Applies to ertugliflozin / sitagliptin: oral tablet.

Serious side effects

Along with its needed effects, ertugliflozin/sitagliptin 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 ertugliflozin / sitagliptin:

More common

• Anxiety
• blurred vision
• chills
• cold sweats
• confusion
• cool, pale skin
• depression
• dizziness
• fast heartbeat
• headache
• increased hunger
• itching of the vagina or outside of the genitals
• loss of consciousness
• nausea
• nervousness
• seizures
• shakiness
• slurred speech
• unusual tiredness or weakness
• vaginal discharge without odor or with mild odor

Less common

• Bladder pain
• bloody or cloudy urine
• blurred vision
• decreased frequency or amount of urine
• difficult, burning, or painful urination
• discharge with a strong odor from the penis
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• fainting
• frequent urge to urinate
• increase in heart rate
• increased blood pressure
• increased thirst
• increased urination
• loss of appetite
• lower back or side pain
• pain in the skin around the penis
• rapid breathing
• redness, itching, or swelling of the penis
• sunken eyes
• swelling of the face, fingers, or lower legs
• trouble breathing
• vomiting
• weight gain

Rare

• Flushed, dry skin
• fruit-like breath odor
• stomach pain
• unexplained weight loss

Incidence not known

• Agitation
• blistering, peeling, or loosening of the skin
• bloating
• chest tightness
• constipation
• cough
• dark urine
• decreased awareness or responsiveness
• decreased urine output
• diarrhea
• difficulty in moving
• difficulty swallowing
• fever
• hives, itching, skin rash
• indigestion
• irritability
• joint or muscle pain
• large, hard skin blisters
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• muscle aching or cramping
• muscle pain, stiffness, or 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, irritated eyes
• red skin lesions, often with a purple center
• severe joint pain
• severe sleepiness
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• swelling of the face, ankles, or hands
• swollen joints
• unusual drowsiness, dullness, or feeling of sluggishness
• yellow eyes or skin

Other side effects

Some side effects of ertugliflozin / sitagliptin 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:

Less common

• Back pain
• decreased weight
• stuffy or runny nose

Incidence not known

• Pain in the arms or legs

For Healthcare Professionals

Applies to ertugliflozin / sitagliptin: oral tablet.

General

The most commonly reported adverse events with have included genital mycotic infections, more common in females, but also occurring in males.^[Ref]

Gastrointestinal

Thirst includes thirst, dry mouth, polydipsia, and dry throat.

In pooled analysis of clinical trials including data from 5429 patients receiving sitagliptin 100 mg daily and 4817 patients receiving comparator or placebo, the incidence of non-adjudicated acute pancreatitis was 0. Per 100 patient-years in each group.

Ertugliflozin:

Common (1% to 10%): Thirst

Sitagliptin:

Frequency not reported: Abdominal pain, nausea, diarrhea

Postmarketing reports: Acute pancreatitis (including fatal and non-fatal hemorrhagic and necrotizing pancreatitis), constipation, vomiting, mouth ulceration, stomatitis

Genitourinary

Female genital mycotic infections include genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis. Male genital mycotic infections balanitis candida, balanoposthitis, genital infection, and genital infection fungal. Urinary tract infections include cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection. Vaginal pruritus includes vulvovaginal pruritus and pruritus genital. Increased urination includes pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.

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]

Ertugliflozin:

Very common (10% or more): Female genital mycotic infections (up to 12.2%)

Common (1% to 10%): Male genital mycotic infections, urinary tract infections, vaginal pruritus, increased urination

Frequency not reported: Pyelonephritis

SGLT2 Inhibitors:

Postmarketing reports: Serious urinary tract infections including urosepsis and pyelonephritis, Fournier's gangrene^[Ref]

Hypersensitivity

Sitagliptin:

Postmarketing reports: Anaphylaxis, angioedema

Dermatologic

Sitagliptin:

Postmarketing reports: Angioedema, rash urticaria, cutaneous vasculitis, exfoliative skin conditions including Stevens-Johnson syndrome, bullous pemphigoid, pruritus

Renal

Ertugliflozin:

Common (1% to 10%): Renal related adverse reactions

Frequency not reported: Increased serum creatinine, decreased eGFR

SGLT2 Inhibitors:

Postmarketing reports: Acute Kidney Injury

Sitagliptin:

Postmarketing reports: Worsening renal function

During clinical trials with ertugliflozin, renal related adverse reactions included acute kidney injury, renal impairment, acute prerenal failure; the incidence of renal related adverse reactions was 0.6%, 2.5%, and 1.3% in patients receiving placebo, ertugliflozin 5 mg, and 15 mg, respectively. There have been postmarketing reports of worsening renal function including acute renal failure, sometimes requiring dialysis with sitagliptin use. A subset of these reports involved patients with renal insufficiency, some of who received inappropriate doses.

Musculoskeletal

Ertugliflozin:

Common (1% to 10%): Back pain

Uncommon (0.1% to 1%): Nontraumatic lower limb amputation

Sitagliptin:

Postmarketing reports: Severe and disabling arthralgia, extremity pain, back pain

Nontraumatic lower limb amputation was reported in 3 (0.2%) patients receiving 5 mg and 8 patients (0.5%) receiving 15 mg; there was 1 report (0.1%) in the comparator group. A causal association between this drug and lower limb amputation has not been definitively established.

Cardiovascular

Adverse reactions related to volume depletion include dehydration, dizziness, postural, presyncope, syncope, hypotension, and orthostatic hypotension.

In a cardiovascular outcomes trials with 2 other dipeptidyl peptidase-4 (DPP-4) inhibitors, an association was observed with the use of DPP-4 inhibitors and heart failure. Subjects had type 2 diabetes and atherosclerotic cardiovascular disease.

Ertugliflozin:

Common (1% to 10%): Adverse reactions related to volume depletion

DPP-4 inhibitors

Frequency not reported: Heart failure

Hepatic

Sitagliptin:

Postmarketing reports: Hepatic enzyme elevations

Nervous system

Common (1% to 10%): Headache

Hematologic

Ertugliflozin:

Rare (0.01% to 0.1%): Hemoglobin increased greater than 2 g/dL and above the upper limit of normal

Respiratory

Common (1% to 10%): Nasopharyngitis

Sitagliptin:

Frequency not reported: Upper respiratory infection

Metabolic

Ertugliflozin:

Very common (10% or more): Hypoglycemia (in combination with insulin and/or insulin secretagogue in patients with moderate renal impairment; up to 27%)

Common (1% to 10%): Decreased weight, hypoglycemia

Rare (0.01% to 0.1%): Ketoacidosis

Frequency not reported: Increases in low-density lipoprotein cholesterol (LDL-C), increased serum phosphate

Ketoacidosis was reported in 3 of 3409 (0.1%) patients treated with ertugliflozin during clinical trials; no cases were identified in comparator-treated patients. Mean increases in low-density lipoprotein cholesterol (LDL-C) relative to placebo were 2.6% and 5.4%, in the 5 mg and 15 mg groups, respectively.