Included as part of the PRECAUTIONS section.

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. This may occur even if patients are taking Kuvan but not adequately controlling their blood Phe levels within recommended target range. Long-term studies of neurocognitive outcomes with Kuvan treatment have not been conducted. 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.

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

Patients with PKU who are being treated with Kuvan should also be treated with a Phe-restricted diet. The initiation of Kuvan therapy does not eliminate the need for appropriate monitoring by trained professionals to assure that blood Phe control is maintained in the context of ongoing dietary management.

Use With Caution in Patients With Hepatic Impairment

Patients with liver impairment have not been evaluated in clinical trials with Kuvan. Patients who have liver impairment should be carefully monitored when receiving Kuvan because hepatic damage has been associated with impaired Phe metabolism.

Monitor for Allergic Reactions

Patients who have a known severe allergy to any of the components of Kuvan should not take Kuvan. In clinical trials conducted with Kuvan, no severe allergic reactions were observed. The risks and benefits of continued treatment with Kuvan in patients with mild to moderate allergic reactions (such as rash) should be considered.

Use With Caution When Co-administering Kuvan and Medications Known to Inhibit Folate Metabolism

Drugs known to affect folate metabolism (e.g., methotrexate) and their derivatives should be used with caution while taking Kuvan because these drugs can decrease BH4 levels by inhibiting the enzyme dihydropteridine reductase (DHPR).

Use With Caution When Co-administering Kuvan and Drugs Known to Affect Nitric Oxide-Mediated Vasorelaxation

Caution should be used with the administration of Kuvan to patients who are receiving 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.

Use With Caution 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.

Patient Counseling Information

See FDA-Approved Patient Information Labeling

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, and reductions in blood Phe levels were observed in patients across the continuum of PKU phenotypes (mild, moderate, and severe PKU).

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. Doses above 20 mg/kg/day have not been evaluated in clinical trials.

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.

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

What Are the Risks of Taking Kuvan?

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, some patients in clinical trials who were following Phe-restricted diets and received treatment with Kuvan experienced substantial reductions of blood Phe. 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 Phe-restricted diet, patients should be monitored closely to ensure that blood Phe levels are not too low, and, if necessary, the dose of Kuvan should be adjusted.

The most serious adverse reactions during Kuvan administration (regardless of relationship to treatment) were gastritis, spinal cord injury, streptococcal infection, testicular carcinoma, and urinary tract infection. Mild to moderate neutropenia was noted during Kuvan administration in 24 of 579 patients (4%). The most common ( ≥ 4% of patients treated with Kuvan) across all studies (n=579) were headache, diarrhea, abdominal pain, upper respiratory tract infection, pharyngolaryngeal pain, vomiting, and nausea [see ADVERSE REACTIONS].

Long-term studies of neurocognitive outcomes have not been conducted with Kuvan.

BioMarin PKU Disease Registries

BioMarin will establish a general disease registry for PKU patients and a pregnancy registry for women who are 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 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 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 was genotoxic in thein vitroAmes 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 was genotoxic in the in vitro chromosomal aberration assay in Chinese hamster lung cells at concentrations of 0.25 and 0.5 mM. Sapropterin 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, 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. Women who are exposed to Kuvan during pregnancy are encouraged to enroll in the Kuvan patient registry [see Patient Counseling Information].

Teratogenicity studies with sapropterin have been conducted in rats at oral doses up to 400 mg/kg/day (about 3 times the maximum recommended human dose of 20 mg/kg/day, based on body surface area) and in rabbits at oral doses of up to 600 mg/kg/day (about 10 times the maximum recommended human dose, based on body surface area). No clear evidence of teratogenic activity was found in either species; however, in the rabbit teratogenicity study, there was an increase (not statistically significant) in the incidence of holoprosencephaly at the 600 mg/kg/day dose compared to controls.

There are no adequate and well-controlled studies of Kuvan in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. A study of 468 pregnancies and 331 live births in PKU-affected women (Maternal Phenylketonuria Collaborative Study, Rouse 1997) has 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 in reducing the incidence of Phe-induced teratogenic effects.

Labor and Delivery

The effects of Kuvan on labor and delivery in pregnant women are unknown.

Nursing Mothers

Sapropterin is excreted in the milk of intravenously, but not orally treated lactating rats. It is not known whether sapropterin is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from sapropterin and because of the potential for tumorigenicity shown for sapropterin in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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 assessed in clinical studies. Frequent blood monitoring is recommended in the pediatric population to ensure adequate blood Phe level control [see Patient Counseling 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. Patients who have renal impairment should be carefully monitored when receiving Kuvan.

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