Empalina

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when both empagliflozin and linagliptin are appropriate treatments.

• SGLT2 inhibitor; SGLT2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion
• DPP-4 inhibitor; increases and prolongs incretin hormone activity, which is inactivated by DPP-4 enzyme; incretins regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and reducing glucagon secretion from pancreatic alpha cells

Antidiabetic

Mechanism of Action

First combination approved by the FDA of a sodium glucose cotransporter-2 (SGLT2) inhibitor and a dipeptidyl peptidase-4 (DPP-4) inhibitor

Empagliflozin: SGLT2 inhibitor; SGLT2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion

Linagliptin: DPP-4 inhibitor; increases and prolongs incretin hormone activity, which is inactivated by DPP-4 enzyme; incretins regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and reducing glucagon secretion from pancreatic alpha cells

Absorption

Bioavailability: 30% (linagliptin)

Empagliflozin

Peak plasma time: 1.5 hr

Peak plasma concentration: 259-687 nmol/L

AUC: 1870-4740 nmol•hr/L

Distribution

Protein bound: 36.8% (empagliflozin); 75-99% (linagliptin; concentration dependent)

Vd: 73.8 L (empagliflozin); 1110 L (linagliptin)

Metabolism

Empagliflozin: Primary route of metabolism is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9

Linagliptin: Majority (~90%) is excreted unchanged, indicating that metabolism represents a minor elimination pathway

Elimination

Half-life: 12.4 hr (empagliflozin)

Oral clearance: 10.6 L/hr (empagliflozin)

Renal clearance: 70 mL/min (linagliptin)

Excretion

Feces: 41.2% (empagliflozin)

Urine: 54.4% (empagliflozin); 5% (linagliptin)

Enterohepatic: 80% (linagliptin)

• 10 mg/5 mg PO qDay in morning, taken with or without food
• Dose may be increased to 25 mg/5mg once daily if needed and tolerated

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. Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased Linagliptin exposure, suggesting that the efficacy of Linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer.

Contraindications Severe renal impairment, end-stage renal disease, or dialysis History of hypersensitivity reaction to Linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity History of serious hypersensitivity reaction to Empagliflozin. Precautions & Warnings Precaution should be taken in some disease conditions like Pancreatitis, Hypotension, Ketoacidosis, Acute kidney injury and impairment in renal function, Urosepsis and Pyelonephritis, Hypoglycemia, Genital Mycotic Infections, Hypersensitivity etc. Pancreatitis: Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with Linagliptin. Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and 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. Volume Depletion: Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. 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. Hypoglycemia with Concomitant Use with Insulin & Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including Empagliflozin. Genital Mycotic Infections: Empagliflozin increases the risk for genital mycotic infections. • Hypersensitivity Reactions. Severe and Disabling Arthralgia Bullous Pemphigoid. Heart Failure: An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

• Urinary tract infection (11.4-12.5%)1-10%
• Upper respiratory tract infection (7%)
• Nasopharyngitis (5.9-6.6%)
• Increased LDL-C (4.6-6.5%)
• Hypoglycemia (2.2-3.6%)
• Increased hematocrit (2.8%)

This is not recommended during the second and third trimesters of pregnancy. The limited available data of this tablet in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

In the event of an overdose with this tablet, contact 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, and removal of Linagliptin by hemodialysis or peritoneal dialysis is unlikely.

Store below 30° C temperature. Keep away from light and wet place. Keep out of reach of children.

As per Physician