JAVYGTOR Sapropterin Dihydrochloride 100 mg Powder, For Solution, 30 packets
Other active recalls for Sapropterin Dihydrochloride (different manufacturers) — 1 · tap to view
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Phenylalanine Hydroxylase Activator class.
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🏭 Manufacturer & labeler
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🩺 Clinical
- Sapropterin gives your body more of a helper molecule called BH4 that the enzyme responsible for breaking down phenylalanine needs to work. If you have BH4-responsive PKU, this can...
- What exactly does sapropterin do, and why do I still have to follow a special diet?
- Your doctor will check your blood phenylalanine levels regularly after you start the medication. If the drug is working, your levels should start to drop within the first 24 hours,...
- How will I know if sapropterin is actually working for me?
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Sapropterin Dihydrochloride — tap one for details:
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
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UNII PQ6CK8PD0R
Ascorbic acid, also known as vitamin C, is a white crystalline powder. It serves as an antioxidant to prevent degradation of other ingredients and may also function as a preservative in the formulation.
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UNII 3OWL53L36A
A natural sugar alcohol derived from seaweed or synthesized in the lab. It's used as a filler to add bulk, a sweetener in sugar-free formulas, and a disintegrant to help tablets break apart in the stomach.
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UNII EE90ONI6FF
Potassium citrate is a salt derived from citric acid and potassium. In medicines, it acts as a buffer to adjust and maintain the pH balance of the product, helping keep it stable and palatable.
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UNII 96K6UQ3ZD4
Sucralose is a synthetic sweetener made from sugar. It's added to medicines to improve taste without adding calories, helping make bitter or unpleasant-tasting drugs easier to take.
4 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | $26.69 | — |
| Medicare drug plans payPart D · Q2 2026 | $26.40 | — |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Sapropterin dihydrochloride 100 mg 31722-0047-30 | Camber | 30 packets | — | AB | FDA listed | — |
| Sapropterin Dihydrochloride 100 mg 42571-0509-41 | Micro | 30 packets | — | AB | FDA listed | — |
| Javygtor 100 mgthis 43598-0097-30 | Dr. | 30 packets | — | AB | FDA listed | — |
| Sapropterin Dihydrochloride 100 mg 49884-0948-72 | Par | 30 packets | — | AB | FDA listed | — |
| Sapropterin Dihydrochloride 100 mg 52817-0850-01 | TRUPHARMA, | 1 powder | — | AB | FDA listed | — |
| Kuvan 100 mg 68135-0301-22 | BioMarin | 30 packets | — | AB | FDA listed | — |
| Sapropterin dihydrochloride 100 mg 72603-0193-30 | NorthStar | 30 packets | — | AB | FDA listed | — |
| Zelvysia 100 mg 73289-0070-02 | Aucta | 30 packets | — | AB | FDA listed | — |
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⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
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🗺️ Medicaid utilization & spend
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 43598-0097-30 You're viewing this | 30 PACKET in 1 CARTON (43598-097-30) / 1 POWDER, FOR SOLUTION in 1 PACKET (43598-097-11) | 2022-09-16 | Active |
🧭 About this NDC listing & data coverage
What data is (and isn’t) available for this NDC — tap to expand
| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | — Not published for this NDC No photo available yet for this listing. |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | ✓ Available |
Questions about this listing
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📄 Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE JAVYGTOR (sapropterin dihydrochloride) 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). JAVYGTOR is to be used in conjunction with a Phe-restricted diet. JAVYGTOR (sapropterin dihydrochloride) 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).
JAVYGTOR is to be used in conjunction with a Phe-restricted diet. (1)
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION All patients with PKU who are being treated with JAVYGTOR (sapropterin dihydrochloride) 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 dose of JAVYGTOR is 10 mg/kg administered orally once daily. (2.2) Patients 7 years and older: The recommended starting dose of JAVYGTOR is 10 to 20 mg/kg administered orally once daily.
(2.2) Dosa g e Adjustment Doses of JAVYGTOR powder for oral solution 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 JAVYGTOR Treatment Treatment with JAVYGTOR should be directed by physicians knowledgeable in the anagement of PKU. All patients with PKU who are being treated with JAVYGTOR should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction.
2.2Recommended Dosage and Administration The recommended starting dosage of JAVYGTOR is: Pediatric Patients 1 month to 6 years: 10 mg/kg (actual body weight) administered orally oncedaily. Patients 7 years and older: 10 to 20 mg/kg (actual body weight) administered orally once daily. Administer JAVYGTOR with a meal, preferably at the same time each day [ see ClinicalPharmacology ( 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 JAVYGTOR at 10 mg/kg per day for a period of up to 1 month.
Blood Phe levels should be checked after 1 week of JAVYGTOR 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 JAVYGTOR 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 JAVYGTOR at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of JAVYGTOR 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 JAVYGTOR 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 )].
2.3Preparation and Administration Instructions JAVYGTOR ( sapropterin dihydrochloride) Powder for Oral Solution Patients weighing greater than 10 kg JAVYGTOR powder for oral solution should be dissolved in 60 to 240 mL of water or apple juice and taken orally within 30 minutes of dissolution. JAVYGTOR powder for oral solution may also be stirred in a small amount of soft foods 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, JAVYGTOR 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…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS JAVYGTOR powder for oral solution is available as a unit dose packet containing 100 mg of sapropterin dihydrochloride (equivalent to 76.8 mg of sapropterin base) and 500 mg of sapropterin dihydrochloride (equivalent to 384 mg of sapropterin base). The powder is off white to pale yellow powder. Powder for Oral Solution: 100 mg and 500 mg sapropterin dihydrochloride. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS None. None (4).
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions including anaphylaxis: JAVYGTOR (sapropterin dihydrochloride) is not recommended in patients with a history of anaphylaxis to sapropterin dihydrochloride; discontinue treatment in patients who experience anaphylaxis and initate 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 JAVYGTOR 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 JAVYGTOR. Frequent blood monitoring is recommended, especially in pediatric patients.
( 5.4 , 2.1 ) Lack of Biochemical Response to JAVYGTOR Treatment: Response to JAVYGTOR treatment cannot be pre-determined by laboratory (e.g., molecular) testing and can only be determined by a therapeutic trial of JAVYGTOR. ( 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 )
5.1Hypersensitivity Reactions Including Anaphylaxis JAVYGTOR 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 JAVYGTOR in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary protein and Phe restriction in patients who experience anaphylaxis.
5.2Upper 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 JAVYGTOR powder for oral solution.
Monitor patients for signs and symptoms of upper GI mucosal inflammation.
5.3Hypophenylalaninemia 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) ].
5.4Monitoring 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 JAVYGTOR powder for oral solution 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 ) ].
5.5Lack of Biochemical Response to JAVYGTOR Some patients with PKU do not show biochemical response (reduction in blood Phe) with treatment with JAVYGTOR. In two clinical trials at a sapropterin dihydroch…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS Most common adverse reactions (≥4%) are: headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 Studies1 to 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 dihydrochloride 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 pati…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Table 4 includes drugs with clinically important drug interactions when administered withsapropterin 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 post-marketing 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 JAVYGTOR 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 USE IN SPECIFIC POPULATIONS
8.1Pregnancy Risk Summary Available data from pregnancy safety studies, pharmacovigilance, and published case reportswith sapropterin use during pregnancy have not identified a drug-associated risk of major birthdefects, miscarriage, or adverse maternal or fetal outcomes ( see Data) . Uncontrolled bloodphenylalanine concentrations before and during pregnancy are associated with an increased riskof 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 embryofetal 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).
8.2Lactation 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 through breastfeeding. No lactation-related safety concerns were…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Available data from pregnancy safety studies, pharmacovigilance, and published case reportswith sapropterin use during pregnancy have not identified a drug-associated risk of major birthdefects, miscarriage, or adverse maternal or fetal outcomes ( see Data) . Uncontrolled bloodphenylalanine concentrations before and during pregnancy are associated with an increased riskof 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 embryofetal 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).
🧒 Pediatric Use ▾
8.4Pediatric 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)
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical studies of sapropterin dihydrochloride 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.
🆘 Overdosage ▾
10 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.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism 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.
12.2Pharmacodynamics 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 sapropterin dihydrochloride powder for oral solution is adequate to maintain stable blood Phe levels over a 24-hour period. Twelve patients with blood Phe levels ranging from 516 to 986 μmol/L (mean 747 ± 153 μmol/L) were assessed with 24-hour blood Phe level monitoring following a daily morning dose of 10 mg/kg per 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. Sapropterin dihydrochloride dose-response relationship was studied in an open-label, forced titration study at doses of 5 mg/kg per day, then 20 mg/kg per day, and then 10 mg/kg per day (Study 3) [see Clinical Studies (14 )] .
Individual blood Phe levels were highly variable among patients. The mean blood Phe level observed at the end of each 2-week dosing period decreased as the dose of sapropterin dihydrochloride increased, demonstrating an inverse relationship between the dose of sapropterin dihydrochloride and mean blood Phe levels. Cardiac Electrophysiology A thorough QTc study was performed in 56 healthy adults.
This randomized, placebo and active controlled crossover study was conducted to determine if a single supra-therapeutic (100 mg/kg) dose of sapropterin dihydrochloride, or a single therapeutic dose (20 mg/kg) of sapropterin dihydrochloride had an effect on cardiac repolarization. In this study, sapropterin dihydrochloride was administered after dissolving tablets in water under fed condition. This study demonstrated a dose-dependent shortening of the QT interval.
The maximum placebo-subtracted mean change from baseline of the QTc interval was -3.69 and -8.32 ms (lower bound of 90% CI: -5.3 and -10.6 ms) at 20 and 100 mg/kg, respectively.
12.3Pharmacokinetics Studies in healthy subjects have shown comparable absorption of sapropterin 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 C max of 84% and AUC of 87% (dissolved in water). However, there was extensive variability in individual subject values for C max and AUC across the different modes of administration and meal conditions.
In the clinical trials of sapropterin dihydrochloride, 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 hours), comparable with values seen in healthy subjects (range 3 to 5.3 hours). A study in healthy adults with 10 mg/kg of sapropterin dihydrochloride demonstrated that the absorption via intact tablet administration was 40% greater than via dissolved tablet administration under fasted conditions based on AUC 0-t .
The administration of intact tablets under fed conditions resulted in an approximately 43% increase in the extent of absorption compared to fasted conditions based on AUC 0-t [see Dosage and Administration ( 2.3) ]. Population pharmacokinetic analysis of sapropterin including patients from 1 month to 49 years of age showed that body weight is the only covariate substantially affecting clearance or distribution volume (see Table 5). Pharmacoki…
🧬 Mechanism of Action ▾
12.1Mechanism 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 / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING JAVYGTOR (sapropterin dihydrochloride) powder for oral solution is off white to pale yellow powder packaged in unit dose packets as follows: 100 mg sapropterin dihydrochloride powder for oral solution per packet: Single unit dose packet NDC 43598-097-11 Carton of 30 unit dose packets NDC 43598-097-30 500 mg sapropterin dihydrochloride powder for oral solution per packet: Single unit dose packet NDC 43598-162-11 Carton of 30 unit dose packets NDC 43598-162-30 Storage Store JAVYGTOR at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].
Protect from moisture.
📋 Description ▾
11 DESCRIPTION JAVYGTOR (sapropterin dihydrochloride) is an orally administered Phenylalanine Hydroxylase activator (or PAH activator). Sapropterin dihydrochloride, the active pharmaceutical ingredient in JAVYGTOR, is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Sapropterin dihydrochloride is a white to off-white 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 C 9 H 15 N 5 O 3 ·2HCl with a molecular weight of 314.17. Sapropterin dihydrochloride has the following structural formula: JAVYGTOR is supplied as powder for oral solution containing 100 mg of sapropterin dihydrochloride (equivalent to 76.8 mg of sapropterin base) and 500 mg of sapropterin dihydrochloride (equivalent to 384 mg of sapropterin base).
JAVYGTOR powder for oral solution is off white to pale yellow powder. Each unit dose packet contains the following inactive ingredients: ascorbic acid, mannitol, potassium citrate and sucralose.
💬 Information for Patients ▾
17 PATIENT COUNSELING 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 JAVYGTOR 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 [seeWarnings and Precautions ( 5.3 )]. Hypophenylalaninemia Advise patients and caregivers that JAVYGTOR 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 JAVYGTOR [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 JAVYGTOR Some patients do not show a biochemical response (blood Phe reduction) when treated with JAVYGTOR. Advise patients and caregivers to discontinue treatment with JAVYGTOR if the patient does not show an adequate biochemical response in blood Phe after one month of treatment with JAVYGTOR 20 mg/kg per day [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.4 )]. Interaction with Levodopa Advise patients and caregivers that patients with underlying neurological disorders taking JAVYGTOR 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 JAVYGTOR [see Warnings and Precautions ( 5.5 )]. Hyperactivity Advise patients and caregivers that JAVYGTOR may cause hyperactivity and to contact their healthcare provider if the patient experiences hyperactivity, restlessness, fidgeting, or excessive talking [see Warnings and Precautions ( 5.6 )]. Dosing and Monitoring [ see Dosage and Administration ( 2.2 ) ].
Advise patients and caregivers of the following: JAVYGTOR 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 JAVYGTOR evaluation period when assessing biochemical response. The patient must be evaluated for changes in blood Phe after being treated with JAVYGTOR 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 JAVYGTOR treatment.
Monitoring of blood Phe levels is important during JAVYGTOR treatment. Preparation and Administration [ see Dosage and Administration ( 2.3 ) ] Advise patients and caregivers: JAVYGTOR 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 JAVYGTOR with a meal, preferably at the same time each day.
Rx only Distributor: Dr. Reddy’s Laboratories Inc., Princeton, NJ 08540 100 mg – Made in India 500 mg - Made in Switz…