Summary

More frequently reported side effects include: decreased vitamin b12 serum concentrate and hypoglycemia. Continue reading for a comprehensive list of adverse effects.

Applies to metformin / saxagliptin: oral tablet extended release.

Serious side effects

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

More common

• Anxiety
• bladder pain
• bloody or cloudy urine
• blurred vision
• body aches or pain
• chills
• cold sweats
• confusion
• cool, pale skin
• cough
• depression
• difficult, burning, or painful urination
• difficulty with breathing
• dizziness
• ear congestion
• fast heartbeat
• fever
• frequent urge to urinate
• headache
• increased hunger
• loss of voice
• lower back or side pain
• nasal congestion
• nausea
• nightmares
• runny nose
• seizures
• shakiness
• slurred speech
• sneezing
• sore throat
• unusual tiredness or weakness

Rare

• Cough or hoarseness

Incidence not known

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• constipation
• darkened urine
• difficulty with swallowing
• hives or skin rash
• indigestion
• large, hard skin blisters
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pinpoint red spots on the skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• tightness in the chest
• unusual bleeding or bruising
• vomiting
• yellow eyes or skin

Other side effects

Some side effects of metformin / 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

• Diarrhea
• muscle aches

Less common

• Abdominal or stomach pain
• itching
• pain or tenderness around the eyes and cheekbones
• redness of the skin
• weakness
• welts

For Healthcare Professionals

Applies to metformin / saxagliptin: oral tablet extended release.

General

Among treatment naive patients' coadministered saxagliptin and metformin, the most commonly reported adverse events included headache and nasopharyngitis. Adverse reactions that are commonly reported with saxagliptin include respiratory tract infection, urinary tract infection, and headache; adverse reactions that are commonly reported with metformin include diarrhea and vomiting, especially on treatment initiation.^[Ref]

Metabolic

Saxagliptin-Metformin:

Very common (10% or more): Hypoglycemia (in combination with insulin or sulfonylurea)

Common (1% to 10%): Hypoglycemia

Uncommon (0.1% to 1%): Blood creatinine phosphokinase increased

Metformin:

Very rare: Lactic Acidosis^[Ref]

In metformin-treated patients, lactic acidosis has been reported in approximately 0.03 cases per 1000 patient-years with approximately half these cases resulting in fatalities. In more than 20,000 patient-years exposure in clinical trials, there were no cases of lactic acidosis. Reported cases have occurred primarily in patients with significant renal insufficiency, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.

In saxagliptin monotherapy clinical trials, hypoglycemia was reported in 4%, 5.6%, and 4.1% of patients receiving saxagliptin 2.5 mg, 5 mg, and placebo, respectively. In add-on to metformin immediate-release, hypoglycemia was reported in 7.8%, 5.8%, and 5%, respectively.^[Ref]

Hypersensitivity

In a 5-study pooled analysis including patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, hypersensitivity-related events were reported in 1.5%, 1.5%, and 0.4%, respectively. None of the events required hospitalization or were reported as life-threatening. One saxagliptin-treated patient discontinued treatment due to generalized urticaria and facial edema. Postmarketing, there have been serious hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions reported.^[Ref]

Saxagliptin:

Common (1% to 10%): Hypersensitivity-related events such as urticaria and facial edema

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

Dermatologic

Uncommon (0.1% to 1%): Rash

Postmarketing reports: Angioedema, dermatitis, pruritus, rash, urticaria^[Ref]

Gastrointestinal

Frequently during treatment initiation of metformin gastrointestinal effects have occurred and these appear to resolve spontaneously in most cases. A slow increase in dose and dividing doses and taking during or after meals may improve gastrointestinal tolerability. In metformin extended-release monotherapy trials, diarrhea and nausea/vomiting were reported in 9.6% and 6.5% of patients compared with 2.6% and 1.5% of placebo patients, respectively.

Acute pancreatitis has been reported during postmarketing use of saxagliptin. In the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial infarction) Trial, the incidence of adjudicated pancreatitis events in the intention to treat population was 0.3% in both the saxagliptin treated patients as well as those receiving placebo.^[Ref]

Saxagliptin-Metformin

Common (1% to 10%): Dyspepsia, gastritis, flatulence

Saxagliptin:

Common (1% to 10%): Abdominal pain, gastroenteritis, vomiting

Postmarketing reports: Acute pancreatitis

Metformin:

Common (1% to 10%): Diarrhea, nausea, vomiting, abdominal pain,^[Ref]

Hematologic

Saxagliptin:

Uncommon (0.1% to 1%): Lymphopenia

Frequency not reported: Thrombocytopenia

Metformin:

Rare (less than 0.1%): Megaloblastic anemia due to reduced vitamin B12 absorption^[Ref]

A dose-related mean decrease in absolute lymphocyte count was observed during clinical trials. The proportion of patients with lymphocyte counts of 750 cells/microL or less was 0.5%, 1.5%, 1.4%, and 0.4% in patients receiving saxagliptin 2.5 mg, 5 mg, 10 mg (not an approved dosage), and placebo, respectively. In most patients, recurrence was not observed with repeated exposure, although some discontinuations were associated with recurrent decrease upon rechallenge. During clinical trials, these decreases in lymphocyte count were not associated with clinically relevant adverse reactions, but whether these decreases may become a concern is unknown. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., HIV) is unknown.^[Ref]

Hepatic

Metformin:

Very rare (less than 0.01%): Liver function disorders, hepatitis^[Ref]

Cardiovascular

Common (1% to 10%): Hospitalization for heart failure, hypertension, peripheral edema (in combination with a thiazolidinedione)^[Ref]

In the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial infarction) Trial, hospitalization for heart failure (secondary composite endpoint) occurred at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), however clinically relevant factors predictive of increased relative risk with saxagliptin could not be definitively identified. Known risk factors for heart failure such as baseline history of heart failure or impaired renal function did confer increased risk, irrespective of treatment assignment. The primary composite endpoints for all-cause mortality showed saxagliptin did not increase the cardiovascular (CV) risk(CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke) in patients with type 2 diabetes mellitus compared to placebo when added to current background therapy.^[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection

Uncommon (0.1% to 1%): Erectile dysfunction^[Ref]

Immunologic

Saxagliptin:

Uncommon (0.1% to 1%): Tuberculosis

Very rare (less than 0.01%): Potential opportunistic infection (salmonella)^[Ref]

Among 4959 saxagliptin-treated patients in clinical trials, 6 cases of tuberculosis have been received; no reports of tuberculosis have been received among the 2868 comparator-treated patients. Causality has not been established and there are too few cases to date to determine any relation to saxagliptin use. None of the cases occurred in the U.S. or in Western Europe; 1 case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia.

One case of a potential opportunistic infection occurred in a saxagliptin-treated patient. Approximately 600 days after starting saxagliptin, this patient developed fatal salmonella sepsis.^[Ref]

Musculoskeletal

Common (1% to 10%): Myalgia

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

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]

Nervous system

Saxagliptin-Metformin:

Common (1% to 10%): Headache

Saxagliptin:

Common (1% to 10%): Dizziness

Metformin:

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

Respiratory

Common (1% to 10%): Upper respiratory tract infection, sinusitis, nasopharyngitis^[Ref]

Renal

Uncommon (0.1% to 1%): Blood creatinine increased^[Ref]

Other

Saxagliptin:

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