empagliflozin/metformin (Synjardy)

Dosing and uses of Empagliflozin/metformin

• Adult
• Pediatric

 

Adult dosage forms and strengths

empagliflozin/metformin

tablet

• 5mg/500mg
• 5mg/1000mg
• 12.5mg/500mg
• 12.5mg/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 12.5 mg/1000 mg PO BId

Take twice daily with meals, with gradual dose escalation to reduce the GI adverse effects due to 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

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

 

Pediatric dosage forms and strengths

<18 years: Safety and efficacy not established

 

Geriatric dosage forms and strengths

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

 

Empagliflozin/metformin adverse (side) 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

 

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

 

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.

 

Pharmacology of Empagliflozin/metformin

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