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 )
AND PRECAUTIONS Hypersensitivity Reactions Including Anaphylaxis : Zelvysia is not recommended in patients with a history of anaphylaxis to Zelvysia ; 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 Zelvysia 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 Zelvysia . Frequent blood monitoring is recommended, especially in pediatric patients. ( 5.4 , 2.1 ) Lack of Biochemical Response to Sapropterin Dihydrochloride T reatment : 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .
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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .
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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .
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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .
5.7 Hyperactivity In the sapropterin dihydrochloride postmarketing safety surveillance program, 2 patients with PKU experienced hyperactivity when treated with sapropterin dihydrochloride <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Monitor patients for hyperactivity.
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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .
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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .
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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .
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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .
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.