Sapropterin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Turky Alkathery, M.D. [2]
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Overview
Sapropterin is a phenylalanine hydroxylase activator that is FDA approved for the treatment of phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin‑ (BH4‑) responsive Phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe‑restricted diet. Common adverse reactions include headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indication
Kuvan® (sapropterin dihydrochloride) is indicated to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe-restricted diet.
Dosage
Patients 1 month to 6 years: The recommended starting dose of Kuvan is 10 mg/kg taken once daily.
Patients 7 years and older: The recommended starting dose of Kuvan is 10 to 20 mg/kg taken once daily.
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 Kuvan at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of Kuvan 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 are non-responders and treatment with Kuvan 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 Kuvan at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of Kuvan treatment and periodically during the first month. Treatment should be discontinued in patients who do not respond to Kuvan.
Once responsiveness to Kuvan has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to response to therapy. Periodic blood Phe monitoring is recommended to assess blood Phe control.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sapropterin in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sapropterin in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sapropterin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sapropterin in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sapropterin in pediatric patients.
Contraindications
None.
Warnings
Hypersensitivity Reactions Including Anaphylaxis
Kuvan is not recommended in patients with a history of anaphylaxis to Kuvan. Hypersensitivity reactions, including anaphylaxis and rash, have occurred. Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Discontinue treatment with Kuvan in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary Phe restrictions in patients who experience anaphylaxis.
Gastritis
During clinical studies, gastritis was reported as a serious adverse reaction. Monitor patients for signs and symptoms of gastritis.
Hypophenylalaninemia
In clinical trials, some patients have experienced low blood Phe levels. Children younger than 7 years treated with Kuvan doses of 20 mg/kg per day are at increased risk for low levels of blood Phe compared with patients 7 years and older.
Monitor Blood Phe Levels During Treatment
Treatment with Kuvan should be directed by physicians knowledgeable in the management of PKU. Prolonged elevations in blood Phe levels in patients with PKU can result in severe neurologic damage, including severe mental retardation, microcephaly, delayed speech, seizures, and behavioral abnormalities. Conversely, prolonged levels of blood Phe that are too low have been associated with catabolism and protein breakdown. Active management of dietary Phe intake while taking Kuvan 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.
Identify Non-Responders to Kuvan Treatment
Not all patients with PKU respond to treatment with Kuvan. In two clinical trials at a dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients responded to treatment with Kuvan, and in one clinical trial at a dose of 10 mg/kg per day, 20% of adult and pediatric PKU patients responded to treatment with Kuvan.
Response to treatment cannot be pre-determined by laboratory testing (e.g., molecular testing), and can only be determined by a therapeutic trial of Kuvan.
Treat All Patients with a Phe-restricted Diet
All patients with PKU who are being treated with Kuvan should also be treated with a Phe-restricted diet.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
PKU Clinical Studies
The safety of Kuvan was evaluated in 6 clinical studies in patients with PKU (aged 1 month to 50 years).
In Studies1-4 (controlled and uncontrolled studies), 579 patients with PKU aged 4 to 49 years received Kuvan in doses ranging from 5 to 20 mg/kg per day for lengths of treatment ranging from 1 to 164 weeks. The patient population was evenly distributed in gender, and approximately 95% of patients were Caucasian. The most common adverse reactions (≥4% of patients) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.
The data described in Table 3 reflect exposure of 74 patients with PKU to Kuvan at doses of 10 to 20 mg/kg per day for 6 to 10 weeks in two double-blind, placebo-controlled clinical trials (Studies 2 and 4).
Table 3 enumerates adverse reactions occurring in at least 4% of patients treated with Kuvan in the double-blind, placebo-controlled clinical trials described above.
In open-label, uncontrolled clinical trials (Studies 1 and 3) all patients received Kuvan in doses of 5 to 20 mg/kg per day, adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials.
In Study 5, 65 pediatric patients with PKU aged 1 month to 6 years received Kuvan 20 mg/kg per day for 6 months. Adverse reactions in these patients were similar in frequency and type as those seen in other Kuvan clinical trials except for an increased incidence of low Phe levels. Twenty-five percent (16 out of 65) of patients developed Phe levels below normal for age.
In Study 6, a long term, open-label, extension study of 111 patients aged 4 to 50 years, receiving Kuvan in doses ranging from 5 to 20 mg/kg per day, adverse reactions were similar in type and frequency to those reported in the previous clinical studies. Fifty-five patients received Kuvan both as dissolved and intact tablets. There were no notable differences in the incidence or severity of adverse reactions between the two methods of administration. The mean (± SD) exposure to sapropterin for the entire study population was 659 ± 221 days (maximum 953 days).
Safety Experience from Clinical Studies for Non-PKU Indications
Approximately 800 healthy volunteers and patients with disorders other than PKU, some of whom had underlying neurologic disorders or cardiovascular disease, have been administered a different formulation of the same active ingredient (sapropterin) in approximately 19 controlled and uncontrolled clinical trials. In these clinical trials, subjects were administered sapropterin at doses ranging from 1 to 100 mg/kg per day for lengths of exposure from 1 day to 2 years. Serious and severe adverse reactions (regardless of causality) during sapropterin administration were convulsions, exacerbation of convulsions, dizziness, gastrointestinal bleeding, post-procedural bleeding, headache, irritability, myocardial infarction, overstimulation, and respiratory failure. Common adverse reactions were headache, peripheral edema, arthralgia, polyuria, agitation, dizziness, nausea, pharyngitis, abdominal pain, upper abdominal pain, and upper respiratory tract infection.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Kuvan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.
In worldwide marketing experience, the most common adverse reactions due to Kuvan are oropharyngeal pain, pharyngitis, esophageal pain, gastritis, dyspepsia, abdominal pain, nausea and vomiting. Hypersensitivity reactions including anaphylaxis and rash have been reported. Most hypersensitivity reactions occurred within several days of initiating treatment. Two cases of hyperactivity have been reported, including one case in a patient who received an accidental overdose of Kuvan.
Drug Interactions
No drug interaction studies were performed.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): C A patient registry has been established that collects data on women who are treated with Kuvan during pregnancy. For more information regarding the registry program call 1-866-906-6100. Risk Summary
There are no adequate and well-controlled studies with Kuvan in pregnant women. 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. Kuvan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Disease-associated maternal and/or embryofetal risk
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 µmol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies. Good dietary control of Phe levels during pregnancy is essential to reduce the incidence of Phe-induced teratogenic effects.
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).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sapropterin in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Sapropterin during labor and delivery.
Nursing Mothers
It is not known whether Kuvan is present in human milk. Sapropterin is present in the milk of intravenously, but not orally, treated lactating rats. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for Kuvan and any potential adverse effects on the human milk-fed child from the drug or from the underlying maternal condition. Exercise caution when Kuvan is administered to a nursing woman.
Pediatric Use
There is no FDA guidance on the use of Sapropterin in pediatric settings.
Geriatic Use
Clinical studies of Kuvan in patients with PKU did not include patients aged 65 years and older. It is not known whether these patients respond differently than younger patients.
Gender
There is no FDA guidance on the use of Sapropterin with respect to specific gender populations.
Race
There is no FDA guidance on the use of Sapropterin with respect to specific racial populations.
Renal Impairment
Patients with renal impairment have not been evaluated in clinical trials. Monitor patients who have renal impairment carefully when they are receiving Kuvan.
Hepatic Impairment
There is no FDA guidance on the use of Sapropterin in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sapropterin in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Sapropterin in patients who are immunocompromised.
Administration and Monitoring
Administration
Kuvan is available as tablets and as powder for oral solution. Kuvan should be taken orally with a meal to increase absorption, preferably at the same time each day. A missed dose should be taken as soon as possible, but two doses should not be taken on the same day.
2.3 Instructions for Use Kuvan Tablets
Kuvan 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. Kuvan tablets may also be crushed and then mixed in a small amount of soft foods such as apple sauce or pudding.
Kuvan Powder for Oral Solution
Kuvan powder for oral solution should be dissolved in 120 to 240 mL of water or apple juice and taken orally within 30 minutes of dissolution. Kuvan powder for oral solution may also be stirred in a small amount of soft foods such as apple sauce or pudding. Empty the contents of the packet(s) in water, apple juice, or a small amount of soft foods and mix thoroughly. The powder should dissolve completely.
For infants weighing 10 kg or less, Kuvan can be dissolved in as little as 5 mL of water or apple juice and a portion of this solution corresponding to a 10 mg/kg dose may be administered orally via an oral dosing syringe. Table 1 provides dosing information for infants at the recommended starting dose of 10 mg/kg per day. Refer to Table 2 for dosing information at 20 mg/kg per day if dosage adjustment is needed.
Monitoring
5.7 Monitor Patients with Hepatic Impairment Patients with liver impairment have not been evaluated in clinical trials with Kuvan. Monitor liver function tests in patients with liver impairment who are receiving Kuvan because hepatic damage has been associated with impaired Phe metabolism.
5.8 Monitor Patients when Co-administering Kuvan and Medications Known to Inhibit Folate Metabolism Co-administering Kuvan with drugs known to affect folate metabolism (e.g., methotrexate) and their derivatives may require more frequent monitoring of blood Phe levels because these drugs can decrease endogenous BH4 levels by inhibiting the enzyme dihydropteridine reductase (DHPR).
5.9 Monitor Patients for Hypotension when Co-administering Kuvan and Drugs Known to Affect Nitric Oxide-Mediated Vasorelaxation Monitor blood pressure when administering Kuvan with drugs that affect nitric oxide‑mediated vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil), because both sapropterin dihydrochloride and PDE-5 inhibitors may induce vasorelaxation. The additive effect of sapropterin and PDE-5 inhibitor co-administration could lead to a reduction in blood pressure; however, the combined use of these medications has not been evaluated in humans. In animal studies, orally administered Kuvan in combination with a PDE-5 inhibitor had no effect on blood pressure.
5.10 Monitor Patients when Co-administering Kuvan and Levodopa Caution should be used with the administration of Kuvan to patients who are receiving levodopa. In a 10-year post-marketing safety surveillance program for a non-PKU indication using another formulation of the same active ingredient (sapropterin), 3 patients with underlying neurologic disorders experienced convulsions, exacerbation of convulsions, over-stimulation, or irritability during co-administration of levodopa and sapropterin. Monitor for change in neurologic status.
5.11 Monitor Patients for Hyperactivity In the post-marketing safety surveillance program for PKU, 2 patients experienced hyperactivity with administration of Kuvan. Monitor patients for hyperactivity.
IV Compatibility
There is limited information regarding the compatibility of Sapropterin and IV administrations.
Overdosage
Two unintentional overdosages with Kuvan have been reported. One adult patient in a Kuvan clinical trial received a single Kuvan dose of 4,500 mg (36 mg/kg) instead of 2,600 mg (20 mg/kg). The patient reported mild headache and mild dizziness immediately after taking the dose; both symptoms resolved within 1 hour with no treatment intervention. There were no associated laboratory test abnormalities. The patient suspended therapy for 24 hours and then restarted Kuvan with no reports of abnormal signs or symptoms. In postmarketing, one pediatric patient received Kuvan doses of 45 mg/kg per day instead of 20 mg/kg per day. The patient reported hyperactivity that began at an unspecified time after overdose and resolved after the Kuvan dose was reduced to 20 mg/kg per day.
In a clinical study to evaluate the effects of Kuvan on cardiac repolarization, a single supra-therapeutic dose of 100 mg/kg (5 times the maximum recommended dose) was administered to 54 healthy adults. No serious adverse reactions were reported during the study. The only adverse reactions reported in more than 1 subject who received the supra-therapeutic dose were upper abdominal pain (6%) and dizziness (4%). A dose-dependent shortening of the QT interval was observed. Patients should be advised to notify their physicians in cases of overdose.
Pharmacology
There is limited information regarding Sapropterin Pharmacology in the drug label.
Mechanism of Action
Kuvan is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme activity, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.
Structure
There is limited information regarding Sapropterin Structure in the drug label.
Pharmacodynamics
In PKU patients who are responsive to BH4 treatment, blood Phe levels decrease within 24 hours after a single administration of sapropterin dihydrochloride, although maximal effect on Phe level may take up to a month, depending on the patient. A single daily dose of Kuvan is adequate to maintain stable blood Phe levels over a 24-hour period. Twelve patients with blood Phe levels ranging from 516 to 986 μmol/L (mean 747 ± 153 μmol/L) were assessed with 24‑hour blood Phe level monitoring following a daily morning dose of 10 mg/kg per day. The blood Phe level remained stable during a 24‑hour observation period. No substantial increases in blood Phe levels were observed following food intake throughout the 24-hour period.
Kuvan dose-response relationship was studied in an open-label, forced titration study at doses of 5 mg/kg per day, then 20 mg/kg per day, and then 10 mg/kg per day (Study 3). Individual blood Phe levels were highly variable among patients. The mean blood Phe level observed at the end of each 2-week dosing period decreased as the dose of sapropterin dihydrochloride increased, demonstrating an inverse relationship between the dose of sapropterin dihydrochloride and mean blood Phe levels.
Effects of Kuvan on the QTc interval
A thorough QTc study was performed in 56 healthy adults. This randomized, placebo and active controlled crossover study was conducted to determine if a single supra-therapeutic (100 mg/kg) of Kuvan, or a single therapeutic dose (20 mg/kg) of Kuvan had an effect on cardiac repolarization. In this study, Kuvan was administered after dissolving tablets in water under fed condition. This study demonstrated a dose-dependent shortening of the QT interval. The maximum placebo-subtracted mean change from baseline of the QTc interval was -3.69 and -8.32 ms (lower bound of 90% CI: -5.3 and -10.6 ms) at 20 and 100 mg/kg, respectively.
Pharmacokinetics
There is limited information regarding Sapropterin Pharmacokinetics in the drug label.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year carcinogenicity study was conducted in F-344 rats, and a 78-week carcinogenicity study was conducted in CD-1 mice. In the 104-week oral carcinogenicity study in rats, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.2, 0.7, and 2 times the maximum recommended human dose of 20 mg/kg per day, respectively, based on body surface area) were used. In the 78-week oral carcinogenicity study in mice, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.1, 0.3, and 2 times the recommended human dose, respectively, based on body surface area) were used. In the 2‑year rat carcinogenicity study, there was a statistically significant increase in the incidence of benign adrenal pheochromocytoma in male rats treated with the 250 mg/kg per day (about 2 times the maximum recommended human dose, based on body surface area) dose, as compared to vehicle treated rats. The mouse carcinogenicity study showed no evidence of a carcinogenic effect, but the study was not ideal due to its duration of 78 instead of 104 weeks.
Sapropterin dihydrochloride was genotoxic in the in vitro Ames test at concentrations of 625 µg (TA98) and 5000 µg (TA100) per plate, without metabolic activation. However, no genotoxicity was observed in the in vitro Ames test with metabolic activation. Sapropterin dihydrochloride was genotoxic in the in vitro chromosomal aberration assay in Chinese hamster lung cells at concentrations of 0.25 and 0.5 mM. Sapropterin dihydrochloride was not mutagenic in the in vivo micronucleus assay in mice at doses up to 2000 mg/kg per day (about 8 times the maximum recommended human dose of 20 mg/kg per day, based on body surface area). Sapropterin dihydrochloride, at oral doses up to 400 mg/kg per day (about 3 times the maximum recommended human dose, based on body surface area) was found to have no effect on fertility and reproductive function of male and female rats.
Clinical Studies
There is limited information regarding Sapropterin Clinical Studies in the drug label.
How Supplied
There is limited information regarding Sapropterin How Supplied in the drug label.
Storage
Store Kuvan tablets at 20ºC to 25ºC (68ºF to 77ºF); excursions allowed between 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture.
Store Kuvan powder for oral solution at 20ºC to 25ºC (68ºF to 77ºF); excursions allowed between 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Protect from moisture.
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Patient Counseling Information
There is limited information regarding Sapropterin Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Sapropterin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Sapropterin Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Sapropterin Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.