Home › Drugs › Dapagliflozin And Metformin Hydrochloride

Dapagliflozin And Metformin Hydrochloride

FDA Drug Information • Also known as: Dapagliflozin And Metformin Hydrochloride, Xigduo Xr

Brand Names
Dapagliflozin And Metformin Hydrochloride, Xigduo Xr
Route
ORAL
Dosage Form
TABLET, FILM COATED, EXTENDED RELEASE
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

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, 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 HCl 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 >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, 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 HCl extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1)

    • Description

    11 DESCRIPTION Dapagliflozin and Metformin HCl extended-release 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 Dapagliflozin and Metformin HCl extended-release tablets Dapagliflozin and Metformin HCl extended-release tablets are available for oral administration as tablets containing the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to 779.86 mg metformin base (Dapagliflozin and Metformin HCl extended-release tablets 5 mg/1,000 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 (Dapagliflozin and Metformin HCl extended-release tablets 10 mg/1,000 mg). Each film-coated tablet of Dapagliflozin and Metformin HCl extended-release tablets 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: iron oxides, polyethylene glycol, polyvinyl alcohol, talc, and...

    • What Is Dapagliflozin And Metformin Hydrochloride Used For?

    1 INDICATIONS AND USAGE Dapagliflozin and Metformin HCl extended-release tablets are 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 Dapagliflozin and Metformin HCl extended-release tablets, is 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 HCl 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 HCl extended-release tablets are limited to patients with type 2 diabetes mellitus for all indications.
  • Dapagliflozin and Metformin HCl 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 HCl extended-release tablets are not expected to be effective in these populations. Dapagliflozin and Metformin HCl extended-release tablets are 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 Dapagliflozin and Metformin HCl extended-release tablets is 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 HCI component, the use of Dapagliflozin and Metformin HCl extended-release tablets are...

    • 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 )
  • Dapagliflozin and Metformin HCl extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.5 )
  • Withhold Dapagliflozin and Metformin HCl extended-release tablets for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.6 ) 2.1 Testing Prior to Initiation of Dapagliflozin and Metformin HCl Extended-Release Tablets
  • Assess renal function prior to initiating Dapagliflozin and Metformin HCl 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 HCl extended-release tablets [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5 , 8.6)]. 2.2 Recommended Administration
  • Take Dapagliflozin and Metformin HCl extended-release tablets orally once daily in the morning with food.
  • Swallow Dapagliflozin and Metformin HCl extended-release tablets whole and never crush, cut, or chew. 2.3 Recommended Dosage
  • Individualize the starting dosage of Dapagliflozin and Metformin HCl 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 HCl extended-release tablets.
  • 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 Dapagliflozin and Metformin HCl extended-release tablets is 5 mg orally once daily. ∘ Metformin HCl extended-release: the recommended starting dosage of metformin HCl extended release in Dapagliflozin and Metformin HCl extended-release tablets is 500 mg orally once daily.
  • For Dapagliflozin and Metformin HCl extended-release tablets indications in adults related to heart failure and chronic kidney disease, the recommended dosage of dapagliflozin in Dapagliflozin and Metformin HCl extended-release tablets is 10 mg...

    • Side Effects (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) ]
  • 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 >5% of patients treated with Dapagliflozin and Metformin HCl extended-release tablets 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 Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to 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...

    • Drug Interactions

    7 DRUG INTERACTIONS Table 6: Clinically Relevant Interactions with Dapagliflozin and Metformin HCl 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 HCl 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 HCl extended-release tablets. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when Dapagliflozin and Metformin HCl extended-release tablets are 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 HCl 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 HCl 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 HCl 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...

    Contraindications

    4 CONTRAINDICATIONS Dapagliflozin and Metformin HCl 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 HCl 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 HCl extended-release tablets. ( 4 )
  • Metabolic acidosis, including diabetic ketoacidosis. ( 4 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, Dapagliflozin and Metformin HCl extended-release tablets are not recommended during the second and third trimesters of pregnancy. Limited data with Dapagliflozin and Metformin HCl 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...

    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.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied 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: Dapagliflozin and Metformin HCl Extended-Release Tablets Presentations Tablet Strength Film-Coated Tablet Color/Shape Tablet Markings Pack Size NDC Code 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 66993-361-60 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 66993-362-30 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].

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.