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KUVAN — sapropterin dihydrochloride tablet
BioMarin Pharmaceutical Inc.

1 INDICATIONS AND USAGE

Kuvan^TM (sapropterin dihydrochloride) Tablets is indicated to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe-restricted diet.

2 DOSAGE AND ADMINISTRATION

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

2.2 Administration

Kuvan^TM (sapropterin dihydrochloride) Tablets should be administered orally with food to increase absorption, preferably at the same time each day. Kuvan Tablets should be dissolved in 4 to 8oz. (120 to 240 mL) of water or apple juice and taken 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. A missed dose should be taken as soon as possible, but 2 doses should not be taken on the same day.

3 DOSAGE FORMS AND STRENGTHS

Kuvan ^TM (sapropterin dihydrochloride) Tablets are unscored, uncoated, immediate-release tablets for oral use. Each tablet contains 100 mg of sapropterin dihydrochloride (equivalent to 76.8 mg of sapropterin base). Tablets are round, off-white to light yellow, mottled, and debossed with “177”.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 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.

5.2 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)].

5.3 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.

5.4 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.

5.5 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.

5.6 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).

5.7 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.

5.8 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.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience in PKU

In clinical trials, Kuvan has been administered to 579 patients with PKU in doses ranging from 5 to 20 mg/kg/day for lengths of treatment ranging from 1 to 30 weeks. Patients were aged 4 to 49 years old. The patient population was nearly evenly distributed in gender, and approximately 95% of patients were Caucasian.

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.

The data described below 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.

Because clinical trials were conducted under varying conditions, the observed adverse reaction rates may not predict the rates observed in patients in clinical practice. Table 1 enumerates treatment-emergent adverse reactions (regardless of relationship) that occurred in at least 4% of patients treated with Kuvan in the double-blind, placebo-controlled clinical trials described above. Reported frequency of adverse reactions was classified by MedDRA terms (Table 1).

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.

6.2 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 20 mg/kg/day for lengths of exposure from 1 day to 2 years. Serious and severe adverse reactions (regardless of relationship) during sapropterin administration were convulsions, exacerbation of convulsions [see Warnings and Precautions (5.8)], 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, and upper respiratory tract infection.

6.3 Post-Marketing Experience

The following adverse reactions have been identified during a 10-year post-approval safety surveillance program in Japan of another formulation of the same active ingredient (sapropterin). This safety surveillance program was conducted in 30 patients, 27 of whom had disorders other than PKU and had an underlying neurologic condition. The most common adverse reactions were convulsions and exacerbation of convulsions in 3 of the non-PKU patients [see Warnings and Precautions (5.8)] and increased gamma-glutamyltransferase (GGT) in 2 of the non-PKU patients.

7 Drug Interactions

No drug interaction studies were performed.

8 USE IN SPECIFIC POPULATIONS

8.1 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 (17.5)].

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-effected 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.

8.2 Labor and Delivery

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

8.3 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.

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 assessed in clinical studies. Frequent blood monitoring is recommended in the pediatric population to ensure adequate blood Phe level control [see Patient Counseling Information (17.2)].