INDICATION

JAVYGTOR is 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). JAVYGTOR is to be used in conjunction with a Phe-restricted diet.

IMPORTANT SAFETY INFORMATION

Treatment with JAVYGTOR should be directed by physicians knowledgeable in the management of PKU. All patients with PKU who are being treated with JAVYGTOR should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction. Prolonged exposure to elevated blood Phe levels can result in severe neurologic damage in PKU patients.

During treatment with JAVYGTOR, monitor blood Phe levels frequently to ensure adequate blood Phe level control, especially in pediatric patients. Also, active management of dietary Phe intake is required to ensure adequate Phe control and nutritional balance. Biochemical response to JAVYGTOR treatment should be determined through a therapeutic trial.

Patients should be advised to notify their physicians in cases of overdose.

WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions Including Anaphylaxis: JAVYGTOR is not recommended in patients with a history of anaphylaxis to SAPROPTERIN DIHYDROCHLORIDE. Hypersensitivity reactions, including anaphylaxis and rash, have occurred. Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Discontinue JAVYGTOR treatment in patients who experience anaphylaxis, and initiate appropriate medical treatment. Continue dietary protein and Phe restrictions in patients who experience anaphylaxis.
• Upper Gastrointestinal Mucosal Inflammation: Gastrointestinal (GI) adverse reactions suggestive of upper GI mucosal inflammation have been reported with JAVYGTOR. Serious adverse reactions included esophagitis and gastritis. 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.
• Hypophenylalaninemia: Some patients receiving SAPROPTERIN DIHYDROCHLORIDE have experienced hypophenylalaninemia (low blood Phe) during treatment. Children younger than 7 years old treated with JAVYGTOR doses of 20 mg/kg per day are at an increased risk for low levels of blood Phe compared with older patients.
• 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.
• Lack of Biochemical Response to JAVYGTOR: Not all patients with PKU respond to treatment with JAVYGTOR. Biochemical response to JAVYGTOR treatment cannot generally be pre-determined by laboratory testing (e.g., molecular testing), and should be determined through a therapeutic trial (evaluation) of JAVYGTOR response.
• Interactions with Levodopa: There have been reports of interactions with levodopa causing seizures, exacerbation of seizures, over-stimulation, and irritability. Monitor patients who are receiving levodopa for a change in neurologic status during treatment with JAVYGTOR.
• Hyperactivity: There have been post-marketing reports of hyperactivity with administration of SAPROPTERIN DIHYDROCHLORIDE. Monitor patients for hyperactivity.

ADVERSE REACTIONS

• Most common: The most common adverse reactions (incidence ≥4%) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.

The following adverse reactions have been reported during post-approval use of sapropterin dihydrochloride:

• Hypersensitivity reactions including anaphylaxis and rash. Most hypersensitivity reactions occurred within several days of initiating treatment;
• Gastrointestinal reactions: esophagitis, gastritis, oropharyngeal pain, pharyngitis, esophageal pain, abdominal pain, dyspepsia, nausea, and vomiting;
• Hyperactivity

DRUG INTERACTIONS

• Levodopa – JAVYGTOR 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. Monitor patients for a change in neurologic status.
• Inhibitors of Folate Synthesis – 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. Frequently monitor blood Phe levels when co-administering JAVYGTOR with medications known to inhibit folate synthesis, such as methotrexate, valproic acid, phenobarbital, trimethoprim.
• Drugs Affecting Nitric Oxide-Mediated Vasorelaxation – Both JAVYGTOR and PDE- 5 inhibitors (such as sildenafil, vardenafil, or tadalafil) may induce vasorelaxation. A reduction in blood pressure could occur. Monitor patients for hypotension when co-administering JAVYGTOR with medications known to affect nitric oxide–mediated vasorelaxation such as PDE-5 inhibitors.

USE IN SPECIFIC POPULATIONS

• Pregnancy: There are no well-controlled clinical studies of Sapropterin Dihydrochloride in pregnant women.
• Lactation: There are insufficient data to assess the presence of sapropterin in human milk and no data on the effects on milk production.
• Pediatric Use: Pediatric patients with PKU, ages 1 month to 16 years, have been treated with sapropterin dihydrochloride in clinical trials. The efficacy and safety of sapropterin dihydrochloride have not been established in neonates.
• 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.

For more detailed information, please refer to the full Prescribing Information at: www. JAVYGTOR.com/PI

To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or by email: medinfo@drreddys.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch