用量と投与方法
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 dosage of sapropterin dihydrochloride tablets is 10 mg/kg administered orally once daily. ( 2.2 ) Patients 7 years and older : The recommended starting dosage of sapropterin dihydrochloride tablets is 10 to 20 mg/kg administered orally once daily. ( 2.2 ) Dosage Adjustment Doses of sapropterin dihydrochloride tablets may be adjusted in the range of 5 to 20 mg/kg taken once daily. ( 2.2 ) Monitor blood Phe regularly, especially in pediatric patients. ( 2.2 , 5.3 ) Preparation and Administration See the full prescribing information for preparation and administration instructions. ( 2.3 ) 2.1 Recommendations Prior to Sapropterin Dihydrochloride Tablets Treatment 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. 2.2 Recommended Dosage and Administration 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) ] . 2.3 Preparation and Administration Instructions 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.
Side Effects Overview
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 Aurobindo Pharma USA, Inc. at 1-866-850-2876, 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) , 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. 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) ].
警告と注意事項
5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Including Anaphylaxis : Sapropterin dihydrochloride is not recommended in patients with a history of anaphylaxis to sapropterin dihydrochloride; 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 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. 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. 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 (2.2) ] . 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 (2.2) ] . 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 postmarketing safety surveillance program, 2 patients with PKU experienced hyperactivity when treated with sapropterin dihydrochloride [see Adverse Reactions (6.2) ] . Monitor patients for hyperactivity.
薬物動態
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 (2.3) ] . 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.