Sapropterin Dihydrochloride

KUVAN ® is indicated to reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age and older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). KUVAN is to be used in conjunction with a Phe-restricted diet. KUVAN is a phenylalanine hydroxylase activator indicated to reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age and older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin‑ (BH4‑) responsive Phenylketonuria (PKU). KUVAN is to be used in conjunction with a Phe‑restricted diet. ( 1 )

KUVAN tablets are for oral use. Each tablet contains 100 mg of sapropterin dihydrochloride. Tablets are round, off-white to light yellow, mottled, and debossed with “177”. KUVAN powder for oral solution is available as a unit dose packet containing 100 mg of sapropterin dihydrochloride and as a unit dose packet containing 500 mg of sapropterin dihydrochloride. The powder is off-white to yellow in color. Tablets: 100 mg sapropterin dihydrochloride. ( 3 ) Powder for Oral Solution: 100 mg and 500 mg sapropterin dihydrochloride. ( 3 )

None. None. ( 4 )

Hypersensitivity Reactions Including Anaphylaxis : KUVAN is not recommended in patients with a history of anaphylaxis to KUVAN; discontinue treatment in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary Phe restrictions. ( 5.1 ) Upper Gastrointestinal Mucosal Inflammation : Monitor patients for signs and symptoms of these conditions including esophagitis and gastritis. ( 5.2 ) Hypophenylalaninemia : Pediatric patients 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. ( 5.3 ) Monitoring Blood Phe Levels During Treatment : Ensure adequate blood Phe control and nutritional balance during treatment with KUVAN. Frequent blood monitoring is recommended, especially in pediatric patients. ( 5.4 , 2.1 ) Lack of Biochemical Response to KUVAN T reatment : Response to KUVAN treatment cannot be pre-determined by laboratory (e.g., molecular) testing and can only be determined by a therapeutic trial of KUVAN. ( 5.5 , 2.1 ) Interaction with Levodopa : Seizures, over-stimulation or irritability may occur; monitor patients for a change in neurologic status. ( 5.6 , 7 ) Hyperactivity : Monitor patients for hyperactivity. ( 5.7 )

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 protein and Phe restriction in patients who experience anaphylaxis.

5.2 Upper Gastrointestinal Mucosal Inflammation Gastrointestinal (GI) adverse reactions suggestive of upper GI mucosal inflammation have been reported with KUVAN. Serious adverse reactions included esophagitis and gastritis [see Adverse Reactions ( 6.2 )] . If left untreated, these could lead to severe sequelae including esophageal stricture, esophageal ulcer, gastric ulcer, and bleeding and such complications have been reported in patients receiving KUVAN. Monitor patients for signs and symptoms of upper GI mucosal inflammation.

5.3 Hypophenylalaninemia In clinical trials of KUVAN, some PKU patients experienced hypophenylalaninemia (low blood Phe) during treatment with KUVAN. In a clinical study of pediatric patients younger than 7 years old treated with KUVAN 20 mg/kg per day, the incidence of hypophenylalaninemia was higher than in clinical trials of older patients [see Adverse Reactions ( 6.1 )] .

5.4 Monitoring Blood Phe Levels During Treatment Prolonged elevations of blood Phe levels in patients with PKU can result in severe neurologic damage, including severe intellectual disability, developmental delay, microcephaly, delayed speech, seizures, and behavioral abnormalities. Conversely, prolonged levels of blood Phe that are too low have been associated with catabolism and endogenous protein breakdown, which has been associated with adverse developmental outcomes. 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 Dosage and Administration ( 2.2 )] .

5.5 Lack of Biochemical Response to KUVAN Some patients with PKU do not show biochemical response (reduction in blood Phe) with treatment with KUVAN. In two clinical trials at a KUVAN dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients showed a biochemical response to KUVAN, and in one clinical trial at a dose of 10 mg/kg per day, 20% of adult and pediatric PKU patients showed a biochemical response to KUVAN [see Clinical Studies ( 14 )] . Biochemical response to KUVAN treatment cannot generally be pre-determined by laboratory testing (e.g., molecular testing), and should be determined through a therapeutic trial (evaluation) of KUVAN response [see Dosage and Administration ( 2.2 )] .

5.6 Interaction with Levodopa In a 10-year post-marketing safety surveillance program for a non-PKU indication using another sapropterin product, 3 patients with underlying neurological disorders experienced seizures, exacerbation of seizures, over-stimulation, and irritability during co-administration of levodopa and sapropterin. Monitor patients who are receiving levodopa for changes in neurological status during treatment with KUVAN [see Drug Interactions ( 7 )] .

5.7 Hyperactivity In the KUVAN postmarketing safety surveillance program, 2 patients with PKU experienced hyperactivity when treated with KUVAN [see Adverse Reactions ( 6.2 )] . Monitor patients for hyperactivity.

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 protein and Phe restriction in patients who experience anaphylaxis.

5.2 Upper Gastrointestinal Mucosal Inflammation Gastrointestinal (GI) adverse reactions suggestive of upper GI mucosal inflammation have been reported with KUVAN. Serious adverse reactions included esophagitis and gastritis [see Adverse Reactions ( 6.2 )] . If left untreated, these could lead to severe sequelae including esophageal stricture, esophageal ulcer, gastric ulcer, and bleeding and such complications have been reported in patients receiving KUVAN. Monitor patients for signs and symptoms of upper GI mucosal inflammation.

5.3 Hypophenylalaninemia In clinical trials of KUVAN, some PKU patients experienced hypophenylalaninemia (low blood Phe) during treatment with KUVAN. In a clinical study of pediatric patients younger than 7 years old treated with KUVAN 20 mg/kg per day, the incidence of hypophenylalaninemia was higher than in clinical trials of older patients [see Adverse Reactions ( 6.1 )] .

5.4 Monitoring Blood Phe Levels During Treatment Prolonged elevations of blood Phe levels in patients with PKU can result in severe neurologic damage, including severe intellectual disability, developmental delay, microcephaly, delayed speech, seizures, and behavioral abnormalities. Conversely, prolonged levels of blood Phe that are too low have been associated with catabolism and endogenous protein breakdown, which has been associated with adverse developmental outcomes. 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 Dosage and Administration ( 2.2 )] .

5.5 Lack of Biochemical Response to KUVAN Some patients with PKU do not show biochemical response (reduction in blood Phe) with treatment with KUVAN. In two clinical trials at a KUVAN dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients showed a biochemical response to KUVAN, and in one clinical trial at a dose of 10 mg/kg per day, 20% of adult and pediatric PKU patients showed a biochemical response to KUVAN [see Clinical Studies ( 14 )] . […]

Most common adverse reactions (≥4%) are: headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-877-695-8826, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction 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 The safety of KUVAN was evaluated in 7 clinical studies in patients with PKU (aged 1 month to 50 years) [see Clinical Studies ( 14 )] . In Studies 1-4 (controlled and uncontrolled studies), 579 patients with PKU aged 4 to 49 years received KUVAN in doses ranging from 5 to 20 mg/kg per day for lengths of treatment ranging from 1 to 164 weeks. The patient population was evenly distributed in gender, and approximately 95% of patients were Caucasian. The most common adverse reactions (≥4% of patients) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion. The data described in Table 3 reflect exposure of 74 patients with PKU to KUVAN at doses of 10 to 20 mg/kg per day for 6 to 10 weeks in two double-blind, placebo-controlled clinical trials (Studies 2 and 4). Table 3 enumerates adverse reactions occurring in at least 4% of patients treated with KUVAN in the double-blind, placebo-controlled clinical trials described above. Table 3: Summary of Adverse Reactions Occurring in ≥4% of Patients in Placebo-Controlled Clinical Studies with KUVAN MedDRA Preferred Term Treatment KUVAN (N=74) Placebo (N=59) No. Patients (%) No. Patients (%) Headache 11 (15) 8 (14) Rhinorrhea 8 (11) 0 Pharyngolaryngeal pain 7 (10) 1 (2) Diarrhea 6 (8) 3 (5) Vomiting 6 (8) 4 (7) Cough 5 (7) 3 (5) Nasal congestion 3 (4) 0 In open-label, uncontrolled clinical trials (Studies 1 and 3) all patients received KUVAN in doses of 5 to 20 mg/kg per day, and adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials [see Clinical Studies ( 14 )] . In Study 5, 65 pediatric patients with PKU aged 1 month to 6 years received KUVAN 20 mg/kg per day for 6 months. Adverse reactions in these patients were similar in frequency and type as those seen in other KUVAN clinical trials except for an increased incidence of low Phe levels. Twenty-five percent (16 out of 65) of patients developed Phe levels below normal for age [see Warnings and Precautions ( 5.3 ), Use In Specific Populations ( 8.4 ), and Clinical Studies ( 14 )] . In Study 6, a long term, open-label, extension study of 111 patients aged 4 to 50 years, receiving KUVAN in doses ranging from 5 to 20 mg/kg per day, 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. The mean (± SD) exposure to sapropterin for the entire study population was 659 ± 221 days (maximum 953 days). In Study 7, 27 pediatric patients with PKU aged 0 to 4 years received KUVAN 10 mg/kg per day or 20 mg/kg per day. Adverse reactions were similar in type and frequency to those observed in other clinical trials, with the addition of rhinitis, which was reported in 2 subjects (7.4%). Safety Experience from Clinical Studies for Non-PKU Indications Approximately 800 healthy subjects 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 per day for lengths of exposure from 1 day to 2 years. Serious and severe adverse reactions (regardless of causality) during sapropterin administration were seizures, exacerbation of seizures [see Warnings and Precautions ( 5.3 )] , 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 Postmarketing Experience The following adverse reactions have been reported 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 a causal relationship to drug exposure. Hypersensitivity reactions including anaphylaxis and rash: Most hypersensitivity reactions occurred within several days of initiating treatment [see Warnings and Precautions ( 5.1 )] . Gastrointestinal reactions: esophagitis, gastritis, oropharyngeal pain, pharyngitis, esophageal pain, abdominal pain, dyspepsia, nausea, and vomiting [see Warnings and Precautions ( 5.2 )] . Hyperactivity: Two cases have been reported. In one case, the patient received an accidental overdosage of KUVAN [see Warnings and Precautions ( 5.6 ), Overdosage ( 10 )] .

Table 4 includes drugs with clinically important drug interactions when administered with sapropterin dihydrochloride and instructions for preventing or managing them. Table 4: Clinically Relevant Drug Interactions Levodopa Clinical Impact Sapropterin dihydrochloride may increase the availability of tyrosine, a precursor of levodopa. Neurologic events were reported postmarketing in patients receiving sapropterin and levodopa concomitantly for a non-PKU indication [see Warnings and Precautions ( 5.5 )] . Intervention Monitor patients for a change in neurologic status. Inhibitors of Folate Synthesis (e.g., methotrexate, valproic acid, phenobarbital, trimethoprim) Clinical Impact In vitro and in vivo nonclinical data suggest that drugs that inhibit folate synthesis may decrease the bioavailability of endogenous BH4 by inhibiting the enzyme dihydrofolate reductase, which is involved in the recycling (regeneration) of BH4. This reduction in net BH4 levels may increase Phe levels. Intervention Consider monitoring blood Phe levels more frequently during concomitant administration. An increased dosage of KUVAN may be necessary to achieve a biochemical response. Drugs Affecting Nitric Oxide‑Mediated Vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil) Clinical Impact Both sapropterin dihydrochloride and PDE-5 inhibitors may induce vasorelaxation. A reduction in blood pressure could occur; however, the combined use of these medications has not been evaluated in humans. Intervention Monitor blood pressure. Inhibitors of Folate Synthesis (e.g., methotrexate, valproic acid, phenobarbital, trimethoprim) : Can decrease endogenous BH4 levels; monitor blood Phe levels more frequently and adjust KUVAN dosage as needed. (7 ) Drugs Affecting Nitric Oxide‑Mediated Vasorelaxation (e.g., PDE-5 inhibitors) : Potential for vasorelaxation; monitor blood pressure. ( 7 )

8.1 Pregnancy Risk Summary Available data from pregnancy safety studies, pharmacovigilance, and published case reports with KUVAN use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects (see Clinical Considerations ) . 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. All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU. Clinical Considerations Disease-Associated Maternal and/or Embryo‑Fetal Risk Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception [see Dosage and Administration 2.2) ] . Data Human Data Uncontrolled Maternal PKU 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 micromol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies. Control of blood phenylalanine during pregnancy is essential to reduce the incidence of Phe-induced teratogenic effects. Pregnancy Registry Data Available data from pregnancy sub-registries within the Phenylketonuria Developmental Outcomes and Safety (PKUDOS) Registry and the KUVAN Adult Maternal Pediatric European Registry (KAMPER) have identified 72 live births (79 pregnancies) in women with PKU exposed to sapropterin during pregnancy. Three birth defects were reported, including one case each of microcephaly, cleft palate, and tongue tie. The two major birth defects (microcephaly and cleft palate) were associated with Phe levels greater than 360 micromol/L during pregnancy. 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).

8.2 Lactation Risk Summary There are insufficient data to assess the presence of sapropterin in human milk and no data on the effects on milk production. In postmarketing pregnancy registries, 13 infants were exposed to KUVAN through breastfeeding. No lactation-related safety concerns were reported in infants of mothers nursing during maternal treatment with KUVAN. There are no data on the effects on milk production. Sapropterin is present in the milk of lactating rats following intravenous administration, but not following oral administration. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KUVAN and any potential adverse effects on the breastfed child from KUVAN or from the underlying maternal condition.

8.4 Pediatric Use Pediatric patients with PKU, ages 1 month to 16 years, have been treated with KUVAN in clinical trials [see Clinical Studies ( 14 )]. 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 ( 6.1 )] . 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 ( 14 )] . 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) * Error bars indicate 95% confidence interval. Figure 1

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.

8.4 Pediatric Use Pediatric patients with PKU, ages 1 month to 16 years, have been treated with KUVAN in clinical trials [see Clinical Studies ( 14 )]. 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 ( 6.1 )] . 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 ( 14 )] . 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) * Error bars indicate 95% confidence interval. Figure 1

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 activity, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.