Dosing & Uses
Dosage Forms & Strengths
empagliflozin/linagliptin
tablet
- 10mg/5mg
- 25mg/5mg
Type 2 Diabetes Mellitus
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
10 mg/5 mg PO qDay in morning, taken with or without food
The dose may be increased to 25 mg/5mg once daily if needed and tolerated
Dosage Modifications
Hepatic impairment: No dose adjustment required
Renal impairment
- eGFR ≥45 mL/min/1.73 m²: No dose adjustment required
- Baseline eGFR 30-45 mL/min/1.73 m²: Do not initiate drug
- Baseline eGFR < 30 mL/min/1.73 ², end-stage renal disease (ESRD), or dialysis: Contraindicated
- Discontinued if eGFR is persistently drops to <45 mL/min/1.73 m²
Dosing Considerations
Empagliflozin is also indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease; however, the effectiveness of empagliflozin/linagliptin on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established
Correct volume depletion before initiating
Assess renal function before initiating and periodically thereafter
Limitations of use
- Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis
- Has not been studied in patients with a history of pancreatitis
Safety and efficacy not established
See Adult Dosing
Higher incidence of adverse reactions related to volume depletion and reduced renal function
Empagliflozin is associated with osmotic diuresis, which could affect hydration status of patients age ≥75 years
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
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
Hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative skin conditions
Rash
Thirst (including polydipsia)
Heart failure
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
Severe and disabling arthralgia
Bullous pemphigoid
Warnings
Contraindications
Severe renal impairment, end-stage renal disease, or dialysis
History of hypersensitivity reaction 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 urospesis 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 100.4 F 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); assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level
- Consider risk factors for ketoacidosis prior to initiating therapy; patients may require temporary discontinuation of therapy in clinical situation that may predispose to ketoacidosis
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 patients 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 renal function prior to initiation of therapy and monitor periodically thereafter; more frequent renal function monitoring is recommended in patients with an eGFR below 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 less than 30 mL/min/1.73 m²
Pregnancy & Lactation
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.
Pharmacology
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)
Administration
Instructions
May take with or without food
Take once daily in the morning
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Formulary
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