Note: This document contains side effect information about empagliflozin / metformin. Some dosage forms listed on this page may not apply to the brand name Synjardy XR.

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

Serious side effects of Synjardy XR

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

• Bladder pain
• bloody or cloudy urine
• blurred vision
• chills
• confusion
• cool, pale skin
• decreased appetite
• difficult, burning, or painful urination
• discouragement
• dizziness
• fast heartbeat
• fast, shallow breathing
• feeling sad or empty
• frequent urge to urinate
• general feeling of discomfort
• headache
• increased hunger
• irritability
• lack of appetite
• loss of consciousness
• loss of interest or pleasure
• lower back or side pain
• muscle pain or cramping
• nausea
• nightmares
• seizures
• shakiness
• sleepiness
• slurred speech
• stomach discomfort
• tiredness
• trouble concentrating
• trouble sleeping
• unusual tiredness or weakness

Less common

• Bad-smelling discharge from the penis
• itching of the vagina or genitals
• itching, stinging, or redness of the vaginal area
• redness, itching, swelling, or pain of the penis
• thick, white vaginal discharge with mild or no odor

Incidence not known

• Dark urine
• decreased frequency or amount of urine
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• fever
• flushed, dry skin
• fruit-like breath odor
• increased thirst
• itching, skin rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
• light-colored stools
• pain, tenderness, redness, or swelling of the area between the anus and genitals
• redness of the skin
• stomach pain, continuing
• unexplained weight loss
• vomiting
• weight gain
• yellow eyes or skin

Other side effects of Synjardy XR

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

• Bloated or feeling of fullness
• diarrhea
• excess air or gas in stomach or bowels
• indigestion
• passing gas
• stomach discomfort

For Healthcare Professionals

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

General

Empagliflozin: The most frequently reported side effects included urinary tract infections and female genital mycotic infections.

Metformin: The most frequently reported side effects included diarrhea, nausea, vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.^[Ref]

Cardiovascular

Empagliflozin is known to cause osmotic diuresis, leading to intravascular volume contraction and adverse reactions related to volume depletion. Adverse reactions related to volume depletion such as decreased ambulatory/systolic blood pressure, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope were reported in 0.5% and 0.3% of patients receiving empagliflozin 10 mg (n=999) or 25 mg (n=977) orally once a day, respectively.^[Ref]

Empagliflozin:

Uncommon (0.1% to 1%): Hypotension, orthostatic hypotension, syncope, decreased systolic blood pressure, decreased ambulatory blood pressure^[Ref]

Genitourinary

During a 24 week study of empagliflozin in combination with metformin plus a sulfonylurea, urinary tract infections (UTIs) were reported in 9.4% and 6.9% of patients receiving empagliflozin 10 mg (n=224) or 25 mg (n=217) once a day, respectively. Pooled data from 5 studies showed the incidence of UTIs (e.g., UTI, asymptomatic bacteriuria, and cystitis), was increased in empagliflozin-treated patients compared to placebo, more frequent in females compared to males, and more likely to occur in patients with a history of chronic or recurrent UTIs. Treatment discontinuation due to UTIs occurred in 0.2% and 0.1% of patients receiving empagliflozin 10 mg or 25 mg once a day, respectively.

In the 5 years (2013 to 2018) since SGLT2 inhibitor approval, 12 cases of Fournier's gangrene have been reported. Reports were almost equal in men and women (men=7; women=5), ages ranged from 38 to 78 years, and the average time to onset after starting an SGLT2 inhibitor was 9.2 months (range 7 days to 25 months). All SGLT2 inhibitor drugs except ertugliflozin were included in the reports. Ertugliflozin being the most recently approved agent, is expected to have the same risk, but insufficient patient use to assess risk. All patients were hospitalized, all required surgery, all required surgical debridement, 5 required more than 1 surgery and 1 required skin grafting. Four cases were complicated by diabetic ketoacidosis, acute kidney injury, and septic shock, leading to prolonged hospitalization, and death in 1 case. In the general population, Fournier's gangrene occurs in about 1.6 out of 100,000 males annually, with the highest incidence in men 50 to 79 years. Since diabetes is a risk factor for Fournier's gangrene, a review of the FAERS database for the last 34 years was done and only 6 cases (all males, median age 57 years) were found with several other classes of antidiabetic drugs. Findings with SGLT2 inhibitors appear to show an association over a shorter time frame and involve both males and females.^[Ref]

Empagliflozin-Metformin:

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

Empagliflozin:

Common (1% to 10%): Urinary tract infections, female genital mycotic infections, male genital mycotic infections, increased urination (e.g., polyuria, pollakiuria, and nocturia)

Uncommon (0.1% to 1%): Dysuria

Rare (less than 0.1%): Phimosis

Postmarketing reports: Urosepsis, pyelonephritis, Fournier's gangrene^[Ref]

Metabolic

The frequency of hypoglycemia depended on the type of background therapy used. When empagliflozin was used as monotherapy, hypoglycemia was reported in 0.4% of patients taking the 10 mg and 25 mg doses. In combination with metformin, hypoglycemia was reported in 1.8% taking 10 mg and 1.4% taking 25 mg. In combination with metformin and a sulfonylurea, hypoglycemia was reported in 16.1% taking the 10 mg dose and 11.5% taking the 25 mg dose. In combination with basal insulin, hypoglycemia was reported in 19.5% taking the 10 mg dose and 28.4% taking the 25 mg dose.

Twenty reports of acidosis, including diabetic ketoacidosis (DKA), ketoacidosis, or ketosis in patients treated with SGLT-2 inhibitors have been identified in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database during the period March 2013 through 06 June 2014. All patients required emergency room treatment or hospitalization. These cases were not typical of ketoacidosis or DKA in that they occurred in patients with type 2 diabetes and their blood sugar levels were only slightly increased. Some factors identified as potentially triggering the acidosis included major illness, reduced food and fluid intake, and reduced insulin dose.^[Ref]

Empagliflozin-Metformin:

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

Empagliflozin:

Common (1% to 10%): Dyslipidemia, polydipsia, increased LDL-C

Uncommon (0.1% to 1%): Dehydration, hypovolemia, hypoglycemia

Frequency not reported: Increased serum creatinine

Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis

Metformin:

Very rare (less than 0.01%): Lactic acidosis^[Ref]

Dermatologic

Empagliflozin-Metformin:

Common (1% to 10%): Pruritus

Empagliflozin:

Postmarketing reports: Skin reactions (e.g., rash, urticaria)

Metformin:

Very rare (less than 0.01%): Erythema, urticaria^[Ref]

Gastrointestinal

Empagliflozin:

Common (1% to 10%): Nausea

Metformin:

Common (1% to 10%): Nausea, vomiting, diarrhea, flatulence, abdominal discomfort, indigestion^[Ref]

Hypersensitivity

Empagliflozin:

Postmarketing reports: Angioedema^[Ref]

Hematologic

Empagliflozin:

Common (1% to 10%): Increased hematocrit

Metformin:

Common (1% to 10%): Subnormal vitamin B12 levels

Postmarketing reports: Hematologic reactions possibly related to subnormal Vitamin B12 levels^[Ref]

Hepatic

Metformin:

Very rare (less than 0.01%): Hepatitis, abnormal liver function tests

Postmarketing reports: Cholestatic, hepatocellular, mixed hepatocellular liver injury^[Ref]

Musculoskeletal

Empagliflozin:

Common (1% to 10%): Arthralgia^[Ref]

Nervous system

Metformin:

Common (1% to 10%): Headache, taste disturbances

Postmarketing reports: Neurologic reactions possibly related to subnormal Vitamin B12 levels^[Ref]

Renal

Postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, have been received for patients treated with SGLT2 inhibitors including empagliflozin. Some reports involved patients younger than 65 years old.^[Ref]

Empagliflozin:

Frequency not reported: Decreased eGFR

Postmarketing reports: Acute Kidney Injury^[Ref]

Respiratory

Empagliflozin-Metformin:

Common (1% to 10%): Nasopharyngitis

Empagliflozin:

Common (1% to 10%): Upper respiratory tract infection^[Ref]

Other

Metformin:

Common (1% to 10%): Asthenia^[Ref]