The following Structured Product Label (SPL) was submitted to the FDA by Aurobindo Pharma Limited for the product Sapropterin Dihydrochloride (NDC 59651-574). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 recommendations prior to sapropterin dihydrochloride tablets treatment, 2.2 recommended dosage and administration, 2.3 preparation and administration instructions, 3 dosage forms and strengths, 4 contraindications, 5.1 hypersensitivity reactions including anaphylaxis, 5.2 upper gastrointestinal mucosal inflammation, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
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.
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.
The recommended starting dosage of sapropterin dihydrochloride tablets are:
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 tablets 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 tablets 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)].
Sapropterin dihydrochloride tablets are for oral use. Each tablet contains 100 mg of sapropterin dihydrochloride. Tablets are off-white to light yellow mottled uncoated round tablets debossed with “S 1” on one side and plain on other side.
None.
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.
Gastrointestinal (GI) adverse reactions suggestive of upper GI mucosal inflammation have been reported with sapropterin dihydrochloride. 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. Monitor patients for signs and symptoms of upper GI mucosal inflammation.
In clinical trials of sapropterin dihydrochloride, some PKU patients experienced hypophenylalaninemia (low blood Phe) during treatment with sapropterin dihydrochloride. In a clinical study of pediatric patients younger than 7 years old treated with sapropterin dihydrochloride 20 mg/kg per day, the incidence of hypophenylalaninemia was higher than in clinical trials of older patients [see Adverse Reactions (6.1)].
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 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)].
Some patients with PKU do not show biochemical response (reduction in blood Phe) with treatment with sapropterin dihydrochloride. In two clinical trials at a sapropterin dihydrochloride dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients showed a biochemical response to sapropterin dihydrochloride, 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 [see Clinical Studies (14)].
Biochemical response to sapropterin dihydrochloride 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 response [see Dosage and Administration (2.2)].
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)].
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.
Because clinical trials are conducted under widely varying conditions, adverse reaction 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 sapropterin dihydrochloride was evaluated in 7 clinical studies in patients with PKU (aged 1 month to 50 years) [see Clinical Studies (14)].
In Studies 1 to 4 (controlled and uncontrolled studies), 579 patients with PKU aged 4 to 49 years received sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride in the double-blind, placebo-controlled clinical trials described above.
| MedDRA Preferred Term | Treatment | |
| Sapropterin dihydrochloride (N=74) | Placebo (N=59) | |
| No. Patients (%) | No. Patients (%) | |
| Headache | 11 (15) | 8 (14) |
| Rhinorrhea | 8 (11) | 0 |
| Pharyngolaryngeal pain | 7 (10) | 1 (2) |
| Diarrhea | 6 (8) | 3 (5) |
| Vomiting | 6 (8) | 4 (7) |
| Cough | 5 (7) | 3 (5) |
| Nasal congestion | 3 (4) | 0 |
In open-label, uncontrolled clinical trials (Studies 1 and 3) all patients received sapropterin dihydrochloride in doses of 5 to 20 mg/kg per day, and adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials [see Clinical Studies (14)].
In Study 5, 65 pediatric patients with PKU aged 1 month to 6 years received sapropterin dihydrochloride 20 mg/kg per day for 6 months. Adverse reactions in these patients were similar in frequency and type as those seen in other sapropterin dihydrochloride 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 [see Warnings and Precautions (5.3), Use In Specific Populations (8.4), and Clinical Studies (14)].
In Study 6, a long term, open-label, extension study of 111 patients aged 4 to 50 years, receiving sapropterin dihydrochloride 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 sapropterin dihydrochloride 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).
In Study 7, 27 pediatric patients with PKU aged 0 to 4 years received sapropterin dihydrochloride 10 mg/kg per day or 20 mg/kg per day. Adverse reactions were similar in type and frequency to those observed in other clinical trials, with the addition of rhinitis, which was reported in 2 subjects (7.4%).
Safety Experience from Clinical Studies for Non-PKU Indications
Approximately 800 healthy subjects 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 seizures, exacerbation of seizures [see Warnings and Precautions (5.3)], 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.
The following adverse reactions have been reported during post-approval use of sapropterin dihydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions including anaphylaxis and rash: Most hypersensitivity reactions occurred within several days of initiating treatment [see Warnings and Precautions (5.1)].
Gastrointestinal reactions: esophagitis, gastritis, oropharyngeal pain, pharyngitis, esophageal pain, abdominal pain, dyspepsia, nausea, and vomiting [see Warnings and Precautions (5.2)].
Hyperactivity: Two cases have been reported. In one case, the patient received an accidental overdosage of sapropterin dihydrochloride [see Warnings and Precautions (5.6), Overdosage (10)].
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 and in 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 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. |
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 Dosage and Administration (2.2)].
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.
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).
Risk Summary
There are insufficient data to assess the presence of sapropterin in human milk and no data on the effects on milk production. In postmarketing pregnancy registries, 13 infants were exposed to sapropterin dihydrochloride through breastfeeding. No lactation-related safety concerns were reported in infants of mothers nursing during maternal treatment with sapropterin dihydrochloride. There is no data on the effects on milk production. Sapropterin is present in the milk of lactating rats following intravenous administration, but not following oral administration.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sapropterin dihydrochloride and any potential adverse effects on the breastfed child from sapropterin dihydrochloride or from the underlying maternal condition.
Pediatric patients with PKU, ages 1 month to 16 years, have been treated with sapropterin dihydrochloride in clinical trials [see Clinical Studies (14)].
The efficacy and safety of sapropterin dihydrochloride have not been established in neonates. The safety of sapropterin dihydrochloride has been established in children younger than 4 years in trials of 6 months duration and in children 4 years and older in trials of up to 3 years in length [see Adverse Reactions (6.1)].
In children aged 1 month and older, the efficacy of sapropterin dihydrochloride has been demonstrated in trials of 6 weeks or less in duration [see Clinical Studies (14)].
In a multicenter, open-label, single arm study, 57 patients aged 1 month to 6 years who were defined as sapropterin dihydrochloride responders after 4 weeks of sapropterin dihydrochloride treatment and Phe dietary restriction were treated for 6 months with sapropterin dihydrochloride at 20 mg/kg per day. The effectiveness of sapropterin dihydrochloride alone on reduction of blood Phe levels beyond 4 weeks could not be determined due to concurrent changes in dietary Phe intake during the study. Mean (±SD) blood Phe values over time for patients aged 1 month to <2 years and 2 to <7 years are shown in Figure 1.
Fig1 (Sapropterin Fig1)
Clinical studies of sapropterin dihydrochloride 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.
Two unintentional overdosages with sapropterin dihydrochloride have been reported. One adult patient in a sapropterin dihydrochloride clinical trial received a single sapropterin dihydrochloride 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 sapropterin dihydrochloride with no reports of abnormal signs or symptoms. In postmarketing, one pediatric patient received sapropterin dihydrochloride 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 overdosage and resolved after the sapropterin dihydrochloride dose was reduced to 20 mg/kg per day.
In a clinical study to evaluate the effects of sapropterin dihydrochloride 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 [see Clinical Pharmacology (12.2)].
Patients should be advised to notify their physicians in cases of overdosage.
Sapropterin dihydrochloride tablets are an orally administered Phenylalanine Hydroxylase activator (or PAH activator). Sapropterin dihydrochloride, the active pharmaceutical ingredient in sapropterin dihydrochloride tablets, is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Sapropterin dihydrochloride is an off-white to pale yellow crystalline powder.
The chemical name of sapropterin dihydrochloride is (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-pteridinone dihydrochloride and the molecular formula is C9H15N5O3·2HCl with a molecular weight of 314.17.
Sapropterin dihydrochloride has the following structural formula:
Chemical Structure (Sapropterin Str)
Sapropterin dihydrochloride 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.
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 sapropterin dihydrochloride 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.
Sapropterin dihydrochloride 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) [see Clinical Studies (14.1)]. 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.
Cardiac Electrophysiology
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) dose of sapropterin dihydrochloride or a single therapeutic dose (20 mg/kg) of sapropterin dihydrochloride had an effect on cardiac repolarization. In this study, sapropterin dihydrochloride 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.
Studies in healthy subjects have shown comparable absorption of sapropterin when tablets are dissolved in water or orange juice and taken under fasted conditions. Administration of dissolved tablets after a high-fat/high-calorie meal resulted in mean increases in Cmax of 84% and AUC of 87% (dissolved in water). However, there was extensive variability in individual subject values for Cmax and AUC across the different modes of administration and meal conditions. In the clinical trials of sapropterin dihydrochloride, drug was administered in the morning as a dissolved tablet without regard to meals. The mean elimination half-life in PKU patients was approximately 6.7 hours (range 3.9 to 17 hours), comparable with values seen in healthy subjects (range 3.0 to 5.3 hours).
A study in healthy adults with 10 mg/kg of sapropterin dihydrochloride demonstrated that the absorption via intact tablet administration was 40% greater than via dissolved tablet administration under fasted conditions based on AUC0-t. The administration of intact tablets under fed conditions resulted in an approximately 43% increase in the extent of absorption compared to fasted conditions based on AUC0-t [see Dosage and Administration (2.3)].
Population pharmacokinetic analysis of sapropterin including patients from 1 month to 49 years of age showed that body weight is the only covariate substantially affecting clearance or distribution volume (see Table 5). Pharmacokinetics in patients >49 years of age have not been studied.
Table 5: Apparent Plasma Clearance by Age
| Parameter | 0 to <1 yr* (N=10) | 1 to <6 yr* (N=57) | 6 to <12 yr† (N=23) | 12 to <18 yr† (N=24) | ≥18 yr† (N=42) |
| CL/F (L/hr/kg) Mean ± SD (Median) | 81.5 ± 92.4 (53.6) | 50.7 ± 20.1 (48.4) | 51.7 ± 21.9 (47.4) | 39.2 ± 9.3 (38.3) | 37.9 ± 20.2 (31.8) |
*Evaluated at 20 mg/kg per day dose.
†Evaluated at 5, 10, or 20 mg/kg per day doses.
Metabolism
Sapropterin is a synthetic form of tetrahydrobiopterin (BH4) and is expected to be metabolized and recycled by the same endogenous enzymes. In vivo endogenous BH4 is converted to quinoid dihydrobiopterin and is metabolized to dihydrobiopterin and biopterin. The enzymes dihydrofolate reductase and dihydropteridine reductase are responsible for the metabolism and recycling of BH4.
Drug Interaction Studies
Clinical Studies
In healthy subjects, administration of a single dose of sapropterin dihydrochloride at the maximum therapeutic dose of 20 mg/kg had no effect on the pharmacokinetics of a single dose of digoxin (P-gp substrate) administered concomitantly.
In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically
The potential for sapropterin to induce or inhibit cytochrome P450 enzymes was evaluated in in vitro studies which showed sapropterin did not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5, nor induce CYP 1A2, 2B6, or 3A4/5.
In vitro sapropterin did not inhibit OAT1, OAT3, OCT2, MATE1, and MATE2-K transporters. The potential for sapropterin to inhibit OATP1B1 and OATP1B3 has not been adequately studied. In vitro, sapropterin inhibits breast cancer resistance protein (BCRP) but the potential for a clinically significant increase in systemic exposure of BCRP substrates by sapropterin dihydrochloride appears to be low.
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 mcg (TA98) and 5000 mcg (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.
The efficacy of sapropterin dihydrochloride was evaluated in five clinical studies in patients with PKU.
Study 1 was a multicenter, open-label, uncontrolled clinical trial of 489 patients with PKU, ages 8 to 48 years (mean 22 years), who had baseline blood Phe levels ≥ 450 μmol/L and who were not on Phe-restricted diets. All patients received treatment with sapropterin dihydrochloride 10 mg/kg per day for 8 days. For the purposes of this study, response to sapropterin dihydrochloride treatment was defined as a ≥ 30% decrease in blood Phe from baseline. At Day 8, 96 patients (20%) were identified as responders.
Study 2 was a multicenter, double-blind, placebo-controlled study of 88 patients with PKU who responded to sapropterin dihydrochloride in Study 1. After a washout period from Study 1, patients were randomized equally to either sapropterin dihydrochloride 10 mg/kg per day (N=41) or placebo (N=47) for 6 weeks. Efficacy was assessed by the mean change in blood Phe level from baseline to Week 6 in the sapropterin dihydrochloride-treated group as compared to the mean change in the placebo group.
The results showed that at baseline, the mean (±SD) blood Phe level was 843 (±300) μmol/L in the sapropterin dihydrochloride-treated group and 888 (±323) μmol/L in the placebo group. At Week 6, the sapropterin dihydrochloride treated group had a mean (±SD) blood Phe level of 607 (±377) μmol/L, and the placebo group had a mean blood Phe level of 891 (±348) μmol/L. At Week 6, the sapropterin dihydrochloride- and placebo treated groups had mean changes in blood Phe level of –239 and 6 μmol/L, respectively (mean percent changes of –29% (±32) and 3% (±33), respectively). The difference between the groups was statistically significant (p < 0.001) (Table 6).
Table 6: Blood Phe Results in Study 2
| | Sapropterin (N=41) | Placebo (N=47) |
| Baseline Blood Phe Level* (µmol/L) | ||
| Mean (±SD) | 843 (±300) | 888 (±323) |
| Percentiles (25th, 75th) | 620, 990 | 618, 1141 |
| Week 6 Blood Phe Level (µmol/L) | ||
| Mean (±SD) | 607 (±377) | 891 (±348) |
| Percentiles (25th, 75th) | 307, 812 | 619, 1143 |
| Mean Change in Blood Phe From Baseline to Week 6 (µmol/L) | ||
| Adjusted Mean (±SE) † | -239 (±38) | 6 (±36) |
| Percentiles (25th, 75th) | -397, -92 | -96, 93 |
| Mean Percent Change in Blood Phe From Baseline to Week 6 | ||
| Mean (±SD) | - 29 (±32) | 3 (±33) |
| Percentiles (25th, 75th) | -61, -11 | -13, 12 |
*The mean baseline levels shown in this table represent the mean of 3 pretreatment levels (Wk -2, Wk -1, and Wk 0). Treatment with sapropterin dihydrochloride or placebo started at Wk 0.
†p-value < 0.001, adjusted mean and standard error from an ANCOVA model with change in blood Phe level from baseline to Week 6 as the response variable, and both treatment group and baseline blood Phe level as covariates.
Change in blood Phe was noted in the sapropterin dihydrochloride-treated group at Week 1 and was sustained through Week 6 (Figure 2).
Fig2 (Sapropterin Fig2)
Study 3 was a multicenter, open-label, extension study in which 80 patients who responded to sapropterin dihydrochloride treatment in Study 1 and completed Study 2 underwent 6 weeks of forced dose-titration with 3 different doses of sapropterin dihydrochloride. Treatments consisted of 3 consecutive 2-week courses of sapropterin dihydrochloride at doses of 5, then 20, and then 10 mg/kg per day. Blood Phe level was monitored after 2 weeks of treatment at each dose level. At baseline, mean (±SD) blood Phe was 844 (±398) μmol/L. At the end of treatment with 5, 10, and 20 mg/kg per day, mean (±SD) blood Phe levels were 744 (±384) μmol/L, 640 (±382) μmol/L, and 581 (±399) μmol/L, respectively (Table 7).
Table 7: Blood Phe Results From Forced Dose-Titration in Study 3
| Sapropterin dihydrochloride Dose Level (mg/kg per day) | No. of Patients | Mean (±SD) Blood Phe Level (µmol/L) | Mean Changes (±SD) in Blood Phe Level From Week 0 (µmol/L) |
| Baseline (No Treatment) | 80 | 844 (±398) | — |
| 5 | 80 | 744 (±384) | -100 (±295) |
| 10 | 80 | 640 (±382) | -204 (±303) |
| 20 | 80 | 581 (±399) | -263 (±318) |
Study 4 was a multicenter study of 90 pediatric patients with PKU, ages 4 to 12 years, who were on Phe-restricted diets and who had blood Phe levels ≤480 μmol/L at screening. All patients were treated with open-label sapropterin dihydrochloride 20 mg/kg per day for 8 days. Response to sapropterin dihydrochloride was defined as a ≥30% decrease in blood Phe from baseline at Day 8. At Day 8, 50 patients (56%) had a ≥30% decrease in blood Phe.
Study 5 was an open label, single arm, multicenter trial in 93 pediatric patients with PKU, aged 1 month to 6 years, who had Phe levels greater than or equal to 360 μmol/L at screening. All patients were treated with sapropterin dihydrochloride at 20 mg/kg per day and maintained on a Phe-restricted diet. At Week 4, 57 patients (61%) were identified as responders (defined as ≥30% decreased in blood Phe from baseline) [see Use in Specific Populations (8.4) Figure 1].
Sapropterin Dihydrochloride Tablets 100 mg are off-white to light yellow mottled uncoated round tablets debossed with “S 1” on one side and plain on other side. The tablets are supplied as follows:
Bottle of 30 NDC 59651-574-30
Bottle of 120 NDC 59651-574-08
Bottle of 240 NDC 59651-574-24
Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture.
Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Hypersensitivity Reactions Including Anaphylaxis
Advise patients and caregivers to discontinue sapropterin dihydrochloride and contact the patient’s healthcare provider immediately if they experience symptoms of anaphylaxis, including (but not limited to) wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Continue nutritional management including dietary protein and Phe restriction [see Warnings and Precautions (5.1)].
Upper Gastrointestinal Mucosal Inflammation
Advise patients and caregivers to contact their healthcare provider if the patient experiences signs and symptoms suggestive of upper GI mucosal inflammation, including nausea, vomiting, dysphagia, dyspepsia, loss of appetite; oropharyngeal, esophageal, or upper abdominal pain [see Warnings and Precautions (5.3)].
Hypophenylalaninemia
Advise patients and caregivers that sapropterin dihydrochloride may cause hypophenylalaninemia (low blood Phe levels), especially in pediatric patients younger than 7 years of age [see Warnings and Precautions (5.3)].
Monitoring of Blood Phe Levels
Advise patients and caregivers that frequent blood Phe monitoring is important to ensure blood Phe levels are in the desirable range and that they should maintain dietary protein and Phe restriction while on sapropterin dihydrochloride [see Warnings and Precautions (5.4)].
Prolonged hyperphenylalaninemia (high blood Phe levels) in patients with PKU can result in severe neurologic damage, including intellectual disability, developmental delay, microcephaly, delayed speech, seizures, and behavioral abnormalities [see Warnings and Precautions (5.4)].
Lack of Biochemical Response to Sapropterin Dihydrochloride
Some patients do not show a biochemical response (blood Phe reduction) when treated with sapropterin dihydrochloride. Advise patients and caregivers to discontinue treatment with sapropterin dihydrochloride if the patient does not show an adequate biochemical response in blood Phe after one month of treatment with sapropterin dihydrochloride 20 mg/kg per day [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].
Interaction with Levodopa
Advise patients and caregivers that patients with underlying neurological disorders taking sapropterin dihydrochloride in combination with levodopa may experience seizures, exacerbation of seizures, over-stimulation or irritability. Inform patients and caregivers to contact their healthcare provider if the patient has a change in neurologic status during treatment with sapropterin dihydrochloride [see Warnings and Precautions (5.5)].
Hyperactivity
Advise patients and caregivers that sapropterin dihydrochloride may cause hyperactivity and to contact their healthcare provider if the patient experiences hyperactivity, restlessness, fidgeting, or excessive talking [see Warnings and Precautions (5.6)].
Dosing and Monitoring [see Dosage and Administration (2.2)]
Advise patients and caregivers of the following:
Preparation and Administration [see Dosage and Administration (2.3)]
Advise patients and caregivers:
Distributed by:
Aurobindo Pharma USA, Inc.
279 Princeton-Hightstown Road
East Windsor, NJ 08520
Manufactured by:
Aurobindo Pharma Limited
Hyderabad-500 032, India
Issued: November 2024
| PATIENT INFORMATION Sapropterin Dihydrochloride (sap'' roe ter' in dye hye'' droe klor' ide) Tablets |
| What is sapropterin dihydrochloride tablets? Sapropterin dihydrochloride tablets are a prescription medicine used to lower blood levels of phenylalanine (Phe), in adults and children one month of age and older with a certain type of Phenylketonuria (PKU). Sapropterin dihydrochloride tablets is used along with a Phe-restricted diet. |
| What should I tell my doctor before taking sapropterin dihydrochloride tablets? Before you take sapropterin dihydrochloride tablets, tell your doctor about all your medical conditions, including if you:
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. |
How should I take sapropterin dihydrochloride tablets?
|
| What are the possible side effects of sapropterin dihydrochloride tablets? Sapropterin dihydrochloride tablets can cause serious side effects, including:
These are not all the possible side effects of sapropterin dihydrochloride tablets. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
How should I store sapropterin dihydrochloride tablets?
|
| General information about the safe and effective use of sapropterin dihydrochloride tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use sapropterin dihydrochloride tablets for a condition for which it was not prescribed. Do not give sapropterin dihydrochloride tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about sapropterin dihydrochloride tablets that is written for health professionals. |
| What are the ingredients in sapropterin dihydrochloride tablets? Active ingredient: sapropterin dihydrochloride. Sapropterin dihydrochloride tablet inactive ingredients: ascorbic acid, crospovidone, dibasic calcium phosphate anhydrous, mannitol, riboflavin and sodium stearyl fumarate. The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876 |
This Patient Information has been approved by the U.S. Food and Drug Administration
Issued: November 2024
Instructions for Use
Sapropterin Dihydrochloride
(sap'' roe ter' in dye hye'' droe klor' ide)
Tablets
Read this Instructions for Use before you start taking sapropterin dihydrochloride tablets and each time you refill your prescription. There may be new information. This information does not take the place of talking with your healthcare provider about your treatment. Talk to your doctor if you have any questions about the right dose of sapropterin dihydrochloride tablets to take or how to mix it.
Important information:
Instructions for taking sapropterin dihydrochloride tablets:
Sapropterin dihydrochloride tablets can be swallowed whole or dissolved in water or apple juice. You may also crush the tablets and mix in a small amount of soft food, such as apple sauce or pudding.
To dissolve sapropterin dihydrochloride tablets:
How should I store sapropterin dihydrochloride tablets?
Keep sapropterin dihydrochloride tablets and all medicines out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed by:
Aurobindo Pharma USA, Inc.
279 Princeton-Hightstown Road
East Windsor, NJ 08520
Manufactured by:
Aurobindo Pharma Limited
Hyderabad-500 032, India
Issued: November 2024
NDC 59651-574-30
Sapropterin Dihydrochloride Tablets
100 mg
Rx only 30 Tablets
Aurobindo
Fig3 (Sapropterin Fig3)
* Please review the disclaimer below.
