FDA label c1c38c7a-3f0d-4ade-ced8-32f500bbdf2d

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 )] .

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.

6 ADVERSE REACTIONS Most common adverse reactions (≥4%) are: headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 1-800-983-4587, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. 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 )].

6.1 Clinical Trials Experience 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. 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><col width="167.8pt"/><col/><col width="98.4pt"/><tbody><tr><td align="center" rowspan="2" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph><content styleCode="bold">MedDRA Preferred Term</content></paragraph></td><td align="center" colspan="2" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph><content styleCode="bold">Treatment</content></paragraph></td></tr><tr><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Sapropterin Dihydrochloride</content></paragraph><paragraph><content styleCode="bold">(N=74)</content></paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N=59)</content></paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule" valign="top"/><td><paragraph>No. Patients (%)</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph>No. Patients (%)</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>11 (15)</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>8 (14)</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph>Rhinorrhea</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>8 (11)</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>0</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph>Pharyngolaryngeal pain</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>7(10)</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>1 (2)</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph>Diarrhea </paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>6 (8)</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>3 (5)</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph>Vomiting </paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>6 (8)</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>4 (7)</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph>Cough</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>5 (7)</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>3 (5)</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule" valign="top"><paragraph>Nasal congestion</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>3 (4)</paragraph></td><td align="center" styleCode="Botrule Toprule Lrule Rrule" valign="bottom"><paragraph>0</paragraph></td></tr></tbody></table>