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Xigduo XR Side Effects

Generic Name: dapagliflozin / metformin

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

In Summary

Common side effects of Xigduo XR include: lactic acidosis. Other side effects include: cystitis, pyelonephritis, urinary tract infection, vulvovaginal candidiasis, bacterial vaginosis, genital candidiasis, genitourinary infection, nasopharyngitis, prostatitis, urethritis, vaginal infection, vulvitis, vulvovaginitis, nausea, and vomiting. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to dapagliflozin / metformin: oral tablet extended release

Warning

Oral route (Tablet, Extended Release)

Fatal metformin-associated lactic acidosis has been reported during postmarketing surveillance. The onset is often subtle and subtle and accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain). Risk factors include concomitant carbonic anhydrase inhibitor use (eg, topiramate), age 65 or older, surgery and other procedures, radiological study with contrast, hypoxic states, excessive alcohol consumption, or hepatic impairment. If suspected, discontinue use and initiate hemodialysis and general supportive measures.

Side effects requiring immediate medical attention

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

More common

  • Bladder pain
  • bloody or cloudy urine
  • change in the color, amount, or odor of vaginal discharge
  • difficult, burning, or painful urination
  • frequent urge to urinate
  • lower back or side pain

Rare

  • Decreased appetite
  • diarrhea
  • fast, shallow breathing
  • general feeling of discomfort
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
  • muscle pain or cramping
  • nausea
  • sleepiness
  • stomach discomfort
  • unusual tiredness or weakness

Incidence not known

  • Anxiety
  • blurred vision
  • chills
  • clay-colored stools
  • cold sweats
  • confusion
  • cool, pale skin
  • dark urine
  • depression
  • dizziness
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fast heartbeat
  • fever
  • headache
  • hives, itching, or rash
  • hoarseness
  • increased hunger
  • irritation
  • joint pain, stiffness, or swelling
  • loss of appetite
  • loss of consciousness
  • nightmares
  • pain, tenderness, redness, or swelling of the area between the anus and genitals
  • redness of the skin
  • seizures
  • shakiness
  • slurred speech
  • sweating
  • swelling of the eyelids, face, lips, hands, or feet
  • tightness in the chest
  • troubled swallowing
  • unpleasant breath odor
  • vomiting of blood
  • yellow eyes or skin

Side effects not requiring immediate medical attention

Some side effects of dapagliflozin / 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

Less common

  • Back pain
  • body aches or pain
  • difficulty having a bowel movement
  • tender, swollen glands in the neck
  • voice changes

For Healthcare Professionals

Applies to dapagliflozin / metformin: oral tablet extended release

General

The most common adverse reactions reported with this combination drug included female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache.[Ref]

Metabolic

Hypoglycemia was reported more frequently when this drug was added to sulfonylurea or insulin (up to 43%). Hypoglycemia was not reported in dapagliflozin monotherapy trials, and was reported infrequently in add-on trials with metformin, or dipeptidyl peptidase-4 inhibitors.

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]

Dapagliflozin-Metformin:

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

Dapagliflozin:

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

Uncommon (0.1% to 1%): Decreased weight, thirst

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

Metformin:

Very rare (less than 0.01%): Lactic acidosis, vitamin B12 deficiency[Ref]

Gastrointestinal

Dapagliflozin-Metformin:

Common (1% to 10%): Diarrhea, nausea, constipation

Dapagliflozin:

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

Metformin:

Very common (10% or more): Gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite occurring most frequently during initiation[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Adverse reactions related to reduced intravascular volume (dehydration, hypovolemia, orthostatic hypotension, or hypotension)[Ref]

Respiratory

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

Dermatologic

Dapagliflozin:

Postmarketing reports: Rash

Metformin:

Very rare (less than 0.01%): Urticaria, erythema, pruritus[Ref]

Endocrine

Small increases in serum parathyroid hormone (PTH) levels were observed with increases larger in subjects with higher baseline PTH concentrations. Bone mineral density in patients with normal or mildly impaired renal function did not indicate bone loss over a period of 2 years.[Ref]

Dapagliflozin:

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

Oncologic

Newly diagnosed bladder cancer was reported in 10 of 6045 (0.17%) patients receiving dapagliflozin 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]

Dapagliflozin:

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

Genitourinary

Genital mycotic infections have been commonly reported with dapagliflozin treatment. Discontinuation due to genital infection occurred in 0.2% of patients in dapagliflozin clinical trials. Infections were more frequently reported in females than males, and patients with a history of genital mycotic infections were more likely to have an infection than those without a history.

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]

Common (1% to 10%): Female genital mycotic infections (including vulvovaginal mycotic infection, vaginal infection, genital infection, vulvovaginitis, fungal genital infection, vulvovaginal candidiasis, vulval abscess, genital candidiasis, and vaginitis bacterial), urinary tract infections (including urinary tract infection cystitis, pyelonephritis, urethritis, and prostatitis), male genital mycotic infections (including balanitis, fungal genital infection, balanitis candida, genital candidiasis, balanoposthitis, balanoposthitis infective, genital infection, posthitis), increased urination, discomfort with urination

Uncommon (0.1% to 1%): Vulvovaginal pruritus

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

Hematologic

Dapagliflozin:

Common (1% to 10): Hematocrit increased

Metformin:

Very rare (less than 0.01%): Decreased vitamin B12 serum levels[Ref]

Hepatic

Metformin:

Very rare (less than 0.01%): Liver function disorders, liver function tests abnormalities, hepatitis

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

Hypersensitivity

Dapagliflozin:

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

Musculoskeletal

Common (1% to 10%): Back pain[Ref]

Nervous system

Dapagliflozin-Metformin:

Common (1% to 10%): Headache, dizziness

Metformin:

Common (1% to 10%): Taste disturbance[Ref]

Renal

Cases of acute kidney injury have been reported during the postmarketing period with dapagliflozin. Some cases required hospitalization and dialysis; some reports were in patients less than 65 years old.[Ref]

Dapagliflozin:

Uncommon (0.1% to 1%): Increased serum creatinine, blood urea increased

Frequency not reported: Decreases in eGFR

Postmarketing reports: Acute kidney injury and impaired renal function[Ref]

Immunologic

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

References

1. Cerner Multum, Inc. "Australian Product Information." O 0

2. "Product Information. Xigduo XR (dapagliflozin-metFORMIN)." Astra-Zeneca Pharmaceuticals, Wilmington, DE.

3. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

4. FDA. U.S. Food and Drug Administration "FDA: SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood Available from: URL: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm44699" (2015 May 15):

5. FDA "FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. Available from: URL: https://www.fda.gov/downloads/Drugs/DrugSafety/UCM618466.pdf." ([2018, Aug 29]):

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.

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