Kuvan 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 (1).
The recommended starting dose of Kuvan is 10 mg/kg/day taken
once daily.
Doses of Kuvan may be adjusted in the range of 5 to 20 mg/kg
taken once daily. Blood Phe must be monitored regularly (2.1).
Kuvan should be taken orally with food to increase the absorption.
Kuvan Tablets should be dissolved in 4 to 8 oz. (120-240 mL) of
water or apple juice and taken within 15 minutes (2.2).
100 mg tablets (3).
---------------CONTRAINDICATIONS--------------
None (4).
FULL PRESCRIBING INFORMATION: CONTENTS *
1. INDICATIONS AND USAGE 2
2. DOSAGE AND ADMINISTRATION 2
2.1 Dosage 2
2.2 Administration 2
3. DOSAGE FORMS AND STRENGTHS 2
| 60 5. WARNINGS AND PRECAUTIONS....................................... 3 91 10. OVERDOSAGE 7 | ||||||
| 61 | 5.1 | Monitor Blood Phe Levels During | 92 | 11. | DESCRIPTION 7 | |
| 62 | Treatment... 3 | 93 | 12. | CLINICAL PHARMACOLOGY 8 | ||
| 63 | 5.2 | Identify Non-Responders to Kuvan | 94 | 12.1 | Mechanism of Action 8 | |
| 64 | Treatment 3 | 95 | 12.2 | Pharmacodynamics 8 | ||
| 65 | 5.3 | Treat All Patients With a Phe-restricted | 96 | 12.3 | Pharmacokinetics 8 | |
| 66 Diet .............................................................................. 3 97 13. NONCLINICAL TOXICOLOGY 8 | ||||||
| 67 68 | 5.4 | Use With Caution in Patients With Hepatic Impairment 3 | 98 99 | 13.1 | Carcinogenesis, Mutagenesis, Impairment of Fertility................... 8 | |
| 69 5.5 | Monitor for Allergic Reactions 3 | 100 | 14. | CLINICAL STUDIES 9 | ||
| 70 5.6 | Use With Caution When Co-administering | 101 | 14.1 Clinical Studies in PKU 9 | |||
| 71 | Kuvan and Medications Known to Inhibit | 102 | 16. | HOW SUPPLIED/STORAGE AND HANDLING 11 | ||
| 72 | Folate Metabolism 3 | 103 | 17. | PATIENT COUNSELING INFORMATION 12 | ||
| 73 74 | 5.7 | Use With Caution When Co-administering Kuvan and Drugs Known to Affect Nitric | 104 105 | 17.1 | Important Information to Consider Prior to Prescribing Kuvan 12 | |
| 75 | Oxide-Mediated Vasorelaxation 3 | 106 | 17.2 | Blood Phe Monitoring and Management 12 | ||
| 76 | 5.8 | Use With Caution When Co-administering | 107 | 17.3 | What Are the Benefits of Taking Kuvan? 13 | |
| 77 | Kuvan and Levodopa 4 | 108 | 17.4 | What Are the Risks of Taking Kuvan? 13 | ||
| 78 6. | ADVERSE REACTIONS 4 | 109 | 17.5 | BioMarin PKU Disease Registries 13 | ||
| 79 | 6.1 | Clinical Trials Experience in PKU 4 | 110 | 17.6 | FDA-Approved Patient Information | |
| 80 | 6.2 | Safety Experience From Clinical Studies | 111 | Labeling....... 14 | ||
| 81 | for Non-PKU Indications 5 | 112 | ||||
| 82 6.3 Post-Marketing Experience ......................................... 5 113 *Sections or subsections omitted from the Full Prescribing | ||||||
4. CONTRAINDICATIONS 2
Monitor Blood Phe Levels During Treatment:
Prolonged exposure to elevated blood Phe levels can injure the
brain and reduce brain function. To ensure adequate blood Phe
control, blood Phe levels must still be carefully monitored even
though patients are receiving Kuvan which can reduce blood Phe
levels (5.1).
Treat All Patients With a Phe-restricted Diet:
The initiation of Kuvan therapy does not eliminate the need for
ongoing dietary management (5.3).
---------------ADVERSE REACTIONS---------------
The most common adverse reactions (incidence >=4%) in patients
treated with Kuvan are headache, diarrhea, abdominal pain, upper
respiratory tract infection, pharyngolaryngeal pain, vomiting, and
nausea (6.1).
1-800-FDA-1088 or www.fda.gov/medwatch.
Pregnancy Category C. This drug should be used during pregnancy
only if clearly needed. There are no adequate and well-controlled
studies in pregnant women. Women who are exposed to Kuvan
during pregnancy are encouraged to enroll in the Kuvan patient
registry (8.1, 17.5).
8.1 Pregnancy 6
8.2 Labor and Delivery 6
8.3 Nursing Mothers 6
8.4 Pediatric Use 6
8.5 Geriatric Use 7
8.6 Patients With Renal Impairment 7
DRUG INTERACTIONS 6
USE IN SPECIFIC POPULATIONS 6
Information are not listed.
Kuvan(tm) 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.
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.
Kuvan (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 8 oz. (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.
Kuvan (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".
None.
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.
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)].
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.
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.
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.
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).
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.
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.
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).
Table 1: Summary of Adverse Reactions by Preferred Term Occurring in >=4% of Patients in Controlled Clinical Studies With Kuvan
| Treatment | ||
| Kuvan | Placebo | |
| Patients Treated | N = 74 | N = 59 |
| Preferred Term | N (%) | N (%) |
| Any Adverse Reaction | 47 (64) | 42 (71) |
| Headache | 11 (15) | 8 (14) |
| Upper respiratory tract infection | 9 (12) | 14 (24) |
| 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) |
| Pyrexia | 5 (7) | 4 (7) |
| Contusion | 4 (5) | 1 (2) |
| Abdominal pain | 4 (5) | 5 (8) |
| Rash | 4 (5) | 4 (7) |
| Nasal congestion | 3 (4) | 0 |
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.
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.
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.
No drug interaction studies were performed.
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-affected women (Maternal Phenylketonuria Collaborative Study, Rouse 1997) has demonstrated that uncontrolled Phe levels above 600 umol/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.
The effects of Kuvan on labor and delivery in pregnant women are unknown.
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 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)].
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 have not been evaluated in clinical trials. Patients who have renal impairment should be carefully monitored when receiving Kuvan.
In the only reported overdosage with Kuvan, a patient participating in a 26-week study received a single dose of 4,500 mg (36 mg/kg) instead of 2,600 mg (20 mg/kg) in Week 16. The patient reported mild headache and mild dizziness immediately after taking the dose; both symptoms resolved within 1 hour with no treatment intervention. Results from liver function laboratory tests obtained immediately following the event were within normal limits. The patient suspended therapy for 24 hours and then restarted Kuvan with no reports of abnormal signs or symptoms.
Sapropterin dihydrochloride, the active pharmaceutical ingredient in Kuvan Tablets, is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Sapropterin dihydrochloride is an off-white to light yellow crystals or crystalline powder. The chemical name of sapropterin dihydrochloride is (6R)-2-amino-6-[(1R,2S)-1,2- dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-pteridinone dihydrochloride and the molecular formula is C9H15N5O3 *2HCl with a molecular weight of 314.17. Sapropterin dihydrochloride has the following structural formula:
H
N
H 3
2 CH3
5 1
H2N
N 8a N
H H
HO H
2 HCl
Each Kuvan 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". Each tablet contains the following inactive ingredients: ascorbic acid (USP), crospovidone (NF), dibasic calcium phosphate (USP), D-mannitol (USP), riboflavin (USP), and sodium stearyl fumarate (NF).
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.
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 mmol/L (mean 747 +- 153 mmol/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. Doses above 20 mg/kg/day have not been evaluated in clinical studies.
Studies in healthy volunteers have shown comparable absorption of sapropterin dihydrochloride 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 population pharmacokinetic analysis of sapropterin that included patients between 9 and 49 years of age showed no effect of age on sapropterin dihydrochloride pharmacokinetics. Pharmacokinetics in patients <9 years and >49 years of age have not been studied.
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 the in vitro Ames test at concentrations of 625 ug (TA98) and 5000 ug (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.
The efficacy and safety of Kuvan were evaluated in 4 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 mmol/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) mmol/L in the Kuvan-treated group and 888 (+-323) mmol/L in the placebo group. At Week 6, the Kuvan-treated group had a mean (+-SD) blood Phe level of 607 (+-377) mmol/L, and the placebo group had a mean blood Phe level of 891 (+-348) mmol/L. At Week 6, the Kuvan- and placebo-treated groups had mean changes in blood Phe level of -239 and 6 mmol/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).
| Sapropterin (N=41) | Placebo (N=47) | |
| Baseline Blood Phe Level 1 ( m mol/L) | ||
| Mean (+-SD) | 843 (+-300) | 888 (+-323) |
| Percentiles (25 th , 75 th ) | 620, 990 | 618, 1141 |
| Week 6 Blood Phe Level ( m mol/L) | ||
| Mean (+-SD) | 607 (+-377) | 891 (+-348) |
| Percentiles (25 th , 75 th ) | 307, 812 | 619, 1143 |
| Mean Change in Blood Phe From Baseline to Week 6 ( m mol/L) | ||
| Adjusted Mean (+-SE) 2 | -239 (+-38) | 6 (+-36) |
| Percentiles (25 th , 75 th ) | -397, -92 | -96, 93 |
| Mean Percent Change in Blood Phe From Baseline to Week 6 | ||
| Mean (+-SD) | - 29 (+-32) | 3 (+-33) |
| Percentiles (25 th , 75 th ) | -61, -11 | -13, 12 |
The mean baseline (BL) levels shown in this table represent the mean of 3 pretreatment levels (Wk -2, Wk -1, and Wk 0). Treatment with Kuvan or placebo started at Wk 0.
p-value < 0.001, adjusted mean and standard error from an ANCOVA model with change in blood Phe level from baseline to Week 6 as the response variable, and both treatment group and baseline blood Phe level as covariates.
Change in blood Phe was noted in the Kuvan-treated group at Week 1 and was sustained through Week 6 (Figure 1).
Wk -2 Wk -1 Wk 0 Wk 1 Wk 2 Wk 4 Wk 6
Error bars indicate 95% confidence interval.
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) mmol/L. At the end of treatment with 5, 10, and 20 mg/kg/day, mean (+-SD) blood Phe levels were 744 (+-384) mmol/L, 640 (+-382) mmol/L, and 581 (+-399) mmol/L, respectively (Table 3).
| Kuvan Dose Level (mg/kg/day) | No. of Patients | Mean ( +- SD) Blood Phe Level ( m mol/L) | Mean Changes ( +- SD) in Blood Phe Level From Week 0 ( m mol/L) |
| Baseline (No Treatment) | 80 | 844 (+-398) | -- |
| 5 | 80 | 744 (+-384) | -100 (+-295) |
| 10 | 80 | 640 (+-382) | -204 (+-303) |
| 20 | 80 | 581 (+-399) | -263 (+-318) |
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 mmol/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.
Kuvan (sapropterin dihydrochloride) Tablets are supplied in high-density polyethylene bottles, sealed with aluminized film, and closed with child-resistant caps. Each bottle contains 120 tablets, a silica gel desiccant cartridge, and a pharmaceutical-grade polyester coil. Each Kuvan Tablet contains 100 mg of sapropterin dihydrochloride (equivalent to 76.8 mg of sapropterin base). Bottle of 120 tablets.............................................................NDC 68135-300-02
Store at 20degC to 25degC (68-77degF); excursions allowed between 15degC to 30degC (59-86degF) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture.
Manufactured for: BioMarin Pharmaceutical Inc. Novato, CA 94949 Manufactured by: Lyne Laboratories, Inc. Brockton, MA 02301