Applies to liraglutide: subcutaneous solution.

Serious side effects of Liraglutide

Along with its needed effects, liraglutide 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 liraglutide:

More common

• Bladder pain
• bloody or cloudy urine
• chills
• cough
• diarrhea
• difficult, burning, or painful urination
• fever
• frequent urge to urinate
• general feeling of discomfort or illness
• headache
• hoarseness
• joint pain
• loss of appetite
• lower back or side pain
• muscle aches and pains
• nausea
• runny nose
• shivering
• sore throat
• sweating
• trouble sleeping
• unusual tiredness or weakness
• vomiting

Less common

• Blurred vision
• dizziness
• nervousness
• pounding in the ears
• slow or fast heartbeat

Rare

• Anxiety
• cold sweats
• confusion
• cool, pale skin
• depression
• hives or welts, itching, or skin rash
• increased hunger
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
• loss of consciousness
• nightmares
• redness of the skin
• seizures
• shakiness
• slurred speech

Incidence not known

• Agitation
• clay-colored stools
• confusion
• dark urine
• decreased awareness or responsiveness
• decreased urine output
• depression
• difficulty with swallowing
• hostility
• irritability
• muscle twitching
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rapid weight gain
• severe sleepiness
• swelling of the face, ankles, or hands
• tightness in the chest
• unpleasant breath odor
• vomiting of blood
• yellow eyes or skin

Other side effects of Liraglutide

Some side effects of liraglutide 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

• Back pain
• belching
• body aches or pain
• constipation
• decreased appetite
• heartburn
• indigestion
• loss of voice
• pain or tenderness around the eyes and cheekbones
• sneezing
• stomach cramps, discomfort, or pain
• stuffy nose
• swollen mouth and tongue
• unpleasant taste
• urge to have bowel movement
• weight loss

Less common

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site

For Healthcare Professionals

Applies to liraglutide: subcutaneous solution.

Gastrointestinal

Chronic Weight Management:

Very common (10% or more): Nausea (39.3%), diarrhea (20.9%), constipation (19.4%), vomiting (15.7%),

Common (1% to 10%): Dyspepsia, abdominal pain, upper abdominal pain, gastroesophageal reflux disease, abdominal distension, eructation, flatulence, dry mouth, gastroenteritis, viral gastroenteritis, increased lipase

Uncommon (0.1% to 1%): Acute pancreatitis, acute gallbladder disease

Type 2 Diabetes Mellitus:

Very common (10% or more): Nausea (up to 28.4%), diarrhea (up to 17.1%), vomiting (up to 10.9%)

Common (1% to 10%): Constipation, dyspepsia, abdominal pain, gastritis, flatulence, abdominal discomfort, toothache, elevated lipase, elevated amylase

Rare (less than 0.1%): Intestinal obstruction

Postmarketing reports: Acute hemorrhagic or necrotizing pancreatitis, including fatalities^[Ref]

Chronic Weight Management:

-The percentage of patients reporting nausea declined as treatment continued. Most gastrointestinal events were mild or moderate and did not lead to discontinuation.

-Acute pancreatitis occurred in 0.3% (9/3291) of liraglutide-treated patients and 0.1% (1/1843) of placebo patients in clinical trials. Three additional cases occurred in liraglutide-treated patients, 2 in patients who prematurely withdrew from the trial and 1 during an off-treatment follow-up period. In a pediatric clinical trial, 1 patient reported pancreatitis.

-Acute gallbladder disease was reported more frequently in liraglutide-treated patients (1.5% versus 0.5%) during clinical trials. Substantial or rapid weight loss can increase the risk of cholelithiasis, but even after accounting for the degree of weight loss, the incidence of acute gallbladder disease was greater in liraglutide-treated patients.

Type 2 Diabetes Mellitus

-Postmarketing reports of acute hemorrhagic or necrotizing pancreatitis, including fatalities have been reported. During clinical trials, 13 cases of pancreatitis were received among liraglutide treated patients, 9 acute and 4 chronic compared with 1 case in the comparator (glimepiride) group; some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse.

-Serum amylase and lipase were routinely measure in the LEADER trial; elevations of 3 times the upper limit of normal were reported in 1% and 7.5% of liraglutide treated patients compared with 0.7 % and 4.5% of placebo, respectively.

-In the LEADER trial, 3.1% of liraglutide treated patients reported an acute event of gallbladder disease such as cholelithiasis or cholecystitis.^[Ref]

Metabolic

Chronic Weight Management:

Very common (10% or more): Hypoglycemia (Type 2 diabetes [23%])

Common (1% to 10%): Decreased appetite; hypoglycemia (pediatric)

Type 2 Diabetes Mellitus:

Very common (10% or more): Hypoglycemia (when used in combination with a sulfonylurea)

Common (1% to 10%): Hypoglycemia, anorexia, decreased appetite

Uncommon (0.1% to 1%): Dehydration

Postmarketing reports: Dehydration resulting from nausea, vomiting and diarrhea^[Ref]

Chronic Weight Management:

In patients with type 2 diabetes mellitus receiving this drug for chronic weight management, severe hypoglycemia occurred in 0.7% (3/422) of liraglutide-treated patients, each of these patients was also receiving a sulfonylurea. Among all patients receiving this drug in combination with a sulfonylurea, symptomatic hypoglycemia occurred in 43.6% (48/110) of patients. The dose of sulfonylurea had been reduced by 50% at the start of the trial. Among patients not taking a sulfonylurea, symptomatic hypoglycemia occurred in 15.7% (49/312) of patients.

Pediatric Studies: Clinically significant hypoglycemia occurred in 1.6% of pediatric patients (placebo=0.8%).

Type 2 Diabetes Mellitus:

Major episodes of hypoglycemia have not been reported in clinical trials in which liraglutide was used as monotherapy, however, when used in combination with a sulfonylurea, hypoglycemia was very commonly reported.

Pediatric Patients: The risk of hypoglycemia was higher in pediatric patients regardless of insulin and/or metformin use.^[Ref]

Nervous system

Very common (10% or more): Headache (up to 13.6%)

Common (1% to 10%): Dizziness

Frequency not reported: dysgeusia^[Ref]

Respiratory

Type 2 Diabetes Mellitus:

Common (1% to 10%): Nasopharyngitis, bronchitis, upper respiratory infection^[Ref]

General

The most commonly reported adverse events for this drug when used for weight management have included nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase.

The most commonly reported adverse events for this drug when used to treat type 2 diabetes mellitus have included nausea, diarrhea, vomiting, constipation, dyspepsia, and decreased appetite.^[Ref]

Cardiovascular

Chronic Weight Management:

Very common (10% or more): Increases in mean resting heart rate

Common (1% to 10%): Hypotension

Uncommon (0.1% to 1%): Cardiac conduction disorder, tachycardia

Type 2 Diabetes Mellitus:

Common (1% to 10%): Increased heart rate^[Ref]

Chronic Weight Management:

Cardiac conduction disorders were reported as first degree atrioventricular block, right bundle branch block, or left bundle branch block.

Increases in mean resting heart rate of 2 to 3 beats per minute (bpm) were observed in clinical trials. Increases of 10 and 20 bpm at 2 consecutive visits were 34% and 5% in liraglutide-treated patients versus 19% and 2% in the placebo group, respectively. Resting heart rate exceeding 100 bpm was recorded for 6% of liraglutide-treated patients versus 4% of placebo patients. Tachycardia was reported in 0.6% of liraglutide-treated patients compared with 0.1% of placebo patients. Monitoring heart rate over 24-hours found that liraglutide treatment was associated with a 4 to 9 bpm higher heart rate than placebo. The clinical significance of this is unknown.

Pediatric Clinical Trials: Mean increase in resting heart rate of 3 to 7 bpm were observed.^[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection^[Ref]

Local

The most common injection site reactions were erythema, pruritus, and rash at the injection site.^[Ref]

Common (1% to 10%): Injection site erythema, injection site reaction^[Ref]

Immunologic

Frequency not reported: Development of anti-liraglutide antibodies^[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Urticaria

Postmarketing reports: Serious hypersensitivity reactions (e.g. anaphylactic reactions and angioedema), allergic reactions (rash and pruritus)^[Ref]

Renal

While this drug has not been found to be directly nephrotoxic in animal studies or clinical trials, postmarketing reports of acute renal failure and worsening of chronic renal failure sometimes requiring dialysis have been received. A majority of reports occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration.^[Ref]

Type 2 Diabetes Mellitus:

Uncommon (0.1% to 1%): Renal impairment, acute renal failure

Postmarketing reports: Acute renal failure and worsening of chronic renal failure, sometimes requiring dialysis, increased serum creatinine^[Ref]

Dermatologic

Common (1% to 10%): Rash

Uncommon (0.1% to 1%): Urticaria, pruritus^[Ref]

Endocrine

Common (1% to 10%): Increased blood calcitonin levels

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

Other

Common (1% to 10%): Fatigue

Uncommon (0.1% to 1%): Asthenia, malaise^[Ref]

Chronic Weight Management:

Fatigue and asthenia were most commonly reported within the first 12 weeks and were often co-reported with gastrointestinal events.^[Ref]

Psychiatric

Chronic Weight Management:

In adult clinical trials, 0.3% (9/3384) of patients receiving liraglutide reported suicidal ideation (placebo=0.1% [2/1941]) and 1 attempted suicide. In pediatric clinical trials, , 1 (0.8%) treated patient died by suicide; there was insufficient information to establish a causal relationship.^[Ref]

Chronic Weight Management:

Common (1% to 10%): Insomnia, anxiety

Uncommon (0.1% to 1%): Suicidal ideation

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

Hepatic

Chronic Weight Management:

Uncommon (0.1% to 1%): ALT increased

Frequency not reported: AST increased

Type 2 Diabetes Mellitus:

Postmarketing reports: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, hepatitis^[Ref]

Oncologic

Chronic Weight Management:

Breast Cancer: During clinical trials, 0.6% (4/2379) of liraglutide-treated patients were diagnosed with breast cancer compared with 0.2% (3/1300) of placebo patients. There were too few cases to determine if these were related to drug treatment and insufficient data to determine whether this drug had an effect on preexisting breast neoplasia.

Papillary Thyroid Cancer: During clinical trials, 0.2% (7/3291) of the liraglutide-treated patients were diagnosed with papillary thyroid carcinoma compared with no cases in 1843 placebo patients.

Colorectal Neoplasms: During clinical trials, 0.5% (17/3291) of the liraglutide-treated patients had benign colorectal neoplasms compared with 0.2% (4/1843) of placebo patients. Malignant colorectal carcinoma was diagnosed in 2 liraglutide-treated patients.

Type 2 Diabetes Mellitus:

In clinical trials, 6 cases of thyroid C-cell hyperplasia were reported among liraglutide-treated patients and 2 cases in the comparator-treated group (1.3 vs 1 case per 1000 patient-years). Medullary thyroid carcinoma was diagnosed in 1 patient in the comparator group who had pretreatment serum calcitonin concentrations greater than 1000 ng/L suggesting preexisting disease. The study required protocol-specified serum calcitonin measurements. All cases of thyroid C-cell hyperplasia were diagnosed after thyroidectomy which was done due to abnormal calcitonin levels. Of the 6 patients with thyroid C-cell hyperplasia, 5 had elevated calcitonin concentrations at baseline and throughout the trial. One patient in both the liraglutide-treated group and the comparator group developed elevated calcitonin concentrations while on treatment.^[Ref]

Chronic Weight Management:

Uncommon (0.1% to 1%): Benign colorectal neoplasms, papillary thyroid cancer, breast cancer, malignant colorectal carcinoma

Type 2 Diabetes Mellitus:

Uncommon (0.1% to 1%): Thyroid neoplasms

Frequency not reported: Thyroid C-cell hyperplasia

Postmarketing reports: Medullary Thyroid Cancer^[Ref]