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Patients & Caregivers | Healthcare Professionals
Full Prescribing Information
Patients & Caregivers | Healthcare Professionals
Full Prescribing Information
 

KUVAN Proven Efficacy

KUVAN® (sapropterin dyhydrochloride) Tablets or Powder for Oral Solution are proven to lower blood Phe levels in many BH4-responsive patients across the spectrum of PKU.1

  • The efficacy and safety of KUVAN Tablets were evaluated in 6 clinical studies in patients with PKU
  • In clinical trials, KUVAN Tablets were administered to patients aged 1 month to 50 years old
  • Clinical research has demonstrated a 56%-75% response rate in pediatric patients treated with a KUVAN dose of 20 mg/kg/day
    • In one clinical trial at a dose of 10 mg/kg/day, 20% of adult and pediatric patients responded to treatment with KUVAN
  • Patients aged 1 month to 6 years: The recommended starting dose is 10 mg/kg taken once daily
  • Patients aged 7 years and older: The recommended starting dose is 10 to 20 mg/kg taken once daily
  • Efficacy in pediatric patients older than 4 years of age has been established in clinical studies with results comparable to those observed in adults

Phase III Pivotal Trial

In the Phase 3, multicenter, double-blind, placebo-controlled study of 88 patients with PKU aged 8 to 49 years who had elevated blood Phe levels (≥450 μmol/L) at screening and who responded to KUVAN in a previous study, patients were randomized to receive KUVAN at 10 mg/kg/day for 6 weeks (n=41) or a corresponding placebo (n=47).2

Mean Blood Phenylalanine (Phe) Level Over Time*†1,2

Efficacy_Mean_Blood_Phe_Chart

*In a 6-week, Phase 3, multicenter, randomized, double-blind, placebo-controlled study of 88 patients who were responders to KUVAN. Patients continued their diet throughout the study. Treatment with KUVAN or placebo started at Week 0.1.

†P<0.001 for difference in mean blood Phe between groups at Week 6.2

References

  1. KUVAN [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2021.
  2. Levy HL, Milanowski A, Chakrapani A, et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6RBH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo controlled study. Lancet. 2007;370(9586):504-510.


INDICATION

KUVAN® (sapropterin dihydrochloride) Tablets for Oral Use and Powder for Oral Solution are indicated to reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age or older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). KUVAN is to be used in conjunction with a Phe-restricted diet.

IMPORTANT SAFETY INFORMATION

Treatment with KUVAN should be directed by physicians knowledgeable in the management of PKU. Prolonged exposure to elevated blood Phe levels can result in severe neurologic damage in PKU patients.

The use of KUVAN does not eliminate the need for careful monitoring of blood Phe levels and ongoing dietary management to ensure adequate Phe control and nutritional balance. Response to KUVAN can only be determined by a therapeutic trial. Patients should be advised to notify their physicians in cases of overdose.

Warnings and Precautions

  • Hypersensitivity Reactions Including Anaphylaxis: KUVAN is not recommended in patients with a history of anaphylaxis to KUVAN. Hypersensitivity reactions, including anaphylaxis and rash, have occurred. Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Discontinue KUVAN treatment in patients who experience anaphylaxis, and initiate appropriate medical treatment. Continue dietary 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 KUVAN. 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 KUVAN. Monitor patients for signs and symptoms of upper GI mucosal inflammation.
  • Hypophenylalaninemia: Some patients receiving KUVAN can experience significant drops in blood Phe levels, and children younger than 7 years old treated with KUVAN doses of 20 mg/kg per day are at an increased risk for low levels of blood Phe compared with children 7 years and older.
  • 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 and frequent blood Phe monitoring while taking KUVAN is required to ensure adequate Phe control and nutritional balance, especially in the pediatric population.
  • Lack of Biochemical Response to KUVAN: Not all patients with PKU respond to treatment with KUVAN. Biochemical response to KUVAN treatment cannot generally be pre-determined by laboratory testing (e.g., molecular testing), and should be determined through a therapeutic trial (evaluation) of KUVAN response.
  • Interactions with Levodopa: In a post-marketing safety surveillance program for a non-PKU indication using another formulation of the same active ingredient (sapropterin), there have been reports of an interaction 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 KUVAN.
  • Hyperactivity: There have been post-marketing reports of hyperactivity with administration of KUVAN. 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.
  • Additional adverse reactions reported in connection with worldwide marketing: hypersensitivity reactions including anaphylaxis and rash, esophagitis, gastritis, oropharyngeal pain, pharyngitis, esophageal pain, abdominal pain, dyspepsia, nausea, vomiting, and hyperactivity.

Additional Drug Interactions

  • Frequently monitor blood Phe levels when co-administering KUVAN with medications known to inhibit folate metabolism, such as methotrexate, valproic acid, phenobarbital, trimethoprim.
  • Monitor patients for hypotension when co-administering KUVAN with medications known to affect nitric oxide–mediated vasorelaxation such as PDE-5 inhibitors including sildenafil, vardenafil, or tadalafil.

To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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