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dapagliflozin and metformin hydrochloride 5 mg; 1000 mg Tablet, Film Coated, Extended Release, 60-count — NDC 67877-0620-60 package photo
Label image from the product's FDA listing (DailyMed) — may show a different pack size or an older label revision.

dapagliflozin and metformin hydrochloride 5 mg; 1000 mg Tablet, Film Coated, Extended Release, 60-count — NDC 67877-620-60 (Billing 67877-0620-60)

by Ascend Laboratories, LLC · 60 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE

This is a package of 60 tablets of dapagliflozin and metformin hydrochloride 5 mg; 1000 mg Tablet, Film Coated, Extended Release from Ascend Laboratories, LLC, marketed since Apr 2026 and currently FDA-listed; retail pharmacies pay about $0.4606 per tablet (NADAC). It is the main listing for this product, which comes in 3 package sizes.

NDC 67877-0620-60
🏷️ FDA NDC (as labeled) 67877-620-60 billing pads the product segment with a zero
This package
Contains60-count Cost per ea$0.4606 NADAC Per package$27.64 / 60 tablets Pack sizes3 compare ↓
Also priced by: Part D plans $1.27/unit — full pricing hub ↓
Main listing for product 67877-620 · Also comes in: 30 tablets 67877-620-30 90 tablets 67877-620-90
Rx only Generic On market Non-controlled ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Aug 20, 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

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 67877-620-60
Product NDC 67877-620
11-digit billing NDC 67877062060
NCPDP billing unit EA — each (per item)
RxCUI 1593058, 1593068, 1593070, 1593072
UNII 786Z46389E, 1ULL0QJ8UC
UPC 0367877621050
Application # ANDA211563
SPL Set ID eadcc3ef-f5c2-4a56-a6aa-12909844144e
Established class (EPC) Sodium-Glucose Cotransporter 2 Inhibitor
Mechanism of action Sodium-Glucose Transporter 2 Inhibitors
DEA schedule Non-controlled
Marketing category ANDA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2026-04-06
Route ORAL
Dosage form TABLET, FILM COATED, EXTENDED RELEASE
Substance DAPAGLIFLOZIN; METFORMIN HYDROCHLORIDE
TE code (Orange Book) AB · RLD · RS

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

GPI-14 27996002297520
GCN Seq No 073031
GCN 37343
HICL code 041188
Ingredient (HICL) Dapagliflozin/Metformin
HIC1 code C
Therapeutic class — broad (HIC1) Electrolyte Balance/Metabolism/Nutrition
HIC2 code C4
Therapeutic class — intermediate (HIC2) Antihyperglycemics
HIC3 code C4E
Therapeutic class — specific (HIC3) Antihyperglycemic-Sglt2 Inhibitor-Biguanide Combs.
AHFS code 68:20.04.00
AHFS class Biguanides
FDB label name DAPAGLIFLOZIN-METFOR ER 5-1000
FDB brand name Dapagliflozin-Metformin Er
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 073031
  • GCN: 37343
  • GPI-14 (Medi-Span): 27996002297520
  • HICL (First Databank): 041188
  • AHFS class code: 68:20.04.00
  • RxCUI (RxNorm): 1593058
Why two NDCs? The FDA registers this code as 67877-620-60 — 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 → 67877-0620-60. 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 Sodium-Glucose Cotransporter 2 Inhibitor class.

Pharmacologic class Sodium-Glucose Cotransporter 2 Inhibitor
Drug family (ATC) Sodium-glucose co-transporter 2 (SGLT2) inhibitors
How it works Sodium-Glucose Transporter 2 Inhibitors
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 DAPAGLIFLOZIN-METFOR ER 5-1000 Ingredient Dapagliflozin/Metformin
📖 What it is MedlinePlus · NLM

Dapagliflozin is used to lower blood sugar in people with type 2 diabetes (condition in which blood sugar is too high because the body does not make or use insulin normally). to reduce the risk of being hospitalized for heart failure in certain adults with type 2 diabetes to reduce the risk of being hospitalized for heart failure and death in adults with heart failure to reduce the risk of worsening of kidney disease, being hospitalized for heart failure, and death in certain adults with kidney disease Dapagliflozin is in a class of medications called sodium-glucose co-transporter 2 (SG...

Read the full MedlinePlus article ↗
📗 Our plain-language guide HelloPharmacist
  • It helps control blood sugar in type 2 diabetes, along with diet and exercise. The dapagliflozin part can also lower your risk of heart failure hospitalization and kidney disease g...
  • Take it once a day in the morning with food, and swallow it whole. Don't crush, cut or chew it. Follow the dose your prescriber gave you.
  • Some people get genital yeast infections, urinary infections, diarrhea, nausea, headache or more frequent urination. Tell your provider if these bother you or persist. Good hygiene...
  • Stop it and get medical help if you have unusual muscle pain, trouble breathing, extreme sleepiness, stomach pain with nausea or vomiting, or feel very unwell. These can signal lac...
📖 Read our full Dapagliflozin / Metformin guide →

Supplement & herbal interactions

🌿 Drug–supplement interaction checker →
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 eaPer package
Retail pharmacies payNADAC · weekly $0.461 $27.64 / 60 tablets
Medicaid paysCMS SDUD · 12 mo No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data.
Medicare drug plans payPart D · Q2 2026 $1.27 $76.15 / 60 tablets
NADAC price history (per ea) — tap or hover for the price & month
Jun 2026 Jul 2026 Sep 2026 $5.826 $0.461
▼ Down 92% over the last 3 months.
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 Per unit Per pack Marketing startMarketing endStatus
67877-0620-30 67877-620-30 30 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE — — 2026-04-06 — Active
67877-0620-60 You're viewing this Main listing 60 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE $0.4606 / ea $27.64 2026-04-06 — Active
67877-0620-90 67877-620-90 90 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE — — 2026-04-06 — Active

You're viewing one of 3 pack sizes for this product.

Pack size FAQ

What quantity is in this package?
This is a 60-count package — 60 tablet, film coated, extended release in 1 bottle.
How does this package differ from NDC 67877-0620-30?
Both are dapagliflozin and metformin hydrochloride 5 mg; 1000 mg Tablet, Film Coated, Extended Release — the drug itself is identical. This page's package is the 60-count one, while NDC 67877-0620-30 is the 30 tablets package.
What NDC number is used to bill for this package of dapagliflozin and metformin hydrochloride 5 mg; 1000 mg Tablet, Film Coated, Extended Release?
Use the 11-digit billing form listed in the identifiers section of this page. Pharmacy and medical claims use the 11-digit form; the FDA label may print a shorter form of the same code.

Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
dapagliflozin and metformin hydrochloride 5 mg/1; 1000 mg 66993-0361-60 Prasco 60 tablets $0.461 AB Availability likely —
dapagliflozin and metformin hydrochloride 5 mg/1; 1000 mgthis 67877-0620-60 Ascend 60 tablets $0.461 AB Availability likely —
Dapagliflozin And Metformin Hydrochloride 5 mg/1; 1000 mg 70748-0102-07 Lupin 60 tablets $0.461 AB Availability likely —
Xigduo Xr 5 mg/1; 1000 mg 00310-6260-60 AstraZeneca 60 tablets $9.592 AB Availability likely +1982%
Dapagliflozin and Metformin Hydrochloride 5 mg/1; 1000 mg 33342-0408-06 Macleods 10 tablets — AB FDA listed —
Dapagliflozin and Metformin hydrochloride 5 mg/1; 1000 mg 59651-0155-04 Aurobindo 400 tablets — AB FDA listed —
Dapagliflozin and Metformin Hydrochloride 5 mg/1; 1000 mg 63304-0026-30 Sun 30 tablets — AB FDA listed —
Dapagliflozin And Metformin Hydrochloride 5 mg/1; 1000 mg 72205-0435-01 Novadoz 30 tablets — AB FDA listed —
Dapagliflozin and Metformin Hydrochloride 5 mg/1; 1000 mg 84677-0020-60 Golden 60 tablets — AB FDA listed —
About this product: this is a generic version of the medicine. FDA equivalence ratings are shown when available, and other versions are listed above, least expensive first.
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

🏛️
2026
First FDA approval
Apr 2026
📍
2026
Currently FDA-listed
listed with the FDA
🔓
·
Generic on the market
this product is a generic
✅This is a generic drug

This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.

🛡️ Latest patent/protection date listed: The latest listed FDA patent/protection lapsed Oct 2026 — those protections no longer apply, though a generic still needs FDA approval and a manufacturer to market it.
📅 FDA approved Apr 6, 2026 AB TE-rated RLD RS

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
Exclusivity PC
Exclusivity PC
Exclusivity PC
Exclusivity PC
2026
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.

FDA exclusivity
CodeWhat it grantsExpires
PCPediatric Exclusivity (+6 months)Oct 3, 2026
PCPediatric Exclusivity (+6 months)Oct 3, 2026
PCPediatric Exclusivity (+6 months)Oct 3, 2026
PCPediatric Exclusivity (+6 months)Oct 3, 2026
Common questions
Is there a generic version of DAPAGLIFLOZIN-METFOR ER 5-1000?
Yes — an FDA-approved generic equivalent is listed in the FDA Orange Book for DAPAGLIFLOZIN-METFOR ER 5-1000. 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 Orange / Pink / Yellow
ShapeOval
ImprintD;M;10;1000
Size2 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.

💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.

  • UNII K679OBS311
    Carboxymethylcellulose sodium is a plant-derived thickening agent made from cellulose. In medicines, it acts as a binder to hold ingredients together, a disintegrant to help the tablet break apart, or a thickener in liquids.
  • UNII D9C330MD8B
    Copovidone is a synthetic polymer made by combining two types of plastic-like molecules. It acts as a binder and film-former to help hold tablet ingredients together and improve how the medicine dissolves in your body.
  • UNII 1K09F3G675
    Ferric oxide red is an inorganic iron compound used as a colorant in medicines. It gives tablets, capsules, or other dosage forms a red or reddish tint for identification and appearance.
  • UNII G7515SW10N
    A waxy liquid derived from vegetable oil and fatty acids. It works as an emulsifier and solubilizer to help blend oil and water-based ingredients together and improve how the medicine dissolves and is absorbed in the body.
  • UNII 0VUT3PMY82
    Hypromellose 2910 is a plant-derived thickening agent made from cellulose. In medicines, it forms protective coatings on tablets or capsules, controls how fast the drug releases, and thickens liquid formulations.
  • UNII EWQ57Q8I5X
    Lactose monohydrate is a natural sugar derived from milk. It serves as a filler and binder in tablets and capsules, helping create the proper size, texture, and consistency of the medicine.
  • UNII 7773C1ROEU
    Low-substituted hydroxypropyl cellulose is a plant-derived thickener and binder made from cellulose. In medicines, it helps bind tablet ingredients together, controls how quickly the medicine dissolves, and improves texture in liquids and semi-solid formulations.
  • UNII 70097M6I30
    Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
  • UNII OP1R32D61U
    Microcrystalline cellulose is a purified form of cellulose, a natural fiber from plant sources. It acts as a binder and filler in tablets and capsules, helping hold ingredients together and give the medicine its shape and size.
  • UNII 532B59J990
    Polyvinyl alcohol is a synthetic polymer made from plant-derived materials. It's used as a binder to hold ingredients together, a film-former in coatings, and a thickener in liquid formulations.
  • UNII RDH86HJV5Z
    Povidone K90 is a synthetic polymer made from a chemical called vinyl pyrrolidone. It acts as a binder to hold pill ingredients together and as a dispersant to help the medicine break down and dissolve properly in your body.
  • UNII ETJ7Z6XBU4
    Silicon dioxide is a naturally occurring mineral used as a glidant and anti-caking agent. It helps powder ingredients flow smoothly and prevents clumping during manufacturing and storage.
  • UNII 368GB5141J
    A detergent and foaming agent derived from coconut or palm oil. In medications, it helps break down and mix oil and water-based ingredients, aids in tablet disintegration, and improves how the drug dissolves and spreads in the mouth or digestive system.
  • UNII 7SEV7J4R1U
    A powder made from a naturally occurring mineral. In medicines, talc works as a glidant and anti-caking agent, helping tablets and capsules flow smoothly during manufacturing and preventing clumping.
  • UNII 15FIX9V2JP
    Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.

15 inactive ingredients listed in the exact product block matched to this NDC.

Where does this data come from?
Data sourced from official FDA Structured Product Labeling (SPL) via DailyMed — 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

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

LabelerAscend Laboratories, LLC
Application holderALKEM LABORATORIES LTD
FDA applicationANDA211563 (ANDA)
Labeler code67877
First marketedApr 2026
Product typeHuman Prescription Drug
Portfolio349 products on file
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.
🚨 Boxed Warning 🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📋 Description 💬 Information for Patients 💬 Medication Guide 🍼 Nursing Mothers 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📄 Recent Major Changes 📄 Package Label / Principal Display Panel
🚨 Boxed Warning ~2 min read ▾

WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by non-specific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL [see Warnings and Precautions ( 5.1 )].

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information [see Dosage and Administration ( 2.1 and 2.4 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Drug Interactions (7 ), and Use in Specific Populations ( 8.6 , 8.7 )].

If metformin-associated lactic acidosis is suspected, immediately discontinue dapagliflozin and metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.1 )]. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL.

(5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age greater than 65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information. ( 5.1 ) If lactic acidosis is suspected, discontinue dapagliflozin and metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting.

Prompt hemodialysis is recommended. (5.1 )

🎯 Indications and Usage ~2 min read ▾

1 INDICATIONS AND USAGE Dapagliflozin and metformin hydrochloride extended-release tablets are combination of dapagliflozin and metformin hydrochloride (HCl) extended-release, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Dapagliflozin, when used as a component of dapagliflozin and metformin hydrochloride extended-release tablets, are indicated in adults with type 2 diabetes mellitus to reduce the risk of: Sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression.

Cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure. Hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors. Limitations of Use Dapagliflozin and metformin hydrochloride extended-release tablets are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions ( 5.2 )].

Because of the metformin HCl component, the use of dapagliflozin and metformin hydrochloride extended-release tablets are limited to patients with type 2 diabetes mellitus for all indications. Dapagliflozin and metformin hydrochloride extended-release tablets are not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. Dapagliflozin and metformin hydrochloride extended-release tablets are not expected to be effective in these populations.

Pediatric use information is approved for AstraZeneca AB’s Xigduo ® XR (dapagliflozin and metformin hydrochloride) Extended-Release Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information. Dapagliflozin and metformin hydrochloride extended-release tablets are combination of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

( 1 ) Dapagliflozin when used as a component of dapagliflozin and metformin hydrochloride extended-release tablets, are indicated in adults with type 2 diabetes mellitus to reduce the risk of: Sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. ( 1 ) Cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure. ( 1 ) Hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.

( 1 ) Limitations of use : Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 ) Because of the metformin HCl component, the use of dapagliflozin and metformin hydrochloride extended-release tablets are limited to patients with type 2 diabetes mellitus for all indications. ( 1 ) Not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for the treatment of kidney disease.

Dapagliflozin and metformin hydrochloride extended-release tablets are not expected to be effective in these populations. ( 1 )

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION Assess renal function prior to initiating and then as clinically indicated. ( 2.1 ) Assess volume status and correct volume depletion before initiating. ( 2.1 ) Individualize the starting dosage based on the patient’s current treatment.

( 2.3 ) Administer orally once daily in the morning with food. ( 2.2 ) To improve glycemic control, for patients not already taking dapagliflozin, the recommended starting dosage for dapagliflozin is 5 mg once daily. ( 2.3 ) For indications in adults related to heart failure and chronic kidney disease the recommended dosage of dapagliflozin is 10 mg once daily.

( 2.3 ) Do not exceed a daily dosage of 10 mg dapagliflozin/2,000 mg metformin HCl extended-release. ( 2.3 ) See Full Prescribing Information for dosage recommendations in patients with renal impairment. ( 2.4 ) Dapagliflozin and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures.

( 2.5 ) Withhold dapagliflozin and metformin hydrochloride extended-release tablets for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.6 )

2.1Testing Prior to Initiation of Dapagliflozin and Metformin Hydrochloride Extended-Release Tablets Assess renal function prior to initiating dapagliflozin and metformin hydrochloride extended-release tablets and then as clinically indicated [see Warnings and Precautions ( 5.1 , 5.3 )] . Assess volume status. In patients with volume depletion, correct this condition before initiating dapagliflozin and metformin hydrochloride extended-release tablets [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.5 , 8.6 )].

2.2Recommended Administration Take dapagliflozin and metformin hydrochloride extended-release tablets orally once daily in the morning with food. Swallow dapagliflozin and metformin hydrochloride extended-release tablets whole and never crush, cut, or chew.

2.3Recommended Dosage Individualize the starting dosage of dapagliflozin and metformin hydrochloride extended-release tablets based upon the patient's current regimen. Patients taking an evening dosage of metformin HCl extended-release should skip their last dose before starting dapagliflozin and metformin hydrochloride extended-release tablets. To improve glycemic control in adults patients not already taking: Dapagliflozin : the recommended starting dosage of dapagliflozin in dapagliflozin and metformin hydrochloride extended-release tablets are 5 mg orally once daily.

Metformin HCl extended-release : the recommended starting dosage of metformin HCl extended-release in dapagliflozin and metformin hydrochloride extended-release tablets are 500 mg orally once daily. For dapagliflozin and metformin hydrochloride extended-release tablets indications in adults related to heart failure and chronic kidney disease, the recommended dosage of dapagliflozin in dapagliflozin and metformin hydrochloride extended-release tablets are 10 mg orally once daily. For all dapagliflozin and metformin hydrochloride extended-release tablets indications, the dosage may be adjusted based on effectiveness and tolerability.

The maximum recommended daily dosage of dapagliflozin is 10 mg and 2,000 mg of metformin HCl extended-release, with gradual dosage escalation to reduce gastrointestinal adverse reactions with metformin HCl [ see Adverse Reactions ( 6.1 )] . Pediatric use information is approved for AstraZeneca AB’s Xigduo ® XR (dapagliflozin and metformin hydrochloride) Extended-Release Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

2.4Recommended Dosage in Patients with Renal Impairment The recommended dosage of dapagliflozin and metformin hydrochloride extended-release tablets in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/min/1.73 m 2 is the same as the recommende… [Excerpted — this section continues on DailyMed.]

💊 Dosage Forms and Strengths 164 words ▾

3 DOSAGE FORMS AND STRENGTHS Dapagliflozin and metformin hydrochloride extended-release tablets are available as follows: 5 mg/500 mg tablets are orange, biconvex, capsule-shaped film-coated tablets debossed with "D/M" on one side and "5/500" on other side, may have matt finish appearance. 5 mg/1000 mg tablets are pink to dark pink, biconvex, oval-shaped film-coated tablets debossed with "D/M" on one side and "5/1000" on other side, may have matt finish appearance. 10 mg/500 mg tablets are pink to light pink, biconvex, capsule-shaped film-coated tablets debossed with "D/M" on one side and "10/500" on other side, may have matt finish appearance.

10 mg/1000 mg tablets are yellow to dark yellow, biconvex, oval-shaped film-coated tablets debossed with "D/M" on one side and "10/1000" on other side, may have matt finish appearance. 5 mg dapagliflozin/500 mg metformin HCl extended-release (3 ) 5 mg dapagliflozin/1,000 mg metformin HCl extended-release (3) 10 mg dapagliflozin/500 mg metformin HCl extended-release ( 3 ) 10 mg dapagliflozin/1,000 mg metformin HCl extended-release (3 )

⛔ Contraindications 155 words ▾

4 CONTRAINDICATIONS Dapagliflozin and metformin hydrochloride extended-release tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease [see Warnings and Precautions ( 5.1 )]. History of a serious hypersensitivity reaction to dapagliflozin, metformin HCl, or any of the excipients in dapagliflozin and metformin hydrochloride extended-release tablets. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin [see Adverse Reactions ( 6.1 )].

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions ( 5.1 ) and Warnings and Precautions ( 5.2 )]. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease.

( 4 ) History of serious hypersensitivity to dapagliflozin, metformin HCl, or any of the excipients in dapagliflozin and metformin hydrochloride extended-release tablets. ( 4 ) Metabolic acidosis, including diabetic ketoacidosis. ( 4 )

⚠️ Warnings and Cautions ~2 min read ▾

5 WARNINGS AND PRECAUTIONS Lactic Acidosis : See boxed warning. ( 5.1 ) Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue dapagliflozin and metformin hydrochloride extended-release tablets if ketoacidosis is suspected.

Monitor patients for resolution of ketoacidosis before restarting. ( 5.2 ) Volume Depletion: Before initiating dapagliflozin and metformin hydrochloride extended-release tablets, assess and correct volume status in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy.

(5.3 ) Urosepsis and Pyelonephritis : Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. ( 5.4 ) Hypoglycemia : Consider a lower dosage of insulin or an insulin secretagogue to reduce the risk of hypoglycemia when used concomitantly with dapagliflozin and metformin hydrochloride extended-release tablets. ( 5.5 ) Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males.

Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. ( 5.6 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels.

Measure hematological parameters annually. ( 5.7 ) Genital Mycotic Infections : Monitor and treat if indicated. ( 5.8 )

5.1Lactic Acidosis There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by non-specific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally greater than 5 mcg/mL.

Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of dapagliflozin and metformin hydrochloride extended-release tablets. In dapagliflozin and metformin hydrochloride extended-release tablets -treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions).

Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur, instruct them to discontinue dapagliflozin and metformin hydrochloride extended-release tablets and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [se… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~3 min read ▾

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions ( 5.2 )] Volume Depletion [see Warnings and Precautions ( 5.3 )] Urosepsis and Pyelonephritis [see Warnings and Precautions ( 5.4 )] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.5 )] Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions ( 5.6 )] Vitamin B 12 Concentrations [see Warnings and Precautions ( 5.7 )] Genital Mycotic Infections [see Warnings and Precautions ( 5.8 )] Adverse reactions reported in greater than 5% of patients treated with dapagliflozin and metformin hydrochloride extended-release tablets were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache.

(6.1) Adverse reactions reported in greater than 5% of patients treated with metformin extended-release are: diarrhea and nausea/vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 o r 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus In placebo-controlled monotherapy trials of metformin HCl extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting).

Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin HCl extended-release. Clinical Trials with Dapagliflozin in Adults Dapagliflozin Dapagliflozin has been evaluated in clinical trials in adult patients with type 2 diabetes mellitus, in adult patients with heart failure, and in adult patients with chronic kidney disease. The overall safety profile of dapagliflozin was consistent across the studied indications.

No new adverse reactions were identified in the DAPA-HF, DELIVER and DAPA-CKD trials. Pools of Placebo-Controlled Clinical Trials for Glycemic Control in Adults Pool of 8 Placebo-Controlled Adult Trials for Dapagliflozin and Metformin HCl for Glycemic Control Data from a prespecified pool of adult patients from 8 short-term, placebo-controlled trials of dapagliflozin coadministered with metformin HCl immediate- or extended-release was used to evaluate safety. This pool included several add-on trials (metformin HCl alone and in combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and metformin HCl, or insulin and metformin HCl, 2 initial combination with metformin HCl trials, and 2 trials of patients with CVD and type 2 diabetes mellitus who received their usual treatment [with metformin HCl as background therapy]).

For trials that included background therapy with and without metformin HCl, only patients who received metformin HCl were included in the 8-trial placebo-controlled pool. Across these 8 trials, 983 patients were treated once daily with dapagliflozin 10 mg and metformin HCl, and 1185 were treated with placebo and metformin HCl. These 8 trials provide a mean duration of exposure of 23 weeks.

The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mi… [Excerpted — this section continues on DailyMed.]

🔄 Drug Interactions ~2 min read ▾

7 DRUG INTERACTIONS Table 6: Clinically Relevant Interactions with Dapagliflozin and Metformin Hydrochloride Extended-Release Tablets Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with dapagliflozin and metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis.

Intervention Consider more frequent monitoring of these patients. Drugs that Reduce Metformin Clearance Clinical Impact Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors, such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology ( 12.3 )].

Intervention Consider the benefits and risks of concomitant use. Alcohol Clinical Impact Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention Warn patients against excessive alcohol intake while receiving dapagliflozin and metformin hydrochloride extended-release tablets.

Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when dapagliflozin and metformin hydrochloride extended-release tablets is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions ( 5.5 )] . Intervention Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.

These medications include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. Intervention When such drugs are administered to a patient receiving dapagliflozin and metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving dapagliflozin and metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia.

Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently during dapagliflozin and metformin hydrochloride extended-release tablets initiation and dosage changes. Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control. Carbonic anhydrase inhibitors: May increase risk of lactic acidosis.

Consider more frequent monitoring. ( 7) Drugs that reduce metformin clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use.

(7 ) See full prescribing information for additional drug interactions and information on interference of dapagliflozin and metformin hydrochloride extended-release tablets with laboratory tests. ( 7)

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS Pregnancy : Advise females of the potential risk to a fetus, especially during the second and third trimesters. ( 8.1 ) Lactation: N ot recommended when breastfeeding. ( 8.2 ) Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy.

( 8.3 ) Geriatrics: Higher incidence of adverse reactions related to hypotension. Assess renal function more frequently. ( 8.5 , 8.6 ) Renal Impairment : Higher incidence of adverse reactions related to volume depletion.

( 8.6 ) Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 ) Pediatric use information is approved for AstraZeneca AB’s Xigduo ® XR (dapagliflozin and metformin hydrochloride) Extended-Release Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

8.1Pregnancy Risk Summary Based on animal data showing adverse renal effects, dapagliflozin and metformin hydrochloride extended-release tablets are not recommended during the second and third trimesters of pregnancy. Limited data with dapagliflozin and metformin hydrochloride extended-release tablets or dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see Data) .

There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data) . The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%.

The estimated background risk of miscarriage for the indicated population is unknown. 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. Clinical Considerations Disease-associated maternal and/or embryofetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data Dapagliflozin Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.

In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Incre… [Excerpted — this section continues on DailyMed.]

🤰 Pregnancy ~3 min read ▾

8.1Pregnancy Risk Summary Based on animal data showing adverse renal effects, dapagliflozin and metformin hydrochloride extended-release tablets are not recommended during the second and third trimesters of pregnancy. Limited data with dapagliflozin and metformin hydrochloride extended-release tablets or dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see Data) .

There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data) . The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%.

The estimated background risk of miscarriage for the indicated population is unknown. 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. Clinical Considerations Disease-associated maternal and/or embryofetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data Dapagliflozin Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.

In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in 21-day-old pups offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137- times, respectively, the human values at the 10 mg clinical dose, based on AUC).

Dose-related reductions in pup body weights were observed at greater or equal to 29- times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19- times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development.

In embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin wa… [Excerpted — this section continues on DailyMed.]

🧒 Pediatric Use ~1 min read ▾

8.4Pediatric Use The use of dapagliflozin and metformin hydrochloride extended-release tablets is supported by evidence from adequate and well-controlled trials of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical trial using metformin HCl immediate-release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, and pharmacokinetic data with metformin HCl extended-release tablets in adults [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 , 14.2 )].

In the clinical trial with pediatric patients receiving metformin HCl immediate-release tablets, adverse reactions with metformin HCl immediate-release tablets were similar to those described in adults [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of dapagliflozin and metformin hydrochloride extended-release tablets for glycemic control in patients with type 2 diabetes mellitus have not been established in pediatric patients less than 10 years of age. The safety and effectiveness of dapagliflozin and metformin hydrochloride extended-release tablets have not been established in pediatric patients to reduce the risk of [see Indications and Usage ( 1 )]: sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure. hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.

Pediatric use information is approved for AstraZeneca AB’s Xigduo ® XR (dapagliflozin and metformin hydrochloride) Extended-Release Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

🧓 Geriatric Use ~2 min read ▾

8.5Geriatric Use Dapagliflozin and metformin hydrochloride extended-release tablets No dapagliflozin and metformin hydrochloride extended-release tablets dosage change is recommended based on age. More frequent assessment of renal function is recommended in elderly patients. Dapagliflozin A total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical trials assessing the efficacy of dapagliflozin in improving glycemic control.

After controlling for level of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥65 years of age, a higher proportion of patients treated with dapagliflozin for glycemic control had adverse reactions of hypotension [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )]. In the DAPA-HF, DELIVER and DAPA-CKD trials, safety and efficacy were similar for patients aged 65 years and younger and those older than 65 in both the overall population and in the patients with type 2 diabetes mellitus.

In the DAPA-HF trial, 2714 (57%) out of 4744 patients with heart failure with reduced ejection fraction (HFrEF) were older than 65 years. Out of 2139 patients with HFrEF and type 2 diabetes mellitus, 1211 (57%) were older than 65 years. In the DELIVER trial, 4759 (76%) out of 6263 patients with heart failure (LVEF >40%) were older than 65 years.

Out of 2806 patients with LVEF >40% and type 2 diabetes mellitus, 2072 (74%) were older than 65 years. In the DAPA-CKD trial, 1818 (42%) out of 4304 patients with chronic kidney disease were older than 65 years. Out of 2906 patients with chronic kidney disease and type 2 diabetes mellitus, 1399 (48%) were older than 65 years.

Metformin HCl Controlled clinical trials of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions ( 5.1 )].

🆘 Overdosage 103 words ▾

10 OVERDOSAGE Dapagliflozin In the event of an overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. The removal of dapagliflozin by hemodialysis has not been studied. Metformin HCl Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams.

Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions ( 5.1 )]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

🧬 Clinical Pharmacology ~3 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Dapagliflozin Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose, and thereby promotes urinary glucose excretion.

Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre-and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback. Metformin HCl Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose.

Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

12.2Pharmacodynamics General Dapagliflozin Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day. A near maximum glucose excretion was observed at the dapagliflozin daily dosage of 20 mg.

This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions ( 6.1 )]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dosage. Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot) Cardiac Electrophysiology Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15- times the recommended maximum dose) in a study of healthy subjects.

In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50-times the recommended maximum dose) of dapagliflozin in healthy subjects. dapagliflozin-fig-1

12.3Pharmacokinetics Dapagliflozin and metformin hydrochloride extended-release tablets The administration of dapagliflozin and metformin hydrochloride extended-release tablets in healthy subjects after a standard meal compared to the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin extended-release. Compared to the fasted state, the standard meal resulted in 35% reduction and a delay of 1 to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is not considered to be clinically meaningful.

Food has no relevant effect on the pharmacokinetics of metformin when administered as dapagliflozin and metformin hydrochloride extended-release combination tablets. Absorption Dapagliflozin Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The C max and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range.

The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour but does not a… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action 167 words ▾

12.1Mechanism of Action Dapagliflozin Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose, and thereby promotes urinary glucose excretion.

Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre-and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback. Metformin HCl Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose.

Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

📦 How Supplied / Storage and Handling 196 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Dapagliflozin and metformin hydrochloride extended-release tablets have markings on both sides, and are available in the strengths and packages listed in Table 21. Table 21: Dapagliflozin and Metformin Hydrochloride Extended-Release Tablets Presentations Tablet Strength Film-Coated Tablet Color/Shape Tablet Markings Pack Size NDC Code 5 mg/500 mg orange, biconvex, capsule-shaped "D/M" on one side and "5/500"on other side Bottle of 30 Bottle of 500 67877-619-30 67877-619-05 5 mg/1000 mg pink to dark pink, biconvex, oval-shaped "D/M" on one side and "5/1000"on other side Bottle of 30 Bottle of 60 Bottle of 90 67877-620-30 67877-620-60 67877-620-90 10 mg/500 mg Pink to light pink, biconvex, capsule-shaped "D/M" on one side and "10/500"on other side Bottle of 30 Bottle of 500 Carton of 100 (10 x 10) tablet 67877-621-30 67877-621-05 67877-621-38 10 mg/1000 mg yellow to dark yellow, biconvex, oval-shaped "D/M" on one side and "10/1000"on other side Bottle of 30 Bottle of 90 Bottle of 400 Carton of 100 (10 x 10) tablet 67877-622-30 67877-622-90 67877-622-40 67877-622-38 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

📋 Description ~2 min read ▾

11 DESCRIPTION Dapagliflozin and metformin hydrochloride extended-release tablets contain two oral antihyperglycemic medications used in the management of type 2 diabetes: dapagliflozin and metformin hydrochloride. Dapagliflozin Dapagliflozin is described chemically as (2S, 3R, 4R, 5S, 6R)-2-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol. The Structuralformula is C 21 H 25 ClO 6 and the Molecular weight 408.88.

The structural formula is: Metformin hydrochloride Metformin hydrochloride ( N,N -dimethylimidodicarbonimidic diamide hydrochloride) is a White fine powder with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone and in methylene chloride. The pKa of metformin is 11.5.

The pH of a 5% aqueous solution of metformin hydrochloride is 6-7. The structural formula is: Dapagliflozin and metformin hydrochloride extended-release tablets Dapagliflozin and metformin hydrochloride extended-release tablets is available for oral administration as tablets containing 5 mg dapagliflozin and 500 mg metformin hydrochloride (dapagliflozin and metformin hydrochloride extended-release tablets 5 mg/500 mg), 5 mg dapagliflozin and 1000 mg metformin hydrochloride (dapagliflozin and metformin hydrochloride extended-release tablets 5 mg/1000 mg), 10 mg dapagliflozin and 500 mg metformin hydrochloride (dapagliflozin and metformin hydrochloride extended-release tablets 10 mg/500 mg) and 10 mg dapagliflozin and 1000 mg metformin hydrochloride (dapagliflozin and metformin hydrochloride extended-release tablets 10 mg/1000 mg).

Each film-coated tablet of dapagliflozin and metformin hydrochloride extended release tablets, 5mg/500 mg, 5mg/1000 mg, 10mg/500 mg and 10mg/1000 mg contains the following inactive ingredients: Lactose Monohydrate, Microcrystalline Cellulose (GR 101 and GR 102), Low-Substituted Hydroxypropyl Cellulose, Hypromellose, Silicon Dioxide, Magnesium Stearate, copovidone, povidone and Carboxymethylcellulose Sodium. The film coatings contain the following inactive ingredients: Dapagliflozin and metformin hydrochloride extended release tablets, 5mg/500 mg contains: polyvinyl alcohol, talc, titanium dioxide, glycerol esters of fatty acids, sodium lauryl sulfate and FD&C Yellow #6/sunset yellow FCF aluminum lake.

Dapagliflozin and metformin hydrochloride extended release tablets, 5mg/1000 mg contains: polyvinyl alcohol, talc, titanium dioxide, glycerol esters of fatty acids, sodium lauryl sulfate and iron oxide red. Dapagliflozin and metformin hydrochloride extended release tablets, 10mg/500 mg contains: polyvinyl alcohol, talc, titanium dioxide, glycerol esters of fatty acids, sodium lauryl sulfate and iron oxide red. Dapagliflozin and metformin hydrochloride extended release tablets, 10mg/1000 mg contains: polyvinyl alcohol, talc, titanium dioxide, glycerol esters of fatty acids, sodium lauryl sulfate and iron oxide yellow. dapagliflozin-structure-a dapagliflozin-metformin-a

💬 Information for Patients ~2 min read ▾

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Lactic Acidosis Inform patients of the risks of lactic acidosis due to the metformin component and its symptoms and conditions that predispose to its development [see Warnings and Precautions ( 5.1 )]. Advise patients to discontinue dapagliflozin and metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur.

Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of dapagliflozin and metformin hydrochloride extended-release tablets therapy; however, inform patients to consult their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease. Counsel patients against excessive alcohol intake while receiving dapagliflozin and metformin hydrochloride extended-release tablets [see Warnings and Precautions ( 5.1 )].

Inform patients about the importance of regular testing of renal function and hematological parameters when receiving treatment with dapagliflozin and metformin hydrochloride extended-release tablets [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. Instruct patients to inform their healthcare provider that they are taking dapagliflozin and metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation of dapagliflozin and metformin hydrochloride extended-release tablets may be required until renal function has been confirmed to be normal [see Warnings and Precautions ( 5.1 )].

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis Inform patients that dapagliflozin and metformin hydrochloride extended-release tablets can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors. Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing).

Inform patients that blood glucose may be normal even in the presence of ketoacidosis. Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue dapagliflozin and metformin hydrochloride extended-release tablets and seek medical attention immediately [ see Warnings and Precautions ( 5.2 )] .

Volume Depletion Inform patients that symptomatic hypotension may occur with dapagliflozin and metformin hydrochloride extended-release tablets and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions ( 5.3 )]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake. Serious Urinary Tract Infections Inform patients of the potential for urinary tract infections, which may be serious.

Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions ( 5.4 )]. Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues Inform patients that the incidence of hypoglycemia may increase when dapagliflozin and metformin hydrochloride extended-release tablets are added to an insulin secretagogue (e.g., sulfonylurea) and/or insulin.

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

💬 Medication Guide ~3 min read ▾

MEDICATION GUIDE Dapagliflozin (dap-a-gli-floe-zin) and Metformin(met-FORE-min) hydrochloride extended-release tablets, for oral use What is the most important information I should know about dapagliflozin and metformin hydrochloride extended-release tablets? Dapagliflozin and metformin hydrochloride extended-release tablets can cause serious side effects, including: Lactic Acidosis . Metformin, one of the medicines in dapagliflozin and metformin hydrochloride extended-release tablets, can cause a rare but serious condition called lactic acidosis (a build-up of an acid in the blood) that can cause death.

Lactic acidosis is a medical emergency and must be treated in the hospital. Stop taking dapagliflozin and metformin hydrochloride extended-release tablets and call your healthcare provider right away if you have any of the following symptoms, which could be signs of lactic acidosis: you feel cold in your hands or feet you feel dizzy or lightheaded you have a slow or irregular heartbeat you feel very weak or tired you have unusual (not normal) muscle pain you have trouble breathing you feel unusual sleepiness or sleep longer than usual you have stomach pains, nausea or vomiting Most people who have had lactic acidosis with metformin have other things that, combined with the metformin use, led to the lactic acidosis.

Tell your healthcare provider if you have any of the following, because you have a higher chance for getting lactic acidosis with dapagliflozin and metformin hydrochloride extended-release tablets if you: have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye. have liver problems. drink alcohol very often or drink a lot of alcohol in the short-term ("binge" drinking). get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea.

Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. have surgery. have new or worsening symptoms of congestive heart failure such as shortness of breath or increased fluid or swelling of the legs. have a heart attack, severe infection, or stroke. are 65 years of age or older. The best way to keep from having a problem with lactic acidosis from metformin is to tell your healthcare provider if you have any of the problems in the list above. Your healthcare provider may decide to stop your dapagliflozin and metformin hydrochloride extended-release tablets for a while if you have any of these things.

Diabetic Ketoacidosis (increased ketones in your blood or urine) in people with type 1 diabetes and other ketoacidosis. dapagliflozin and metformin hydrochloride extended-release tablets can cause ketoacidosis that can be life-threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis.

People with type 2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis. Ketoacidosis can also happen in people who are sick, cannot eat or drink as usual, skip meals, are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the body (volume depletion), or who have surgery or a procedure that requires not having food for a long time (prolonged fasting).

Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. Your healthcare provider may ask you to periodically check ketones in your urine or blood. Stop taking dapagliflozin and metformin hydrochloride extended-release tablets and call your healthcare provider or get medical help right away if you get any of the following.

If possible, check for ketones in your urine or blood, even if your blood sugar is less than 250 mg/dL. o nausea o tiredness o vomiting o stomach area (abdominal) pain o trouble breathing o… [Excerpted — this section continues on DailyMed.]

🍼 Nursing Mothers 28 words ▾

8.3Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

🧬 Pharmacokinetics ~3 min read ▾

12.3Pharmacokinetics Dapagliflozin and metformin hydrochloride extended-release tablets The administration of dapagliflozin and metformin hydrochloride extended-release tablets in healthy subjects after a standard meal compared to the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin extended-release. Compared to the fasted state, the standard meal resulted in 35% reduction and a delay of 1 to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is not considered to be clinically meaningful.

Food has no relevant effect on the pharmacokinetics of metformin when administered as dapagliflozin and metformin hydrochloride extended-release combination tablets. Absorption Dapagliflozin Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The C max and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range.

The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.

Metformin HCl Following a single oral dose of metformin HCl extended-release, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. The extent of metformin absorption (as measured by AUC) from the metformin HCl extended-release tablet increased by approximately 50% when given with food. There was no effect of food on C max and T max of metformin.

Metformin HCl extended-release tablets and metformin HCl immediate-release tablets have a similar extent of absorption (as measured by AUC), while peak plasma levels of metformin extended-release tablets are approximately 20% lower than those of metformin immediate-release tablets at the same dose. Distribution Dapagliflozin Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.

Metformin HCl Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes.

Metabolism Dapagliflozin The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [ 14 C]-dapagliflozin dose and is the predominant drug-related component in human plasma.

Metformin HCl Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted. Elimination Dapagliflozin Dapagliflozin and related metabolites are primarily eliminated via the renal pathway.

Following a single 50 mg dose of [ 14 C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug.

The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg. Metformin HCl Renal clearance is approximately 3.5-times greater than… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacodynamics 219 words ▾

12.2Pharmacodynamics General Dapagliflozin Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day. A near maximum glucose excretion was observed at the dapagliflozin daily dosage of 20 mg.

This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions ( 6.1 )]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dosage. Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot) Cardiac Electrophysiology Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15- times the recommended maximum dose) in a study of healthy subjects.

In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50-times the recommended maximum dose) of dapagliflozin in healthy subjects. dapagliflozin-fig-1

🔬 Clinical Studies ~3 min read ▾

14 CLINICAL STUDIES

14.1Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus The effectiveness of dapagliflozin and metformin hydrochloride extended-release tablets has been established in clinical trials of the coadministration of oral dapagliflozin and metformin HCl extended-release tablets in treatment-naive adult patients inadequately controlled on diet and exercise alone. The coadministration of dapagliflozin and metformin HCl immediate-release or extended-release tablets has been studied in adult patients with type 2 diabetes mellitus inadequately controlled on metformin HCl and compared with a sulfonylurea (glipizide) in combination with metformin HCl.

Treatment with dapagliflozin plus metformin HCl at all doses produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) compared to placebo in combination with metformin HCl (initial or add-on therapy). HbA1c reductions were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI). Dapagliflozin Initial Combination Therapy with Metformin HCl Extended-Release A total of 1236 treatment-naive adult patients with inadequately controlled type 2 diabetes mellitus (HbA1c ≥7.5% and ≤12%) participated in 2 active-controlled trials of 24-week duration to evaluate initial therapy with dapagliflozin 5 mg (NCT00643851) or 10 mg (NCT00859898) in combination with metformin extended-release formulation.

In one trial, 638 patients randomized to 1 of 3 treatment arms following a 1-week lead-in period received: dapagliflozin 10 mg plus metformin HCl extended-release (up to 2,000 mg/day), dapagliflozin 10 mg plus placebo, or metformin HCl extended-release (up to 2,000 mg/day) plus placebo. Metformin HCl extended-release dosage was up-titrated weekly in 500 mg increments, as tolerated, with a median dosage achieved of 2,000 mg. The combination treatment of dapagliflozin 10 mg plus metformin HCl extended-release provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin HCl extended-release alone (see Table 11 and Figure 2).

Dapagliflozin 10 mg as monotherapy also provided statistically significant improvements in FPG and statistically significant reduction in body weight compared with metformin HCl alone and was non-inferior to metformin HCl extended-release monotherapy in lowering HbA1c. Table 11: Results at Week 24 (LOCF * ) in an Active-Controlled Trial of Dapagliflozin Initial Combination Therapy with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus Efficacy Parameter Dapagliflozin 10 mg + Metformin HCl extended-release N=211 † Dapagliflozin 10 mg N=219 † Metformin HCl extended-release N=208 † HbA1c (%) Baseline (mean) 9.1 9.0

9.0Change from baseline (adjusted mean ‡ ) −2.0 −1.5 −1.4 Difference from dapagliflozin (adjusted mean ‡ ) (95% CI) −0.5§ (−0.7, −0.3) Difference from metformin HCl extended-release (adjusted mean ‡ ) (95% CI) −0.5§ (−0.8, −0.3) 0.0¶ (−0.2, 0.2) Percent of patients achieving HbA1c less than 7% adjusted for baseline 46.6% 31.7% 35.2% FPG (mg/dL) Baseline (mean) 189.6 197.5 189.9 Change from baseline (adjusted mean ‡ ) −60.4 −46.4 −34.8 Difference from dapagliflozin (adjusted mean ‡ ) (95% CI) −13.9§ (−20.9, −7.0) Difference from metformin HCl extended-release (adjusted mean ‡ ) (95% CI) −25.5§ (−32.6, −18.5) −11.6# (−18.6, −4.6) Body Weight (kg) Baseline (mean) 88.6 88.5

87.2Change from baseline (adjusted mean ‡ ) −3.3 −2.7 −1.4 Difference from metformin HCl extended-release (adjusted mean ‡ ) (95% CI) −2.0§ (−2.6, −1.3) −1.4§ (−2.0, −0.7) * LOCF: last observation (prior to rescue for rescued patients) carried forward. † All randomized patients who took at least one dose of double-blind trial medication during the short-term double-blind period. ‡ Least squares mean adjusted for baseline value. § p-value less than 0.00… [Excerpted — this section continues on DailyMed.]

🧪 Nonclinical Toxicology ~2 min read ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Dapagliflozin and metformin hydrochloride extended-release tablets No animal studies have been conducted with dapagliflozin and metformin hydrochloride extended-release tablets to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with dapagliflozin and metformin individually. Dapagliflozin Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies.

Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10 and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72-times (males) and 105-times (females) the clinical dose of 10 mg per day, based on AUC exposure. In rats, the highest dose was approximately 131- times (males) and 186-times (females) the clinical dose of 10 mg per day, based on AUC exposure.

Dapagliflozin was negative in the Ames mutagenicity assay and was positive in a series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations greater than or equal to 100 μg/mL. Dapagliflozin was negative for clastogenicity in a series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples greater than 2100-times the clinical dose. There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent a genotoxic risk to humans.

Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples less than or equal to 1708-times and 998-times the maximum recommended human dose in males and females, respectively. Metformin HCl Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 and 1,500 mg/kg/day, respectively. These doses are both approximately 4-times the maximum recommended human dose of 2,000 mg based on body surface area comparisons.

No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3-times the maximum recommended human dose based on body surface area comparisons.

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ~2 min read ▾

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Dapagliflozin and metformin hydrochloride extended-release tablets No animal studies have been conducted with dapagliflozin and metformin hydrochloride extended-release tablets to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with dapagliflozin and metformin individually. Dapagliflozin Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies.

Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10 and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72-times (males) and 105-times (females) the clinical dose of 10 mg per day, based on AUC exposure. In rats, the highest dose was approximately 131- times (males) and 186-times (females) the clinical dose of 10 mg per day, based on AUC exposure.

Dapagliflozin was negative in the Ames mutagenicity assay and was positive in a series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations greater than or equal to 100 μg/mL. Dapagliflozin was negative for clastogenicity in a series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples greater than 2100-times the clinical dose. There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent a genotoxic risk to humans.

Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples less than or equal to 1708-times and 998-times the maximum recommended human dose in males and females, respectively. Metformin HCl Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 and 1,500 mg/kg/day, respectively. These doses are both approximately 4-times the maximum recommended human dose of 2,000 mg based on body surface area comparisons.

No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3-times the maximum recommended human dose based on body surface area comparisons.

📄 Recent Major Changes 14 words ▾

Indications and Usage ( 1 ) 12/2024 Dosage and Administration ( 2.3 ) 06/2024

📄 Package Label / Principal Display Panel 70 words ▾

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 67877-619-30 Dapagliflozin and Metformin HCl Extended-Release Tablets 5 mg/500 mg Rx Only 30 Tablets NDC 67877-620-60 Dapagliflozin and Metformin HCl Extended-Release Tablets 5 mg/1000 mg Rx Only 60 Tablets NDC 67877-621-05 Dapagliflozin and Metformin HCl Extended-Release Tablets 10 mg/500 mg Rx Only 500 Tablets NDC 67877-622-38 Dapagliflozin and Metformin HCl Extended-Release Tablets 10 mg/1000 mg Rx Only 100 Tablets (10X10 Unit-Dose) dapagliflozin-30tab-a dapagliflozin-60tab-a dapagliflozin-500tab-a dapagliflozin-cart-100tab-a

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗
← 67877-0619-05 · Ascend 67877-0621-05 · Ascend →
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.