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Empagliflozin / metformin Side Effects

Medically reviewed by Drugs.com. Last updated on May 16, 2023.

Applies to empagliflozin / metformin: oral tablet, oral tablet extended release.

Warning

Oral route (Tablet; Tablet, Extended Release)

Lactic AcidosisPostmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information.If metformin-associated lactic acidosis is suspected, immediately discontinue empagliflozin/metformin hydrochloride and institute general supportive measures in the hospital setting. Prompt hemodialysis is recommended.

Serious side effects

Along with its needed effects, empagliflozin / metformin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking empagliflozin / metformin:

More common

Less common

Incidence not known

Other side effects

Some side effects of empagliflozin / metformin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

For Healthcare Professionals

Applies to empagliflozin / metformin: oral tablet, oral tablet extended release.

General

The most common adverse reactions associated with empagliflozin were urinary tract infection and female genital mycotic infections. The most common adverse reactions associated with metformin were diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.[Ref]

Cardiovascular

Adverse reactions related to volume depletion included decreased blood pressure (ambulatory), decreased systolic blood pressure, hypotension, and orthostatic hypotension.

Empagliflozin:

-Frequency not reported: Decreased blood pressure (ambulatory), decreased systolic blood pressure, hypotension, orthostatic hypotension

Dermatologic

Common (1% to 10%): Rash

Uncommon (0.1% to 1%): Urticaria, angioedema

Empagliflozin:

-Common (1% to 10%): Generalized pruritus

-Postmarketing reports: Angioedema, skin reactions (e.g., rash, urticaria)

Metformin:

-Common (1% to 10%): Pruritus, generalized pruritus

-Very rare (less than 0.01%): Erythema, urticaria

Gastrointestinal

Gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea, abdominal pain, loss of appetite) occurred most often during initiation of metformin therapy and resolved spontaneously in most cases.

In clinical trials of metformin, diarrhea, nausea/vomiting, flatulence, abdominal discomfort, and indigestion were reported in greater than 5% of patients. In clinical trials of extended-release metformin plus glyburide, diarrhea and nausea were reported in 12.5% and 6.7% of patients, respectively.

Common (1% to 10%): Constipation

Empagliflozin:

-Common (1% to 10%): Nausea

-Postmarketing reports: Constipation

Metformin:

-Very common (10% or more): Gastrointestinal symptoms

-Frequency not reported: Diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion

Genitourinary

Common (1% to 10%): Urinary tract infection

Very rare (less than 0.01%): Tubulointerstitial nephritis

Empagliflozin:

-Common (1% to 10%): Female genital mycotic infections, increased urination, male genital mycotic infections, vaginal moniliasis, vulvovaginitis, balanitis, other genital infection, urinary tract infection

-Uncommon (0.1% to 1%): Nocturia, dysuria

-Rare (0.01% to 0.1%): Phimosis

-Postmarketing reports: Urosepsis, phimosis

Urinary tract infection included (but was not limited to) asymptomatic bacteriuria, cystitis, and urinary tract infection. Urinary tract infections occurred more often in female patients and were more likely to occur in patients with history of chronic or recurrent urinary tract infections.

Female genital mycotic infections included vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, fungal genital infection, genitourinary tract infection, vulvovaginitis, cervicitis, fungal urogenital infection, and bacterial vaginitis. Genital mycotic infections occurred more frequently in female than male patients.

Increased urination included (but was not limited to) polyuria, pollakiuria, and nocturia.

Male genital mycotic infections included balanoposthitis, balanitis, fungal genital infections, genitourinary tract infection, Candida balanitis, scrotal abscess, and penile infection.

Hematologic

Empagliflozin:

-Common (1% to 10%): Increased hematocrit

Hepatic

Metformin:

-Very rare (less than 0.01%): Abnormal liver function tests, hepatitis

-Postmarketing reports: Cholestatic liver injury, hepatocellular liver injury, mixed hepatocellular liver injury

Hypersensitivity

Empagliflozin:

-Postmarketing reports: Serious hypersensitivity reactions (e.g., angioedema)

Metabolic

Very common (10% or more): Hypoglycemia (up to 15.6%)

Empagliflozin:

-Common (1% to 10%): Dyslipidemia

-Uncommon (0.1% to 1%): Hypoglycemia, volume depletion, volume depletion-related adverse reactions

-Frequency not reported: Dehydration, hypovolemia

-Postmarketing reports: Ketoacidosis

Metformin:

-Common (1% to 10%): Decreased vitamin B12 levels

-Very rare (less than 0.01%): Lactic acidosis, vitamin B12 deficiency

-Frequency not reported: Hypoglycemia

-Postmarketing reports: Drug-associated lactic acidosis

The incidence of hypoglycemia increased when empagliflozin was administered with insulin or sulfonylurea. The incidence of overall hypoglycemic events (plasma/capillary glucose 70 mg/dL or less) was 0.4% with empagliflozin monotherapy, up to 1.8% with empagliflozin plus metformin, up to 16.1% with empagliflozin plus metformin plus sulfonylurea, up to 2.4% with empagliflozin plus pioglitazone (with/without metformin), up to 28.4% with empagliflozin plus basal insulin (with/without metformin), and up to 41.3% with empagliflozin plus multiple daily injections of insulin (with/without metformin).

In clinical trials in adults, adverse reactions related to volume depletion (e.g., decreased blood pressure [ambulatory], decreased systolic blood pressure, dehydration, hypotension, hypovolemia, orthostatic hypotension, syncope) were reported in up to 0.5% of patients treated with empagliflozin.

In clinical trials of extended-release metformin plus glyburide, hypoglycemia was reported in 13.7% of patients.

Musculoskeletal

Across 4 empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5 events per 1000 patient-years in the placebo and empagliflozin groups, respectively. In a long-term cardiorenal outcome trial in patients with chronic kidney disease, lower limb amputations event rates were 2.9 and 4.3 events per 1000 patient-years in the placebo and empagliflozin arms, respectively.

Empagliflozin:

-Common (1% to 10%): Arthralgia

-Frequency not reported: Lower limb amputation

-Postmarketing reports: Necrotizing fasciitis of the perineum (Fournier's gangrene)

Nervous system

Empagliflozin:

-Frequency not reported: Syncope

Metformin:

-Common (1% to 10%): Taste disturbance

-Frequency not reported: Headache

Adverse reactions related to volume depletion included syncope.

In clinical trials of metformin, headache was reported in greater than 5% of patients.

Other

Empagliflozin:

-Common (1% to 10%): Thirst, increased serum lipids

-Frequency not reported: Increased low-density lipoprotein cholesterol, increased total cholesterol, increased high-density lipoprotein cholesterol, increased triglycerides

Metformin:

-Frequency not reported: Asthenia

Thirst included polydipsia.

In clinical trials of metformin, asthenia was reported in greater than 5% of patients.

Renal

Empagliflozin:

-Frequency not reported: Increased serum creatinine, decreased estimated GFR, osmotic diuresis

-Postmarketing reports: Pyelonephritis, acute kidney injury

Respiratory

Common (1% to 10%): Nasopharyngitis

Empagliflozin:

-Common (1% to 10%): Upper respiratory tract infection

References

1. Product Information. Synjardy (empagliflozin-metformin). Boehringer Ingelheim. 2023;SUPPL-39.

2. Product Information. Jardiamet (empagliflozin-metformin). Boehringer Ingelheim Pty Ltd. 2022;PI0157-16.

3. Product Information. Synjardy (empagliflozin-metformin). Boehringer Ingelheim Ltd. 2023.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.