Empalo M

Overview

Innovator Brand: Synjardy

Composition

1. Empalo M 12.5/500: Empagliflozin 12.5 mg Metformin 500 mg 2. Empalo M 12.5/1000: Empagliflozin 12.5 mg Metformin 1000 mg

Dosage Form & Strength

1. Individualize the starting dose of Empalo M based on the patient’s current regimen 2. The maximum recommended dose is 12.5 mg empagliflozin/1000 mg metformin hydrochloride twice daily 3. Take twice daily with meals, with gradual dose escalation to reduce the gastrointestinal side effects due to metformin

Dosage in Special Population

Because of the potential for serious adverse reactions in a breastfed infant, Empalo M is not recommended when breastfeeding Half-Life: Empagliflozin: The apparent terminal elimination half-life of empagliflozin is estimated to be 12.4 h. Metformin: The plasma elimination half-life of metformin is approximately 6.2 hours

Indications

1. As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and metformin hydrochloride is appropriate. 2. To reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease.

Contraindications

1. Assess renal function before initiaing Empalo M. Empalo M is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2 2. Empalo M may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. 3. Metabolic acidosis, including diabetic ketoacidosis 4. History of serious hypersensitivity reaction to empagliflozin or metformin

Adverse Effects

Empagliflozin: 1. Urinary tract infections 2. Female genital mycotic infections Metformin: 1. Diarrhea 2. Nausea/vomiting 3. Flatulence 4. Abdominal discomfort 5. Indigestion 6. Asthenia 7. Headache

Special Warnings & Precautions

1. 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. 2. 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. 3. If lactic acidosis is suspected, discontinue Empalo M and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. 4. Acute kidney injury and impairment in renal function: Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat. Monitor renal function during therapy. 5. Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. 6. Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating Empalo M 7. Genital mycotic infections: Monitor and treat as appropriate 8. Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually. 9. Increased LDL-C: Monitor and treat as appropriate 10. Discontinue Empalo M at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Empalo M if renal function is stable.

Drug Interactions

1. Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. 2. Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. 3. Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. 4. DIuretics: Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion. 5. Insulin or Insulin Secretagogues: Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia 6. Positive Urine Glucose Test: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control. 7. Interference with 1,5-anhydroglucitol Assay: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. 8. Carbonic anhydrase inhibitors: 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 Empalo M may increase the risk of lactic acidosis. Consider more frequent monitoring of these patients. 9. Drugs affecting glycemic control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Empalo M, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving Empalo M, the patient should be observed closely for hypoglycemia.

Mechanism of Action

Empagliflozin: Empagliflozin is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2), the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions such as lowering both pre-and afterload of the heart and downregulating sympathetic activity. Metformin: Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. 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 actually decrease.

Pharmacokinetics

Empagliflozin: 1. Absorption After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Systemic exposure of empagliflozin increased in a dose proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time. Empagliflozin may be administered with or without food. 2. Distribution: The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%. 3. Metabolism: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5′-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. 4. Excretion: The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). Metformin: 1. Absorption: The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower Cmax, a 25% lower AUC, and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. 2. Distribution: The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin hydrochloride tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins, in contrast to SUs, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin tablets, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. 3. Metabolism: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. 4. Excretion: 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.

Absorption, Distribution, Metabolism & Excretion

Absorption: Empagliflozin: After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Systemic exposure of empagliflozin increased in a dose proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time. Empagliflozin may be administered with or without food. Metformin: The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower Cmax, a 25% lower AUC, and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. —x-x— Bioavailability: Empagliflozin: The absolute oral bioavailability of empagliflozin is approximately 78%. Metformin: The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately 50% to 60%. —x-x— Metabolism: Empagliflozin: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5′-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. Metformin: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. —x-x— Excretion: Empagliflozin: The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). Metformin: 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.

Drug Use in Pregnancy

Empalo M is not recommended during the second and third trimesters of pregnancy.

Drug Use in Renal Impairment

Assess renal function prior to initiation of Empalo M and periodically, thereafter. Empalo M is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2

Drug Use in Hepatic Impairment

Avoid use in patients with hepatic impairment

Drug Use in Pediatric Population

Safety and effectiveness of Empalo M in pediatric patients under 18 years of age have not been established.

Drug Use in Geriatric Population

The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients