Zelvysia (Sapropterin Dihydrochloride): Uses, Dosage, Side Effects & Warnings

Q: Who makes Zelvysia?

Zelvysia is listed by 1 labeler in the FDA NDC directory, including Aucta Pharmaceuticals, Inc..

Uses

Zelvysia 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). Zelvysia is to be used in conjunction with a Phe-restricted diet. Zelvysia 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). Zelvysia is to be used in conjunction with a Phe‑restricted diet. ( 1 )

Dosage and administration

All patients with PKU who are being treated with Zelvysia should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction. ( 2.1 ) Starting Dosage Pediatric patients 1 month to 6 years: The recommended starting dosage of Zelvysia is 10 mg/kg administered orally once daily. ( 2.2 ) Patients 7 years and older : The recommended starting dosage of Zelvysia is 10 to 20 mg/kg administered orally once daily. ( 2.2 ) Dosage Adjustment Doses of Zelvysia may be adjusted in the range of 5 to 20 mg/kg taken once daily. ( 2.2 ) Monitor blood Phe regularly, especially in pediatric patients. ( 2.2 , 5.3 ) Preparation and Administration See the full prescribing information for preparation and administration instructions. ( 2.3 ) 2.1Recommendations Prior to Zelvysia Treatment Treatment with Zelvysia should be directed by physicians knowledgeable in the management of PKU. All patients with PKU who are being treated with Zelvysia should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction. 2.2 Recommended Dosage and Administration The recommended starting dosage of Zelvysia is: Pediatric Patients 1 month to 6 years : 10 mg/kg (actual body weight) administered orally once daily. Patients 7 years and older : 10 to 20 mg/kg (actual body weight) administered orally once daily. Administer Zelvysia with a meal, preferably at the same time each day [see Clinical Pharmacology (12.3) ] . A missed dose should be administered as soon as possible, but two doses should not be administered on the same day. Evaluation Period Existing dietary protein and Phe intake should not be modified during the evaluation period. If a 10 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with Zelvysia at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of Zelvysia treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day do not show a biochemical response and treatment with Zelvysia should be discontinued in these patients. If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with Zelvysia at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of Zelvysia treatment and periodically during the first month. Treatment should be discontinued in patients who do not show a biochemical response (blood Phe does not decrease) after 1 month of treatment at 20 mg/kg per day [see Warnings and Precautions ( 5.4 )] . Dosage Adjustment Once responsiveness to Zelvysia has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to biochemical response to therapy (blood Phe). Periodic blood Phe monitoring is recommended to assess blood Phe control, especially in pediatric patients [see Warnings and Precautions ( 5.3 )] . 2.3 Preparation and Administration Instructions Zelvysia Powder for Oral Solution Patients weighing greater than 10 kg Zelvysia powder for oral solution should be dissolved in 120 to 240 mL of water or apple juice and taken orally within 30 minutes of dissolution. Zelvysia powder for oral solution may also be stirred in a small amount of soft food such as apple sauce or pudding. Empty the contents of the packet(s) in water, apple juice, or a small amount of soft foods and mix thoroughly. The powder should dissolve completely. Patients weighing 10 kg or less (use 100 mg packets) For infants weighing 10 kg or less, Zelvysia powder for oral solution can be dissolved in as little as 5 mL of water or apple juice and a portion of this solution corresponding to a 10 mg/kg dose may be administered orally via an oral dosing syringe. Table 1 provides dosing information for infants at the recommended starting dose of 10 mg/kg per day. Refer to Table 2 for dosing information at 20 mg/kg per day if dosage adjustment is needed. Table 1: 10 mg/kg per day Dosing Table for Infants Weighing 10 kg or Less Patient Weight (kg) Starting Dose: 10 mg/kg per day* Dose (mg) Zelvysia Powder for Oral Solution 100 mg Packets Dissolved † Dilution Volume (mL) ‡ Administered Dose volume (mL) § 1 10 1 10 1 2 20 1 10 2 3 30 1 10 3 4 40 1 10 4 5 50 1 10 5 6 60 1 5 3 7 70 1 5 3.5 8 80 1 5 4 9 90 1 5 4.5 10 100 1 5 5 *Starting dose for infants is 10 mg/kg per day. Dosing information for 20 mg/kg per day is provided in Table 2. † Powder for oral solution provided in single use packets containing 100 mg sapropterin dihydrochloride per packet. ‡ Volume of water or apple juice to dissolve Zelvysia Powder for Oral Solution. § Discard remainder of mixture after volume to be administered is drawn. Table 2: 20 mg/kg per day Dosing Table for Infants Weighing 10 kg or Less Patient Weight (kg) 20 mg/kg per day Dose (mg) Zelvysia Powder for Oral Solution 100 mg Packets * Dissolved Dilution Volume (mL) † Administered Dose volume (mL) § 1 20 1 5 1 2 40 1 5 2 3 60 1 5 3 4 80 1 5 4 5 100 1 5 5 6 120 2 5 3 7 140 2 5 3.5 8 160 2 5 4 9 180 2 5 4.5 10 200 2 5 5 * Powder for oral solution provided in single use packets containing 100 mg sapropterin dihydrochloride per packet. † Volume of water or apple juice to dissolve Zelvysia Powder for Oral Solution. § Discard remainder of mixture after volume to be administered is drawn. 2.1Recommendations Prior to Zelvysia Treatment Treatment with Zelvysia should be directed by physicians knowledgeable in the management of PKU. All patients with PKU who are being treated with Zelvysia should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction.

Dosage forms and strengths

Zelvysia 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. Powder for Oral Solution: 100 mg and 500 mg sapropterin dihydrochloride. ( 3 )

Contraindications

None. None. ( 4 )

Warnings and precautions

Hypersensitivity Reactions Including Anaphylaxis : Zelvysia is not recommended in patients with a history of anaphylaxis to Zelvysia ; 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 Zelvysia 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 Zelvysia . Frequent blood monitoring is recommended, especially in pediatric patients. ( 5.4 , 2.1 ) Lack of Biochemical Response to Sapropterin Dihydrochloride T reatment : Response to sapropterin dihydrochloride treatment cannot be pre-determined by laboratory (e.g., molecular) testing and can only be determined by a therapeutic trial of sapropterin dihydrochloride . ( 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 Sapropterin dihydrochloride is not recommended in patients with a history of anaphylaxis to sapropterin dihydrochloride . 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride . 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 sapropterin dihydrochloride . Monitor patients for signs and symptoms of upper GI mucosal inflammation. 5.3 Hypophenylalaninemia In clinical trials of sapropterin dihydrochloride , some PKU patients experienced hypophenylalaninemia (low blood Phe) during treatment with sapropterin dihydrochloride . In a clinical study of pediatric patients younger than 7 years old treated with sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 Sapropterin Dihydrochloride Some patients with PKU do not show biochemical response (reduction in blood Phe) with treatment with sapropterin dihydrochloride . In two clinical trials at a sapropterin dihydrochloride dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients showed a biochemical response to sapropterin dihydrochloride , 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 sapropterin dihydrochloride [see Clinical Studies ( 14 )] . Biochemical response to sapropterin dihydrochloride treatment cannot generally be pre-determined by laboratory testing (e.g., molecular testing), and should be determined through a therapeutic trial (evaluation) of sapropterin dihydrochloride 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 sapropterin dihydrochloride [see Drug Interactions ( 7 )] . 5.7 Hyperactivity In the sapropterin dihydrochloride postmarketing safety surveillance program, 2 patients with PKU experienced hyperactivity when treated with sapropterin dihydrochloride [see Adverse Reactions ( 6.2 )] . Monitor patients for hyperactivity. 5.1 Hypersensitivity Reactions Including Anaphylaxis Sapropterin dihydrochloride is not recommended in patients with a history of anaphylaxis to sapropterin dihydrochloride . 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 sapropterin dihydrochloride in patients who experience anaphylaxis and initiate appropriate medical treatment.

Side effects

Most common adverse reactions (≥4%) are: headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact contact Aucta Pharmaceuticals, Inc. at 1-800-655-9902 , 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 Sapropterin Dihydrochloride MedDRA Preferred Term Treatment Sapropterin Dihydrochloride (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 sapropterin dihydrochloride 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 sapropterin dihydrochloride 20 mg/kg per day for 6 months. Adverse reactions in these patients were similar in frequency and type as those seen in other sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride . 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 sapropterin dihydrochloride [see Warnings and Precautions ( 5.6 ), Overdosage ( 10 )] .

Drug interactions

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 sapropterin dihydrochloride 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 sapropterin dihydrochloride dosage as needed. (7 ) Drugs Affecting Nitric Oxide‑Mediated Vasorelaxation (e.g., PDE-5 inhibitors) : Potential for vasorelaxation; monitor blood pressure. ( 7 )

Use in specific populations

8.1 Pregnancy Risk Summary Available data from pregnancy safety studies, pharmacovigilance, and published case reports with sapropterin dihydrochloride 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 Sapropterin dihydrochloride 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 sapropterin dihydrochloride through breastfeeding. No lactation-related safety concerns were reported in infants of mothers nursing during maternal treatment with sapropterin dihydrochloride . 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 sapropterin dihydrochloride and any potential adverse effects on the breastfed child from sapropterin dihydrochloride or from the underlying maternal condition. 8.4 Pediatric Use Pediatric patients with PKU, ages 1 month to 16 years, have been treated with sapropterin dihydrochloride in clinical trials [see Clinical Studies ( 14 )]. The efficacy and safety of sapropterin dihydrochloride have not been established in neonates. The safety of sapropterin dihydrochloride 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 sapropterin dihydrochloride 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 sapropterin dihydrochloride responders after 4 weeks of sapropterin dihydrochloride treatment and Phe dietary restriction were treated for 6 months with sapropterin dihydrochloride at 20 mg/kg per day. The effectiveness of sapropterin dihydrochloride 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.

Pregnancy

8.1 Pregnancy Risk Summary Available data from pregnancy safety studies, pharmacovigilance, and published case reports with sapropterin dihydrochloride 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 Sapropterin dihydrochloride 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).

Overdosage

Two unintentional overdosages with sapropterin dihydrochloride have been reported. One adult patient in a sapropterin dihydrochloride clinical trial received a single sapropterin dihydrochloride dose of 4,500 mg (36 mg/kg) instead of 2,600 mg (20 mg/kg). The patient reported mild headache and mild dizziness immediately after taking the dose; both symptoms resolved within 1 hour with no treatment intervention. There were no associated laboratory test abnormalities. The patient suspended therapy for 24 hours and then restarted sapropterin dihydrochloride with no reports of abnormal signs or symptoms. In postmarketing, one pediatric patient received sapropterin dihydrochloride doses of 45 mg/kg per day instead of 20 mg/kg per day. The patient reported hyperactivity that began at an unspecified time after overdosage and resolved after the sapropterin dihydrochloride dose was reduced to 20 mg/kg per day. In a clinical study to evaluate the effects of sapropterin dihydrochloride on cardiac repolarization, a single supra-therapeutic dose of 100 mg/kg (5 times the maximum recommended dose) was administered to 54 healthy adults. No serious adverse reactions were reported during the study. The only adverse reactions reported in more than 1 subject who received the supra-therapeutic dose were upper abdominal pain (6%) and dizziness (4%). A dose-dependent shortening of the QT interval was observed [see Clinical Pharmacology ( 12.2 )]. Patients should be advised to notify their physicians in cases of overdosage.

Description

Zelvysia (sapropterin dihydrochloride) is an orally administered Phenylalanine Hydroxylase activator (or PAH activator). Sapropterin dihydrochloride, the active pharmaceutical ingredient in Zelvysia , is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Sapropterin dihydrochloride is an off-white to pale yellow 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 C 9 H 15 N 5 O 3 ·2HCl with a molecular weight of 314.17. Sapropterin dihydrochloride has the following structural formula: Zelvysia is supplied as powder for oral solution containing 100 mg of sapropterin dihydrochloride (equivalent to 76.8 mg of sapropterin base). Zelvysia is also supplied as powder for oral solution containing 500 mg of sapropterin dihydrochloride (equivalent to 384 mg of sapropterin base). Zelvysia powder for oral solution is off-white to yellow in color. Each unit dose packet contains the following inactive ingredients: ascorbic acid, mannitol (USP) and potassium citrate (USP). descrip

Mechanism of action

12.1 Mechanism of Action Sapropterin dihydrochloride 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.

How supplied

Zelvysia for Oral Solution Supplied as an off-white to yellow powder supplied in unit dose packets as follows: 100 mg sapropterin dihydrochloride per packet: NDC 73289-0070-2 Carton of 30 unit dose packets NDC 73289-0070-1 Single unit dose packet 500 mg sapropterin dihydrochloride per packet: NDC 73289-0071-2 Carton of 30 unit dose packets NDC 73289-0071-1 Single unit dose packet Storage Store Zelvysia for oral solution at 20ºC to 25ºC (68ºF to 77ºF); excursions allowed between 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Protect from moisture.

Patient information

Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Hypersensitivity Reactions Including Anaphylaxis Advise patients and caregivers to discontinue Zelvysia and contact the patient’s healthcare provider immediately if they experience symptoms of anaphylaxis, including (but not limited to) wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Continue nutritional management including dietary protein and Phe restriction [see Warnings and Precautions ( 5.1 )] . Upper Gastrointestinal Mucosal Inflammation Advise patients and caregivers to contact their healthcare provider if the patient experiences signs and symptoms suggestive of upper GI mucosal inflammation, including nausea, vomiting, dysphagia, dyspepsia, loss of appetite; oropharyngeal, esophageal, or upper abdominal pain [see Warnings and Precautions ( 5.3 )] . Hypophenylalaninemia Advise patients and caregivers that Zelvysia may cause hypophenylalaninemia (low blood Phe levels), especially in pediatric patients younger than 7 years of age [see Warnings and Precautions ( 5.3 )] . Monitoring of Blood Phe Levels Advise patients and caregivers that frequent blood Phe monitoring is important to ensure blood Phe levels are in the desirable range and that they should maintain dietary protein and Phe restriction while on Zelvysia [see Warnings and Precautions ( 5.4 )] . Prolonged hyperphenylalaninemia (high blood Phe levels) in patients with PKU can result in severe neurologic damage, including intellectual disability, developmental delay, microcephaly, delayed speech,seizures, and behavioral abnormalities [see Warnings and Precautions ( 5.4 )] . Lack of Biochemical Response to Zelvysia Some patients do not show a biochemical response (blood Phe reduction) when treated with Zelvysia . Advise patients and caregivers to discontinue treatment with Zelvysia if the patient does not show an adequate biochemical response in blood Phe after one month of treatment with Zelvysia 20 mg/kg per day [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5 )] . Interaction with Levodopa Advise patients and caregivers that patients with underlying neurological disorders taking Zelvysia in combination with levodopa may experience seizures, exacerbation of seizures, over-stimulation or irritability. Inform patients and caregivers to contact their healthcare provider if the patient has a change in neurologic status during treatment with Zelvysia [see Warnings and Precautions ( 5.6 )] . Hyperactivity Advise patients and caregivers that Zelvysia may cause hyperactivity and to contact their healthcare provider if the patient experiences hyperactivity, restlessness, fidgeting, or excessive talking [see Warnings and Precautions ( 5.7 )] . Dosing and Monitoring [see Dosage and Administration ( 2.2 )] Advise patients and caregivers of the following: Zelvysia should be used in conjunction with a PKU-specific diet, including dietary protein and Phe restriction. Dietary protein and Phe intake should not be modified during the Zelvysia evaluation period when assessing biochemical response. The patient must be evaluated for changes in blood Phe after being treated with Zelvysia at the recommended dose(s) for age to determine if they have a biochemical response and that blood Phe levels and dietary Phe intake should be assessed frequently during the first month of Zelvysia treatment. Monitoring of blood Phe levels is important during Zelvysia treatment. Preparation and Administration [see Dosage and Administration (2.3) ] Advise patients and caregivers: Zelvysia powder for oral solution should be dissolved in water or apple juice or stirred in a small amount of soft food such as apple sauce or pudding. Take Zelvysia with a meal, preferably at the same time each day. Manufactured for: Aucta Pharmaceuticals, Inc. Piscataway, NJ 08854

Active ingredients

Sapropterin Dihydrochloride in 2 products

Zelvysia NDC products (2)

NDC	Strength & form	Labeler	Type
73289-0070	Sapropterin Dihydrochloride 100 mg/1 Powder, For Solution	Aucta Pharmaceuticals, Inc.	ANDA
73289-0071	Sapropterin Dihydrochloride 500 mg/1 Powder, For Solution	Aucta Pharmaceuticals, Inc.	ANDA

Frequently asked questions

What is Zelvysia used for?

Zelvysia 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). Zelvysia is to be used in conjunction with a Phe-restricted diet. Zelvysia is a phenylalanine hydroxylase activator indicated to reduce blood phenylalanine (Phe) levels in…

What are the side effects of Zelvysia?

Most common adverse reactions (≥4%) are: headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact contact Aucta Pharmaceuticals, Inc. at 1-800-655-9902 , 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,… See the full label for the complete list.

Who makes Zelvysia?

Zelvysia is listed by 1 labeler in the FDA NDC directory, including Aucta Pharmaceuticals, Inc..