Summary

Commonly reported side effects of empagliflozin/linagliptin include: urinary tract infection. Other side effects include: increased ldl cholesterol. Continue reading for a comprehensive list of adverse effects.

Applies to empagliflozin / linagliptin: oral tablet, tablet oral.

Serious side effects

Along with its needed effects, empagliflozin/linagliptin 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 / linagliptin:

More common

• Bladder pain
• bloody or cloudy urine
• difficult, burning, or painful urination
• frequent urge to urinate
• lower back or side pain

Incidence not known

• Anxiety
• bloating
• blurred vision
• chest pain or tightness
• chills
• cold sweats
• confusion
• constipation
• cool, pale skin
• dark urine
• depression
• dizziness
• dry mouth
• fast heartbeat
• fever
• flushed, dry skin
• fruit-like breath odor
• headache
• increased hunger
• increased thirst
• indigestion
• large, hard skin blisters
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
• loss of appetite
• loss of consciousness
• nausea
• nightmares
• pain, tenderness, redness, or swelling of the area between the anus and genitals
• pains in the stomach, side, or abdomen, radiating to the back
• seizures
• severe joint pain
• shakiness
• slurred speech
• stomach pain
• sweating
• trouble breathing
• unexplained weight loss
• unusual tiredness or weakness
• vomiting
• yellow eyes or skin

Other side effects

Some side effects of empagliflozin / linagliptin 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

• Body aches or pain
• difficulty with breathing
• ear congestion
• headache
• loss of voice
• runny or stuffy nose
• sneezing
• sore throat

Incidence not known

• Discharge with a strong odor from the penis
• redness, itching, swelling, or pain around the penis
• vaginal discharge, itching, or odor

For Healthcare Professionals

Applies to empagliflozin / linagliptin: oral tablet.

General

The most commonly occurring adverse events have included urinary tract infections, nasopharyngitis, and upper respiratory tract infections.^[Ref]

Gastrointestinal

During clinical trials, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure in linagliptin-treated patients compared to 3.7 cases per 10,000 in those receiving active comparator (placebo or sulfonylurea). Following completion of clinical trials, 3 additional cases of pancreatitis were reported. Postmarketing reports of acute pancreatitis, including fatalities, have been reported.^[Ref]

Empagliflozin-linagliptin

Postmarketing reports: Acute Pancreatitis, mouth ulcerations, stomatitis

Empagliflozin:

Common (1% to 10%): Nausea

Linagliptin:

Common (1% to 10%): Diarrhea

Frequency not reported: Pancreatitis

Postmarketing reports: Acute pancreatitis, mouth ulceration^[Ref]

Dermatologic

Empagliflozin-linagliptin

Postmarketing reports: Bullous pemphigoid, skin reactions (e.g., rash, urticaria)

Empagliflozin:

Common (1% to 10%): Pruritus

Postmarketing reports: Rash

Linagliptin:

Postmarketing reports: Rash, bullous pemphigoid^[Ref]

Postmarketing reports of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitors. Discontinuation of therapy and treatment with topical or systemic immunosuppressive agents led to resolution in reported cases.^[Ref]

Metabolic

Empagliflozin-linagliptin:

Common (1% to 10%): Hypoglycemia, increased cholesterol, thirst

Postmarketing reports: Ketoacidosis

Empagliflozin:

Common (1% to 10%): Increased low-density lipoprotein cholesterol, dyslipidemia

Rare (Less than 0.1%): Ketoacidosis

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

Linagliptin:

Common (1% to 10%): Increased uric acid^[Ref]

When this combination product was added to metformin therapy, the overall incidence of hypoglycemia was 2.2% and 3.6% in patients receiving empagliflozin 10 mg-linagliptin 5 mg and empagliflozin 25 mg-linagliptin 5 mg, respectively. There were no reports of serious hypoglycemia.

Twenty reports of acidosis 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 diabetic ketoacidosis (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]

Genitourinary

Empagliflozin-linagliptin:

Very Common (10% or more): Urinary tract infection (up to 12.5%)

Postmarketing reports: Urosepsis, pyelonephritis, Fournier's gangrene

Empagliflozin:

Common (1% to 10%): Urinary tract infection, female genital mycotic infections, vaginal moniliasis, vulvovaginitis, balanitis, increased urination, male genital mycotic infections

Uncommon (0.1% to 1%): Dysuria

Postmarketing reports: Fournier's gangrene^[Ref]

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]

Hypersensitivity

Empagliflozin-linagliptin:

Uncommon (0.1% to 1%): Hypersensitivity

Postmarketing reports: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions

Linagliptin:

Frequency not reported: Hypersensitivity reactions including urticaria, angioedema, localized skin exfoliation, or bronchial hyper-reactivity

Postmarketing reports: Serious hypersensitivity reactions including anaphylaxis, angioedema^[Ref]

Postmarketing, serious hypersensitivity reactions including angioedema, anaphylaxis, and exfoliative skin conditions have been reported in patients treated with linagliptin. These reactions have occurred within the first 3 months and some have occurred after the first dose.^[Ref]

Renal

Postmarketing reports of AKI, 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-linagliptin

Postmarketing reports: Acute kidney injury

Empagliflozin:

Frequency not reported: Increased serum creatinine, decreased eGFR

Postmarketing reports: Acute kidney injury (AKI)^[Ref]

Respiratory

Empagliflozin-Linagliptin:

Common (1% to 10%): Nasopharyngitis, upper respiratory infection

Empagliflozin:

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

Linagliptin:

Common (1% to 10%): Nasopharyngitis, cough^[Ref]

Musculoskeletal

Between October 2006 and December 2013, thirty-three cases of severe arthralgia have been reported to the FDA Adverse Event Reporting System Database. Each case involved the use of 1 or more dipeptidyl peptidase-4 (DPP-4) inhibitor. In all cases, substantial reduction in prior activity level was reported, 10 patients were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 month of starting therapy, in 23 cases symptoms resolved less than 1 month after discontinuation. A positive rechallenge was reported in 8 cases, with 6 cases involving use of a different DPP-4 inhibitor. Sitagliptin had the greatest number of cases reported (n=28) followed by saxagliptin (n=5), linagliptin (n=2), alogliptin (n=1), and vildagliptin (n=2).^[Ref]

Empagliflozin-linagliptin

Postmarketing reports: Severe and disabling arthralgia, rhabdomyolysis

Dipeptidyl peptidase-4 (DPP-4) inhibitors:

Common (1% to 10%): Arthralgia

Postmarketing cases: Severe and disabling arthralgia^[Ref]

Cardiovascular

Empagliflozin:

Uncommon (0.1% to 1%): Volume depletion

Hematologic

Empagliflozin-Linagliptin:

Frequency not reported: Increased hematocrit

Empagliflozin:

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