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. 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 dosage as needed. (7 ) drugs affecting nitric oxide?mediated vasorelaxation (e.g., pde-5 inhibitors) : potential for vasorelaxation; monitor blood pressure. ( 7 )

e to sapropterin dihydrochoride 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. ( 5.5 , 2.1 ) interaction with levodopa : seizures, over-stimulation or irritability may occur; monitor patients for a change in neurologic status. ( 5.6 , 7 ) hyperactivity : monitor patients for hyperactivity. ( 5.7 ) 5.1 hypersensitivity reactions including anaphylaxis 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. 5.2 upper gastrointestinal mucosal inflammation 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. 5.3 hypophenylalaninemia 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 )]. 5.4 monitoring blood phe levels during treatment 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 ( 2.1 )] . 5.5 lack of biochemical response to sapropterin dihydrochloride 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 ( 2.1 )] . 5.6 interaction with levodopa 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 )] . 5.7 hyperactivity in the sapropterin dihydrochloride post-marketing safety surveillance program, 2 patients with pku experienced hyperactivity when treated with sapropterin dihydrochloride [see adverse reactions ( 6.2 )] . monitor patients for hyperactivity.

information for complete information on mixing with food or liquid. ( 2.2 ) 2.1 dosage treatment with sapropterin dihydrochloride should be directed by physicians knowledgeable in the management of pku. all patients with pku who are being treated with sapropterin dihydrochloride 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 dose of sapropterin dihydrochloride is 10 mg/kg taken once daily. patients 7 years and older: the recommended starting dose of sapropterin dihydrochloride is 10 to 20 mg/kg taken once daily. dosage adjustment (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 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 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 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 )] . once responsiveness to sapropterin dihydrochloride 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 )] . 2.2 preparation and administration instructions take sapropterin dihydrochloride tablets orally with a meal, preferably at the same time each day [see clinical pharmacology ( 12.3 )] . a missed dose should be taken as soon as possible, but two doses should not be taken on the same day. s apropterin 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 powder for oral solution patients weighing greater than 10 kg sapropterin dihydrochloride powder for oral solution should be dissolved in 120 to 240 mlof water or apple juice and taken orally within 30 minutes of dissolution. sapropterindihydrochloride powder for oral solution may also be stirred in a small amount of softfoods such as apple sauce or pudding. empty the contents of the packet(s) in water, applejuice, or a small amount of soft foods and mix thoroughly. the powder should dissolvecompletely. patients weighing 10 kg or less (use 100 mg packets) for infants weighing 10 kg or less, sapropterin dihydrochloride powder for oral solutioncan be dissolved in as little as 5 ml of water or apple juice and a portion of this solutioncorresponding 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 of10 mg/kg per day. refer to table 2 for dosing information at 20 mg/kg per day if dosageadjustment is needed. table 1: 10 mg/kg per day dosing table for infants weighing 10 kg or less patient weight (kg) starting dose: 10 mg/kg per day* dose (mg) sapropterin dihydrochloride powder for oral solution 100 mg packets dissolved † dilution volume (ml) ‡ administered dose volume (ml) § 1 10 1 10 1 2 20 1 10 2 3 30 1 10 3 4 40 1 10 4 5 50 1 10 5 6 60 1 5 3 7 70 1 5 3.5 8 80 1 5 4 9 90 1 5 4.5 10 100 1 5 5 *starting dose for infants is 10 mg/kg per day. dosing information for 20 mg/kg per day is provided in table 2. † powder for oral solution provided in single use packets containing 100 mg sapropterin dihydrochloride per packet ‡ volume of water or apple juice to dissolve sapropterin dihydrochloride powder for oral solution. § discard remainder of mixture after volume to be administered is drawn. table 2: 20 mg/kg per day dosing table for infants weighing 10 kg or less patient weight (kg) 20 mg/kg per day dose (mg) sapropterin dihydrochloride powder for oral solution 100 mg packets * dissolved dilution volume (ml) † administered dose volume (ml) § 1 20 1 5 1 2 40 1 5 2 3 60 1 5 3 4 80 1 5 4 5 100 1 5 5 6 120 2 5 3 7 140 2 5 3.5 8 160 2 5 4 9 180 2 5 4.5 10 200 2 5 5 * powder for oral solution provided in single use packets containing 100 mg sapropterin dihydrochloride per packet † volume of water or apple juice to dissolve sapropterin dihydrochloridepowder for oral solution. § discard remainder of mixture after volume to be administered is drawn.

ent 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 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 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 )] . once responsiveness to sapropterin dihydrochloride 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 )] .

tablets may also be crushed and then mixed in a small amount of soft foods such as apple sauce or pudding. sapropterin dihydrochloride powder for oral solution patients weighing greater than 10 kg sapropterin dihydrochloride powder for oral solution should be dissolved in 120 to 240 mlof water or apple juice and taken orally within 30 minutes of dissolution. sapropterindihydrochloride powder for oral solution may also be stirred in a small amount of softfoods such as apple sauce or pudding. empty the contents of the packet(s) in water, applejuice, or a small amount of soft foods and mix thoroughly. the powder should dissolvecompletely. patients weighing 10 kg or less (use 100 mg packets) for infants weighing 10 kg or less, sapropterin dihydrochloride powder for oral solutioncan be dissolved in as little as 5 ml of water or apple juice and a portion of this solutioncorresponding 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 of10 mg/kg per day. refer to table 2 for dosing information at 20 mg/kg per day if dosageadjustment is needed. table 1: 10 mg/kg per day dosing table for infants weighing 10 kg or less patient weight (kg) starting dose: 10 mg/kg per day* dose (mg) sapropterin dihydrochloride powder for oral solution 100 mg packets dissolved † dilution volume (ml) ‡ administered dose volume (ml) § 1 10 1 10 1 2 20 1 10 2 3 30 1 10 3 4 40 1 10 4 5 50 1 10 5 6 60 1 5 3 7 70 1 5 3.5 8 80 1 5 4 9 90 1 5 4.5 10 100 1 5 5 *starting dose for infants is 10 mg/kg per day. dosing information for 20 mg/kg per day is provided in table 2. † powder for oral solution provided in single use packets containing 100 mg sapropterin dihydrochloride per packet ‡ volume of water or apple juice to dissolve sapropterin dihydrochloride powder for oral solution. § discard remainder of mixture after volume to be administered is drawn. table 2: 20 mg/kg per day dosing table for infants weighing 10 kg or less patient weight (kg) 20 mg/kg per day dose (mg) sapropterin dihydrochloride powder for oral solution 100 mg packets * dissolved dilution volume (ml) † administered dose volume (ml) § 1 20 1 5 1 2 40 1 5 2 3 60 1 5 3 4 80 1 5 4 5 100 1 5 5 6 120 2 5 3 7 140 2 5 3.5 8 160 2 5 4 9 180 2 5 4.5 10 200 2 5 5 * powder for oral solution provided in single use packets containing 100 mg sapropterin dihydrochloride per packet † volume of water or apple juice to dissolve sapropterin dihydrochloridepowder for oral solution. § discard remainder of mixture after volume to be administered is drawn.

e 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. table 3: summary of adverse reactions occurring in ?4% of patients in placebo-controlled clinical studies with sapropterin dihydrochloride 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 ), pediatric use ( 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. 6.2 postmarketing experience 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 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. table 3: summary of adverse reactions occurring in ?4% of patients in placebo-controlled clinical studies with sapropterin dihydrochloride 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 ), pediatric use ( 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.

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. 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 dosage as needed. (7 ) drugs affecting nitric oxide?mediated vasorelaxation (e.g., pde-5 inhibitors) : potential for vasorelaxation; monitor blood pressure. ( 7 )

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 (2.1 )]. 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 data from 62 live births reported 3 abnormalities at birth (one case each of microcephaly, cleft palate, and tongue tie). these outcomes 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). 8.2 lactation 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, a total of 16 women from both registries were identified as breastfeeding for a mean of 3.5 months. no lactation-related safety concerns were reported in infants of mothers nursing during maternal treatment with sapropterin dihydrochloride. 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. 8.4 pediatric use 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. figure1 8.5 geriatric use 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.

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. figure1

y 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 (2.1 )]. 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 data from 62 live births reported 3 abnormalities at birth (one case each of microcephaly, cleft palate, and tongue tie). these outcomes 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).

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. 12.3 pharmacokinetics 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 c max of 84% and auc of 87% (dissolved in water). however, there was extensive variability in individual subject values for c max 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 auc 0-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 auc 0-t [see dosage and administration ( 2.2 )] . 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.

er fasted conditions based on auc 0-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 auc 0-t [see dosage and administration ( 2.2 )] . 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.

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 2,000 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.

wed 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 2,000 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.

d 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) micromol/l in the sapropterin dihydrochloride-treated group and 888 (±323) micromol/l in the placebo group. at week 6, the sapropterin dihydrochloride treated group had a mean (±sd) blood phe level of 607 (±377) micromol/l, and the placebo group had a mean blood phe level of 891 (±348) micromol/l. at week 6, the sapropterin dihydrochloride- and placebo treated groups had mean changes in blood phe level of –239 and 6 micromol/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 * (micro mol/l) mean (±sd) 843 (±300) 888 (±323) percentiles (25 th , 75 th ) 620, 990 618, 1141 week 6 blood phe level (micro mol/l) mean (±sd) 607 (±377) 891 (±348) percentiles (25 th , 75 th ) 307, 812 619, 1143 mean change in blood phe from baseline to week 6 (micro mol/l) adjusted mean (±se) † -239 (±38) 6 (±36) percentiles (25 th , 75 th ) -397, -92 -96, 93 mean percent change in blood phe from baseline to week 6 mean (±sd) - 29 (±32) 3 (±33) percentiles (25 th , 75 th ) -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 tablets 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). figure 2: mean blood phenylalanine (phe) level over time* 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) micromol/l. at the end of treatment with 5, 10, and 20 mg/kg per day, mean (±sd) blood phe levels were 744 (±384) micromol/l, 640 (±382) micromol/l, and 581 (±399) micromol/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 micro mol/l) mean changes ( ± sd) in blood phe level from week 0 (micro mol/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 micromol/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 micromol/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 figure 1 section 8.4). figure2

nd precautions ( 5.3 )] advise patients and caregivers that sapropterin dihydrochloride may cause hypophenylalaninemia (low blood phe levels), especially in pediatric patients younger than 7 years of age. monitoring of blood phe levels [see warnings and precautions ( 5.4 )] 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. 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. 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 ( 2.1 ), 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 dihydrochloridemay 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 ( 2.1 )] advise patients and caregivers of the following: sapropterin dihydrochloride should be used in conjunction with a pku-specific diet, including dietary protein and phe restriction. dietary protein and phe intake should not be modified during the sapropterin dihydrochloride evaluation period when assessing biochemical response . the patient must be evaluated for changes in blood phe after being treated with sapropterin dihydrochloride at the recommended dose(s) for age to determine if they have a biochemical response and that blood phe levels and dietary phe intake should be assessed frequently during the first month of sapropterin dihydrochloride treatment. monitoring of blood phe levels is important during sapropterin dihydrochloride treatment. preparation and administration [see dosage and administration ( 2.2 )] advise patients and caregivers: sapropterin dihydrochloride tablets can be swallowed whole, dissolved in water or apple juice, or crushed and mixed with a small amount of soft food such as apple sauce or pudding. sapropterin dihydrochloride powder for oral solution should be dissolved in water orapple juice or stirred in a small amount of soft food such as apple sauce or pudding. take sapropterin dihydrochloride with a meal, preferably at the same time each day. pregnancy advise patients that there is a product registry for pku patients to collect data on women with pku who become pregnant while receiving sapropterin dihydrochloride treatment [see use in specific populations ( 8.1 )] . distributed by: dr. reddy’s laboratories, inc. princeton, nj 085409 usa

or have loss of appetite. are pregnant or plan to become pregnant. pregnancy exposure registry : there is a pregnancy exposure registry for women who take sapropterin dihydrochloride during pregnancy. the purpose of this registry is to collect information about the health of you and your baby. talk to your doctor about how you can take part in this registry or contact the registry program at 1-800-983-4587. are breastfeeding or plan to breastfeed. it is not known if sapropterin dihydrochloride passes into your breast milk. talk to your doctor about the best way to feed your baby if you take sapropterin dihydrochloride. tell your doctor about all the medicines you take , including prescription and over-the-counter medicines, vitamins, herbal, and dietary supplements. sapropterin dihydrochloride and other medicines may interact with each other. especially tell your doctor if you take: a medicine that contains levodopa an antifolate medicine sildenafil (revatio, viagra), tadalafil (adcirca, cialis), vardenafil (staxyn, levitra) tell your doctor if you are not sure if your medicine is one that is listed above. 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? take sapropterin dihydrochloride exactly as your doctor tells you. your doctor should tell you how much sapropterin dihydrochloride to take and when to take it. your doctor may change your dose of sapropterin dihydrochloride depending on how you respond to treatment. take sapropterin dihydrochloride 1 time each day with a meal. it is best to take sapropterin dihydrochloride at the same time each day. sapropterin dihydrochloride comes as a tablet and powder for oral solution. you can swallow sapropterin dihydrochloride tablets wholeor dissolve the tablets in water or apple juice. you may alsocrush the tablets and mix in a small amount of soft food, suchas apple sauce or pudding before taking. be sure that you know what dose of sapropterin dihydrochloride powder your doctor prescribed and whether you should use sapropterin dihydrochloride 100 mg packets, sapropterin dihydrochloride 500 mg packets, or both types of packets to prepare your dose . open sapropterin dihydrochloride powder packets only whenyou are ready to use them. sapropterin dihydrochloride powder for oral solution should be dissolved in water or apple juice. you may also mix the powder for oral solution in a small amount of soft food, such as apple sauce or pudding before taking. see the detailed “instructions for use” that comes with sapropterin dihydrochloride for information about the correct way to dissolve and take a dose of sapropterin dihydrochloride tablets or sapropterin dihydrochloride powder for oral solution. it is not possible to know if sapropterin dihydrochloride will work for you until you start taking sapropterin dihydrochloride. your doctor will check your blood phe levels when you start taking sapropterin dihydrochloride to see if the medicine is working. during treatment with sapropterin dihydrochloride: any change you make to your diet may affect your blood phe level. follow your doctor’s instructions carefully and do not make any changes to your dietary phe intake without first talking with your doctor. even if you take sapropterin dihydrochloride, if your phe blood levels are not well controlled, you can develop severe neurologic problems. your doctor should continue to monitor your blood phe levels often during your treatment with sapropterin dihydrochloride, to make sure that your blood phe levels are not too high or too low . if you have a fever, or if you are sick, your blood phe level may go up. tell your doctor as soon as possible so they can change your dose of sapropterin dihydrochloride to help keep your blood phe levels in the desired range. if you forget to take your dose of sapropterin dihydrochloride, take it as soon as you remember that day. do not take 2 doses in a day. if you take too much sapropterin dihydrochloride, call your doctor for advice. what are the possible side effects of sapropterin dihydrochloride? sapropterin dihydrochloride can cause serious side effects, including: severe allergic reactions. stop taking sapropterin dihydrochloride and get medical help right away if you develop any of these symptoms of a severe allergic reaction: wheezing or trouble breathing coughing feeling lightheaded or you faint flushing nausea rash inflammation of the lining of the stomach (gastritis) or esophagus (esophagitis). gastritis or esophagitis can happen with sapropterin dihydrochloride and may be severe. call your doctor right away if you have any of these signs or symptoms: severe upper stomach-area (abdominal) discomfort or pain, nausea and vomiting blood in your vomit or stool black, tarry stools difficulty swallowing loss of appetite pain in the throat phe levels that are too low. some children under the age of 7 years who take high doses of sapropterin dihydrochloride each day may experience low phe levels. too much or constant activity (hyperactivity) can happen with sapropterin dihydrochloride . tell your doctor if you have any signs of hyperactivity, including: fidgeting or moving around too much talking too much the most common side effects of sapropterin dihydrochloride are: headache runny nose and nasal congestion sore throat diarrhea vomiting cough tell your doctor if you have any side effect that bothers you or that does not go away. these are not all the possible side effects of sapropterin dihydrochloride. 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? store sapropterin dihydrochloride at room temperature between 68°f to 77°f (20°c to 25°c). keep sapropterin dihydrochloride tablets in the original bottle with the cap closed tightly. protect from moisture. keep sapropterin dihydrochloride tablets and all medicines out of the reach of children. general information about the safe and effective use of sapropterin dihydrochloride . medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use sapropterin dihydrochloride for a condition for which it was not prescribed. do not give sapropterin dihydrochloride 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 that is written for health professionals. what are the ingredients in sapropterin dihydrochloride? active ingredient: sapropterin dihydrochloride. sapropterin dihydrochloride tablet inactive ingredients: ascorbic acid, crospovidone, dibasic calcium phosphate, d-mannitol,riboflavin, and sodium stearyl fumarate. sapropterin dihydrochloride powder for oral solution inactiveingredients: ascorbic acid, d-mannitol, potassium citrate, and sucralose. dr. reddy’s only markets sapropterin dihydrochloride tablets. distributed by: dr. reddy’s laboratories, inc. princeton, nj 08540 usa. for more information, call 1-800-983-4587. this patient information has been approved by the u.s. food and drug administration issued: 09/2020