warnings and cautions
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 initate 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 Inflamation 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.