| Composition | : | Each F.C.Tablet contains Empagliflozin 5 mg + Metformin HCl 500 mg. |
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| Excipients | : | Copovidon, Maize starch, Colloidal anhydrous silica, Magnesium stearate, Hypromellose, Titanium dioxide, Talc, Macrogol (400). |
| Mechanism of Action | : | The Combination: The Combination combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a member of the biguanide class. Empagliflozin : Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin hydrochloride: 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. |
| Pharmacokinetics | : | The combination: Administration of The Combination with food resulted in no change in overall exposure of empagliflozin. For metformin hydrochloride high-fat meals increased systemic exposure to metformin [AUC] by approximately 70% relative to fasting, while Cmax is not affected. Empagliflozin : Absorption: After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Distribution: The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Metabolism: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates. Elimination: The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h. Following administration of empagliflozin, approximately 95.6% of the drug was eliminated in feces (41.2%) or urine (54.4%). The majority of drug recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug. Metformin hydrochloride : Absorption: Following a single oral dose of 1000 mg (2 x 500 mg tablets) metformin hydrochloride extended-release after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7 to 8 hours. Distribution: 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. 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. Elimination: 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. |
| INDICATIONS | : | Diacol Plus is a combination of empagliflozin and metformin hydrochloride indicated 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. Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease . However, the effectiveness of THE COMBINATION on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established. Limitations of Use The Combination is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. |
| CONTRAINDICATIONS | : | The Combination is contraindicated in patients with: • Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end stage renal disease, or dialysis . • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin . • History of serious hypersensitivity reaction to empagliflozin or metformin. |
| DOSAGE AND ADMINISTRATION | : | Recommended Dosage : • In patients with volume depletion not previously treated with empagliflozin, correct this condition before initiating Diacol Plus. • Individualize the starting dose of Diacol Plus based on the patient’s current regimen: − In patients on metformin hydrochloride, switch to Diacol Plus containing a similar total daily dose of metformin hydrochloride and a total daily dose of empagliflozin 5 mg. − In patients on empagliflozin, switch to Diacol Plus containing the same total daily dose of empagliflozin and a total daily dose of metformin hydrochloride extended-release 500 mg. − In patients already treated with empagliflozin and metformin hydrochloride, switch to Diacol Plus containing the same total daily doses of empagliflozin and a similar total daily dose of metformin hydrochloride. Take Diacol Plus twice daily with meals; with gradual dose escalation to reduce the gastrointestinal side effects due to metformin. • Adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of metformin hydrochloride 2000 mg and empagliflozin 25 mg. • Swallow the product tablets whole. Do not split, crush, dissolve, or chew before swallowing. There have been reports of incompletely dissolved tablets being eliminated in the feces for other tablets containing metformin hydrochloride extended-release. If a patient reports seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control. • Diacol Plus 10 mg/1000 mg and 25 mg/1000 mg tablets should be taken as a single tablet once daily. Diacol Plus 5 mg/1000 mg and 12.5 mg/1000 mg tablets should be taken as two tablets together once daily. Recommended Dosage in Patients with Renal Impairment: • Assess renal function prior to initiation of The Combination and periodically, thereafter. • THE COMBINATION is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 . Discontinuation for Iodinated Contrast Imaging Procedures : Discontinue The Combination 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 THE COMBINATION if renal function is stable. |
| WARNINGS AND PRECAUTIONS | : | Lactic Acidosis : There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of The Combination. In THE COMBINATION -treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney . • Before initiating The Combination, obtain an estimated glomerular filtration rate (eGFR). • The Combination is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2. • Obtain an eGFR at least annually in all patients taking The Combination. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions: The concomitant use of The Combination with specific drugs may increase the risk of metformin-associated lactic acidosis those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation. Therefore, consider more frequent monitoring of patients. Age 65 or Greater: 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 . Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop The Combination 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 hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart The Combination if renal function is stable. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. The Combination should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue the drug. Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving The Combination. Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of The Combination in patients with clinical or laboratory evidence of hepatic disease. Hypotension : Empagliflozin causes intravascular volume contraction. Symptomatic hypotension may occur after initiating empagliflozin particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Before initiating The Combination, assess for volume contraction and correct volume status if indicated. Monitor for signs and symptoms of hypotension after initiating therapy and increase monitoring in clinical situations where volume contraction is expected. Ketoacidosis : Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. The Combination is not indicated for the treatment of patients with type 1 diabetes mellitus . Patients treated with The Combination who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with The Combination may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, The Combination should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement. Before initiating The Combination, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with The Combination consider monitoring for ketoacidosis and temporarily discontinuing The Combination in clinical situations known to predispose to ketoacidosis. Acute Kidney Injury and Impairment in Renal Function: Empagliflozin causes intravascular volume contraction and can cause renal impairment .There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age. Before initiating The Combination, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing The Combination in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue The Combination promptly and institute treatment. Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating The Combination. Renal function should be evaluated prior to initiation of THE COMBINATION and monitored periodically thereafter. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. Use of The Combination is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 . Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated . Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues : Empagliflozin : Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in concomitant with The Combination. Metformin : Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs. Monitor for a need to lower the dose of The Combination to minimize the risk of hypoglycemia in these patients. Genital Mycotic Infections : Empagliflozin increases the risk for genital mycotic infections. Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop mycotic genital infections. Monitor and treat as appropriate. Vitamin B12 Levels: A decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Increased Low-Density Lipoprotein Cholesterol (LDL-C): Increases in LDL-C can occur with empagliflozin. Monitor and treat as appropriate. |
| ADVERSE REACTIONS | : | • Lactic Acidosis. • Hypotension. • Ketoacidosis . • Acute Kidney Injury and Impairment in Renal Function . • Urosepsis and Pyelonephritis. • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues. • Genital Mycotic Infections . • Vitamin B12 Deficiency • Increased Low-Density Lipoprotein Cholesterol (LDL-C). • Nasopharyngitis . • Upper respiratory tract infection . • Increased urination . • Dyslipidemia. • Arthralgia . • Nausea . • Volume Depletion . |
| DRUG INTERACTIONS | : | - Drug Interactions with Empagliflozin : Diuretics : Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion . Insulin or Insulin Secretagogues: Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia. 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. Interference with 1,5-anhydroglucitol (1,5-AG) 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. - Drug Interactions with Metformin Hydrochloride : Drugs that Reduce Metformin Clearance : 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 . Consider the benefits and risks of concomitant use. 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 The Combination may increase the risk of lactic acidosis. Consider more frequent monitoring of these patients . 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 The Combination, the patient should be closely observed to maintain adequate glycemic control .When such drugs are withdrawn from a patient receiving The Combination, the patient should be observed closely for hypoglycemia. Alcohol : Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving The Combination. |
| OVERDOSAGE | : | In the event of an overdose with The Combination, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of empagliflozin by hemodialysis has not been studied. However, metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom The Combination overdosage is suspected. Metformin hydrochloride : Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases . |
| Packaging | : | Diacol Plus 5/500: Cartoon box of 20 F.C.Tablets packed inside blisters with a leaflet. |