sapropterin dihydrochloride

1. INDICATIONS AND USAGE 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. Sapropterin dihydrochloride tablets are a phenylalanine hydroxylase activator 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. (1)

2. DOSAGE AND ADMINISTRATION 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. (2.1) Starting Dosage Pediatric patients 1 month to 6 years: The recommended starting dose of sapropterin dihydrochloride tablets is 10 mg/kg taken once daily. (2.1) Patients 7 years and older: The recommended starting dose of sapropterin dihydrochloride tablets is 10 to 20 mg/kg taken once daily. (2.1) Dosage Adjustment Doses of sapropterin dihydrochloride tablets may be adjusted in the range of 5 to 20 mg/kg taken once daily. (2.1) Monitor blood Phe regularly, especially in pediatric patients. (2.1, 5.3) Preparation and Administration Take with a meal. (2.2) Swallow tablets whole or after mixing in a small amount of soft foods or dissolving in recommended liquid. Swallow oral solution after mixing powder in a small amount of soft foods or dissolving in recommended liquids. See full prescribing information for complete information on mixing with food or liquid. (2.2) 2.1. Dosage Treatment with sapropterin dihydrochloride tablets should be directed by physicians knowledgeable in the management of PKU. All patients with PKU who are being treated with sapropterin dihydrochloride tablets should also be treated with a Phe­-restricted diet, including dietary protein and Phe restriction. Starting Dosage Pediatric Patients 1 month to 6 years : The recommended starting dose of sapropterin dihydrochloride tablets is 10 mg/kg taken once daily. Patients 7 years and older: The recommended starting dose of sapropterin dihydrochloride tablets 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 tablets at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day do not show a biochemical response and treatment with sapropterin dihydrochloride tablets should be discontinued in these patients. If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically during the first month. Treatment should be discontinued in patients who do not show a biochemical response (blood Phe does not decrease) after 1 month of treatment at 20 mg/kg per day [see Warnings and Precautions (5.4)] . 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)] . 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. Sapropterin Dihydrochloride Tablets Sapropterin dihydrochloride tablets may be swallowed either as whole tablets or dissolved in 120 to 240 mL of water or apple juice and taken orally within 15 minutes of dissolution. It may take a few minutes for the tablets to dissolve. To make the tablets dissolve faste…

5. WARNINGS AND PRECAUTIONS Hypersensitivity reactions including anaphylaxis : Sapropterin dihydrochloride tablets are not recommended in patients with a history of anaphylaxis to sapropterin dihydrochloride tablets; discontinue treatment in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary Phe restrictions. (5.1) Upper Gastrointestinal Mucosal Inflammation : Monitor patients for signs and symptoms of these conditions including esophagitis and gastritis. (5.2) Hypophenylalaninemia : Pediatric patients younger than 7 years treated with Sapropterin dihydrochloride tablets doses of 20 mg/kg per day are at increased risk for low levels of blood Phe compared with patients 7 years and older. (5.3) Monitoring Blood Phe Levels During Treatment: Ensure adequate blood Phe control and nutritional balance during treatment with Sapropterin dihydrochloride tablets. Frequent blood monitoring is recommended, especially in pediatric patients. (5.4, 2.1) Lack of Biochemical Response to Sapropterin Dihydrochloride Treatment : Response to sapropterin dihydrochloride treatment cannot be pre-determined by laboratory (e.g., molecular) testing and can only be determined by a therapeutic trial of sapropterin dihydrochloride. (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 tablets. Serious adverse reactions included esophagitis and gastritis [see Adverse Reactions (6.2)] . If left untreated, these could lead to severe sequelae including esophageal stricture, esophageal ulcer, gastric ulcer, and bleeding and such complications have been reported in patients receiving sapropterin dihydrochloride tablets. Monitor patients for signs and symptoms of upper GI mucosal inflammation. 5.3. Hypophenylalaninemia In clinical trials of sapropterin dihydrochloride tablets, some PKU patients experienced hypophenylalaninemia (low blood Phe) during treatment with sapropterin dihydrochloride tablets. In a clinical study of pediatric patients younger than 7 years old treated with sapropterin dihydrochloride tablets 20 mg/kg per day, the incidence of hypophenylalaninemia was higher than in clinical trials of older patients [see Adverse Reactions (6.1)]. 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 tablets are 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 R…

4. CONTRAINDICATIONS None. None.

7. DRUG INTERACTIONS 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 post-marketing 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 tablets may be necessary to achieve a biochemical response. Drugs Affecting Nitric Oxide-Mediated Vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil) Clinical Impact Both sapropterin dihydrochloride and PDE-5 inhibitors may induce vasorelaxation. A reduction in blood pressure could occur; however, the combined use of these medications has not been evaluated in humans. Intervention Monitor blood pressure. Inhibitors of Folate Synthesis (e.g., methotrexate, valproic acid, phenobarbital, trimethoprim) : Can decrease endogenous BH4 levels; monitor blood Phe levels more frequently and adjust Sapropterin dihydrochloride tablets dosage as needed. (7) Drugs Affecting Nitric Oxide-Mediated Vasorelaxation (e.g., PDE-5 inhibitors) : Potential for vasorelaxation; monitor blood pressure. (7)

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 Par Health at 1-800-828-9393, 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 1-4 (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. T able 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 n…