloride tablets should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction.
•
Lack of Biochemical Response to Sapropterin Dihydrochloride Treatment:
Response to sapropterin dihydrochloride treatment cannot be pre-determined by laboratory (e.g., molecular) testing and can only be determined by a therapeutic trial of sapropterin dihydrochloride. (Some patients with PKU do not show biochemical response (reduction in blood Phe) with treatment with sapropterin dihydrochloride tablets. In two clinical trials at a sapropterin dihydrochloride tablets dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients showed a biochemical response to sapropterin dihydrochloride tablets, and in one clinical trial at a dose of 10 mg/kg per day, 20% of adult and pediatric PKU patients showed a biochemical response to sapropterin dihydrochloride tablets
[see Clinical Studies (14)]
.Biochemical response to sapropterin dihydrochloride tablets treatment cannot generally be pre-determined by laboratory testing (e.g., molecular testing), and should be determined through a therapeutic trial (evaluation) of sapropterin dihydrochloride tablets response
[see Dosage and Administration (2.2)]
.Treatment with sapropterin dihydrochloride tablets should be directed by physicians knowledgeable in the management of PKU.
All patients with PKU who are being treated with sapropterin dihydrochloride tablets should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction.
•
Interaction with Levodopa:
Seizures, over-stimulation or irritability may occur; monitor patients for a change in neurologic status. (In a 10-year post-marketing safety surveillance program for a non-PKU indication using another sapropterin product, 3 patients with underlying neurological disorders experienced seizures, exacerbation of seizures, over-stimulation, and irritability during co-administration of levodopa and sapropterin. Monitor patients who are receiving levodopa for changes in neurological status during treatment with sapropterin dihydrochloride
[see Drug Interactions (7)]
.Table 4 includes drugs with clinically important drug interactions when administered with sapropterin dihydrochloride and instructions for preventing or managing them.
Table 4: Clinically Relevant Drug Interactions
Levodopa | |
Clinical Impact | Sapropterin dihydrochloride may increase the availability of tyrosine, a precursor of levodopa. Neurologic events were reported postmarketing in patients receiving sapropterin and levodopa concomitantly for a non-PKU indication [see Warnings and Precautions (5.5)]. |
Intervention | Monitor patients for a change in neurologic status. |
Inhibitors of Folate Synthesis (e.g., methotrexate, valproic acid, phenobarbital, trimethoprim) | |
Clinical Impact | In vitro andin vivo nonclinical data suggest that drugs that inhibit folate synthesis may decrease the bioavailability of endogenous BH4 by inhibiting the enzyme dihydrofolate reductase, which is involved in the recycling (regeneration) of BH4. This reduction in net BH4 levels may increase Phe levels. |
Intervention | Consider monitoring blood Phe levels more frequently during concomitant administration. An increased dosage of sapropterin dihydrochloride tablets may be necessary to achieve a biochemical response. |
Drugs Affecting Nitric Oxide-Mediated Vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil) | |
Clinical Impact | Both sapropterin dihydrochloride and PDE-5 inhibitors may induce vasorelaxation. A reduction in blood pressure could occur; however, the combined use of these medications has not been evaluated in humans. |
Intervention | Monitor blood pressure. |
•
Inhibitors of Folate Synthesis (e.g., methotrexate, valproic acid, phenobarbital, trimethoprim):
Can decrease endogenous BH4 levels; monitor blood Phe levels more frequently and adjust sapropterin dihydrochloride tablets dosage as needed. •
Drugs Affecting Nitric Oxide-Mediated Vasorelaxation (e.g., PDE-5 inhibitors):
Potential for vasorelaxation; monitor blood pressure. •
Hyperactivity:
Monitor patients for hyperactivity. (In the sapropterin dihydrochloride postmarketing safety surveillance program, 2 patients with PKU experienced hyperactivity when treated with sapropterin dihydrochloride
[see Adverse Reactions (6.2)]
. Monitor patients for hyperactivity.We receive information directly from the FDA and PrescriberPoint is updated as frequently as changes are made available