Summary

More frequently reported side effects include: cystitis, pyelonephritis, urinary tract infection, vulvovaginal candidiasis, bacterial vaginosis, genital candidiasis, genitourinary infection, prostatitis, urethritis, vaginal infection, vulvitis, and vulvovaginitis. Continue reading for a comprehensive list of adverse effects.

Applies to dapagliflozin: oral tablets.

Side effects include:

Dapagliflozin monotherapy: Female genital mycotic infection, nasopharyngitis, urinary tract infection, back pain, increased urination, male genital mycotic infection, nausea, dyslipidemia, constipation, discomfort with urination, pain in extremity.

Dapagliflozin in combination with extended-release metformin hydrochloride: Female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, headache, male genital mycotic infection, influenza, nausea, back pain, dizziness, cough, constipation, dyslipidemia, pharyngitis, increased urination, discomfort with urination.

Dapagliflozin in combination with saxagliptin and extended-release metformin hydrochloride: Upper respiratory tract infection, urinary tract infection, dyslipidemia, headache, diarrhea, back pain, genital infection, arthralgia.

For Healthcare Professionals

Applies to dapagliflozin: oral tablet.

General

The most common adverse reactions included female genital mycotic infections, nasopharyngitis, and urinary tract infections.^[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infections increased urination, discomfort with urination, female genital mycotic infections (including vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial), and male mycotic infections (including balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, posthitis)

Postmarketing reports: Urosepsis, pyelonephritis, 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]

Cardiovascular

Common (1% to 10%): Dyslipidemia

Uncommon (0.1% to 1%): adverse reactions related to reduced intravascular volume (postural hypotension, orthostatic hypotension, hypotension, dehydration, and syncope)^[Ref]

Metabolic

Hypoglycemia was reported more frequently when this drug was added to sulfonylurea or insulin (up to 43%). Hypoglycemia was not reported in monotherapy trials, and was reported infrequently in add-on trials with metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitors (up to 1.5%,2.1%, and 1.8% respectively). Severe hypoglycemia and diabetic ketoacidosis (DKA) have only been observed in patients with diabetes mellitus.

Ketoacidosis has been reported in patients with type 1 and type 2 diabetes mellitus receiving SGLT2 inhibitors including this drug. Fatalities have been reported. The presentation of ketoacidosis in many cases was atypical with only moderately increased blood glucose values (below 250 mg/dL [14 mmol/L] ). Factors that appear to have predisposed patients to ketoacidosis included insulin deficiency from any cause (including insulin pump failure, insulin dose reduction, history of pancreatitis or pancreatic surgery), reduced caloric intake or increased insulin requirements due to infections, low carbohydrate diet, acute illness, surgery, a previous ketoacidosis, dehydration and alcohol abuse.

In the DECLARE (Dapagliflozin Effect on Cardiovascular Events) study, DKA was reported in 27 and 12 patients in the dapagliflozin (n=8574) and placebo (n=8569) groups, respectively. Mean changes in LDL cholesterol were 0.4 mg/dL and -2.5 mg/dL in the dapagliflozin and placebo groups, respectively.^[Ref]

Very common (10% or more): Hypoglycemia (up to 43%)

Common (1% to 10%): Hyperphosphatemia, increases in low-density lipoprotein cholesterol (LDL-C)

Uncommon (0.1% to 1%): Decreased weight

Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis^[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, constipation

Uncommon (0.1% to 1%): Thirst, dry mouth^[Ref]

Hypersensitivity

Rare (less than 0.1%): Serious anaphylactic reactions, severe cutaneous reactions, and angioedema^[Ref]

Musculoskeletal

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

Frequency not reported: Bone fracture^[Ref]

Bone fractured occurred in 13 patients receiving this drug compared with no placebo patients in a study of patients with an eGFR of 30 to less than 60 mL/min/1.73 m2.^[Ref]

Immunologic

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

Oncologic

Newly diagnosed bladder cancer was reported in 10 of 6045 (0.17%) patients receiving this drug in clinical trials compared with 1 of 3512 (0.3%) patients receiving placebo or comparator. Upon excluding patients in whom exposure to study drug was less than 1 year at time of diagnosis, there were no cases associated with placebo and 4 cases with this drug. Due to the low number of cases, further studies are needed.^[Ref]

Uncommon (0.1% to 1%): Bladder cancer^[Ref]

Renal

Frequency not reported: Renal failure, serum creatinine increase

Postmarketing reports: Acute kidney injury, renal impairment^[Ref]

From March 2013 to October 2015, the US FDA received 101 confirmable case reports of acute kidney injury (AKI) with use of canagliflozin (n=73) or dapagliflozin (n=28). Hospitalization was necessary for evaluation and management in 96 cases; admission to the intensive care unit occurred in 22 cases, and death occurred in 4 patients, of which 2 were cardiac-related. Dialysis was necessary in 15 patients, 3 of whom had a history of chronic kidney disease or previous AKI. In 58 cases, time to onset of AKI was within 1 month or less of initiating therapy. In 78 cases in which drug discontinuation was reported, 56 reported subsequent improvement; 3 patients recovered with sequelae, 11 patients did not recover (including the 4 deaths mentioned earlier). Median age was 57 years (range 28 to 78 years; based on 84 cases reporting age). Concomitant ACE inhibitor therapy was reported in 51 cases, diuretic use in 26 cases, and NSAID use in 6 cases. Almost half the patients reported a change in renal function at time of diagnosis (median elevation of serum creatinine from baseline 1.6 mg/dL [based on 32 cases reporting serum creatinine] and median decrease in eGFR 46 mL/min/1.73m2 [based on 13 cases reporting eGFR]).^[Ref]

Endocrine

Frequency not reported: Small increases in serum parathyroid hormone levels^[Ref]

Nervous system

Common (1% to 10%): Dizziness, headache^[Ref]

Hepatic

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

Respiratory

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

Dermatologic

Postmarketing reports: Rash^[Ref]