KUVAN

Metabolic Agents, PKU Metabolism

Administer sapropterin with food at the same time each day. Administer a missed dose as soon as possible, but do not administer 2 doses on the same day.

Oral tablets:
Tablets may be swallowed whole, dissolved in liquid, or crushed.
If dissolving in liquid: Dissolve tablets in 120—240 ml of water or apple juice. Administer within 15 minutes of tablet dissolution. Crushing or stirring of the tablets may be needed to facilitate dissolution. Full dissolution may not occur; patients may swallow any small tablet fragments that do not dissolve. If any tablet fragments remain in the cup, rinse the cup and administer to ensure receipt of the full dose.
Crushed tablets may be mixed in a small amount of soft foods such as apple sauce or pudding.

Powder for oral solution:
For patients weighing > 10 kg, dissolve dose in 120—240 ml of water or apple juice, and administer to the patient within 30 minutes of dissolution. Mix thoroughly to dissolve. The powder should dissolve rapidly and completely.  
For patients weighing <= 10 kg, the volume of liquid for dissolving powder depends on the dose and patient weight. Once dissolved, administer an appropriate volume of solution to provide the prescribed dose via an oral dosing syringe.
For doses of 10 mg/kg/day:
For doses of 10—50 mg, dissolve 1 packet in 10 ml of water or apple juice.
For doses of 60—100 mg, dissolve 1 packet in 5 ml of water or apple juice.
For doses of 20 mg/kg/day:
For doses of 20—100 mg, dissolve 1 packet in 5 ml of water or apple juice.
For doses of 120—200 mg, dissolve 2 packets in 5 ml of water or apple juice.
Alternatively, the powder can be stirred in a small amount of soft foods such as apple sauce or pudding.

anaphylactoid reactions / Rapid / Incidence not known
seizures / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known

bleeding / Early / Incidence not known
gastritis / Delayed / Incidence not known
esophagitis / Delayed / Incidence not known
peripheral edema / Delayed / Incidence not known

headache / Early / 15.0-15.0
rhinorrhea / Early / 11.0-11.0
rhinitis / Early / 1.0-10.0
diarrhea / Early / 8.0-8.0
vomiting / Early / 8.0-8.0
cough / Delayed / 7.0-7.0
nasal congestion / Early / 4.0-4.0
hyperactivity / Early / 0-1.0
pharyngitis / Delayed / Incidence not known
abdominal pain / Early / Incidence not known
nausea / Early / Incidence not known
dyspepsia / Early / Incidence not known
rash / Early / Incidence not known
irritability / Delayed / Incidence not known
dizziness / Early / Incidence not known
agitation / Early / Incidence not known
polyuria / Early / Incidence not known
arthralgia / Delayed / Incidence not known

JAVYGTOR, KUVAN

Rx

Synthetic form of BH4, a cofactor to PAH for conversion of phenylalanine to tyrosine
Used to reduce blood phenylalanine in patients with hyperphenylalaninemia due to BH4-responsive PKU
Must be used in conjunction with phenylalanine-restricted diet

Initially, 10 to 20 mg/kg/dose PO once daily. Measure blood phenylalanine (Phe) concentrations at baseline, after 1 week of treatment, and periodically for 1 month. If an initial dose of 10 mg/kg is used and blood Phe concentrations do not decrease from baseline after 1 month of therapy, the dose may be increased to 20 mg/kg PO once daily. Not all patients will respond to therapy; discontinue sapropterin if blood Phe concentrations do not decrease after 1 month of treatment at 20 mg/kg/day. Once responsiveness is established, adjust the dose within the range of 5 to 20 mg/kg PO once daily to maintain target blood Phe concentrations.

Initially, 10 mg/kg PO once daily. Check blood phenylalanine (Phe) concentration at baseline, after 1 week, and periodically for 1 month. In clinical trials, children younger than 7 years treated with 20 mg/kg/day sapropterin were at increased risk for low concentrations of blood Phe compared with patients 7 years and older. Blood Phe concentrations that are too low for prolonged periods of time may be associated with catabolism and protein breakdown. Titrate dosages carefully and with appropriate blood Phe concentration monitoring. Not all patients will respond to therapy; discontinue sapropterin if blood Phe concentrations do not decrease after 1 month of treatment at 20 mg/kg/day. Once responsiveness is established, adjust the dose within the range of 5 to 20 mg/kg PO once daily to maintain target blood Phe concentrations.

Specific guidelines for dosage adjustments in hepatic impairment are not available. Patients with hepatic impairment have not been evaluated in clinical trials. Monitor liver function tests because hepatic damage has been associated with impaired Phe metabolism. Monitor Phe response closely.

Specific guidelines for dosage adjustments in renal impairment are not available. Closely monitor patients with renal impairment, as renally impaired patients were not evaluated in clinical trials.

Avanafil: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
Carbidopa; Levodopa: (Major) Coadministration of sapropterin and levodopa has been associated with seizures. Post-marketing safety surveillance showed 3 patients (all with underlying neurologic disorder) develop convulsions, exacerbation of convulsions, over-stimulation, or irritability while receiving concomitant levodopa and sapropterin.
Carbidopa; Levodopa; Entacapone: (Major) Coadministration of sapropterin and levodopa has been associated with seizures. Post-marketing safety surveillance showed 3 patients (all with underlying neurologic disorder) develop convulsions, exacerbation of convulsions, over-stimulation, or irritability while receiving concomitant levodopa and sapropterin.
Finasteride; Tadalafil: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
Folate analogs: (Moderate) Significant increases in serum phenylalanine concentrations have been noted after methotrexate infusions of 58 g/m2 to 46 patients with an unknown PKU status. Increased concentrations occurred at the end of the infusion in 95% of methotrexate cycles, but large inter-individual variations in the concentrations existed. Individual predispositions may exist, as maximal phenylalanine concentrations were of the same magnitude in a given patient. Phenylalanine concentrations returned to baseline concentrations 24 hours after the end of the methotrexate infusion. Methotrexate has been shown to decrease endogenous tetrahydrobiopterin (BH4) concentrations by inhibiting the enzyme dihydropteridine reductase; a similar reaction could be expected in patients receiving sapropterin. Dihydropteridine reductase recycles quinonoid dihydropterin (q-BH2) back to the active cofactor BH4. Reduction of BH4 could make management of hyperphenylalaninemia more difficult. Drugs that inhibit folate metabolism should be used with caution in patients taking sapropterin.
Levodopa: (Major) Coadministration of sapropterin and levodopa has been associated with seizures. Post-marketing safety surveillance showed 3 patients (all with underlying neurologic disorder) develop convulsions, exacerbation of convulsions, over-stimulation, or irritability while receiving concomitant levodopa and sapropterin.
Phenobarbital: (Moderate) Drugs that inhibit folate metabolism, such as phenobarbital, should be used with caution in patients taking sapropterin. More frequent monitoring of blood phenylalanine concentrations is warranted in patients receiving these agents concurrently. An increased dosage of sapropterin may be necessary to achieve a biochemical response. Phenobarbital may decrease the bioavailability of endogenous tetrahydrobiopterin (BH4) by inhibiting the enzyme dihydrofolate reductase. Reduction of BH4 could make management of hyperphenylalaninemia with sapropterin more difficult.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Drugs that inhibit folate metabolism, such as phenobarbital, should be used with caution in patients taking sapropterin. More frequent monitoring of blood phenylalanine concentrations is warranted in patients receiving these agents concurrently. An increased dosage of sapropterin may be necessary to achieve a biochemical response. Phenobarbital may decrease the bioavailability of endogenous tetrahydrobiopterin (BH4) by inhibiting the enzyme dihydrofolate reductase. Reduction of BH4 could make management of hyperphenylalaninemia with sapropterin more difficult.
Phosphodiesterase inhibitors: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
Pyrimethamine: (Moderate) Drugs that inhibit folate metabolism, such as pyrimethamine, should be used with caution in patients taking sapropterin. For example, methotrexate has been shown to decrease endogenous tetrahydrobiopterin (BH4) concentrations by inhibiting the enzyme dihydropteridine reductase; a similar reaction could be expected in patients receiving pyrimethamine. Reduction of BH4 could make management of hyperphenylalaninemia with sapropterin more difficult. Folic acid supplementation has been shown to decrease the toxicity of pyrimethamine. Careful monitoring of blood phenylalanine concentrations is warranted in patients receiving these agents concurrently.
Sildenafil: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Drugs that inhibit folate metabolism, such as trimethoprim, should be used with caution in patients taking sapropterin. More frequent monitoring of blood phenylalanine concentrations is warranted in patients receiving these agents concurrently. An increased dosage of sapropterin may be necessary to achieve a biochemical response. Trimethoprim may decrease the bioavailability of endogenous tetrahydrobiopterin (BH4) by inhibiting the enzyme dihydrofolate reductase. Reduction of BH4 could make management of hyperphenylalaninemia with sapropterin more difficult.
Tadalafil: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
Trimethoprim: (Moderate) Drugs that inhibit folate metabolism, such as trimethoprim, should be used with caution in patients taking sapropterin. More frequent monitoring of blood phenylalanine concentrations is warranted in patients receiving these agents concurrently. An increased dosage of sapropterin may be necessary to achieve a biochemical response. Trimethoprim may decrease the bioavailability of endogenous tetrahydrobiopterin (BH4) by inhibiting the enzyme dihydrofolate reductase. Reduction of BH4 could make management of hyperphenylalaninemia with sapropterin more difficult.
Valproic Acid, Divalproex Sodium: (Moderate) Drugs that inhibit folate metabolism, such as valproic acid, should be used with caution in patients taking sapropterin. More frequent monitoring of blood phenylalanine concentrations is warranted in patients receiving these agents concurrently. An increased dosage of sapropterin may be necessary to achieve a biochemical response. Valproic acid may decrease the bioavailability of endogenous tetrahydrobiopterin (BH4) by inhibiting the enzyme dihydrofolate reductase. Reduction of BH4 could make management of hyperphenylalaninemia with sapropterin more difficult.
Vardenafil: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.

JAVYGTOR/KUVAN/Sapropterin/Sapropterin Dihydrochloride Oral Pwd F/Recon: 100mg, 500mg
JAVYGTOR/KUVAN/Sapropterin/Sapropterin Dihydrochloride Oral Tab: 100mg

20 mg/kg/day.

Safety and efficacy have not been established.

20 mg/kg/day.

20 mg/kg/day.

20 mg/kg/day.

Safety and efficacy have not been established.

Mechanism of Action: Sapropterin is a biologically active synthetic form of the naturally occurring enzyme cofactor tetrahydrobiopterin (BH4). Endogenous BH4 is a cofactor in multiple reactions including serving as a catalyst to phenylalanine hydroxylase (PAH) in the hydroxylation of phenylalanine (Phe) to tyrosine. Patients with phenylketonuria (PKU) have genetic mutations that result in deficient production or activity of PAH, which causes an increase in blood Phe concentrations. Over 500 mutations have been identified with considerable variability in the amount of residual PAH activity. Mutation severity is graded on the degree of PAH impairment. Severity of mutation does not accurately predict for responsiveness to BH4, only a trial of BH4 or sapropterin can determine responsiveness. Patients with PKU do not have an inherent deficiency in BH4 production or regeneration; however, increasing available BH4 has been shown to decrease blood Phe concentrations. The precise mechanism for this is unknown. One possible mechanism is that mutant PAH may require additional BH4 cofactor. Increasing available BH4 allows additional binding to PAH. Another possible mechanism is that BH4 exhibits a protective effect on mutant PAH. BH4 may increase the half-life of mutant PAH by preventing misfolding, which is a common PAH mutation.BH4 is also a cofactor in the hydroxylation of tyrosine to L-DOPA and of tryptophan to serotonin. Adverse reactions from BH4 supplementation may be a result of these pathways (see Adverse Reactions). Increased BH4 concentrations may lead to an increase in L-DOPA and serotonin.

Sapropterin is administered orally. Sapropterin is a synthetic form of tetrahydrobiopterin (BH4) and is expected to be metabolized and recycled by the same endogenous enzymes (dihydrofolate reductase and dihydropteridine reductase). The elimination half-life of sapropterin in patients with phenylketonuria (PKU) is approximately 6.7 hours (range 3.9 to 17 hours). Population pharmacokinetic analysis of sapropterin in patients 1 month to 49 years of age showed that body weight is the only covariate substantially affecting clearance or volume of distribution.
Mean CL/F (L/hour/kg) +/- SD (Median) by age:
0 to less than 1 year: 81.5 +/- 92.4 (53.6)
1 to less than 6 years: 50.7 +/- 20.1 (48.4)
6 to 11 years: 51.7 +/- 21.9 (47.4)
12 to 17 years: 39.2 +/- 9.3 (38.3)
18 years or more: 37.9 +/- 20.2 (31.8)
 
Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: BCRP
In healthy subjects, administration of a single dose of sapropterin 20 mg/kg had no effect on the pharmacokinetics of a single dose of digoxin (P-gp substrate) administered concomitantly. Based on in vitro studies, sapropterin does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5, nor induce CYP 1A2, 2B6, or 3A4/5. In vitro sapropterin did not inhibit OAT1, OAT3, OCT2, MATE1, and MATE2-K transporters. The potential to inhibit OATP1B1 and OATP1B3 has not been adequately studied. In vitro, sapropterin inhibits breast cancer resistance protein (BCRP), but the potential for a clinically significant increase in systemic exposure of BCRP substrates by sapropterin appears to be low.

To increase absorption, sapropterin should be administered with food. Administration after a high-fat/high-calorie meal caused mean increases of 84% in Cmax and 87% in AUC; however, extensive variability was noted across administration modes and meal conditions.
 
In a study of 88 patients with PKU not on phenylalanine (Phe)-restricted diets previously determined to have tetrahydrobiopterin (BH4)-responsive disease, a mean decrease in blood Phe concentration from baseline of 236 micromol/L was seen at 6 weeks with sapropterin 10 mg/kg/day compared to a 3 micromol/L increase over the same time period with placebo. Responders in this trial showed significantly decreased blood Phe concentrations at the initial assessment after 1 week, and this benefit persisted throughout the 6 week trial. In patients who respond to sapropterin, blood Phe concentrations generally decrease within 24 hours of a single dose of sapropterin. Maximum effect may take up to 4 weeks. A trial of 80 patients with a known response to sapropterin was conducted in which patients were titrated in two-week intervals through three separate dose levels. Blood Phe concentrations measured after each two-week course reflected a more pronounced response with increased dosage. Decreases in blood Phe concentrations from baseline at 5, 10, and 20 mg/kg/day were 100, 204, and 263 micromol/L, respectively.

There is a pregnancy exposure registry that has been established that monitors pregnancy outcomes in women who are exposed to sapropterin (Kuvan) during pregnancy. For more information regarding the registry program call 1-800-983-4587. Available pregnancy registry data have not reported an association with sapropterin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when the drug was used during pregnancy. 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. 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. 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 from 62 live births reported 3 abnormalities at birth (one case each of microcephaly, cleft palate, and tongue tie). These outcomes were associated with Phe levels greater than 360 micromol/L during pregnancy.

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, a total of 16 women from both registries were identified as breast-feeding for a mean of 3.5 months. No lactation-related safety concerns were reported in infants of mothers nursing during maternal treatment with sapropterin. Sapropterin is present in the milk of lactating rats following intravenous administration, but not following oral administration. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.