Applies to dapagliflozin / saxagliptin: oral tablet.

Serious side effects

Along with its needed effects, dapagliflozin/saxagliptin 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 dapagliflozin / saxagliptin:

More common

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

Less common

• Anxiety
• blurred vision
• chills
• cold sweats
• confusion
• cool, pale skin
• decreased frequency or amount of urine
• depression
• dizziness
• fast heartbeat
• headache
• increased hunger
• increased thirst
• loss of appetite
• loss of consciousness
• nausea
• nightmares
• seizures
• shakiness
• slurred speech
• swelling of the face, fingers, or lower legs
• trouble breathing
• unusual tiredness or weakness
• vomiting
• weight gain

Incidence not known

• Agitation
• bloating
• chest pain or tightness
• constipation
• cough
• cracks in the skin
• dark urine
• decreased awareness or responsiveness
• decreased urine output
• difficulty with swallowing
• dilated neck veins
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• fever
• flushed, dry skin
• fruit-like breath odor
• hives, itching, or skin rash
• hostility
• increased urination
• indigestion
• irregular heartbeat
• irritability
• large, hard skin blisters
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
• loss of consciousness
• loss of heat from the body
• muscle twitching
• pain, tenderness, redness, or swelling of the area between the anus and genitals
• pains in the stomach, side, or abdomen, possibly radiating to the back
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rapid weight gain
• red, swollen skin
• redness, itching, swelling, or pain around the penis
• scaly skin
• severe joint pain
• severe sleepiness
• shakiness
• sweating
• unexplained weight loss
• unusual drowsiness, dullness, or feeling of sluggishness
• yellow eyes or skin

Other side effects

Some side effects of dapagliflozin / saxagliptin 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
• ear congestion
• loss of voice
• runny or stuffy nose
• sneezing
• sore throat

Less common

• Back pain
• diarrhea

For Healthcare Professionals

Applies to dapagliflozin / saxagliptin: oral tablet.

General

The more commonly reported adverse reactions have been upper respiratory tract infection, urinary tract infection, and dyslipidemia.^[Ref]

Renal

Dapagliflozin-Saxagliptin

Common (1% to 10%): Renal impairment

Dapagliflozin:

Frequency not reported: Serum creatinine increases, eGFR decreases

Postmarketing reports: Acute kidney injury^[Ref]

With this therapy, adverse reactions related to decreased renal function occurred in 2% of patients and included decreased glomerular filtration rate, renal impairment, increased blood creatinine, acute renal failure, and decreased urine output. None of the events were serious. Three subjects discontinued therapy due to decreased eGFR.

Postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, have been received in patients receiving dapagliflozin. Some cases have occurred in non-elderly patients.^[Ref]

Genitourinary

The majority of genital infections were in females; reported genital infections included vulvovaginal mycotic infection, balanoposthitis, genital fungal infection, vaginal infection, and vulvovaginitis. The majority of urinary tract infections were also in females and included urinary tract infections, Escherichia urinary tract infection, prostatitis, and pyelonephritis.

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]

Dapagliflozin-Saxagliptin:

Common (1% to 10%): Urinary tract infection, genital infection, increased urination, dysuria

Dapagliflozin:

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

Hypersensitivity

Saxagliptin:

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

Respiratory

Dapagliflozin-saxagliptin

Very common (10% or more): Upper respiratory tract infection (13.6%)^[Ref]

Cardiovascular

Events relating to volume depletion including hypotension, dehydration, and hypovolemia were reported in 2 patients (0.4%) in clinical trials with dapagliflozin-saxagliptin.

In a saxagliptin cardiovascular outcomes trial among patients with established atherosclerotic cardiovascular disease (ASCVD) or with multiple risk factors for ASCVD, hospitalization for heart failure occurred in 3.5% (289/8280) of patients receiving saxagliptin compared to 2.8% (228/8212) of patients receiving placebo. Hospitalization, irrespective of treatment, occurred more frequently among patients with renal impairment and a history of heart failure.^[Ref]

Dapagliflozin-Saxagliptin:

Frequency not reported: Hypotension

Saxagliptin:

Frequency not reported: Heart failure requiring hospitalization^[Ref]

Oncologic

Newly diagnosed bladder cancer was reported in 0.17% (10/6045) of patients treated with dapagliflozin compared with 0.03% (1/3512) of patients receiving comparator/placebo therapy. After excluding cases in which exposure to drug was less than 1 year, 4 cases occurred in the dapagliflozin group and no cases in comparator/placebo group. Due to the low numbers, there is insufficient evidence to determine whether this is attributable to dapagliflozin nor is there data to determine whether there is an effect on preexisting bladder tumors.^[Ref]

Dapagliflozin

Rare (0.01% to 0.1%): Bladder cancer^[Ref]

Dermatologic

DPP-4 Inhibitors:

Postmarketing reports: Bullous pemphigoid

Dapagliflozin:

Postmarketing reports: Rash^[Ref]

Endocrine

Dapagliflozin-Saxagliptin:

Uncommon (0.1% to 1%): Erectile dysfunction, pruritus genital, vulvovaginal pruritus^[Ref]

Gastrointestinal

Dapagliflozin-Saxagliptin:

Common (1% to 10%): Diarrhea, abdominal pain, dyspepsia, gastritis, nausea, vomiting

Uncommon (0.1% to 1%): Constipation, dry mouth

Saxagliptin:

Postmarketing reports: Acute pancreatitis^[Ref]

In a saxagliptin cardiovascular outcomes trial among patients with established atherosclerotic cardiovascular disease (ASCVD) or with multiple risk factors for ASCVD, acute pancreatitis was confirmed in 0.2% (17/8240) of patients receiving saxagliptin compared to 0.1% (9/8173) of patients receiving placebo. Preexisting factors were reported in 15 and 9 patients receiving saxagliptin and placebo, respectively.^[Ref]

Metabolic

Dapagliflozin-Saxagliptin:

Very common (10% or more): Hypoglycemia (when combined with sulfonylurea)

Common (1% to 10%): Dyslipidemia, hypoglycemia

Uncommon (0.1% to 1%): Volume depletion, thirst, decreased weight

Dapagliflozin

Frequency not reported: Increase in low-density lipoprotein cholesterol

Postmarketing reports: Ketoacidosis, including fatalities^[Ref]

Increases in LDL-cholesterol with dapagliflozin use have ranged from 2.1% to 6.9%.^[Ref]

Musculoskeletal

Dapagliflozin-Saxagliptin:

Common (1% to 10%): Back pain, arthralgia

DPP-4 inhibitors:

Postmarketing reports: Severe and disabling arthralgia^[Ref]

Nervous system

Dapagliflozin-Saxagliptin:

Common (1% to 10%): Headache, dizziness^[Ref]

Hematologic

Dapagliflozin:

Common (1% to 10%): Increase in mean hematocrit

Saxagliptin:

Common (1% to 10%): Decrease in absolute lymphocyte count^[Ref]

Increase from baseline in mean hematocrit has been observed with dapagliflozin. Hematocrit values greater than 55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4% of placebo subjects.

A dose related mean decrease in absolute lymphocyte count has been observed with saxagliptin use; mean decreases to less than 750 cells/micro were observed in 0.5%, 1.5%, and 0.4% of patients receiving saxagliptin 2.5 mg or 5 mg, and placebo groups, respectively. The clinical significance of this is not known.^[Ref]