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These highlights do not include all the information needed to use DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE EXTENDED-RELEASE
TABLETS safely and effectively. See full prescribing information for DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS. DAPAGLIFLOZIN and METFORMIN HYDROCHLORIDE extended-release tablets, for oral use Initial U.S. Approval: 2014 · Lupin Pharmaceuticals, Inc.
- 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 hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1 )].
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, 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 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 tablet is 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 available as follows:
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Dapagliflozin Strength
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Metformin HCl Strength
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Color/Shape
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Tablet Markings
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| 5 mg |
500 mg |
light orange to orange, biconvex, capsule shaped, film coated tablets |
"L108" debossed on one side and plain on other side without any layer separation |
| 5 mg |
1000 mg |
purple to light purple, biconvex, oval shaped, film coated tablets |
"L109" debossed on one side and plain on other side without any layer separation |
| 10 mg |
500 mg |
pink to light pink, biconvex, capsule shaped, film coated tablets |
"L110" debossed on one side and plain on other side without any layer separation |
| 10 mg |
1000 mg |
yellow to dark yellow, biconvex, oval shaped, film coated tablets |
"L111" debossed on one side and plain on other side without any layer separation |
Dapagliflozin and metformin hydrochloride extended-release tablets are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2) 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)].
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Carbonic Anhydrase Inhibitors
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Clinical Impact
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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. |
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Intervention
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Consider more frequent monitoring of these patients. |
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Drugs that Reduce Metformin Clearance
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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)] . |
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Intervention
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Consider the benefits and risks of concomitant use. |
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Alcohol
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Clinical
Impact |
Alcohol is known to potentiate the effect of metformin on lactate metabolism. |
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Intervention
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Warn patients against excessive alcohol intake while receiving dapagliflozin and metformin hydrochloride extended-release tablets. |
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Insulin or Insulin Secretagogues
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Clinical
Impact |
The risk of hypoglycemia may be increased when dapagliflozin and metformin hydrochloride extended-release tablet is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions (5.5)] . |
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Intervention
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Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. |
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Drugs Affecting Glycemic Control
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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. |
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Intervention
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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. |
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Lithium
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Clinical
Impact |
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. |
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Intervention
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Monitor serum lithium concentration more frequently during dapagliflozin and metformin hydrochloride extended-release tablets initiation and dosage changes. |
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Positive Urine Glucose Test
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Clinical Impact
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SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. |
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Intervention
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Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. |
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Interference with 1,5-anhydroglucitol (1,5-AG) Assay
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Clinical Impact
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Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. |
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Intervention
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Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control. |
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 B12Concentrations [see Warnings and Precautions (5.7)]
- Genital Mycotic Infections [see Warnings and Precautions (5.8)]
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 was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose-related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).
Metformin HCl
Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Risk Summary
There is no information regarding the presence of dapagliflozin and metformin hydrochloride extended-release tablets or dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production.
Limited published studies report that metformin is present in human milk (see Data). However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Dapagliflozin is present in the milk of lactating rats (see Data). However, due to species specific differences in lactation physiology, the clinical relevance of these data is not clear. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.
Because of the potential for serious adverse reactions in breastfed infants, advise women that use of dapagliflozin and metformin hydrochloride extended-release tablets are not recommended while breastfeeding.
Data
Dapagliflozin:
Dapagliflozin was present in rat milk at a milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at a concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
Metformin HCl:
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.
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 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.
Dapagliflozin and Metformin Hydrochloride Extended-Release Tablets
No dapagliflozin and metformin hydrochloride extended-release tablet 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)].
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.
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 non- specific 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. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.5)].
Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)
Inform patients that necrotizing infections of the perineum (Fournier's Gangrene) have occurred with dapagliflozin, a component of dapagliflozin and metformin hydrochloride extended-release tablets. Counsel 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 (5.6)].
Genital Mycotic Infections in Females (e.g., Vulvovaginitis)
Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8)].
Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)
Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8)].
Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions (e.g., urticaria, anaphylactic reactions, and angioedema) have been reported with the components of dapagliflozin and metformin hydrochloride extended-release tablets. Advise patients to immediately report any signs or symptoms suggesting allergic reaction or angioedema, and to take no more of the drug until they have consulted prescribing physicians.
Pregnancy
Advise pregnant patients of the potential risk to a fetus with treatment with dapagliflozin and metformin hydrochloride extended-release tablets. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see Use in Specific Populations (8.1)].
Lactation
Advise patients that use of dapagliflozin and metformin hydrochloride extended-release tablets are not recommended while breastfeeding [see Use in Specific Populations (8.2)].
Females and Males of Reproductive Potential
Inform female patients that treatment with metformin may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)].
Administration
Instruct patients that dapagliflozin and metformin hydrochloride extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
Laboratory Tests
Due to the mechanism of action of dapagliflozin, patients taking dapagliflozin and metformin hydrochloride extended-release tablets will test positive for glucose in their urine.
Missed Dose
If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of dapagliflozin and metformin hydrochloride extended-release tablets at the same time.
The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products.
LUPIN and the [image: IMGID1601] are registered trademarks of Lupin Pharmaceuticals, Inc.
Manufactured for:
Lupin Pharmaceuticals, Inc.
Naples, FL 34108
United States
Manufactured by:
Lupin Limited,
Nagpur 441 108
India
Revised: February 2026 ID#: 283091
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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. |
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MEDICATION GUIDE
Dapagliflozin (dap-a-gli-FLOE-zin) and Metformin Hydrochloride (met-FOR-min HYE-droe-KLOR-ide) Extended-Release Tablets, for oral use |
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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: o you feel cold in your hands or feet o you feel dizzy or lightheaded o you have a slow or irregular heartbeat o you feel very weak or tired o you have unusual (not normal) muscle pain o you have trouble breathing o you feel unusual sleepiness or sleep longer than usual o 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: 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. 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. 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 vomiting o stomach area (abdominal) pain o tiredness o trouble breathing o ketones in your urine or blood Dapagliflozin and metformin hydrochloride extended-release tablets can have other serious side effects. See "What are the possible side effects of dapagliflozin and metformin hydrochloride extended-release tablets?" |
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What are dapagliflozin and metformin hydrochloride extended-release tablets?
• Dapagliflozin and metformin hydrochloride extended-release tablets are prescription medicine that contains 2 prescription medicines called dapagliflozin (FARXIGA) and metformin HCl. • Dapagliflozin and metformin hydrochloride extended-release tablet can be used along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes. • One of the medicines in dapagliflozin and metformin hydrochloride extended-release tablet, dapagliflozin (FARXIGA), can also be used in adults with type 2 diabetes who have: o chronic kidney disease and dapagliflozin is needed to reduce the risk of further worsening of your kidney disease, end-stage kidney disease (ESKD), death due to cardiovascular disease, and hospitalization for heart failure. o heart failure (when the heart cannot pump enough blood to the rest of your body) and dapagliflozin is needed to reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure visit. o known cardiovascular disease or multiple cardiovascular risk factors and dapagliflozin is needed to reduce the risk of hospitalization for heart failure. • Dapagliflozin and metformin hydrochloride extended-release tablets are not for use to improve blood sugar (glucose) control in people with type 1 diabetes. • Dapagliflozin and metformin hydrochloride extended-release tablets are only for use in people with type 2 diabetes mellitus, because it contains the prescription medicine metformin HCl. • Dapagliflozin and metformin hydrochloride extended-release tablet is not for use for treatment of chronic kidney disease in people with certain genetic forms of polycystic kidney disease, or who are taking or have recently received immunosuppressive therapy to treat kidney disease. If you have these conditions, dapagliflozin and metformin hydrochloride extended-release tablet is not expected to work for treatment of chronic kidney disease. • It is not known if dapagliflozin and metformin hydrochloride extended-release tablet is safe and effective to lower blood sugar (glucose) in children younger than 10 years of age with type 2 diabetes mellitus. • It is not known if dapagliflozin and metformin hydrochloride extended-release tablets are safe and effective for treatment of heart failure or chronic kidney disease in children younger than 18 years of age. |
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Who should not take dapagliflozin and metformin hydrochloride extended-release tablets? Do not take dapagliflozin and metformin hydrochloride extended-release tablets if you:
• have severe kidney problems. • are allergic to dapagliflozin, metformin HCl, or any of the ingredients in dapagliflozin and metformin hydrochloride extended-release tablets. See the end of this Medication Guide for a complete list of ingredients in dapagliflozin and metformin hydrochloride extended-release tablets. Symptoms of a serious allergic reaction to dapagliflozin and metformin hydrochloride extended-release tablets may include: o rash o raised red patches on your skin (hives) o swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing |
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| If you have any of these symptoms, stop taking dapagliflozin and metformin hydrochloride extended-release tablets and contact your healthcare provider or go to the nearest hospital emergency room right away. • have a condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine). |
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What should I tell my healthcare provider before taking dapagliflozin and metformin hydrochloride extended-release tablets? Before you take dapagliflozin and metformin hydrochloride extended-release tablets, tell your healthcare provider if you:
• have type 1 diabetes or have had diabetic ketoacidosis. • have a decrease in your insulin dose. • have a serious infection. • have a history of infection of the vagina or penis. • have kidney problems. • have liver problems. • have a history of urinary tract infections or problems with urination. • are on a low sodium (salt) diet. Your healthcare provider may ask you to change your diet. • have heart problems, including congestive heart failure. • are 65 years of age or older. • are going to have surgery or a procedure that requires not having food for a long time (prolonged fasting). Your healthcare provider may stop dapagliflozin and metformin hydrochloride extended-release tablets before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking dapagliflozin and metformin hydrochloride extended-release tablets and when to start it again. • are eating less, or there is a change in your diet. • are dehydrated. • have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas. • drink alcohol very often or drink a lot of alcohol in the short-term ("binge" drinking). • are going to get an injection of dye or contrast agents for an x-ray procedure. Dapagliflozin and metformin hydrochloride extended-release tablets may need to be stopped for a short time. Talk to your healthcare provider about when you should stop dapagliflozin and metformin hydrochloride extended-release tablets and when you should start dapagliflozin and metformin hydrochloride extended-release tablets again. See "What is the most important information I should know about dapagliflozin and metformin hydrochloride extended-release tablets?" • have low levels of vitamin B12 in your blood. • are pregnant or plan to become pregnant. Dapagliflozin and metformin hydrochloride extended-release tablets may harm your unborn baby. If you are pregnant or plan to become pregnant, talk to your healthcare provider about the best way to control your blood sugar. • are breastfeeding or plan to breastfeed. It is not known if dapagliflozin and metformin hydrochloride passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you are taking dapagliflozin and metformin hydrochloride extended-release tablets. You should not breastfeed if you take dapagliflozin and metformin hydrochloride extended-release tablets. • are a person who has not gone through menopause (premenopausal) who does not have periods regularly or at all. Dapagliflozin and metformin hydrochloride extended-release tablets can cause the release of an egg from an ovary in a person (ovulation). This can increase your chance of getting pregnant. Tell your healthcare provider right away if you become pregnant while taking dapagliflozin and metformin hydrochloride extended-release tablets. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Dapagliflozin and metformin hydrochloride extended-release tablets may affect the way other medicines work and other medicines may affect the way dapagliflozin and metformin hydrochloride extended-release tablets works. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. |
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How should I take dapagliflozin and metformin hydrochloride extended-release tablets?
• Take dapagliflozin and metformin hydrochloride extended-release tablets exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how much dapagliflozin and metformin hydrochloride extended-release tablets to take and when to take it. Your healthcare provider may change your dose if needed. • Take dapagliflozin and metformin hydrochloride extended-release tablets by mouth 1 time each day with meals to lower your chance of an upset stomach. Talk to your healthcare provider about the best time of day for you. • Swallow dapagliflozin and metformin hydrochloride extended-release tablets whole. Do not crush, cut, or chew dapagliflozin and metformin hydrochloride extended-release tablets. • You may sometimes pass a soft mass in your stools (bowel movement) that looks like dapagliflozin and metformin hydrochloride extended-release tablets. • If you miss a dose of dapagliflozin and metformin hydrochloride extended-release tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take 2 doses of dapagliflozin and metformin hydrochloride extended-release tablets at the same time. Talk with your healthcare provider if you have questions about a missed dose. • If you take too much dapagliflozin and metformin hydrochloride extended-release tablets, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away. • When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare provider's instructions. • Your healthcare provider may tell you to stop taking dapagliflozin and metformin hydrochloride extended-release tablets at least 3 days before any surgery or procedure that requires not having food or water for a long time (prolonged fasting). • Your healthcare provider may tell you to take dapagliflozin and metformin hydrochloride extended-release tablets along with other diabetes medicines. Low blood sugar can happen more often when dapagliflozin and metformin hydrochloride extended-release tablets are taken with certain other diabetes medicines. See "What are the possible side effects of dapagliflozin and metformin hydrochloride extended-release tablets?". • Dapagliflozin and metformin hydrochloride extended-release tablets will cause your urine to test positive for glucose. • Your healthcare provider may do certain blood tests before you start dapagliflozin and metformin hydrochloride extended-release tablets and during treatment as needed. • Your healthcare provider may change your dose of dapagliflozin and metformin hydrochloride extended-release tablets based on the results of your blood tests. |
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What should I avoid while taking dapagliflozin and metformin hydrochloride extended-release tablets?
• Avoid drinking alcohol very often or drinking a lot of alcohol in a short period of time ("binge" drinking). It can increase your chances of getting serious side effects. |
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What are the possible side effects of dapagliflozin and metformin hydrochloride extended-release tablets? Dapagliflozin and metformin hydrochloride extended-release tablets may cause serious side effects including:
See "What is the most important information I should know about dapagliflozin and metformin hydrochloride extended-release tablets?" • Dehydration. Dapagliflozin and metformin hydrochloride extended-release tablets can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden kidney injury in people with type 2 diabetes mellitus who are taking dapagliflozin, a medicine in dapagliflozin and metformin hydrochloride extended-release tablets. You may be at a higher risk of dehydration if you: ο take medicines to lower your blood pressure, including water pills (diuretics) ο are on a low salt diet ο have kidney problems ο are 65 years of age or older Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on a daily basis. Call your healthcare provider right away if you reduce the amount of food or liquid you drink, for example if you cannot eat or you start to lose liquids from your body, for example from vomiting, diarrhea, or being in the sun too long. |
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| • Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking dapagliflozin, one of the medicines in dapagliflozin and metformin hydrochloride extended-release tablets. Tell your healthcare provider if you have any signs or symptoms of a urinary tract infection, such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting. • Low blood sugar (hypoglycemia). If you take dapagliflozin and metformin hydrochloride extended-release tablets with another medicine that can cause low blood sugar, such as sulfonylureas or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take dapagliflozin and metformin hydrochloride extended-release tablets. Signs and symptoms of low blood sugar may include: |
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| ο headache ο confusion ο hunger ο shaking or feeling jittery |
ο drowsiness ο dizziness ο fast heartbeat |
ο weakness ο sweating ο irritability |
| • A rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take dapagliflozin, one of the medicines in dapagliflozin and metformin hydrochloride extended-release tablets. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries and may lead to death. Seek medical attention right away if you have a fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals:
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| ο pain or tenderness |
ο swelling |
ο redness of skin (erythema) |
| • Serious allergic reaction. If you have any symptoms of a serious allergic reaction, stop taking dapagliflozin and metformin hydrochloride extended-release tablets and call your healthcare provider right away or go to the nearest hospital emergency room. See "Who should not take dapagliflozin and metformin hydrochloride extended-release tablets?" . Your healthcare provider may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes. • Low vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause a decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 levels before. Your healthcare provider may do blood tests to check your vitamin B12 levels. |
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| • Vaginal yeast infection. Women who take dapagliflozin and metformin hydrochloride extended-release tablets may get vaginal yeast infections. Symptoms of a vaginal yeast infection include: ο vaginal odor ο white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese) ο vaginal itching • Yeast infection of the penis (balanitis). Men who take dapagliflozin and metformin hydrochloride extended-release tablets may get a yeast infection of the skin around the penis. Men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of a yeast infection of the penis include: ο redness, itching, or swelling of the penis ο foul smelling discharge from the penis ο rash of the penis ο pain in the skin around the penis Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medicine and your symptoms do not go away. The most common side effects of dapagliflozin and metformin hydrochloride extended-release tablets include: |
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| ο vaginal yeast infections ο diarrhea ο headache |
ο stuffy or runny nose and sore throat ο urinary tract infection |
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| Tell your healthcare provider or pharmacist if you have any side effect that bothers you or does not go away. These are not all of the possible side effects of dapagliflozin and metformin hydrochloride extended-release tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effect to Lupin Pharmaceuticals, Inc. at 1800-399-2561. |
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How should I store dapagliflozin and metformin hydrochloride extended-release tablets?
Store dapagliflozin and metformin hydrochloride extended-release tablets at room temperature between 68°F and 77°F (20°C and 25°C). Keep dapagliflozin and metformin hydrochloride extended-release tablets and all medicines out of the reach of children. |
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General information about the safe and effective use of dapagliflozin and metformin hydrochloride extended-release tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use dapagliflozin and metformin hydrochloride extended-release tablets for a condition for which it is not prescribed. Do not give dapagliflozin and metformin hydrochloride extended-release tablets to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about dapagliflozin and metformin hydrochloride extended-release tablets. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about dapagliflozin and metformin hydrochloride extended-release tablets that is written for health professionals. For more information, go to www.lupinpharmaceuticals.com or call 1-800-399-2561. |
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What are the ingredients in dapagliflozin and metformin hydrochloride extended-release tablets?
Active ingredients: dapagliflozin and metformin hydrochloride Inactive ingredients: crospovidone, colloidal silicon dioxide, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, povidone, sodium carboxymethyl cellulose, sodium stearyl fumarate. The film coatings contain the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide. Additionally, the film coating for the dapagliflozin and metformin hydrochloride extended-release tablets 5 mg/500 mg tablets contains iron oxide red and iron oxide yellow. The film coating for the dapagliflozin and metformin hydrochloride extended-release tablets 5 mg/1000 mg contains iron oxide red and iron oxide black. The film coating for the dapagliflozin and metformin hydrochloride extended-release tablets 10 mg/500 mg contains iron oxide red and iron oxide yellow. The film coating for the dapagliflozin and metformin hydrochloride extended-release tablets 10 mg/1000 mg tablets contains D & C yellow #10 aluminum lake, FD & C yellow #6/ sunset yellow FCF aluminum lake, FD & C blue #2/ indigo carmine aluminum lake. This Medication Guide has been approved by the U.S. Food and Drug Administration. The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products. |
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[image: IMGID2831] Manufactured for: Lupin Pharmaceuticals, Inc. Naples, FL 34108 United States Manufactured by: Lupin Limited, Nagpur 441 108 India Revised: February 2026 ID#: 283093 |
Dapagliflozin and metformin hydrochloride extended-release tablets contain: dapagliflozin, a SGLT2 inhibitor, and metformin HCl, a biguanide.
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 empirical formula is C21H25ClO6 and the formula weight is 408.88. The structural formula is:
[image: MM1]Metformin hydrochloride
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.6. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, and methylene chloride. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is:
[image: MM2]Dapagliflozin and Metformin Hydrochloride Extended-Release Tablets
Dapagliflozin and metformin hydrochloride extended-release tablets are available for oral administration as tablets containing 5 mg dapagliflozin and 500 mg metformin hydrochloride, 5 mg dapagliflozin and 1000 mg metformin hydrochloride, 10 mg dapagliflozin and 500 mg metformin hydrochloride, or 10 mg dapagliflozin and 1000 mg metformin hydrochloride.
Each film-coated tablet of dapagliflozin and metformin hydrochloride extended-release tablet contains the following inactive ingredients: crospovidone, colloidal silicon dioxide, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, povidone, sodium carboxymethyl cellulose, sodium stearyl fumarate.
The film coatings contain the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide. Additionally, the film coating for the dapagliflozin and metformin hydrochloride extended-release tablets 5 mg/500 mg tablets contains iron oxide red and iron oxide yellow. The film coating for the dapagliflozin and metformin hydrochloride extended-release tablets 5 mg/1000 mg contains iron oxide red and iron oxide black. The film coating for the dapagliflozin and metformin hydrochloride extended-release tablets 10 mg/500 mg contains iron oxide red and iron oxide yellow. The film coating for the dapagliflozin and metformin hydrochloride extended-release tablets 10 mg/1000 mg tablets contains D & C Yellow #10 Aluminum lake, FD & C Yellow #6/ sunset yellow FCF aluminum lake, FD & C Blue #2/ indigo carmine aluminum lake.
Dapagliflozin and metformin hydrochloride extended-release tablet
5/500 mg
70748-101-06
Bottle of 30 tablets
[image: MM12]Dapagliflozin and metformin hydrochloride extended-release tablet
5/1000 mg
70748-102-06
Bottle of 30 tablets
[image: MM13]Dapagliflozin and metformin hydrochloride extended-release tablet
10/500 mg
70748-103-06
Bottle of 30 tablets
[image: MM14]Dapagliflozin and metformin hydrochloride extended-release tablet
10/1000 mg
70748-104-06
Bottle of 30 tablets
[image: MM15]How Supplied
Dapagliflozin and metformin hydrochloride 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.
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Tablet Strength
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Film-Coated Tablet
C olor/Shape |
T
ablet Markings
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P
ack Size
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ND
C Code
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5 mg/ 500 mg
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Light orange to orange, biconvex, capsule shaped |
"L108" debossed on one side and plain on other side |
Bottle of 30 Bottle of 500 |
70748-101-06 70748-101-02 |
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5 mg/ 1000 mg
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Purple to light purple, biconvex, oval shaped |
"L109" debossed on one side and plain on other side |
Bottle of 30 Bottle of 60 Bottle of 90 Bottle of 400 |
70748-102-06 70748-102-07 70748-102-09 70748-102-18 |
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10 mg/ 500 mg
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Pink to light pink, biconvex, capsule shaped |
"L110" debossed on one side and plain on other side |
Bottle of 30 Bottle of 500 |
70748-103-06 70748-103-02 |
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10 mg/ 1000 mg
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Yellow to dark yellow, biconvex, oval shaped |
"L111" debossed on one side and plain on other side |
Bottle of 30 Bottle of 400 |
70748-104-06 70748-104-18 |
Storage and Handling
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
What it looks like
Photos of the product and/or packaging supplied by the manufacturer.
Package codes (NDC)
- 70748-101-06
- 70748-102-07
- 70748-103-06
- 70748-104-06
Full prescribing information (for healthcare professionals)
12 CLINICAL PHARMACOLOGY
12.1 Mechanism 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.
12.2 Pharmacodynamics
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)
[image: MM3]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.
12.3 Pharmacokinetics
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 (Cmax) is usually attained within 2 hours under fasting state. The Cmax 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 Cmax by up to 50% and prolongs Tmax 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, Cmax 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 Cmax and Tmax 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 [14C]-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 [14C]-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 creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations
Geriatric Patients
Dapagliflozin:
Based on a population pharmacokinetic analysis, age does not have a clinically meaningful effect on systemic exposures of dapagliflozin.
Metformin HCl:
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Pediatric Patients
Metformin HCl
After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.
Male and Female Patients
Dapagliflozin:
Based on a population pharmacokinetic analysis, gender does not have a clinically meaningful effect on systemic exposures of dapagliflozin.
Metformin HCl
Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Racial or Ethnic Groups
Dapagliflozin:
Based on a population pharmacokinetic analysis, race (White, Black or African American, or Asian) does not have a clinically meaningful effect on systemic exposures of dapagliflozin.
Metformin HCl:
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Black or African Americans (n=51), and Hispanic or Latino Ethnicity (n=24).
Patients with Renal Impairment:
Dapagliflozin
At steady-state (20 mg once daily dapagliflozin for 7 days), adult patients with type 2 diabetes mellitus with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 100% and 200% higher, respectively, as compared to patients with type 2 diabetes mellitus with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.4), Warnings and Precautions (5.3), Use in Specific Populations (8.6) and Clinical Studies (14)].
Metformin HCl
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1)].
Patients with Hepatic Impairment:
Dapagliflozin
In adult patients with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In adult patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls.
Metformin HCl
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see Warnings and Precautions (5.1) ].
Body Weight:
Dapagliflozin
Based on a population pharmacokinetic analysis, body weight does not have a clinically meaningful effect on systemic exposures of dapagliflozin.
Drug Interactions
Specific pharmacokinetic drug interaction studies with dapagliflozin and metformin hydrochloride extended-release tablets have not been performed, although such studies have been conducted with the individual dapagliflozin and metformin components.
In Vitro Assessment of Drug Interactions:
Dapagliflozin
In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.
Effects of Other Drugs on Metformin
Table 7 shows the effect of coadministered drugs on the pharmacokinetics of metformin in adults.
|
Coadministered Drug
(Dose Regimen) |
Metformin
(Dose Regimen) |
Metformin
|
|
|
Change in AUC
|
Change in Cmax
|
||
|
No dosing adjustments required for the following:
|
|||
| Glyburide (5 mg) |
850 mg |
↓9%
|
↓7%
|
| Furosemide (40 mg) |
850 mg |
↑15%
|
↑22%
|
| Nifedipine (10 mg) |
850 mg |
↑9% |
↑20% |
| Propranolol (40 mg) |
850 mg |
↓10% |
↓6% |
| Ibuprofen (400 mg) |
850 mg |
↑5%
|
↑7%
|
|
Drugs eliminated by renal tubular secretion may increase the accumulation of metformin
[
s
ee Drug Interactions (7)].
|
|||
| Cimetidine (400 mg) |
850 mg |
↑40% |
↑60% |
Effects of Metformin on Other Drugs
Table 8 shows the effect of metformin on the pharmacokinetics coadministered drugs in adults.
|
Coadministered Drug
( Dose Regimen) * |
Metformin
( Dose Regimen) |
Coadministered Drug
|
|
|
Change
in AUC
|
Change
in C
max
|
||
|
No dosing adjustments required for the following:
|
|||
| Glyburide (5 mg) |
850 mg |
↓22%
|
↓37%
|
| Furosemide (40 mg) |
850 mg |
↓12%
|
↓31%
|
| Nifedipine (10 mg) |
850 mg |
↑10%
|
↑8% |
| Propranolol (40 mg) |
850 mg |
↑1%
|
↑2% |
| Ibuprofen (400 mg) |
850 mg |
↓3%
|
↑1%
|
| Cimetidine (400 mg) |
850 mg |
↓5%
|
↑1% |
Effects of Other Drugs on Dapagliflozin
Table 9 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin in adults. No dose adjustments are recommended for dapagliflozin.
|
Coadministered Drug
(Dose Regimen) |
Dapagliflozin
(Dose Regimen) |
Dapagliflozin
|
|
|
Change in AUC
|
Change in Cmax
|
||
|
No dosing adjustments required for the following:
|
|||
|
Oral Antidiabetic Agents
|
|||
| Metformin (1000 mg) |
20 mg |
↓1% |
↓7% |
| Pioglitazone (45 mg) |
50 mg |
0% |
↑9% |
| Sitagliptin (100 mg) |
20 mg |
↑8% |
↓4% |
| Glimepiride (4 mg) |
20 mg |
↓1% |
↑1% |
| Voglibose (0.2 mg three times daily) |
10 mg |
↑1% |
↑4% |
|
Other Medications
|
|||
| Hydrochlorothiazide (25 mg) |
50 mg |
↑7% |
↓1% |
| Bumetanide (1 mg) |
10 mg once daily for 7 days |
↑5% |
↑8% |
| Valsartan (320 mg) |
20 mg |
↑2% |
↓12% |
| Simvastatin (40 mg) |
20 mg |
↓1% |
↓2% |
|
Anti-infective Agent
|
|||
| Rifampin (600 mg once daily for 6 days) |
10 mg |
↓22% |
↓7% |
|
Nonsteroidal Anti-inflammatory Agent
|
|||
| Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours) |
10 mg |
↑51% |
↑13% |
Effects of Dapagliflozin on Other Drugs
Table 10 shows the effect of dapagliflozin on other coadministered drugs in adults. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.
|
Coadministered Drug
( Dose Regimen) |
Dapagliflozin
( Dose Regimen) |
Coadministered Drug
|
|
|
Change
in AUC
|
Change
in Cmax
|
||
|
No dosing adjustments required for the following:
|
|||
|
O
ral Antidiabetic Agents
|
|||
| Metformin (1000 mg) |
20 mg |
0% |
↓5% |
| Pioglitazone (45 mg) |
50 mg |
0% |
↓7% |
| Sitagliptin (100 mg) |
20 mg |
↑1% |
↓11% |
| Glimepiride (4 mg) |
20 mg |
↑13% |
↑4% |
|
Other Medications
|
|||
| Hydrochlorothiazide (25 mg) |
50 mg |
↓1% |
↓5% |
| Bumetanide (1 mg) |
10 mg once daily for 7 days |
↑13% |
↑13% |
| Valsartan (320 mg) |
20 mg |
↑5% |
↓6% |
| Simvastatin (40 mg) |
20 mg |
↑19% |
↓6% |
| Digoxin (0.25 mg) |
20 mg loading dose then 10 mg once daily for 7 days |
0% |
↓1% |
| Warfarin (25 mg) S-warfarin R-warfarin |
20 mg loading dose then 10 mg once daily for 7 days |
↑3% ↑6% |
↑7% ↑8% |
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, 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 mcg/mL. Dapagliflozin was negative for clastogenicity in a series of i n 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 1500 mg/kg/day, respectively. These doses are both approximately 4-times the maximum recommended human dose of 2000 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.