2.1  Dosage

The recommended starting dose of Kuvan is 10 mg/kg/day taken once daily.

Response to therapy is determined by change in blood Phe following treatment with Kuvan at 10 mg/kg/day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of Kuvan treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg/day, the dose may be increased to 20 mg/kg/day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg/day are non-responders, and treatment with Kuvan should be discontinued in these patients.

Once responsiveness to Kuvan has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg/day according to response to therapy. 

2.2  Administration

Kuvan is available as tablets and as powder for oral solution. Kuvan should be taken orally with food to increase absorption, preferably at the same time each day. A missed dose should be taken as soon as possible, but 2 doses should not be taken on the same day.

2.3 Instructions for Use

Kuvan Tablets

Kuvan tablets may be swallowed either as whole tablets or dissolved in 4 to 8 oz. (120 to 240 mL) of water or apple juice and taken orally within 15 minutes of dissolution. It may take a few minutes for the tablets to dissolve. To make the tablets dissolve faster, stir or crush them. The tablets may not dissolve completely. Patients may see small pieces floating on top of the water or apple juice. This is normal and safe for patients to swallow. If after drinking the medicine patients still see pieces of the tablet, they can add more water or apple juice to make sure that they take all of the medicine.

Kuvan Powder for Oral Solution

Kuvan powder for oral solution should be dissolved in 4 to 8 oz. (120 to 240 mL) of water or apple juice and taken orally within 30 minutes of dissolution. Empty the contents of the packet(s) in water or apple juice and mix thoroughly. The powder should dissolve rapidly and completely.

5.1  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 (6.2)]. 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.

5.2 Gastritis

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

5.3 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 Counseling Information (17.4)].

5.4 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 (14.1)]. 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 (2.1)].

5.5 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.

5.6 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.

5.7 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).

5.8 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.

5.9 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.

5.10 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 

PKU Clinical Studies

In clinical studies, Kuvan was administered to 579 patients with PKU in doses ranging from 5 to 20 mg/kg/day for lengths of treatment ranging from 1 to 164 weeks. Patients were aged 4 to 50 years old. The patient population was nearly evenly distributed in gender, and approximately 95% of patients were Caucasian. 

The most common adverse reactions (≥4% of patients) across all investigational studies (n=579) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.

The data described in Table 1 reflect exposure of 74 patients with PKU to Kuvan at doses of 10 to 20 mg/kg/day for 6 to 10 weeks in 2 double-blind, placebo-controlled clinical trials. The overall incidence of adverse reactions in patients receiving Kuvan was similar to that reported with patients receiving placebo. 

Table 1 enumerates adverse reactions occurring in at least 4% of patients treated with Kuvan in the double-blind, placebo-controlled clinical trials described above. 

In open-label, uncontrolled clinical trials in which all patients received Kuvan in doses of 5 to 20 mg/kg/day, adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials [see Clinical Studies (14.1)].

In a long term, open-label, extension study of 111 patients receiving Kuvan in doses of ranging from 5 to 20 mg/kg/day [see Clinical Studies (14.1)], adverse reactions were similar in type and frequency to those reported in the previous clinical studies. Fifty five patients received Kuvan both as dissolved and intact tablets. There were no notable differences in the incidence or severity of adverse reactions between the two methods of administration.

Safety Experience from Clinical Studies for Non-PKU Indications

Approximately 800 healthy volunteers and patients with disorders other than PKU, some of whom had underlying neurologic disorders or cardiovascular disease, have been administered a different formulation of the same active ingredient (sapropterin) in approximately 19 controlled and uncontrolled clinical trials. In these clinical trials, subjects were administered sapropterin at doses ranging from 1 to 100 mg/kg/day for lengths of exposure from 1 day to 2 years. Serious and severe adverse reactions (regardless of causality) during sapropterin administration were convulsions, exacerbation of convulsions [see Warnings and Precautions (5.9)], dizziness, gastrointestinal bleeding, post-procedural bleeding, headache, irritability, myocardial infarction, overstimulation, and respiratory failure. Common adverse reactions were headache, peripheral edema, arthralgia, polyuria, agitation, dizziness, nausea, pharyngitis, abdominal pain, upper abdominal pain, and upper respiratory tract infection.

6.2  Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Kuvan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.

In worldwide marketing experience, the most common adverse reactions due to Kuvan are oropharyngeal pain, pharyngitis, esophageal pain, gastritis, dyspepsia, abdominal pain, nausea and vomiting. Hypersensitivity reactions including anaphylaxis and rash have been reported. Most hypersensitivity reactions occurred within several days of initiating treatment. Two cases of hyperactivity have been reported, including one case in a patient who received an accidental overdose of Kuvan [see Warnings and Precautions (5.1, 5.10)]. 

8.1  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). 

8.3  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.

8.4  Pediatric Use

Pediatric patients with PKU, ages 4 to 16 years, have been treated with Kuvan in clinical studies [see Clinical Studies (14.1)]. 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 Counseling Information (17.4)].

8.5  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.

8.6  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.

12.1 Mechanism of Action

Kuvan is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.

12.2 Pharmacodynamics

In PKU patients who are responsive to BH4 treatment, blood Phe levels decrease within 24 hours after a single administration of sapropterin dihydrochloride, although maximal effect on Phe level may take up to a month, depending on the patient. A single daily dose of Kuvan is adequate to maintain stable blood Phe levels over a 24-hour period. Twelve patients with blood Phe levels ranging from 516 to 986 μmol/L (mean 747 ± 153 μmol/L) were assessed with 24‑hour blood Phe level monitoring following a daily morning dose of 10 mg/kg/day. The blood Phe level remained stable during a 24‑hour observation period. No substantial increases in blood Phe levels were observed following food intake throughout the 24-hour period.

Effects of Kuvan on the QTc interval

A thorough QTc study was performed in 56 healthy adults.  This randomized, placebo and active controlled crossover study was conducted to determine if a single supra-therapeutic (100 mg/kg) of Kuvan, or a single therapeutic dose (20 mg/kg) of Kuvan had an effect on cardiac repolarization. In this study, Kuvan was administered after dissolving tablets in water under fed condition. This study demonstrated a dose-dependent shortening of the QT interval. The maximum placebo-subtracted mean change from baseline of the QTc interval was -3.69 and -8.32 ms (lower bound of 90% CI: -5.3 and -10.6 ms) at 20 and 100 mg/kg, respectively.   

12.3 Pharmacokinetics

Studies in healthy volunteers have shown comparable absorption of sapropterin when tablets are dissolved in water or orange juice and taken under fasted conditions. Administration of dissolved tablets after a high-fat/high-calorie meal resulted in mean increases in Cmax of 84% and AUC of 87% (dissolved in water). However, there was extensive variability in individual subject values for Cmax and AUC across the different modes of administration and meal conditions. In the clinical trials of Kuvan, drug was administered in the morning as a dissolved tablet without regard to meals. The mean elimination half-life in PKU patients was approximately 6.7 hours (range 3.9 to 17 hr), comparable with values seen in healthy subjects (range 3.0 to 5.3 hr). 

A study in healthy adults with 10 mg/kg of Kuvan demonstrated the absorption via intact tablet administration was 40% greater than via dissolved tablet administration under fasted conditions based on AUC0-t. The administration of intact tablets under fed conditions resulted in an approximately 43% increase in the extent of absorption compared to fasted conditions based on AUC0-t.

A population pharmacokinetic analysis of sapropterin including patients between 9 and 49 years of age showed no effect of age on sapropterin pharmacokinetics. Pharmacokinetics in patients <9 years and >49 years of age have not been studied.

Metabolism

Sapropterin is a synthetic form of tetrahydrobiopterin (BH4) and is expected to be metabolized and recycled by the same endogenous enzymes. In vivo endogenous BH4 is converted to quinoid dihydrobiopterin and is metabolized to dihydrobiopterin and biopterin. The enzymes dihydrofolate reductase and dihydropteridine reductase are responsible for the metabolism and recycling of BH4.

13.1  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.

14.1  Clinical Studies in PKU

The efficacy and safety of Kuvan were evaluated in 5 clinical studies in patients with PKU.

Study 1 was a multicenter, open-label, uncontrolled clinical trial of 489 patients with PKU, ages 8 to 48 years (mean 22 years), who had baseline blood Phe levels ≥ 450 μmol/L and who were not on Phe-restricted diets. All patients received treatment with Kuvan 10 mg/kg/day for 8 days. For the purposes of this study, response to Kuvan treatment was defined as a ≥ 30% decrease in blood Phe from baseline. At Day 8, 96 patients (20%) were identified as responders.

Study 2 was a multicenter, double-blind, placebo-controlled study of 88 patients with PKU who responded to Kuvan in Study 1. After a washout period from Study 1, patients were randomized equally to either Kuvan 10 mg/kg/day (N=41) or placebo (N=47) for 6 weeks. Efficacy was assessed by the mean change in blood Phe level from baseline to Week 6 in the Kuvan-treated group as compared to the mean change in the placebo group.

The results showed that at baseline, the mean (±SD) blood Phe level was 843 (±300) μmol/L in the Kuvan-treated group and 888 (±323) μmol/L in the placebo group. At Week 6, the Kuvan treated group had a mean (±SD) blood Phe level of 607 (±377) μmol/L, and the placebo group had a mean blood Phe level of 891 (±348) μmol/L. At Week 6, the Kuvan- and placebo treated groups had mean changes in blood Phe level of –239 and 6 μmol/L, respectively (mean percent changes of –29% (±32) and 3% (±33), respectively). The difference between the groups was statistically significant (p < 0.001) (Table 2).

Change in blood Phe was noted in the Kuvan-treated group at Week 1 and was sustained through Week 6 (Figure 1).

Study 3 was a multicenter, open-label, extension study in which 80 patients who responded to Kuvan treatment in Study 1 and completed Study 2 underwent 6 weeks of forced dose-titration with 3 different doses of Kuvan. Treatments consisted of 3 consecutive 2-week courses of Kuvan at doses of 5, then 20, and then 10 mg/kg/day. Blood Phe level was monitored after 2 weeks of treatment at each dose level. At baseline, mean (±SD) blood Phe was 844 (±398) μmol/L. At the end of treatment with 5, 10, and 20 mg/kg/day, mean (±SD) blood Phe levels were 744 (±384) μmol/L, 640 (±382) μmol/L, and 581 (±399) μmol/L, respectively (Table 3).

Study 4 was a multicenter study of 90 children with PKU, ages 4 to 12 years, who were on Phe‑restricted diets and who had blood Phe levels ≤480 μmol/L at screening. All patients were treated with open-label Kuvan 20 mg/kg/day for 8 days. Response to Kuvan was defined as a ≥30% decrease in blood Phe from baseline at Day 8. At Day 8, 50 patients (56%) had a ≥30% decrease in blood Phe.

Study 5 demonstrated the long-term safety of Kuvan in patients with PKU.  The study was a multicenter, open-label extension study of 111 patients with PKU who participated in Study 3 or Study 4.  Doses ranged in this study between 5-20mg/kg. The mean ± SD exposure to sapropterin for the entire study population was 659 ± 221 days (maximum 953) and 799 + 237 days (maximum 1151) including the previous studies.

17.1 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 (5.3, 5.4)].

17.2 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 (5.5)].

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 (2.1)].

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. 

17.3 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.

17.4 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 (5.1)].

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 (5.2)].

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 Phe-restricted 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 (5.3, 5.4, 5.5)].

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 (5.6, 5.7, 5.8, 5.9)].

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 (5.10)].  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 (6.1)].

17.5 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.