June 29, 2016
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Kuvan

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Kuvan




Warnings
Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

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 [see ADVERSE REACTIONS]. Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Discontinue treatment with Kuvan in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary Phe restrictions in patients who experience anaphylaxis.

Gastritis

During clinical studies, gastritis was reported as a serious adverse reaction. Monitor patients for signs and symptoms of gastritis.

Hypophenylalaninemia

In clinical trials, some patients have experienced low blood Phe levels. Children younger than 7 years treated with Kuvan doses of 20 mg/kg per day are at increased risk for low levels of blood Phe compared with patients 7 years and older [see ADVERSE REACTIONS].

Monitor Blood Phe Levels During Treatment

Treatment with Kuvan should be directed by physicians knowledgeable in the management of PKU. Prolonged elevations in blood Phe levels in patients with PKU can result in severe neurologic damage, including severe mental retardation, microcephaly, delayed speech, seizures, and behavioral abnormalities. Conversely, prolonged levels of blood Phe that are too low have been associated with catabolism and protein breakdown. Active management of dietary Phe intake while taking Kuvan 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 [Patient Counseling Information].

Identify Non-Responders To Kuvan Treatment

Not all patients with PKU respond to treatment with Kuvan. In two clinical trials at a dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients responded to treatment with Kuvan, and in one clinical trial at a dose of 10 mg/kg per day, 20% of adult and pediatric PKU patients responded to treatment with Kuvan [see Clinical Studies].

Response to treatment cannot be pre-determined by laboratory testing (e.g., molecular testing), and can only be determined by a therapeutic trial of Kuvan [see DOSAGE AND ADMINISTRATION].

Treat All Patients With A Phe-Restricted Diet

All patients with PKU who are being treated with Kuvan should also be treated with a Phe-restricted diet.

Monitor Patients With Hepatic Impairment

Patients with liver impairment have not been evaluated in clinical trials with Kuvan. Monitor liver function tests in patients with liver impairment who are receiving Kuvan because hepatic damage has been associated with impaired Phe metabolism.

Monitor Patients When Co-administering Kuvan And Medications Known To Inhibit Folate Metabolism

Co-administering Kuvan with drugs known to affect folate metabolism (e.g., methotrexate) and their derivatives may require more frequent monitoring of blood Phe levels because these drugs can decrease endogenous BH4 levels by inhibiting the enzyme dihydropteridine reductase (DHPR).

Monitor Patients For Hypotension When Co-administering Kuvan And Drugs Known To Affect Nitric Oxide-Mediated Vasorelaxation

Monitor blood pressure when administering Kuvan with drugs that affect nitric oxide-mediated vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil), because both sapropterin dihydrochloride and PDE-5 inhibitors may induce vasorelaxation. The additive effect of sapropterin and PDE-5 inhibitor co-administration could lead to a reduction in blood pressure; however, the combined use of these medications has not been evaluated in humans. In animal studies, orally administered Kuvan in combination with a PDE-5 inhibitor had no effect on blood pressure.

Monitor Patients when Co-Administering Kuvan And Levodopa

Caution should be used with the administration of Kuvan to patients who are receiving levodopa. In a 10-year post-marketing safety surveillance program for a non-PKU indication using another formulation of the same active ingredient (sapropterin), 3 patients with underlying neurologic disorders experienced convulsions, exacerbation of convulsions, over-stimulation, or irritability during co-administration of levodopa and sapropterin. Monitor for change in neurologic status.

Monitor Patients For Hyperactivity

In the post-marketing safety surveillance program for PKU, 2 patients experienced hyperactivity with administration of Kuvan. Monitor patients for hyperactivity.

Patient Counseling Information

See FDA-approved patient labeling (Patient Information and Instructions for Use)

Patients should be advised of the following information before beginning treatment with Kuvan:

  • Advise patients that Kuvan may cause low blood Phe levels. Advise patients that children younger than 7 years treated with Kuvan doses of 20 mg/kg per day are at increased risk for low levels of blood Phe compared with children 7 years and older. Blood Phe levels that are too low for prolonged periods of time may be associated with catabolism and protein breakdown [see WARNINGS AND PRECAUTIONS].
  • Advise patients that Kuvan is to be used in conjunction with a Phe-restricted diet [see WARNINGS AND PRECAUTIONS].
  • Advise patients that not all patients with PKU respond to treatment with Kuvan and that response to Kuvan can only be determined by a therapeutic trial [see WARNINGS AND PRECAUTIONS].
  • Advise patients that they must be evaluated for changes in blood Phe after being treated with Kuvan at the recommended dose(s) for age to determine if they are a responder and that blood Phe levels and dietary Phe intake should be measured frequently during the first month [see WARNINGS AND PRECAUTIONS].
  • Advise patients that they should have frequent blood Phe measurements and nutritional counseling with their physician and other members of the health care team knowledgeable in the management of PKU to ensure maintenance of blood Phe levels in the desirable range [see WARNINGS AND PRECAUTIONS].
  • Advise patients not to modify their existing dietary Phe intake during the evaluation period in order to get an accurate assessment of the effect of Kuvan on blood Phe levels.
  • Advise patients not to continue treatment with Kuvan if they are determined to be a non-responder during the evaluation period [see DOSAGE AND ADMINISTRATION].
  • Advise patients that reduction of blood Phe levels through dietary control is an important determinant of long-term neurologic outcome in PKU patients. Advise patients that the effect of Kuvan on long-term neurologic function in patients with PKU has not been assessed.
  • Advise patients that Kuvan may cause hypersensitivity reactions including anaphylaxis and rash [see WARNINGS AND PRECAUTIONS].
  • Advise patients to notify their physician for symptoms of severe gastritis [see WARNINGS AND PRECAUTIONS].
  • Advise patients that blood Phe levels that are too high for prolonged periods of time can result in neurologic impairment.
  • Advise patients that adequate blood Phe control needs to be maintained to avoid blood Phe levels that are too high or too low.
  • Advise patients that to ensure maintenance of adequate blood Phe control, close monitoring is recommended and that the dose of Kuvan should be adjusted if necessary.
  • Advise patients with hepatic impairment and patients who are taking Kuvan in combination with drugs that inhibit folate metabolism, drugs that affect nitric oxide-mediated vasorelaxation, or levodopa that they may require additional clinical monitoring while taking Kuvan[see WARNINGS AND PRECAUTIONS].
  • Advise patients that Kuvan may cause hyperactivity [see WARNINGS AND PRECAUTIONS].
  • Advise patients that BioMarin has a product registry for PKU patients to collect data on women who become pregnant while receiving Kuvan treatment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

A 2-year carcinogenicity study was conducted in F-344 rats, and a 78-week carcinogenicity study was conducted in CD-1 mice. In the 104-week oral carcinogenicity study in rats, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.2, 0.7, and 2 times the maximum recommended human dose of 20 mg/kg per day, respectively, based on body surface area) were used. In the 78-week oral carcinogenicity study in mice, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.1, 0.3, and 2 times the recommended human dose, respectively, based on body surface area) were used. In the 2-year rat carcinogenicity study, there was a statistically significant increase in the incidence of benign adrenal pheochromocytoma in male rats treated with the 250 mg/kg per day (about 2 times the maximum recommended human dose, based on body surface area) dose, as compared to vehicle treated rats. The mouse carcinogenicity study showed no evidence of a carcinogenic effect, but the study was not ideal due to its duration of 78 instead of 104 weeks.

Sapropterin dihydrochloride was genotoxic in the in vitro Ames test at concentrations of 625 μg (TA98) and 5000 μg (TA100) per plate, without metabolic activation. However, no genotoxicity was observed in the in vitro Ames test with metabolic activation. Sapropterin dihydrochloride was genotoxic in the in vitro chromosomal aberration assay in Chinese hamster lung cells at concentrations of 0.25 and 0.5 mM. Sapropterin dihydrochloride was not mutagenic in the in vivo micronucleus assay in mice at doses up to 2000 mg/kg per day (about 8 times the maximum recommended human dose of 20 mg/kg per day, based on body surface area). Sapropterin dihydrochloride, at oral doses up to 400 mg/kg per day (about 3 times the maximum recommended human dose, based on body surface area) was found to have no effect on fertility and reproductive function of male and female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C

A patient registry has been established that collects data on women who are treated with Kuvan during pregnancy. For more information regarding the registry program call 1-866-906-6100.

Risk Summary

There are no adequate and well-controlled studies with Kuvan in pregnant women. An embryo-fetal development study with sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended human dose (MRHD) given during the period of organogenesis showed no effects. In a rabbit study using oral administration of sapropterin dihydrochloride during the period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD. Kuvan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Disease-associated maternal and/or embryofetal risk

Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in PKU-affected women demonstrated that uncontrolled Phe levels above 600 μmol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies. Good dietary control of Phe levels during pregnancy is essential to reduce the incidence of Phe-induced teratogenic effects.

Animal Data

No effects on embryo-fetal development were observed in a reproduction study in rats using oral doses of up to 400 mg/kg per day sapropterin dihydrochloride (about 3 times the MRHD of 20 mg/kg per day, based on body surface area) administered during the period of organogenesis. However, in a rabbit reproduction study, oral administration of a maximum dose of 600 mg/kg per day (about 10 times the MRHD, based on body surface area) during the period of organogenesis was associated with a non-statistically significant increase in the incidence of holoprosencephaly in two high dose-treated litters (4 fetuses), compared to one control-treated litter (1 fetus).

Nursing Mother

It is not known whether Kuvan is present in human milk. Sapropterin is present in the milk of intravenously, but not orally, treated lactating rats. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for Kuvan and any potential adverse effects on the human milk-fed child from the drug or from the underlying maternal condition. Exercise caution when Kuvan is administered to a nursing woman.

Pediatric Use

Pediatric patients with PKU, ages 1 month to 16 years, have been treated with Kuvan in clinical trials [see Clinical Studies].

The efficacy and safety of Kuvan have not been established in neonates. The safety of Kuvan has been established in children younger than 4 years in trials of 6 months duration and in children 4 years and older in trials of up to 3 years in length [see ADVERSE REACTIONS].

In children aged 1 month and older, the efficacy of Kuvan has been demonstrated in trials of 6 weeks or less in duration [see Clinical Studies].

In a multicenter, open-label, single arm study, 57 patients aged 1 month to 6 years who were defined as Kuvan responders after 4 weeks of Kuvan treatment and Phe dietary restriction were treated for 6 months with Kuvan at 20 mg/kg per day. The effectiveness of Kuvan alone on reduction of blood Phe levels beyond 4 weeks could not be determined due to concurrent changes in dietary Phe intake during the study. Mean (±SD) blood Phe values over time for patients aged 1 month to <2 years and 2 to <7 years are shown in Figure 1.

Figure 1: Mean Blood Phe Level Over Time by Age (years) (N=57)

Mean Blood Phe Level Over Time - Illustration

*Error bars indicate 95% confidence interval.

Geriatric Use

Clinical studies of Kuvan 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.

Patients With Renal Impairment

Patients with renal impairment have not been evaluated in clinical trials. Monitor patients who have renal impairment carefully when they are receiving Kuvan.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 6/27/2016

Warnings
Precautions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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