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Kuvan SAPROPTERIN DIHYDROCHLORIDE 100 mg Powder, For Solution, 30 packets — NDC 68135-0301-22 package photo
Label image from the product's FDA listing (DailyMed) — may show a different pack size or an older label revision.

Kuvan SAPROPTERIN DIHYDROCHLORIDE 100 mg Powder, For Solution, 30 packets — NDC 68135-301-22 (Billing 68135-0301-22)

by BioMarin Pharmaceutical Inc. · 30 PACKET in 1 CARTON / 1 POWDER, FOR SOLUTION in 1 PACKET

This is a package of 30 packets of Kuvan SAPROPTERIN DIHYDROCHLORIDE 100 mg Powder, For Solution from BioMarin Pharmaceutical Inc., marketed since Feb 2014 and currently FDA-listed. It is this product's only package size.

NDC 68135-0301-22
🏷️ FDA NDC (as labeled) 68135-301-22 billing pads the product segment with a zero
Rx only Brand On market Non-controlled ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Jul 24, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

NDC database record

One package, one record: these facts belong to NDC 68135-301-22 alone.

Record
FDA NDC Directory package listing · Human prescription drug
Code segments
68135 labeler · 301 product · 22 package
Package marketed since
Feb 21, 2014
Sample package
No — commercial package
Listing certified through
Dec 31, 2026
Billing quantity
30 EA per package
Barcode (UPC-A, from the NDC)
3 6813530122 6
Medicaid fills, this package
428 prescriptions in the last four reported quarters
FDA record last changed
Jul 24, 2026
⚠️
Other active recalls for Sapropterin Dihydrochloride (different manufacturers) — 2 · tap to view
These affect other manufacturers’ products for the same ingredient — not necessarily the exact NDC on this page.
Class III · Nov 22, 2024 — Failed Impurities/Degradation Specifications (Dr. Reddy's Laboratories, Inc.) · FDA recall D-0117-2025
Class I · Apr 8, 2024 — Sub-potent Drug; powder discoloration associated with decreased potency (Dr. Reddy's Laboratories, Inc.) · FDA recall D-0485-2024
Each entry is an official FDA enforcement report — look up any recall number in the FDA recall database ↗

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 68135-301-22
Product NDC 68135-301
11-digit billing NDC 68135030122
NCPDP billing unit EA — each (per item)
RxCUI 1111018, 1111020, 1486687, 1486691, 1653217, 1653221
UNII RG277LF5B3
Application # NDA205065
SPL Set ID af38711e-8873-4790-a92d-4d583e23fb89
Established class (EPC) Phenylalanine Hydroxylase Activator
Mechanism of action Breast Cancer Resistance Protein Inhibitors; P-Glycoprotein Inhibitors; Phenylalanine Hydroxylase Activators
DEA schedule Non-controlled
Marketing category NDA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2014-02-21
Route ORAL
Dosage form POWDER, FOR SOLUTION
Substance SAPROPTERIN DIHYDROCHLORIDE
TE code (Orange Book) AB · RLD · RS

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GPI-14 30908565103020
GPI class Kuvan
GCN Seq No 071802
GCN 35789
HICL code 035266
Ingredient (HICL) Sapropterin Dihydrochloride
HIC1 code C
Therapeutic class — broad (HIC1) Electrolyte Balance/Metabolism/Nutrition
HIC2 code C7
Therapeutic class — intermediate (HIC2) Metabolic Inhibitors And Stimulants
HIC3 code C7H
Therapeutic class — specific (HIC3) Pku Tx Agent-Cofactor Of Phenylalanine Hydroxylase
AHFS code 44:08.00.00
AHFS class Enzyme Cofactors/Chaperones
FDB label name KUVAN 100 MG POWDER PACKET
FDB brand name Kuvan
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 071802
  • GCN: 35789
  • GPI-14 (Medi-Span): 30908565103020
  • HICL (First Databank): 035266
  • AHFS class code: 44:08.00.00
  • RxCUI (RxNorm): 1111018
Why two NDCs? The FDA registers this code as 68135-301-22 — a 5-3-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the product segment → 68135-0301-22. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Phenylalanine Hydroxylase Activator class.

Pharmacologic class Phenylalanine Hydroxylase Activator
Drug family (ATC) Various alimentary tract and metabolism products
How it works P-Glycoprotein Inhibitors, Breast Cancer Resistance Protein Inhibitors, Phenylalanine Hydroxylase Activators
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

Label name KUVAN 100 MG POWDER PACKET Ingredient Sapropterin Dihydrochloride
📖 What it is MedlinePlus · NLM

Sapropterin is used along with a restricted diet to control blood phenylalanine levels in adults and children 1 month of age and older who have phenylketonuria (PKU; an inborn condition in which phenylalanine may build up in the blood and causes decreased intelligence and a decreased ability to focus, remember, and organize information). Sapropterin will only work for some people who have PKU, and the only way to tell if sapropterin will help a particular patient is to give the medication for a period of time and see whether his or her phenylalanine level decreases. Sapropterin is in a class o...

Read the full MedlinePlus article ↗
📗 Our plain-language guide HelloPharmacist
  • 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?
📖 Read our full Sapropterin guide →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

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 systemPer mLPer package
Retail pharmacies payNADAC · weekly Not in the retail survey — common for institutional, discontinued, or low-volume packs.
Medicaid paysCMS SDUD · 12 mo $43.29 —
Medicare drug plans payPart D · Q2 2026 $41.34 —
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
68135-0301-22 You're viewing this Main listing 30 PACKET in 1 CARTON / 1 POWDER, FOR SOLUTION in 1 PACKET 2014-02-21 — Active

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice 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 mg 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 mgthis 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 —
About this product: this is the brand-name version. Some generic versions are approved by the FDA, but we could not confirm current pharmacy availability from our pricing/market data.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2013
First FDA approval
Dec 2013
📍
2026
Currently FDA-listed
13 years listed
🛡️
2033
Latest patent/protection listed
not a guaranteed launch date
🔒Generic approved by FDA, but pharmacy availability is not confirmed

The FDA lists approved generic versions of this medicine, but that does not always mean a pharmacy can get one today. Patent rules, launch agreements, supply and pricing can affect when generics actually arrive.

🛡️ Latest patent/protection date listed: FDA patent/protection data lists protections through May 2033. This may affect when a full generic version becomes widely available, but it is not a guaranteed launch date.
📅 FDA approved Dec 19, 2013 AB TE-rated RLD RS ⏳ ~6.6 yr to latest listed protection

Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.

Patents & exclusivity — FDA Orange Book
US 9216178 — drug product
US 9216178 — drug product
US 9216178*PED — drug product
US 9216178*PED — drug product
2013 2015 2017 2019 2021 2023 2025 2027 2029 2031 2033
Today
LOE
Substance patent Formulation patent Method-of-use patent Exclusivity Pediatric +6mo
🏛️FDA exclusivity
FDA-granted marketing protection. It’s separate from patents and may be shorter than patent protection.
🧪Product / substance patents
Patents covering the active ingredient, product, formulation, or related drug features.
🎯Method-of-use patents
Patents covering specific approved uses. These can sometimes be carved out with a “skinny label,” but not always.
🛈 What do these terms mean?
Patent
Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
Substance patent
Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
Formulation (product) patent
Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
Method-of-use patent
A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
Skinny label
A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
Exclusivity
FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
Paragraph IV
A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
RLD / RS
Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
TE / AB rating
FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
LOE (loss of exclusivity)
The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.

Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.

Listed patents (4)
PatentTypeUse codeExpires
US 9216178 ↗ Drug product — Nov 1, 2032
US 9216178 ↗ Drug product — Nov 1, 2032
US 9216178*PED ↗ Drug product — May 1, 2033
US 9216178*PED ↗ Drug product — May 1, 2033
Common questions
Is there a generic version of KUVAN 100 MG POWDER PACKET?
Yes — an FDA-approved generic equivalent is listed in the FDA Orange Book for KUVAN 100 MG POWDER PACKET. See the alternatives section for substitutable, lower-cost products.
The FDA approved a generic — why can’t I get it at my pharmacy yet?
FDA approval and pharmacy availability are two different things. The FDA can approve a generic years before it actually reaches pharmacies, because the brand company may still hold patents or have a settlement that delays the launch. A manufacturer also has to choose to make and sell it, and have supply ready. So a drug can be “FDA-approved generic exists” and still be brand-only at the counter today.
Why do different websites show different generic release dates?
Generic availability is not based on one single date. Some sources use the first exclusivity expiration, some use the last product patent, and others use the latest method-of-use patent. Patent challenges, settlements, licenses, and label carve-outs can also change the real-world launch date. This page shows the underlying Orange Book dates so you can see why estimates may differ.
What does “FDA listed” mean?
It means the product appears in the FDA’s official NDC directory. That’s a good sign a product exists and is intended for the U.S. market, but on its own it does not confirm a pharmacy can fill it today. Where we have recent retail pricing data (NADAC) for a product, we label it “Availability likely” instead.
What does a patent or protection date mean here?
It’s the latest date currently listed in the FDA Orange Book for a patent or exclusivity on the brand product. It can affect when a full generic version becomes widely available — but it is not a guaranteed generic launch date. Generics sometimes arrive earlier (through a settlement or patent challenge) or later (a manufacturer still has to make and sell one).
What does “current Orange Book estimate” mean?
It means we are using the latest patent and exclusivity dates currently listed in the FDA Orange Book. It is not a guaranteed launch date.
Can a generic come out before the last patent expires?
Sometimes. A generic company may challenge a patent, settle with the brand manufacturer, receive a license, or obtain approval with a narrower label that avoids a patented use. In other cases, the last listed protection may delay full-label generic competition.
Can a generic come out after the listed dates?
Yes. Even after patents or exclusivity expire, a generic still needs FDA approval and a manufacturer must choose to market it. Supply, litigation, business decisions, or regulatory issues can delay actual availability.
What is the difference between patents and exclusivity?
Patents are legal protections usually issued by the U.S. Patent and Trademark Office. FDA exclusivity is marketing protection granted by the FDA. They are separate, and either one can affect generic timing.
Why are there multiple patent dates?
One drug can have several patents covering different things: the active ingredient, a formulation, a manufacturing process, or a specific approved use. That is why a page may show several expiration dates instead of one simple generic date.
Built from FDA Orange Book patent and exclusivity data. Dates are refreshed from public FDA data when available; the marker is max(latest patent expiry, latest exclusivity expiry). Paragraph-IV settlements and first-filer 180-day exclusivity can shift the real date; a method-of-use patent may allow an earlier skinny-label generic for non-protected indications. Generic launch timing is an estimate, not a guarantee.
Where does this data come from?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

What it looks like

Color White / white
ShapeRound
Imprint177
Size1 mm
ScoringNot scored
One label can cover several strengths, so colors may be combined — always confirm a loose pill against the dispensed prescription label or a pharmacist.
Where does this data come from?
Physical description (imprint, shape, color, scoring, coating) from this product’s FDA Structured Product Labeling (SPL), mirrored from DailyMed / openFDA.

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.

A current SPL was checked, but it does not contain a structured or narrative inactive-ingredient list for this product. This does not mean the product has no inactive ingredients.
Where does this data come from?
Source: official FDA Structured Product Labeling (SPL) via DailyMed and the openFDA label index. Structured IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerBioMarin Pharmaceutical Inc.
Application holderBIOMARIN PHARMACEUTICAL INC
FDA applicationNDA205065 (NDA)
Labeler code68135
First marketedFeb 2014
Product typeHuman Prescription Drug
Portfolio17 products on file

More NDCs from BioMarin Pharmaceutical Inc. labeler code 68135

The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📋 Description 💬 Information for Patients 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📄 Patient Package Insert 📖 Instructions for Use 📄 Package Label / Principal Display Panel
🎯 Indications and Usage 94 words ▾

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

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

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION All patients with PKU who are being treated with KUVAN 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 KUVAN is 10 mg/kg administered orally once daily. ( 2.2 ) Patients 7 years and older : The recommended starting dosage of KUVAN is 10 to 20 mg/kg administered orally once daily.

( 2.2 ) Dosage Adjustment Doses of KUVAN 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 KUVAN Treatment Treatment with KUVAN should be directed by physicians knowledgeable in the management of PKU. All patients with PKU who are being treated with KUVAN 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 KUVAN 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 KUVAN 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 KUVAN at 10 mg/kg per day for a period of up to 1 month.

Blood Phe levels should be checked after 1 week of KUVAN treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg 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 KUVAN 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 KUVAN at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of KUVAN 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 KUVAN 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 KUVAN Tablets KUVAN tablets may be swallowed either as whole tablets or dissolved in 120 to 240 mL of water or apple juice and taken orally within 15 minutes of dissolution. It may take a few minutes for the tablets to dissolve. To make the tablets dissolve faster, tablets may be stirred or crushed.

The tablets may not dissolve completely. Patients may see small pieces floating on top of the water or apple juice. This is normal and safe for patients to swallow.

If after drinking the medicine, patients still see pieces of the tablet in the container, more water or apple juice can be added to make sure all of the medicine is consumed. KUVAN tablets may also be crushed and then mixed in a small amount of soft foods such as apple sauce or pudding. KUVAN Powder for Oral Solution Patients weighing greater than 10 kg KUVAN powder f… [Excerpted — this section continues on DailyMed.]

💊 Dosage Forms and Strengths 91 words ▾

3 DOSAGE FORMS AND STRENGTHS KUVAN tablets are for oral use. Each tablet contains 100 mg of sapropterin dihydrochloride. Tablets are round, off-white to light yellow, mottled, and debossed with “177”.

KUVAN powder for oral solution is available as a unit dose packet containing 100 mg of sapropterin dihydrochloride and as a unit dose packet containing 500 mg of sapropterin dihydrochloride. The powder is off-white to yellow in color. Tablets: 100 mg sapropterin dihydrochloride.

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

⛔ Contraindications 7 words ▾

4 CONTRAINDICATIONS None. None. ( 4 )

⚠️ Warnings and Cautions ~3 min read ▾

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Including Anaphylaxis : KUVAN is not recommended in patients with a history of anaphylaxis to KUVAN; discontinue treatment in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary Phe restrictions. ( 5.1 ) Upper Gastrointestinal Mucosal Inflammation : Monitor patients for signs and symptoms of these conditions including esophagitis and gastritis.

( 5.2 ) Hypophenylalaninemia : Pediatric patients younger than 7 years treated with KUVAN doses of 20 mg/kg per day are at increased risk for low levels of blood Phe compared with patients 7 years and older. ( 5.3 ) Monitoring Blood Phe Levels During Treatment : Ensure adequate blood Phe control and nutritional balance during treatment with KUVAN. Frequent blood monitoring is recommended, especially in pediatric patients.

( 5.4 , 2.1 ) Lack of Biochemical Response to KUVAN T reatment : Response to KUVAN treatment cannot be pre-determined by laboratory (e.g., molecular) testing and can only be determined by a therapeutic trial of KUVAN. ( 5.5 , 2.1 ) Interaction with Levodopa : Seizures, over-stimulation or irritability may occur; monitor patients for a change in neurologic status. ( 5.6 , 7 ) Hyperactivity : Monitor patients for hyperactivity.

( 5.7 )

5.1Hypersensitivity Reactions Including Anaphylaxis KUVAN is not recommended in patients with a history of anaphylaxis to KUVAN. Hypersensitivity reactions, including anaphylaxis and rash, have occurred [see Adverse Reactions ( 6.2 )] . Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.

Discontinue treatment with KUVAN in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary protein and Phe restriction in patients who experience anaphylaxis.

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

Monitor patients for signs and symptoms of upper GI mucosal inflammation.

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

5.4Monitoring 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 KUVAN is required to ensure adequate Phe control and nutritional balance.

Monitor blood Phe levels during treatment to ensure adequate blood Phe level control. Frequent blood monitoring is recommended in the pediatric population [see Dosage and Administration ( 2.2 )] .

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

🤒 Adverse Reactions ~3 min read ▾

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 BioMarin Pharmaceutical Inc. at 1-877-695-8826, 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 KUVAN was evaluated in 7 clinical studies in patients with PKU (aged 1 month to 50 years) [see Clinical Studies ( 14 )] . In Studies 1-4 (controlled and uncontrolled studies), 579 patients with PKU aged 4 to 49 years received KUVAN in doses ranging from 5 to 20 mg/kg per day for lengths of treatment ranging from 1 to 164 weeks.

The patient population was evenly distributed in gender, and approximately 95% of patients were Caucasian. The most common adverse reactions (≥4% of patients) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion. The data described in Table 3 reflect exposure of 74 patients with PKU to KUVAN at doses of 10 to 20 mg/kg per day for 6 to 10 weeks in two double-blind, placebo-controlled clinical trials (Studies 2 and 4).

Table 3 enumerates adverse reactions occurring in at least 4% of patients treated with KUVAN in the double-blind, placebo-controlled clinical trials described above. Table 3: Summary of Adverse Reactions Occurring in ≥4% of Patients in Placebo-Controlled Clinical Studies with KUVAN MedDRA Preferred Term Treatment KUVAN (N=74) Placebo (N=59) No. Patients (%) No.

Patients (%) Headache 11 (15) 8 (14) Rhinorrhea 8 (11) 0 Pharyngolaryngeal pain 7 (10) 1 (2) Diarrhea 6 (8) 3 (5) Vomiting 6 (8) 4 (7) Cough 5 (7) 3 (5) Nasal congestion 3 (4) 0 In open-label, uncontrolled clinical trials (Studies 1 and 3) all patients received KUVAN in doses of 5 to 20 mg/kg per day, and adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials [see Clinical Studies ( 14 )] . In Study 5, 65 pediatric patients with PKU aged 1 month to 6 years received KUVAN 20 mg/kg per day for 6 months.

Adverse reactions in these patients were similar in frequency and type as those seen in other KUVAN clinical trials except for an increased incidence of low Phe levels. Twenty-five percent (16 out of 65) of patients developed Phe levels below normal for age [see Warnings and Precautions ( 5.3 ), Use In Specific Populations ( 8.4 ), and Clinical Studies ( 14 )] . In Study 6, a long term, open-label, extension study of 111 patients aged 4 to 50 years, receiving KUVAN in doses ranging from 5 to 20 mg/kg per day, adverse reactions were similar in type and frequency to those reported in the previous clinical studies.

Fifty-five patients received KUVAN both as dissolved and intact tablets. There were no notable differences in the incidence or severity of adverse reactions between the two methods of administration. The mean (± SD) exposure to sapropterin for the entire study population was 659 ± 221 days (maximum 953 days).

In Study 7, 27 pediatric patients with PKU aged 0 to 4 years received KUVAN 10 mg/kg per day or 20 mg/kg per day. Adverse reactions were similar in type and frequency to those observed in other clinical trials, with the addition of rhinitis, which was reported in 2 subjects (7.4%). Safety Experience from Clinical Studies for Non-PKU Indications Approximately 800 healthy subjects and patients with disorders other than PKU, some of whom had underlying neurologic disorders or cardiovascular disease, have been administered a different formulation of the same active ingredient (sapropterin) in approximately 19 controlled and uncontrolled clinical trials.

In these clinical… [Excerpted — this section continues on DailyMed.]

🔄 Drug Interactions ~1 min read ▾

7 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 KUVAN may be necessary to achieve a biochemical response. Drugs Affecting Nitric Oxide‑Mediated Vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil) Clinical Impact Both sapropterin dihydrochloride and PDE-5 inhibitors may induce vasorelaxation.

A reduction in blood pressure could occur; however, the combined use of these medications has not been evaluated in humans. Intervention Monitor blood pressure. Inhibitors of Folate Synthesis (e.g., methotrexate, valproic acid, phenobarbital, trimethoprim) : Can decrease endogenous BH4 levels; monitor blood Phe levels more frequently and adjust KUVAN dosage as needed.

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

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS

8.1Pregnancy Risk Summary Available data from pregnancy safety studies, pharmacovigilance, and published case reports with KUVAN use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects (see Clinical Considerations ) . An embryo-fetal development study with sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended human dose (MRHD) given during the period of organogenesis showed no effects.

In a rabbit study using oral administration of sapropterin dihydrochloride during the period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD. All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU. Clinical Considerations Disease-Associated Maternal and/or Embryo‑Fetal Risk Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception [see Dosage and Administration 2.2) ] .

Data Human Data Uncontrolled Maternal PKU Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in PKU‑affected women demonstrated that uncontrolled Phe levels above 600 micromol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies. Control of blood phenylalanine during pregnancy is essential to reduce the incidence of Phe-induced teratogenic effects. Pregnancy Registry Data Available data from pregnancy sub-registries within the Phenylketonuria Developmental Outcomes and Safety (PKUDOS) Registry and the KUVAN Adult Maternal Pediatric European Registry (KAMPER) have identified 72 live births (79 pregnancies) in women with PKU exposed to sapropterin during pregnancy.

Three birth defects were reported, including one case each of microcephaly, cleft palate, and tongue tie. The two major birth defects (microcephaly and cleft palate) were associated with Phe levels greater than 360 micromol/L during pregnancy. Animal Data No effects on embryo-fetal development were observed in a reproduction study in rats using oral doses of up to 400 mg/kg per day sapropterin dihydrochloride (about 3 times the MRHD of 20 mg/kg per day, based on body surface area) administered during the period of organogenesis.

However, in a rabbit reproduction study, oral administration of a maximum dose of 600 mg/kg per day (about 10 times the MRHD, based on body surface area) during the period of organogenesis was associated with a non-statistically significant increase in the incidence of holoprosencephaly in two high dose-treated litters (4 fetuses), compared to one control-treated litter (1 fetus).

8.2Lactation 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 KUVAN through breastfeeding. No lactation-related safety concerns were reported in infants of mother… [Excerpted — this section continues on DailyMed.]

🤰 Pregnancy ~2 min read ▾

8.1Pregnancy Risk Summary Available data from pregnancy safety studies, pharmacovigilance, and published case reports with KUVAN use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects (see Clinical Considerations ) . An embryo-fetal development study with sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended human dose (MRHD) given during the period of organogenesis showed no effects.

In a rabbit study using oral administration of sapropterin dihydrochloride during the period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD. All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU. Clinical Considerations Disease-Associated Maternal and/or Embryo‑Fetal Risk Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception [see Dosage and Administration 2.2) ] .

Data Human Data Uncontrolled Maternal PKU Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in PKU‑affected women demonstrated that uncontrolled Phe levels above 600 micromol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies. Control of blood phenylalanine during pregnancy is essential to reduce the incidence of Phe-induced teratogenic effects. Pregnancy Registry Data Available data from pregnancy sub-registries within the Phenylketonuria Developmental Outcomes and Safety (PKUDOS) Registry and the KUVAN Adult Maternal Pediatric European Registry (KAMPER) have identified 72 live births (79 pregnancies) in women with PKU exposed to sapropterin during pregnancy.

Three birth defects were reported, including one case each of microcephaly, cleft palate, and tongue tie. The two major birth defects (microcephaly and cleft palate) were associated with Phe levels greater than 360 micromol/L during pregnancy. Animal Data No effects on embryo-fetal development were observed in a reproduction study in rats using oral doses of up to 400 mg/kg per day sapropterin dihydrochloride (about 3 times the MRHD of 20 mg/kg per day, based on body surface area) administered during the period of organogenesis.

However, in a rabbit reproduction study, oral administration of a maximum dose of 600 mg/kg per day (about 10 times the MRHD, based on body surface area) during the period of organogenesis was associated with a non-statistically significant increase in the incidence of holoprosencephaly in two high dose-treated litters (4 fetuses), compared to one control-treated litter (1 fetus).

🆘 Overdosage 218 words ▾

10 OVERDOSAGE Two unintentional overdosages with KUVAN have been reported. One adult patient in a KUVAN clinical trial received a single KUVAN 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 KUVAN with no reports of abnormal signs or symptoms. In postmarketing, one pediatric patient received KUVAN 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 KUVAN dose was reduced to 20 mg/kg per day. In a clinical study to evaluate the effects of KUVAN 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 ~3 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action KUVAN is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme activity, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.

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 KUVAN is adequate to maintain stable blood Phe levels over a 24-hour period. Twelve patients with blood Phe levels ranging from 516 to 986 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. KUVAN 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 ( 14.1 )] .

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 KUVAN or a single therapeutic dose (20 mg/kg) of KUVAN had an effect on cardiac repolarization. In this study, KUVAN 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 KUVAN, drug was administered in the morning as a dissolved tablet without regard to meals. The mean elimination half-life in PKU patients was approximately 6.7 hours (range 3.9 to 17 hours), comparable with values seen in healthy subjects (range 3.0 to 5.3 hours). A study in healthy adults with 10 mg/kg of KUVAN 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). Pharmacokinetics in patients >49 years of age have not been studied.

Table 5: Apparent Plasma Clearance by Age Parameter 0 to <1 yr * (N=10) 1 to <6 yr * (N=57) 6 to <12 yr † (N=23) 12 to <18 yr † (N=24) ≥18… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action 62 words ▾

12.1Mechanism of Action KUVAN is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme activity, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.

📦 How Supplied / Storage and Handling 153 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING KUVAN Tablets 100 mg sapropterin dihydrochloride, are round, off-white to light yellow, mottled, and debossed with “177”. The tablets are supplied as follows: NDC 68135-300-02 Bottle of 120 tablets KUVAN 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 68135-301-22 Carton of 30 unit dose packets NDC 68135-301-11 Single unit dose packet 500 mg sapropterin dihydrochloride per packet: NDC 68135-482-11 Carton of 30 unit dose packets NDC 68135-482-10 Single unit dose packet Storage Store KUVAN tablets at 20ºC to 25ºC (68ºF to 77ºF); excursions allowed between 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].

Keep container tightly closed. Protect from moisture. Store KUVAN 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.

📋 Description 199 words ▾

11 DESCRIPTION KUVAN (sapropterin dihydrochloride) is an orally administered Phenylalanine Hydroxylase activator (or PAH activator). Sapropterin dihydrochloride, the active pharmaceutical ingredient in KUVAN, is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Sapropterin dihydrochloride is an off-white to light yellow crystals or crystalline powder.

The chemical name of sapropterin dihydrochloride is (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-pteridinone dihydrochloride and the molecular formula is C 9 H 15 N 5 O 3 ·2HCl with a molecular weight of 314.17. Sapropterin dihydrochloride has the following structural formula: KUVAN is supplied as tablets and powder for oral solution containing 100 mg of sapropterin dihydrochloride (equivalent to 76.8 mg of sapropterin base). KUVAN is also supplied as powder for oral solution containing 500 mg of sapropterin dihydrochloride (equivalent to 384 mg of sapropterin base).

Tablets are round, off-white to light yellow, mottled, and debossed with “177”. Each tablet contains the following inactive ingredients: ascorbic acid (USP), crospovidone (NF), dibasic calcium phosphate (USP), D-mannitol (USP), riboflavin (USP), and sodium stearyl fumarate (NF). KUVAN powder for oral solution is off-white to yellow in color.

Each unit dose packet contains the following inactive ingredients: ascorbic acid (USP), D-mannitol (USP), potassium citrate (USP), and sucralose (NF). Structural Formula

💬 Information for Patients ~3 min read ▾

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 KUVAN 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 KUVAN 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 KUVAN [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 KUVAN Some patients do not show a biochemical response (blood Phe reduction) when treated with KUVAN. Advise patients and caregivers to discontinue treatment with KUVAN if the patient does not show an adequate biochemical response in blood Phe after one month of treatment with KUVAN 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 KUVAN 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 KUVAN [see Warnings and Precautions ( 5.5 )] . Hyperactivity Advise patients and caregivers that KUVAN 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: KUVAN 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 KUVAN evaluation period when assessing biochemical response. The patient must be evaluated for changes in blood Phe after being treated with KUVAN 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 KUVAN treatment. Monitoring of blood Phe levels is important during KUVAN treatment.

Preparation and Administration [see Dosage and Administration (2.3) ] Advise patients and caregivers: KUVAN tablets can be swallowed whole, dissolved in water or apple juice, or crushed and mixed with a small amount of soft food such as apple sauce or pudding. KUVAN 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 KUVAN with a meal, preferably at the same time each day.

Manufactur… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacokinetics ~2 min read ▾

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 KUVAN, drug was administered in the morning as a dissolved tablet without regard to meals. The mean elimination half-life in PKU patients was approximately 6.7 hours (range 3.9 to 17 hours), comparable with values seen in healthy subjects (range 3.0 to 5.3 hours). A study in healthy adults with 10 mg/kg of KUVAN 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). Pharmacokinetics in patients >49 years of age have not been studied.

Table 5: Apparent Plasma Clearance by Age Parameter 0 to <1 yr * (N=10) 1 to <6 yr * (N=57) 6 to <12 yr † (N=23) 12 to <18 yr † (N=24) ≥18 yr † (N=42) CL/F (L/hr/kg) Mean ± SD (Median) 81.5 ± 92.4 (53.6) 50.7 ± 20.1 (48.4) 51.7 ± 21.9 (47.4) 39.2 ± 9.3 (38.3) 37.9 ± 20.2 (31.8) * Evaluated at 20 mg/kg per day dose. † Evaluated at 5, 10, or 20 mg/kg per day doses. Metabolism Sapropterin is a synthetic form of tetrahydrobiopterin (BH4) and is expected to be metabolized and recycled by the same endogenous enzymes. In vivo endogenous BH4 is converted to quinoid dihydrobiopterin and is metabolized to dihydrobiopterin and biopterin.

The enzymes dihydrofolate reductase and dihydropteridine reductase are responsible for the metabolism and recycling of BH4. Drug Interaction Studies Clinical Studies In healthy subjects, administration of a single dose of KUVAN at the maximum therapeutic dose of 20 mg/kg had no effect on the pharmacokinetics of a single dose of digoxin (P-gp substrate) administered concomitantly. In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically The potential for sapropterin to induce or inhibit cytochrome P450 enzymes was evaluated in in vitro studies which showed sapropterin did 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 for sapropterin 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 KUVAN appears to be low.

🧬 Pharmacodynamics ~1 min read ▾

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 KUVAN is adequate to maintain stable blood Phe levels over a 24-hour period. Twelve patients with blood Phe levels ranging from 516 to 986 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. KUVAN 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 ( 14.1 )] .

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 KUVAN or a single therapeutic dose (20 mg/kg) of KUVAN had an effect on cardiac repolarization. In this study, KUVAN 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.

🔬 Clinical Studies ~3 min read ▾

14 CLINICAL STUDIES The efficacy of KUVAN was evaluated in five clinical studies in patients with PKU. Study 1 was a multicenter, open-label, uncontrolled clinical trial of 489 patients with PKU, ages 8 to 48 years (mean 22 years), who had baseline blood Phe levels ≥ 450 μmol/L and who were not on Phe-restricted diets. All patients received treatment with KUVAN 10 mg/kg per day for 8 days.

For the purposes of this study, response to KUVAN treatment was defined as a ≥ 30% decrease in blood Phe from baseline. At Day 8, 96 patients (20%) were identified as responders. Study 2 was a multicenter, double-blind, placebo-controlled study of 88 patients with PKU who responded to KUVAN in Study 1.

After a washout period from Study 1, patients were randomized equally to either KUVAN 10 mg/kg per day (N=41) or placebo (N=47) for 6 weeks. Efficacy was assessed by the mean change in blood Phe level from baseline to Week 6 in the KUVAN-treated group as compared to the mean change in the placebo group. The results showed that at baseline, the mean (±SD) blood Phe level was 843 (±300) μmol/L in the KUVAN-treated group and 888 (±323) μmol/L in the placebo group.

At Week 6, the KUVAN treated group had a mean (±SD) blood Phe level of 607 (±377) μmol/L, and the placebo group had a mean blood Phe level of 891 (±348) μmol/L. At Week 6, the KUVAN- and placebo treated groups had mean changes in blood Phe level of –239 and 6 μmol/L, respectively (mean percent changes of –29% (±32) and 3% (±33), respectively). The difference between the groups was statistically significant (p < 0.001) (Table 6).

Table 6: Blood Phe Results in Study 2 Sapropterin (N=41) Placebo (N=47) Baseline Blood Phe Level * (μ mol/L) Mean (±SD) 843 (±300) 888 (±323) Percentiles (25 th , 75 th ) 620, 990 618, 1141 Week 6 Blood Phe Level (μ mol/L) Mean (±SD) 607 (±377) 891 (±348) Percentiles (25 th , 75 th ) 307, 812 619, 1143 Mean Change in Blood Phe From Baseline to Week 6 (μ mol/L) Adjusted Mean (±SE)† -239 (±38) 6 (±36) Percentiles (25 th , 75 th ) -397, -92 -96, 93 Mean Percent Change in Blood Phe From Baseline to Week 6 Mean (±SD) - 29 (±32) 3 (±33) Percentiles (25 th , 75 th ) -61, -11 -13, 12 * The mean baseline levels shown in this table represent the mean of 3 pretreatment levels (Wk -2, Wk -1, and Wk 0).

Treatment with KUVAN or placebo started at Wk 0. † p-value < 0.001, adjusted mean and standard error from an ANCOVA model with change in blood Phe level from baseline to Week 6 as the response variable, and both treatment group and baseline blood Phe level as covariates. Change in blood Phe was noted in the KUVAN-treated group at Week 1 and was sustained through Week 6 (Figure 2). Study 3 was a multicenter, open-label, extension study in which 80 patients who responded to KUVAN treatment in Study 1 and completed Study 2 underwent 6 weeks of forced dose-titration with 3 different doses of KUVAN.

Treatments consisted of 3 consecutive 2-week courses of KUVAN at doses of 5, then 20, and then 10 mg/kg per day. Blood Phe level was monitored after 2 weeks of treatment at each dose level. At baseline, mean (±SD) blood Phe was 844 (±398) μmol/L.

At the end of treatment with 5, 10, and 20 mg/kg per day, mean (±SD) blood Phe levels were 744 (±384) μmol/L, 640 (±382) μmol/L, and 581 (±399) μmol/L, respectively (Table 7). Table 7: Blood Phe Results From Forced Dose-Titration in Study 3 KUVAN Dose Level (mg/kg per day) No. of Patients Mean ( ± SD) Blood Phe Level (μ mol/L) Mean Changes ( ± SD) in Blood Phe Level From Week 0 (μ mol/L) Baseline (No Treatment) 80 844 (±398) — 5 80 744 (±384) ‑100 (±295) 10 80 640 (±382) ‑204 (±303) 20 80 581 (±399) -263 (±318) Study 4 was a multicenter study of 90 pediatric patients with PKU, ages 4 to 12 years, who were on Phe‑restricted diets and who had blood Phe levels ≤480 μmol/L at screening.

All patients were treated with open-label KUVAN 20 mg/kg per day for 8 days. Response to KUVAN was defined as a ≥30% decrease in blood Phe from baseline at Day 8.… [Excerpted — this section continues on DailyMed.]

🧪 Nonclinical Toxicology ~1 min read ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year carcinogenicity study was conducted in F-344 rats, and a 78-week carcinogenicity study was conducted in CD-1 mice. In the 104-week oral carcinogenicity study in rats, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.2, 0.7, and 2 times the maximum recommended human dose of 20 mg/kg per day, respectively, based on body surface area) were used. In the 78-week oral carcinogenicity study in mice, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.1, 0.3, and 2 times the recommended human dose, respectively, based on body surface area) were used.

In the 2‑year rat carcinogenicity study, there was a statistically significant increase in the incidence of benign adrenal pheochromocytoma in male rats treated with the 250 mg/kg per day (about 2 times the maximum recommended human dose, based on body surface area) dose, as compared to vehicle treated rats. The mouse carcinogenicity study showed no evidence of a carcinogenic effect, but the study was not ideal due to its duration of 78 instead of 104 weeks. Sapropterin dihydrochloride was genotoxic in the in vitro Ames test at concentrations of 625 µg (TA98) and 5000 µg (TA100) per plate, without metabolic activation.

However, no genotoxicity was observed in the in vitro Ames test with metabolic activation. Sapropterin dihydrochloride was genotoxic in the in vitro chromosomal aberration assay in Chinese hamster lung cells at concentrations of 0.25 and 0.5 mM. Sapropterin dihydrochloride was not mutagenic in the in vivo micronucleus assay in mice at doses up to 2000 mg/kg per day (about 8 times the maximum recommended human dose of 20 mg/kg per day, based on body surface area).

Sapropterin dihydrochloride, at oral doses up to 400 mg/kg per day (about 3 times the maximum recommended human dose, based on body surface area) was found to have no effect on fertility and reproductive function of male and female rats.

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ~1 min read ▾

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year carcinogenicity study was conducted in F-344 rats, and a 78-week carcinogenicity study was conducted in CD-1 mice. In the 104-week oral carcinogenicity study in rats, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.2, 0.7, and 2 times the maximum recommended human dose of 20 mg/kg per day, respectively, based on body surface area) were used. In the 78-week oral carcinogenicity study in mice, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.1, 0.3, and 2 times the recommended human dose, respectively, based on body surface area) were used.

In the 2‑year rat carcinogenicity study, there was a statistically significant increase in the incidence of benign adrenal pheochromocytoma in male rats treated with the 250 mg/kg per day (about 2 times the maximum recommended human dose, based on body surface area) dose, as compared to vehicle treated rats. The mouse carcinogenicity study showed no evidence of a carcinogenic effect, but the study was not ideal due to its duration of 78 instead of 104 weeks. Sapropterin dihydrochloride was genotoxic in the in vitro Ames test at concentrations of 625 µg (TA98) and 5000 µg (TA100) per plate, without metabolic activation.

However, no genotoxicity was observed in the in vitro Ames test with metabolic activation. Sapropterin dihydrochloride was genotoxic in the in vitro chromosomal aberration assay in Chinese hamster lung cells at concentrations of 0.25 and 0.5 mM. Sapropterin dihydrochloride was not mutagenic in the in vivo micronucleus assay in mice at doses up to 2000 mg/kg per day (about 8 times the maximum recommended human dose of 20 mg/kg per day, based on body surface area).

Sapropterin dihydrochloride, at oral doses up to 400 mg/kg per day (about 3 times the maximum recommended human dose, based on body surface area) was found to have no effect on fertility and reproductive function of male and female rats.

📄 Patient Package Insert ~3 min read ▾

PATIENT INFORMATION PATIENT INFORMATION KUVAN (COO-van) (sapropterin dihydrochloride) tablets KUVAN (COO-van) (sapropterin dihydrochloride) powder for oral solution What is KUVAN? Kuvan is a prescription medicine used to lower blood levels of phenylalanine (Phe), in adults and children one month of age and older with a certain type of Phenylketonuria (PKU). Kuvan is used along with a Phe-restricted diet.

What should I tell my doctor before taking Kuvan? Before you take Kuvan, tell your doctor about all your medical conditions, including if you: are allergic to sapropterin dihydrochloride or any of the ingredients in Kuvan. See the list of ingredients in Kuvan at the end of this leaflet. have poor nutrition or have loss of appetite. are pregnant or plan to become pregnant.

Pregnancy Exposure Registry : There is a pregnancy exposure registry for women who take Kuvan during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry or contact the registry program at 1-800-983-4587. are breastfeeding or plan to breastfeed.

It is not known if Kuvan passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take Kuvan. Tell your doctor about all the medicines you take , including prescription and over-the-counter medicines, vitamins, herbal, and dietary supplements.

Kuvan and other medicines may interact with each other. Especially tell your doctor if you take: a medicine that contains levodopa an antifolate medicine sildenafil (Revatio, Viagra), tadalafil (Adcirca, Cialis), vardenafil (Staxyn, Levitra) Tell your doctor if you are not sure if your medicine is one that is listed above. Know the medicines you take.

Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take KUVAN? Take Kuvan exactly as your doctor tells you.

Your doctor should tell you how much Kuvan to take and when to take it. Your doctor may change your dose of Kuvan depending on how you respond to treatment. Take Kuvan 1 time each day with a meal.

It is best to take Kuvan at the same time each day. Kuvan comes as a tablet and powder for oral solution. You can swallow Kuvan tablets whole or dissolve the tablets in water or apple juice.

You may also crush the tablets and mix in a small amount of soft food, such as apple sauce or pudding before taking. Be sure that you know what dose of Kuvan powder your doctor prescribed and whether you should use Kuvan 100 mg packets, Kuvan 500 mg packets, or both types of packets to prepare your dose. Open Kuvan powder packets only when you are ready to use them.

Kuvan powder for oral solution should be dissolved in water or apple juice. You may also mix the powder for oral solution in a small amount of soft food, such as apple sauce or pudding before taking. See the detailed “Instructions for Use” that comes with Kuvan for information about the correct way to dissolve and take a dose of Kuvan tablets or Kuvan powder for oral solution.

It is not possible to know if Kuvan will work for you until you start taking Kuvan. Your doctor will check your blood Phe levels when you start taking Kuvan to see if the medicine is working. During treatment with Kuvan: Any change you make to your diet may affect your blood Phe level.

Follow your doctor’s instructions carefully and do not make any changes to your dietary Phe intake without first talking with your doctor. Even if you take Kuvan, if your Phe blood levels are not well controlled, you can develop severe neurologic problems. Your doctor should continue to monitor your blood Phe levels often during your treatment with Kuvan, to make sure that your blood Phe levels are not too high or too low .

If you have a fever, or if you are sick, your blood Phe level may go up. Tell your doctor as soon as possible so they can change your dose of Kuvan to help keep your blood Phe levels in the desired range. If you f… [Excerpted — this section continues on DailyMed.]

📖 Instructions for Use ~3 min read ▾

INSTRUCTIONS FOR USE Kuvan (COO-van) (sapropterin dihydrochloride) tablets Kuvan (COO-van) (sapropterin dihydrochloride) powder for oral solution Read this Instructions for Use before you start taking Kuvan and each time you refill your prescription. There may be new information. This information does not take the place of talking with your healthcare provider about your treatment.

Talk to your doctor if you have any questions about the right dose of Kuvan to take or how to mix it. Important information: Kuvan comes as a tablet or in a packet containing powder. Take Kuvan exactly as your doctor tells you.

Your doctor should tell you how much Kuvan to take and when to take it. Your doctor may change your dose of Kuvan depending on how you respond to treatment, or based on your baby’s weight. If your baby weighs 22 pounds or less, follow the section called “ Instructions for giving Kuvan powder for oral solution (Kuvan 100 mg packets) to babies who weigh 22 pounds or less ”.

Take Kuvan 1 time each day with a meal. It is best to take Kuvan at the same time each day. Instructions for taking Kuvan tablets: Kuvan tablets can be swallowed whole or dissolved in water or apple juice.

You may also crush the tablets and mix in a small amount of soft food, such as apple sauce or pudding. To dissolve Kuvan tablets: Mix Kuvan tablets in 4 ounces to 8 ounces (½ cup to 1 cup) of water or apple juice. It may take a few minutes for the tablets to dissolve.

To make the tablets dissolve faster, you can stir or crush them. The tablets may not dissolve completely. You may see small pieces floating on top of the water or apple juice.

This is normal and safe for you to swallow. Drink within 15 minutes. After drinking your medicine, if you still see small pieces of the tablet, add more water or apple juice and drink to make sure that you take all of your medicine.

Instructions for taking Kuvan powder for oral solution: For babies who weigh 22 pounds or less, see the section below called “ Instructions for giving Kuvan powder for oral solution (Kuvan 100 mg packets) to babies who weigh 22 pounds or less.” Kuvan powder for oral solution should be dissolved in water or apple juice. The powder for oral solution may also be mixed in a small amount of soft foods, such as apple sauce or pudding. To dissolve Kuvan powder for oral solution: Be sure that you know what dose of Kuvan your doctor has prescribed and whether you should use Kuvan 100 mg packets, Kuvan 500 mg packets, or both types of packets to prepare your dose.

Open the packet(s) of Kuvan powder for oral solution by folding and tearing, or cutting at the dotted line in the upper right corner of the packet. Open the packet(s) only when you are ready to use them. Empty the contents of the packet(s) into 4 ounces to 8 ounces (1/2 cup to 1 cup) of water or apple juice.

Drink within 30 minutes. Instructions for giving Kuvan powder for oral solution (Kuvan 100 mg packets) to babies who weigh 22 pounds or less: The dose of Kuvan is based on body weight. This will change as your baby grows.

Your doctor will tell you: the number of Kuvan 100 mg packets needed for one dose the amount of water or apple juice needed to mix one dose of Kuvan the amount of the mixture (powder and water or apple juice) you will need to give your baby his or her prescribed dose of medicine. Give your baby the prescribed amount of mixture (powder and water or apple juice) within 30 minutes after mixing. If you are not able to give your baby’s dose within 30 minutes after mixing, pour the unused medicine into the trash.

You will need to mix a new dose. Supplies needed to mix and give your baby’s dose of Kuvan powder for oral solution: the number of Kuvan 100 mg packets needed for one dose a small cup of water or apple juice one 30 mL medicine cup for mixing small spoon or clean utensil for mixing 10 mL oral dosing syringe scissors (optional) Ask your pharmacist for a 30 mL medicine cup for mixing and an oral dosing syringe if you do… [Excerpted — this section continues on DailyMed.]

📄 Package Label / Principal Display Panel 102 words ▾

100 MG TABLETS NDC 68135-300-02 KUVAN ® (sapropterin dihydrochloride) Tablets 100 mg* * Equivalent to 76.8 mg of sapropterin Rx only 120 Tablets BIOMARIN ® 100 mg Tablet PDP

100 MG POWDER FOR ORAL SOLUTION NDC 68135-301-22 KUVAN ® (sapropterin dihydrochloride) Powder for Oral Solution 100 mg* Rx only 30 individual packets per carton BIOMARIN ® 100 mg Powder PDP

500 MG POWDER FOR ORAL SOLUTION NDC 68135-482-11 KUVAN ® (sapropterin dihydrochloride) Powder for Oral Solution 500 mg* per single use packet * Equivalent to 384 mg of sapropterin Rx only 30 individual packets per carton BIOMARIN ® Kuvan 500 Carton PDP

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

Medicaid utilization & spend

📍 This exact package only: Medicaid data is reported per full 11-digit NDC — labeler, product and pack size — so every number here is for this package alone, not the drug overall. Other pack sizes report separately.
💊 Pharmacy benefit only: These are Medicaid outpatient pharmacy claims, billed by NDC. They exclude the medical benefit — clinic- or hospital-administered drugs billed under HCPCS J-codes — so drugs used mostly that way (e.g. Avastin, Lucentis, Keytruda) can look low or missing here. That’s expected, not an error.
📅 Q1 2025 – Q1 2026 · 5 quarters of data
ⓘ The newest quarter is usually incomplete when first published; states restate recent quarters in later CMS releases, so the latest figures typically revise upward. State coverage-policy changes can also shift quarter-to-quarter totals.
Prescriptions last 4 qtrs
428
Units reimbursed last 4 qtrs
37.3K
Gross reimbursed last 4 qtrs
$1.61M
Avg / prescription
$3,768.77
Avg / unit
$43.2913
Latest quarter Q1 2026
63Rx
Fee-for-service vs managed care ⓘ
75% FFS 25% MCO
Fee-for-service · 320 Rx Managed care · 108 Rx
State Medicaid map
Alaska: no data reported AK Maine: no data reported ME Washington: no data reported WA Idaho: no data reported ID Montana: no data reported MT North Dakota: no data reported ND Minnesota: no data reported MN Wisconsin: 1,380 units · 23.4 per 100k residents WI Michigan: 6,810 units · 67.8 per 100k residents MI New York: no data reported NY Vermont: no data reported VT New Hampshire: no data reported NH Oregon: no data reported OR Nevada: no data reported NV Wyoming: no data reported WY South Dakota: no data reported SD Iowa: no data reported IA Illinois: no data reported IL Indiana: no data reported IN Ohio: no data reported OH Pennsylvania: 4,530 units · 35.0 per 100k residents PA New Jersey: no data reported NJ Massachusetts: no data reported MA California: 17,400 units · 44.7 per 100k residents CA Utah: no data reported UT Colorado: no data reported CO Nebraska: no data reported NE Missouri: no data reported MO Kentucky: no data reported KY West Virginia: no data reported WV Virginia: no data reported VA Maryland: no data reported MD Connecticut: no data reported CT Rhode Island: no data reported RI Arizona: 1,110 units · 14.9 per 100k residents AZ New Mexico: no data reported NM Kansas: no data reported KS Arkansas: no data reported AR Tennessee: 2,790 units · 39.2 per 100k residents TN North Carolina: no data reported NC South Carolina: no data reported SC Delaware: no data reported DE Oklahoma: no data reported OK Louisiana: no data reported LA Mississippi: no data reported MS Alabama: no data reported AL Georgia: no data reported GA D.C.: no data reported DC Hawaii: no data reported HI Texas: no data reported TX Florida: 3,240 units · 14.3 per 100k residents FL
Units reimbursed · per 100k residents
14.367.8
gray = no data reported ⓘ
Colors are per 100,000 residents, so big states don’t automatically dominate. Tap or hover a state for its actual totals.
Tap or hover a state
…for its Medicaid breakdown
🏆 Top states by units · per 100k residents
1 Michigan 67.8 /100k
2 California 44.7 /100k
3 Tennessee 39.2 /100k
4 Pennsylvania 35.0 /100k
5 Wisconsin 23.4 /100k
6 Arizona 14.9 /100k
7 Florida 14.3 /100k
National units — by quarter
💵 About the dollar figures: “reimbursed” is what Medicaid paid pharmacies before confidential manufacturer rebates, so the program’s real net cost is lower than these numbers. Fee-for-service and managed-care claims are combined unless split above. Source: CMS State Drug Utilization Data; per-100k rates use 2023 Census population estimates.

Medicare Part D spend CMS · PART D · 2026 (Q1)

Medicare Part D (outpatient prescription) spending for Kuvan — the program that covers self-administered drugs. 1 manufacturer.
⚠️ Drug-level data: CMS publishes Part D spending by drug, not by NDC — these figures combine every manufacturer, strength and package size sold under the name Kuvan. That’s a different level of aggregation than the Medicaid card above, which is specific to this exact 11-digit NDC (pack size included), so the two aren’t directly comparable.
Period
Total Part D spend
$539K
Claims incl. refills
38
Beneficiaries
11
Spend / beneficiary
$49,002.62
Spend / claim
$14,184.97
Trend by period
💵 About the dollar figures: spending is what Part D plans paid before confidential manufacturer rebates, so the program’s real net cost is lower. A blank patient count means fewer than 11 people — CMS hides counts that small to protect privacy. Source: CMS Medicare Quarterly Part D Spending by Drug (data.cms.gov), updated quarterly.

Reported adverse events (FAERS)

Read carefully: FAERS reports are voluntary and unverified. Counts are not incidence, do not establish causation, are subject to reporting bias, and cannot be used to compare one drug to another. Shown for signal context only. Reports for Kuvan (this brand).

Top reported reactions

Headache356
Vomiting291
Diarrhoea269
Nausea217
Amino Acid Level Increased206
Abdominal Pain Upper198
Anxiety183

Age at onset

Neonate8
Infant34
Child267
Adolescent133
Adult554
Elderly9

Reporter sex

5,871 reports
Male · 39%
Female · 61%
Unknown · 0%

Serious outcomes

Hospitalization412
Death72
Life-threatening24
Disabling12
Reports over time (by year) — tap or hover for the count & year
2019 2021 2023 2026 726 0
Most recent year is provisional (FAERS lags ~3 months).
Where does this data come from?
Adverse-event reports from the FDA Adverse Event Reporting System (FAERS) via openFDA. FAERS reports are voluntary and unverified — counts are not incidence and don’t establish causation.

About this NDC listing & data coverage

Finished prescription product
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 ✓ Available
Inactive ingredients (structured) — Not published for this NDC The labeler did not submit a structured excipient list, or no SPL is 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
“Not published” reflects what the public FDA / CMS / NLM sources provide for this exact package code — it is a property of the data feeds, not a judgment about the product.

Questions about this listing

Why is there no price listed?
The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
Is the NDC printed on the package the same as the 11-digit billing NDC?
Yes, they identify this exact package in different formats. The form printed on the packaging and shown on DailyMed is the one the FDA registered. Insurance claims use a fixed 11-digit 5-4-2 format, so the short segment is padded with a leading zero and the dashes are dropped. The Identity section at the top of this page lists each form of this code.
Is this package still being marketed?
Yes, per the latest FDA NDC Directory data on this page: this package is listed as actively marketed, with no marketing end date reported by BioMarin Pharmaceutical Inc.. Listing status can change — the directory data on this page refreshes weekly.
Who lists this product with the FDA?
BioMarin Pharmaceutical Inc. is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
Do I need a prescription for this product?
This NDC is listed with FDA as a prescription product, so it is dispensed under a prescriber's order. Your pharmacist can tell you whether any over-the-counter forms of the same medication exist.
This page identifies an FDA-listed package (the NDC) and reports public regulatory and pricing data about the listing. It is reference information, not a medical recommendation — talk to your pharmacist or prescriber about your own medication.
Where does this data come from?
Listing facts (marketing category, packager status, marketing dates) from the FDA openFDA NDC Directory; label availability from DailyMed; pricing coverage from CMS NADAC; equivalence scope from the FDA Orange Book.
← 68135-0300-02 · BioMarin 68135-0482-11 · BioMarin →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.