empagliflozin/linagliptin (Rx)

Brand and Other Names:Glyxambi
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

empagliflozin/linagliptin

tablet

  • 10mg/5mg
  • 25mg/5mg
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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

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Interactions

Interaction Checker

and empagliflozin/linagliptin

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            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

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            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

            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 m&sup2
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            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.

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            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)
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            Administration

            Instructions

            May take with or without food

            Take once daily in the morning

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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