empagliflozin/linagliptin (Rx)

Also see individual drugs

>10%

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%)

Postmarketing Reports

Acute pancreatitis, including fatal pancreatitis

Ketoacidosis

Urosepsis and pyelonephritis

Necrotizing fasciitis of the perineum (Fournier gangrene)

Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions

Severe and disabling arthralgia

Bullous pemphigoid

Skin reactions (eg, rash, urticaria)

Mouth ulceration, stomatitis

Rhabdomyolysis

Contraindications

Severe renal impairment, end-stage renal disease, or dialysis

Hypersensitivity to empagliflozin, linagliptin, or excipients (eg, anaphylaxis, angioedema, exfoliative skin conditions, urticaria, bronchial hyperreactivity)

Cautions

Acute pancreatitis, including fatal pancreatitis, reported; if pancreatitis is suspected, promptly discontinue

Hypotension: Before initiating, assess and correct volume status in patients with renal impairment, elderly patients, patients with low systolic blood pressure, and patients on diuretics; monitor for hypotension during therapy

Heart failure has been observed with two other members of the DPP-4 inhibitor class; consider risks and benefits of empagliflozin in patients with risk factors for heart failure; monitor for signs and symptoms; if heart failure develops, manage accordingly to standard of care and consider interrupting treatment

Bullous pemphigoid reported with DPP-4 inhibitor use, which required hospitalization; in reported cases, patients recovered with topical or systemic immunosuppressive treatment and discontinuation of DPP-4 inhibitor; patients should report development blisters/erosions; discontinue DPP-4 therapy and consult a dermatologist if bullous pemphigoid suspected

Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or the insulin secretagogue may be required

Genital mycotic infections may occur; patients with history of genital mycotic infections and uncircumcised males are more susceptible

Empagliflozin increases risk for urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs

Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors; signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4ºF or a general feeling of being unwell; if suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary

Reports of serious hypersensitivity reactions in patients treated with linagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions; if signs and symptoms occur, promptly institute appropriate monitoring and treatment and initiate alternative treatment for diabetes

Dose-related increases in LDL-C reported

No conclusive evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent

Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as possible cause for severe joint pain and discontinue drug if appropriate

Ketoacidosis

• Fatal cases of ketoacidosis reported in patients taking empagliflozin (SGLT2 inhibitors) reported; monitor for signs of ketoacidosis and advise patients to seek immediate medical attention for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness)
• Before initiating therapy, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse
• Consider temporarily discontinuing therapy for at least 3 days for patients who undergo scheduled surgery
• Restart once the patient’s oral intake is back to baseline and any other risk factors for ketoacidosis (blood acid buildup) are resolved
• Consider monitoring for ketoacidosis and temporarily discontinuing therapy in other clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or post-surgery); ensure risk factors for ketoacidosis are resolved prior to restarting therapy

Acute kidney injury and renal impairment

• Empagliflozin causes intravascular volume contraction and can cause renal impairment; before initiating therapy, 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 therapy in setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor for signs and symptoms of acute kidney injury
• If acute kidney injury occurs, discontinue therapy promptly and institute treatment; renal function abnormalities can occur after initiating therapy; evaluate and monitor renal function periodically thereafter; more frequent renal function monitoring is recommended in patients with an eGFR >60 mL/min/1.73 m² therapy is not recommended when eGFR is persistently < 45 mL/min/1.73 m² and is contraindicated in patients with an eGFR <30 mL/min/1.73 m²

Pregnancy

Based on animal data showing adverse renal effects from empagliflozin, it is not recommended during the second and third trimesters of pregnancy

There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy; an alternate diabetic therapy appropriate for pregnant women should be initiated

Lactation

There is no information regarding presence in human milk, effects on breastfed infant, or effects on milk production; since potential for serious adverse reactions, including potential for empagliflozin to affect postnatal renal development, in a breastfed infant, advise patients that therapy is not recommended while breastfeeding; a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother should be initiated

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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)

Instructions

May take with or without food

Take once daily in the morning