XIGDUO XR dapagliflozin and metformin hydrochloride 10 mg; 500 mg Tablet, Film Coated, Extended Release, 30-count
🆔 Identity & classification
Where does this data come from?
🏷️ RxNorm drug class
This medicine belongs to the Sodium-Glucose Cotransporter 2 Inhibitor class.
Where does this data come from?
🏭 Manufacturer & labeler
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🩺 Clinical
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 ↗- It does more than just lower blood sugar. The metformin part helps your body handle glucose more efficiently, while the dapagliflozin part flushes excess sugar out through your uri...
- What is this medication actually doing for me — is it just for blood sugar?
- Lactic acidosis is real and listed as a serious warning, but it's also quite rare when metformin is used carefully in the right patients. The risk is higher if you have kidney prob...
- I heard metformin can cause a dangerous condition called lactic acidosis. Should I be worried?
Patient education
Supplement & herbal interactions
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💊 What it looks like
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII 3SY5LH9PMK
Anhydrous lactose is a milk sugar with no water content. It acts as a filler and binder in tablets and capsules, adding bulk and helping ingredients stick together.
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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.
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UNII 2S7830E561
Crospovidone is a synthetic polymer derived from povidone. It acts as a disintegrant, helping the tablet or capsule break apart quickly in the stomach so the active ingredient can be absorbed.
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UNII VM7F0B23ZI
Hypromellose 2208 is a plant-derived thickening agent that forms a protective coating on tablets and capsules. It slows down how quickly the medicine dissolves, controlling drug release into your body.
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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.
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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.
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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.
7 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
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?
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $19.226 | $576.78 / 30 tablets |
| Medicaid paysCMS SDUD · 12 mo | $19.26 | $577.82 / 30 tablets |
| Medicare drug plans payPart D · Q2 2026 | $19.18 | $575.46 / 30 tablets |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Dapagliflozin and Metformin Hydrochloride 10 mg/1; 500 mg 63304-0027-30 | Sun | 30 tablets | $0.856 | AB | Availability likely | save 96% |
| Dapagliflozin And Metformin Hydrochloride 10 mg/1; 500 mg 70748-0103-06 | Lupin | 30 tablets | $0.856 | AB | Availability likely | save 96% |
| Dapagliflozin And Metformin Hydrochloride 10 mg/1; 500 mg 72205-0436-01 | Novadoz | 30 tablets | $0.856 | AB | Availability likely | save 96% |
| Xigduo Xr 10 mg/1; 500 mgthis 00310-6270-30 | AstraZeneca | 30 tablets | $19.226 | AB | Availability likely | — |
| Dapagliflozin and Metformin Hydrochloride 10 mg/1; 500 mg 33342-0407-06 | Macleods | 10 tablets | — | AB | FDA listed | — |
| Dapagliflozin and Metformin hydrochloride 10 mg/1; 500 mg 59651-0156-05 | Aurobindo | 500 tablets | — | AB | FDA listed | — |
| dapagliflozin and metformin hydrochloride 10 mg/1; 500 mg 67877-0621-05 | Ascend | 500 tablets | — | AB | FDA listed | — |
| Dapagliflozin and Metformin Hydrochloride 10 mg/1; 500 mg 84677-0021-30 | Golden | 30 tablets | — | AB | FDA listed | — |
Where does this data come from?
⏳ Availability & generic status
FDA-approved generic versions are listed, and recent pricing/market data suggests they may be available — see Therapeutic equivalents.
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.
🛈 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.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 6515117 ↗ | Drug substance | U-493 | Oct 4, 2025 |
| US 6515117 ↗ | Drug substance | U-493 | Oct 4, 2025 |
| US 8501698 ↗ | Method of use | U-493 | Jun 20, 2027 |
| US 6515117 ↗ | Drug substance | U-493 | Oct 4, 2025 |
| US 8501698 ↗ | Method of use | U-493 | Jun 20, 2027 |
| US 8685934 ↗ | Method of use | U-1522 | May 26, 2030 |
| US 8501698 ↗ | Method of use | U-493 | Jun 20, 2027 |
| US 8685934 ↗ | Method of use | U-1522 | May 26, 2030 |
| US 8501698 ↗ | Method of use | U-493 | Jun 20, 2027 |
| US 8685934 ↗ | Method of use | U-1522 | May 26, 2030 |
| US 8685934 ↗ | Method of use | U-1522 | May 26, 2030 |
| US 6515117 ↗ | Drug substance | U-493 | Oct 4, 2025 |
| US 6515117 ↗ | Drug substance | U-493 | Oct 4, 2025 |
| US 8501698 ↗ | Method of use | U-493 | Jun 20, 2027 |
| US 8685934 ↗ | Method of use | U-1522 | May 26, 2030 |
| US 9616028 ↗ | Drug product | — | Nov 12, 2030 |
| US 7919598 ↗ | Drug substance | — | Dec 16, 2029 |
| US 9616028 ↗ | Drug product | — | Nov 12, 2030 |
| US 7919598 ↗ | Drug substance | — | Dec 16, 2029 |
| US 7919598 ↗ | Drug substance | — | Dec 16, 2029 |
| US 7919598 ↗ | Drug substance | — | Dec 16, 2029 |
| US 7919598 ↗ | Drug substance | — | Dec 16, 2029 |
| US 9616028 ↗ | Drug product | — | Nov 12, 2030 |
| US 9616028 ↗ | Drug product | — | Nov 12, 2030 |
| US 9616028 ↗ | Drug product | — | Nov 12, 2030 |
| US 8501698*PED ↗ | Drug product | — | Dec 20, 2027 |
| US 7919598*PED ↗ | Drug product | — | Jun 16, 2030 |
| US 8685934*PED ↗ | Drug product | — | Nov 26, 2030 |
| US 6515117*PED ↗ | Drug product | — | Apr 4, 2026 |
| US 6515117*PED ↗ | Drug product | — | Apr 4, 2026 |
| US 8685934*PED ↗ | Drug product | — | Nov 26, 2030 |
| US 7919598*PED ↗ | Drug product | — | Jun 16, 2030 |
| US 8501698*PED ↗ | Drug product | — | Dec 20, 2027 |
| US 6515117*PED ↗ | Drug product | — | Apr 4, 2026 |
| US 8501698*PED ↗ | Drug product | — | Dec 20, 2027 |
| US 8685934*PED ↗ | Drug product | — | Nov 26, 2030 |
| US 7919598*PED ↗ | Drug product | — | Jun 16, 2030 |
| US 6515117*PED ↗ | Drug product | — | Apr 4, 2026 |
| US 7919598*PED ↗ | Drug product | — | Jun 16, 2030 |
| US 8501698*PED ↗ | Drug product | — | Dec 20, 2027 |
| US 8685934*PED ↗ | Drug product | — | Nov 26, 2030 |
| US 8501698*PED ↗ | Drug product | — | Dec 20, 2027 |
| US 6515117*PED ↗ | Drug product | — | Apr 4, 2026 |
| US 8685934*PED ↗ | Drug product | — | Nov 26, 2030 |
| US 7919598*PED ↗ | Drug product | — | Jun 16, 2030 |
| US 9616028*PED ↗ | Drug product | — | May 12, 2031 |
| US 9616028*PED ↗ | Drug product | — | May 12, 2031 |
| US 9616028*PED ↗ | Drug product | — | May 12, 2031 |
| US 9616028*PED ↗ | Drug product | — | May 12, 2031 |
| US 9616028*PED ↗ | Drug product | — | May 12, 2031 |
| Code | What it grants | Expires |
|---|---|---|
| NPP | New Patient Population | Jun 12, 2027 |
| NPP | New Patient Population | Jun 12, 2027 |
| NPP | New Patient Population | Jun 12, 2027 |
| NPP | New Patient Population | Jun 12, 2027 |
| NPP | New Patient Population | Jun 12, 2027 |
| PED | Pediatric Exclusivity (+6 months) | Dec 12, 2027 |
| PED | Pediatric Exclusivity (+6 months) | Dec 12, 2027 |
| PED | Pediatric Exclusivity (+6 months) | Dec 12, 2027 |
| PED | Pediatric Exclusivity (+6 months) | Dec 12, 2027 |
| PED | Pediatric Exclusivity (+6 months) | Dec 12, 2027 |
Is there a generic version of XIGDUO XR 10 MG-500 MG TABLET?
The FDA approved a generic — why can’t I get it at my pharmacy yet?
Why do different websites show different generic release dates?
What does “FDA listed” mean?
What does a patent or protection date mean here?
What does “current Orange Book estimate” mean?
Can a generic come out before the last patent expires?
Can a generic come out after the listed dates?
What is the difference between patents and exclusivity?
Why are there multiple patent dates?
Where does this data come from?
🗺️ Medicaid utilization & spend
💊 Medicaid utilization by pack size
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
Where does this data come from?
📦 Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Status |
|---|---|---|---|---|---|
| 00310-6270-30 You're viewing this | 30 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE, PLASTIC (0310-6270-30) | $19.23 / ea | $576.78 | 2014-11-11 | Active |
| 00310-6270-95 | 1 BLISTER PACK in 1 CARTON (0310-6270-95) / 7 TABLET, FILM COATED, EXTENDED RELEASE in 1 BLISTER PACK | — | — | 2014-11-11 | Discontinued by firm |
In Medicaid, this is the most-dispensed pack of this product — about 100% of fills over the last four reported quarters. See all packs ↓
Pack size FAQ
What quantity is in NDC 00310-6270-30?
What is the difference between NDC 00310-6270-30 and NDC 00310-6270-95?
What NDC number is used to bill for this package of XIGDUO XR dapagliflozin and metformin hydrochloride 10 mg; 500 mg Tablet, Film Coated, Extended Release?
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.
📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
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 (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >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, hepatic impairment and mitochondrial diseases [see Warnings and Precautions (5.1) ] . • 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 XIGDUO XR 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 >5 mcg/mL. ( 5.1 ) • Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, hepatic impairment, and mitochondrial diseases. 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 XIGDUO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE XIGDUO XR is a combination of dapagliflozin and metformin hydrochloride (HCl) extended-release, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Dapagliflozin, when used as a component of XIGDUO XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: • Sustained eGFR decline, end‑stage kidney disease, (CV) death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. • CV 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 CV disease or multiple CV risk factors.
Limitations of Use • XIGDUO XR is 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 XIGDUO XR is limited to patients with type 2 diabetes mellitus for all indications. • XIGDUO XR is 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. XIGDUO XR is not expected to be effective in these populations.
XIGDUO XR is a 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 and pediatric patients aged 10 years and older with type 2 diabetes mellitus. ( 1 ) Dapagliflozin when used as a component of XIGDUO XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: • Sustained eGFR decline, end-stage kidney disease, cardiovascular (CV) death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression.
( 1 ) • CV 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 CV disease or multiple CV 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 XIGDUO XR is 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. XIGDUO XR is not expected to be effective in these populations.
( 1 )
⏱️ Dosage and Administration ▾
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 aged 10 years and older 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 ) • XIGDUO XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures.
( 2.5 ) • Withhold XIGDUO XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.6 )
2.1Testing Prior to Initiation of XIGDUO XR • Assess renal function prior to initiating XIGDUO XR 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 XIGDUO XR [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5 , 8.6)].
2.2Recommended Administration • Take XIGDUO XR orally once daily in the morning with food. • Swallow XIGDUO XR tablets whole and never crush, cut, or chew.
2.3Recommended Dosage • Individualize the starting dosage of XIGDUO XR based upon the patient’s current regimen. Patients taking an evening dosage of metformin HCl extended‑release should skip their last dose before starting XIGDUO XR. • To improve glycemic control in adults and pediatric patients aged 10 years and older not already taking: ∘ Dapagliflozin: the recommended starting dosage of dapagliflozin in XIGDUO XR is 5 mg orally once daily. ∘ Metformin HCl extended‑release: the recommended starting dosage of metformin HCl extended‑release in XIGDUO XR is 500 mg orally once daily. • For XIGDUO XR indications in adults related to heart failure and chronic kidney disease, the recommended dosage of dapagliflozin in XIGDUO XR is 10 mg orally once daily. • For all XIGDUO XR 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) ] .
2.4Recommended Dosage in Patients with Renal Impairment • The recommended dosage of XIGDUO XR 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 recommended dosage in patients with normal renal function. • Initiation of XIGDUO XR is not recommended in patients with an eGFR between 30 and 45 mL/min/1.73 m 2 . Assess the benefit and risk of continuing therapy if eGFR falls persistently below this level. ∘ Dapagliflozin is likely to be ineffective to improve glycemic control in patients with eGFR less than 45 mL/min/1.73 m 2 . ∘ Metformin HCl initiation is not recommended for patients with eGFR less than 45 mL/min/1.73 m 2 . • XIGDUO XR is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2 and end‑stage renal disease due to the metformin HCl component [ see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.6) ] .
2.5Discontinuation for Iodinated Contrast Imaging Procedures Discontinue XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 , in patients with a history of liver disease, alcoholism or heart failure; or in pat…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS XIGDUO XR (dapagliflozin and metformin HCl) extended-release tablets are available as follows: Table 1: Dosage Forms and Strengths for XIGDUO XR Dapagliflozin Strength Metformin HCl Strength Color/Shape Tablet Markings 2.5 mg 1,000 mg light brown to brown, biconvex, oval-shaped, and film-coated tablet "1074" and "2.5/1000" debossed on one side and plain on the reverse side 5 mg 500 mg orange, biconvex, capsule-shaped, and film-coated tablet "1070" and "5/500" debossed on one side and plain on the reverse side 5 mg 1,000 mg pink to dark pink, biconvex, oval-shaped, and film-coated tablet "1071" and "5/1000" debossed on one side and plain on the reverse side 10 mg 500 mg pink, biconvex, capsule-shaped, and film-coated tablet "1072" and "10/500" debossed on one side and plain on the reverse side 10 mg 1,000 mg yellow to dark yellow, biconvex, oval-shaped, and film-coated tablet "1073" and "10/1000" debossed on one side and plain on the reverse side • 2.5 mg dapagliflozin/1,000 mg metformin HCl extended-release ( 3 ) • 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 ▾
4 CONTRAINDICATIONS XIGDUO XR is 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 XIGDUO XR. 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 XIGDUO XR. ( 4 ) • Metabolic acidosis, including diabetic ketoacidosis.
( 4 )
⚠️ Warnings and Cautions ▾
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 XIGDUO XR if ketoacidosis is suspected.
Monitor patients for resolution of ketoacidosis before restarting. ( 5.2 ) • Volume Depletion: Before initiating XIGDUO XR, 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 ) • Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections: Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis and if suspected, discontinue XIGDUO XR, and promptly institute appropriate medical and/or surgical intervention.
( 5.4 ) • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Consider a lower dosage of insulin or an insulin secretagogue to reduce the risk of hypoglycemia when used concomitantly with XIGDUO XR. ( 5.5 ) • Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually.
( 5.6 )
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 (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >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 XIGDUO XR. In XIGDUO XR-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 XIGDUO XR 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 [see Dosage and Administration (2.1 , 2.4) and Clinical Pharmacology (12.3) ] : • Before initiating XIGDUO XR, obtain an estimated glomerular filtration rate (eGFR). • XIGDUO XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4…
🤒 Adverse Reactions ▾
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) ] • Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.4 )] • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.5) ] • Vitamin B 12 Deficiency [see Warnings and Precautions (5.6) ] • Adverse reactions reported in >5% of patients treated with XIGDUO XR were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache.
( 6.1 ) • Adverse reactions reported in >5% of patients treated with metformin extended-release are: diarrhea and nausea/vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to 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 and pediatric patients 10 years of age and older 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 mildly impaired in 90% of patients and moderately impaired in 10% of patients.
The overa…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Table 6: Clinically Relevant Interactions with XIGDUO XR 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 XIGDUO XR 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 XIGDUO XR. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when XIGDUO XR 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 XIGDUO XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving XIGDUO XR, 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 XIGDUO XR 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 XIGDUO XR with laboratory tests. ( 7 )
👥 Use in Specific Populations ▾
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: Not 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)
8.1Pregnancy Risk Summary Based on animal data showing adverse renal effects, XIGDUO XR is not recommended during the second and third trimesters of pregnancy. Limited data with XIGDUO XR 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 m…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Based on animal data showing adverse renal effects, XIGDUO XR is not recommended during the second and third trimesters of pregnancy. Limited data with XIGDUO XR 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 was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC)…
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of XIGDUO XR as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of XIGDUO XR for this indication is supported by a 26‑week placebo-controlled trial of dapagliflozin with a 26‑week extension in 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, pediatric pharmacokinetic data, and trials in adults with type 2 diabetes mellitus [see Clinical Pharmacology (12.3) and Clinical Studies (14.1 , 14.2) ] .
The safety profile observed in the placebo-controlled trial of dapagliflozin in pediatric patients with type 2 diabetes mellitus was similar to that observed in adults [see Adverse Reactions (6.1) ] . The use of XIGDUO XR for this indication is also 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 [see 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 XIGDUO XR 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 XIGDUO XR have not been established in pediatric patients to reduce the risk of [see Indications and Usage (1) ] : • sustained eGFR decline, end-stage kidney disease, CV death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. • CV 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 CV disease or multiple CV risk factors.
🧓 Geriatric Use ▾
8.5Geriatric Use XIGDUO XR No XIGDUO XR 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 ▾
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 >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 ▾
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. Figure 1
12.3Pharmacokinetics XIGDUO XR The administration of XIGDUO XR 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 XIGDUO XR 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…
🧬 Mechanism of Action ▾
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 ▾
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied XIGDUO ® XR (dapagliflozin and metformin HCl extended-release) tablets have markings on one side, are plain on the reverse side, and are available in the strengths and packages listed in Table 21. Table 21: XIGDUO XR Tablet Presentations Tablet Strength Film-Coated Tablet Color/Shape Tablet Markings Pack Size NDC Code 2.5 mg/ 1,000 mg Light brown to brown, biconvex, oval-shaped "1074" and "2.5/1000" debossed on one side and plain on the reverse side Bottle of 60 0310-6225-60 5 mg/ 500 mg orange, biconvex, capsule-shaped "1070" and "5/500" debossed on one side and plain on the reverse side Bottle of 30 0310-6250-30 5 mg/ 1,000 mg pink to dark pink, biconvex, oval-shaped "1071" and "5/1000" debossed on one side and plain on the reverse side Bottle of 60 0310-6260-60 10 mg/ 500 mg pink, biconvex, capsule-shaped "1072" and "10/500" debossed on one side and plain on the reverse side Bottle of 30 0310-6270-30 10 mg/ 1,000 mg yellow to dark yellow, biconvex, oval-shaped "1073" and "10/1000" debossed on one side and plain on the reverse side Bottle of 30 0310-6280-30 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 ▾
11 DESCRIPTION XIGDUO XR tablets contain: dapagliflozin, a SGLT2 inhibitor, and metformin HCl, a biguanide. Dapagliflozin Dapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The empirical formula is C 21 H 25 ClO 6 •C 3 H 8 O 2 •H 2 O and the formula weight is 502.98.
The structural formula is: Dapagliflozin chemical structure Metformin HCl Metformin HCl (N,N-dimethylimidodicarbonimidic diamide HCl) is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pK a of metformin is 12.4.
The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula is: Metformin hydrochloride chemical structure XIGDUO XR XIGDUO XR is available for oral administration as tablets containing the equivalent of 2.5 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to 779.86 mg metformin base (XIGDUO XR 2.5 mg/1,000 mg), 5 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin HCl which is equivalent to 389.9 mg metformin base (XIGDUO XR 5 mg/500 mg), the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to 779.86 mg metformin base (XIGDUO XR 5 mg/1,000 mg), the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin HCl which is equivalent to 389.9 mg metformin base (XIGDUO XR 10 mg/500 mg), or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to 779.86 mg metformin base (XIGDUO XR 10 mg/1,000 mg).
Each film-coated tablet of XIGDUO XR contains the following inactive ingredients: anhydrous lactose, carboxymethylcellulose sodium, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, and silicon dioxide. The film coatings contain the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Additionally, the film coating for the XIGDUO XR 5 mg/500 mg tablets contains FD&C Yellow No.
6/Sunset Yellow FCF aluminum lake. The film coating for the XIGDUO XR 2.5 mg/1,000 mg, 5 mg/1,000 mg, 10 mg/500 mg, and 10 mg/1,000 mg tablets contains iron oxides.
💬 Information for Patients ▾
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 XIGDUO XR 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 non-specific symptoms occur.
Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of XIGDUO XR 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 XIGDUO XR [see Warnings and Precautions (5.1) ] .
Inform patients about the importance of regular testing of renal function and hematological parameters when receiving treatment with XIGDUO XR [see Contraindications (4) and Warnings and Precautions (5.1) ]. Instruct patients to inform their healthcare provider that they are taking XIGDUO XR prior to any surgical or radiological procedure, as temporary discontinuation of XIGDUO XR 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 XIGDUO XR 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 XIGDUO XR and seek medical attention immediately [see Warnings and Precautions (5.2) ] . Volume Depletion Inform patients that symptomatic hypotension may occur with XIGDUO XR 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.
Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections Counsel patients that genitourinary infections may occur when taking XIGDUO XR and may become serious. Educate patients on the symptoms and advise them to seek medical advice if symptoms occur. Specifically, advise patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [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 XIGDUO XR is added to an insulin secretagogue (e.g., sulfonylurea) and/or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.5) ] . Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions (e.g., urticaria, anaphylactic reactions, and angioedema) have been reporte…
💬 Medication Guide ▾
MEDICATION GUIDE MEDICATION GUIDE XIGDUO ® XR [ZIG-DO-OH X-R] (dapagliflozin and metformin hydrochloride extended-release) tablets, for oral use What is the most important information I should know about XIGDUO XR? XIGDUO XR can cause serious side effects, including: • Lactic Acidosis . Metformin, one of the medicines in XIGDUO XR, 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 XIGDUO XR 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 have unusual (not normal) muscle pain ∘ you feel dizzy or lightheaded ∘ you have trouble breathing ∘ you have a slow or irregular heartbeat ∘ you feel unusual sleepiness or sleep longer than usual ∘ you feel very weak or tired ∘ 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 XIGDUO XR if you: o have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye. o have liver problems. o drink alcohol very often or drink a lot of alcohol in the short-term ("binge" drinking). o 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. o have surgery. o have new or worsening symptoms of congestive heart failure such as shortness of breath or increased fluid or swelling of the legs. o have a heart attack, severe infection, or stroke. o are 65 years of age or older. o have a genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD).
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 XIGDUO XR 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. XIGDUO XR 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 XIGDUO XR 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. ∘ nausea ∘ tiredness ∘ vomiting ∘ trouble breathing ∘ stomach area (abdominal) pain ∘ ketones in your urine or blood • Genital and urinary tract infections. XIGDUO XR can cause serious infections in your genital area or urinary tra…