empagliflozin/metformin (Rx)

Brand and Other Names:Synjardy, Synjardy XR
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Adult Dosing

AdultPediatricGeriatric

Dosage Forms & Strengths

empagliflozin/metformin

tablet (twice daily dosing)

  • 5mg/500mg
  • 5mg/1000mg
  • 12.5mg/500mg
  • 12.5mg/1000mg

tablet, extended-release (once daily dosing)

  • 5mg/1000mg
  • 10mg/1000mg
  • 12.5mg/1000mg
  • 25mg/1000mg

Type 2 Diabetes Mellitus

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 is appropriate

Individualize the starting dose based on the patient’s current drug regimen

Not to exceed 25 mg/2000 mg per day

Tablet (twice daily)

  • Take twice daily with meals, with gradual dose escalation to reduce the GI adverse effects due to metformin
  • Switching to Synjardy
    • Patients on metformin: Switch to tablet containing empagliflozin 5 mg with a similar total daily dose of metformin
    • Patients on empagliflozin: Switch to tablet containing metformin 500 mg with a similar total daily dose of empagliflozin
    • Patients already treated with empagliflozin and metformin: Switch to tablet containing the same total daily doses of each component

Extended-release tablet (once daily)

  • Take once daily with a meal in the morning, with gradual dose escalation to reduce the GI adverse effects due to metformin
  • Switching to Synjardy XR
    • Patients on metformin: Switch to XR tablet containing a similar total daily dose of metformin and a total daily dose of empagliflozin 10 mg
    • Patients on empagliflozin: Switch to XR tablet containing the same total daily dose of empagliflozin and a total daily dose of metformin extended-release 1000 mg
    • Patients already treated with empagliflozin and metformin: Switch to XR tablet containing the same total daily doses of empagliflozin and a similar total daily dose of metformin

Dosage Modifications

Hepatic impairment: No dosage change required

Renal impairment

  • Obtain eGFR before starting metformin
  • eGFR <45 mL/min/1.73 m²: Contraindicated
  • Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
  • If eGFR falls to <45 mL/min/1.73 m² during treatment: Discontinue

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/metformin 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 if not previously treated with empagliflozin

Limitations of use

  • Not for patients with type 1 diabetes
  • Not for treatment of diabetic ketoacidosis

<18 years: Safety and efficacy not established

Monitor renal function more frequently after initiating drug in elderly patients, and then adjust dose based on renal function

Renal function abnormalities can occur after initiating empagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function

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Interactions

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    Contraindicated

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            Adverse Effects

            1-10%

            Urinary tract infection (7.6-9.3%)

            Decreased vitamin B12 levels (7%)

            Increased LDL-C (4.6-6.5%)

            Female genital mycotic infections (5.4-6.4%)

            Dyslipidemia (2.9-3.9%)

            Increased urination (3.2-3.4%)

            Male genital mycotic infections (1.6-3.1%)

            Nausea (1.1-2.3%)

            Hypoglycemia, with monotherapy (1.4-1.8%)

            <1%

            Volume depletion

            Impaired renal function

            Postmarketing Reports

            Ketoacidosis

            Urosepsis and pyelonephritis

            Angioedema

            Skin reactions (e.g., rash, urticaria)

            Cholestatic, hepatocellular, and mixed hepatocellular liver injury

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            Warnings

            Black Box Warnings

            Lactic acidosis

            • Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation
            • Risk increases with renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure
            • Onset is often subtle, accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress)
            • Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate
            • If acidosis is suspected, discontinue drug and hospitalize the patient immediately

            Contraindications

            Moderate-to-severe renal disease (eGFR <45 mL/min/1.73 m²), end-stage renal disease, or dialysis

            Acute or chronic metabolic acidosis, including diabetic ketoacidosis (treat ketoacidosis with insulin)

            History of serious hypersensitivity reaction to empagliflozin or metformin

            Cautions

            Lactic acidosis is a metabolic complication that can occur due to metformin accumulation during treatment and is fatal in ~50% of cases (see Black Box Warnings)

            Fatal cases of ketoacidosis have been reported in patients taking empagliflozin

            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

            Empagliflozin causes intravascular volume contraction; symptomatic hypotension may occur after initiating, particularly in patients with renal impairment, elderly patients, patients with low systolic blood pressure, or patients taking diuretics

            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 suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of therapy; prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin; hemodialysis has often resulted in reversal of symptoms and recovery

            Educate patients and their families about symptoms of lactic acidosis and if symptoms occur instruct them to discontinue therapy and report them to their healthcare provider

            Before initiating therapy, obtain estimated glomerular filtration rate (eGFR)

            Obtain an eGFR at least annually in all patients receiving therapy; in patients at increased risk for development of renal impairment (e.g., the elderly), renal function should be assessed more frequently

            Risk of metformin-associated lactic acidosis increases with age; elderly patients (>65 years) have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients; assess renal function more frequently in elderly patients

            Withholding of food and fluids during surgical or other procedures may increase risk for volume depletion, hypotension and renal impairment; therapy should be temporarily discontinued while patients have restricted food and fluid intake

            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 therapy

            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 with empagliflozin; patients with history of genital mycotic infections and uncircumcised males are more susceptible

            Empagliflozin increases the risk for urinary tract infections

            Metformin associated with decreased vitamin B12 levels

            Alcohol is known to potentiate metformin’s effect on lactate metabolism; warn patients against excessive alcohol intake while in therapy

            Cardiovascular collapse (shock) from whatever cause is associated with lactic acidosis and may also cause prerenal azotemia; discontinue drug immediately

            Empagliflozin may increase LDL-C

            Iodinated contrast imaging procedures

            • Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 45-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
            • Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable
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            Pregnancy

            Pregnancy

            There are no adequate and well-controlled studies in pregnant women with empagliflozin/metformin or its individual components

            Animal studies

            • Based on results from animal studies, empagliflozin may affect renal development and maturation
            • In studies conducted in rats, empagliflozin crosses the placenta and reaches fetal tissues; during pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters

            Lactation

            Unknown if distributed in human breast milk As individual components, both empagliflozin and metformin were secreted in the milk of lactating rats

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

            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

            Empagliflozin: Selective sodium-glucose transporter-2 (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

            Metformin: Decreases hepatic glucose production; decreases GI glucose absorption; increases target cell insulin sensitivity

            Pharmacokinetics

            Empagliflozin

            • Peak plasma time: 1.5 hr
            • Peak plasma concentration: 259 nmol/L
            • AUC: 1870 nmol·h/L
            • Protein bound: 86.2%
            • Vd: 73.8 L
            • Red blood cell partitioning: 36.8%
            • Metabolism: Primary route of metabolism is glucuronidation by the uridine 5'-diphospho-glucuronosyl transferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9
            • Half-life: 12.4 hr
            • Excretion: 54.4% urine; 41.2% feces

            Metformin

            • Bioavailability: 50-60% (fasting)
            • Protein bound: Negligible
            • Vd: 654 L
            • Red blood cell partitioning: Partitions into erythrocytes, most likely as a function of time
            • Metabolism: Does not undergo hepatic metabolism nor biliary excretion
            • Half-life: 17.6 hr (blood); 6.2 hr (plasma)
            • Excretion: 90% urine
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            Administration

            Oral Administration

            When initiating, gradually increase dose to avoid GI adverse effects from metformin

            Take with meal(s)

            Extended-release

            • Swallow extended-release 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 extended-release; if a patient reports seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control
            • 10 mg/1000 mg XR and 25 mg/1000 mg XR tablets should be taken as a single tablet once daily
            • 5 mg/1000 mg XR and 12.5 mg/1000 mg XR tablets should be taken as 2 tablets together once daily

            Storage

            Controlled room temperature (25°C [77°F]); excursions permitted to 15-30°C (59-86°F)

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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.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.