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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.

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 [see PATIENT INFORMATION].

Identify Non-Responders To Kuvan Treatment

Not all patients with PKU respond to treatment with Kuvan. In clinical trials, approximately 20% to 56% of PKU patients responded to treatment with Kuvan [see Clinical Studies]. Response to treatment cannot be pre-determined by laboratory testing (e.g., genetic 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 Pherestricted 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 PatientsFor 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)

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

Important Information To Consider Prior To Prescribing Kuvan

Patients with residual PAH enzyme activity may benefit from taking Kuvan; however, not all patients with PKU respond to treatment with Kuvan. In clinical trials, approximately 20% to 56% of PKU patients responded to treatment with Kuvan.

Since patients have varying degrees of residual PAH enzyme activity and BH4 responsiveness, it is not possible to accurately predict the extent of response before administering Kuvan to the patient, and response to treatment cannot be pre-determined by laboratory testing (e.g., genetic testing). Response to Kuvan can only be determined by a therapeutic trial.

To determine if a patient may respond to treatment with Kuvan, the patient must be treated with Kuvan and evaluated for changes in blood Phe. Blood Phe levels and dietary Phe intake should be measured frequently [see WARNINGS AND PRECAUTIONS].

Blood Phe Monitoring And Management

Treatment with Kuvan should be directed by physicians knowledgeable in the management of PKU, and the initiation of Kuvan therapy does not eliminate the need for appropriate monitoring by trained professionals. Patients being treated with Kuvan should have frequent blood Phe measurements and nutritional counseling with their physician and other members of the health care team to ensure maintenance of blood Phe levels in the desirable range.

Since changes in dietary Phe intake can obscure the effect of Kuvan on blood Phe levels, and since not all patients will respond to treatment with Kuvan, all patients with PKU should be treated with a Phe-restricted diet in addition to treatment with Kuvan [see WARNINGS AND PRECAUTIONS].

To determine if a patient responds to Kuvan therapy, patients must not 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. Baseline blood Phe measurements should be taken just prior to initiation of a Kuvan response test. Patients should be started at a dose of 10 mg/kg/day. Blood Phe levels should be checked after 1 week of Kuvan treatment and periodically for up to a month to determine response. A response to treatment with Kuvan may be determined by a decrease in blood Phe level compared to baseline level. If blood Phe level does not decrease at 10 mg/kg/day, the dose may be increased to 20 mg/kg/day. Patients whose blood Phe does not decrease from baseline after 1 month of treatment at 20 mg/kg/day are non-responders, and treatment with Kuvan should be discontinued in these patients [see DOSAGE AND ADMINISTRATION].

For patients who respond to Kuvan treatment, the dosage may be adjusted within the range of 5 to 20 mg/kg/day according to response to therapy.

After the dose of Kuvan has been established, continued active management of dietary Phe intake using medical foods and natural sources of proteins is required to ensure blood Phe control and adequate nutritional balance.

What Are The Benefits Of Taking Kuvan?

Prolonged high blood Phe levels are neurotoxic and lead to impairment of intelligence and other brain functions (such as attentiveness). Reduction of blood Phe levels through dietary control is an important determinant of long-term neurologic outcome in PKU patients, and reduction of blood Phe levels in patients with PKU has been shown to decrease the long-term risk of neurologic injury. It is difficult for many patients to maintain reduced blood Phe, and many patients with PKU experience some degree of neurological impairment despite efforts to maintain dietary Phe control.

Kuvan may help maintain reduced blood Phe levels as an adjunct to a Phe-controlled diet. In clinical trials with Kuvan in patients with PKU, reductions in blood Phe levels were observed in some patients. However, long-term neurologic function in patients with PKU receiving Kuvan for the treatment of elevated blood Phe has not been assessed.

What Are The Risks Of Taking Kuvan?

Hypersensitivity reactions including anaphylaxis and rash have been reported. Most hypersensitivity reactions occurred within several days of initiating treatment. Patients should be informed to seek immediate medical attention for evidence of severe allergic reactions [see WARNINGS AND PRECAUTIONS].

During clinical studies, gastritis was reported as a serious adverse reaction. Patients should be informed to notify their physician for symptoms of severe gastritis [see WARNINGS AND PRECAUTIONS].

Response to Kuvan treatment in PKU patients is variable. Not all patients responded to treatment with Kuvan in clinical trials, and the initiation of Kuvan treatment does not eliminate the need to monitor for adequate blood Phe control. Prolonged elevations in blood Phe levels can result in neurologic impairment. Conversely, levels of blood Phe that are too low may be associated with catabolism and protein breakdown. Therefore, when Kuvan is used in combination with a Pherestricted diet, patients should be monitored closely to ensure adequate control of blood Phe levels and, if necessary, the dose of Kuvan should be adjusted. Frequent blood monitoring is recommended in the pediatric population. All patients with PKU who are being treated with Kuvan should also be treated with a Phe-restricted diet [see WARNINGS AND PRECAUTIONS].

Some patients may require additional clinical monitoring while taking Kuvan, including 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, and levodopa [see WARNINGS AND PRECAUTIONS].

There have been postmarketing reports of hyperactivity while taking Kuvan. Patients should be informed to notify their physician for symptoms of hyperactivity [see WARNINGS AND PRECAUTIONS]. The most common adverse reactions ( ≥ 4% of patients) during clinical studies were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion [see ADVERSE REACTIONS].

BioMarin PKU Disease Registry

BioMarin established a product registry for PKU patients that also 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/day (0.2, 0.7, and 2 times the maximum recommended human dose of 20 mg/kg/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/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/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/day (about 8 times the maximum recommended human dose of 20 mg/kg/day, based on body surface area). Sapropterin dihydrochloride, at oral doses up to 400 mg/kg/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/day sapropterin dihydrochloride (about 3 times the MRHD of 20 mg/kg/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/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 Mothers

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 4 to 16 years, have been treated with Kuvan in clinical studies [see Clinical Studies]. The safety and efficacy of Kuvan in pediatric patients less than 4 years of age have not been established in clinical studies. Frequent blood monitoring is recommended in the pediatric population to ensure adequate blood Phe level control [see PATIENT INFORMATION].

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.

Last reviewed on RxList: 1/6/2014
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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