Applies to insulin degludec / liraglutide: subcutaneous solution.

Serious side effects

Along with its needed effects, insulin degludec/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 insulin degludec / liraglutide:

Incidence not known

• Anxiety
• bloating
• bloody urine
• blurred vision
• chest tightness
• chills
• cold, clammy skin
• cold sweats
• confusion
• constipation
• cool, pale skin
• cough
• dark urine
• decreased frequency or amount of urine
• depression
• difficulty swallowing
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• fast heartbeat
• fast, weak pulse
• fever
• flushed, dry skin
• fruit-like breath odor
• headache
• hives, itching, skin rash
• hoarseness when speaking
• increased hunger
• increased thirst
• increased urination
• indigestion
• irregular heartbeat
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
• lightheadedness
• loss of appetite
• loss of consciousness
• lower back or side pain
• lumps in the neck
• muscle pain or cramps
• nausea
• nightmares
• noisy, rattling breathing
• numbness or tingling in the hands, feet, or lips
• 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
• seizures
• slurred speech
• sweating
• trouble breathing or swallowing
• unexplained weight loss
• unusual tiredness or weakness
• vomiting
• weight gain
• yellow eyes or skin

Other side effects

Some side effects of insulin degludec / 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

• Body aches or pain
• diarrhea
• ear congestion
• loss of voice
• muscle aches
• sneezing
• sore throat
• stuffy or runny nose

Incidence not known

• 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 insulin degludec / liraglutide: subcutaneous solution.

General

The most frequently reported adverse reactions included hypoglycemia and gastrointestinal adverse reactions, such as nausea diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, gastroesophageal reflux disease, and abdominal distention.^[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, gastroesophageal reflux disease, abdominal distension, decreased appetite, increased lipase

Uncommon (0.1% to 1%): Pancreatitis, including necrotizing pancreatitis

Liraglutide:

Postmarketing reports: Acute pancreatitis, hemorrhagic and necrotizing pancreatitis (sometimes resulting in death)^[Ref]

Gastrointestinal adverse events occur more frequently at the beginning of therapy and generally diminish within a few days or weeks of continued use. Nausea was transient for most patients.^[Ref]

Metabolic

Very common (10% or more): Hypoglycemia

Common (1% to 10%): Decreased appetite

Uncommon (0.1% to 1%): Dehydration

Frequency not reported: Weight gain^[Ref]

Weight gain may occur and has been attributed to the anabolic effects of insulin. After 26 weeks of insulin degludec / liraglutide 100/3.6, a mean increase of 2 kg occurred.^[Ref]

Endocrine

Liraglutide:

Frequency not reported: Increased blood calcitonin, goitre^[Ref]

Hypersensitivity

Hypersensitivity reactions including urticaria, pruritus, and/or swelling of the face have been reported following administration of this drug. Few case of anaphylactic reaction with additional symptoms such as hypotension, palpitations, dyspnea, and edema has been reported postmarketing.^[Ref]

Uncommon (0.1% to 1%): Urticaria, rash, pruritus, face swelling

Rare (less than 0.1%): Hypersensitivity manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching

Postmarketing reports: Anaphylactic reaction

Liraglutide:

Postmarketing reports: Angioedema, anaphylactic reactions, rash, pruritus^[Ref]

Local

Common (1% to 10%): Injection site reaction

Frequency not reported: Lipodystrophy^[Ref]

Injection site reactions included injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discolorations, pruritus, warmth, and injection site mass. These reactions are generally mild and transient, disappearing with continued treatment. Lipodystrophy may occur at the injection site. Rotation of injection site may help reduce the risk of developing these reactions.^[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Increased heart rate

Frequency not reported: Peripheral edema^[Ref]

Mean increase in heart rate of 2 to 3 beats per minute has been observed; long-term clinical effects are unknown.^[Ref]

Dermatologic

Uncommon (0.1% to 1%): Rash, pruritus, urticaria

Insulin degludec:

Postmarketing period: Localized cutaneous amyloidosis^[Ref]

Immunologic

Rare (less than 0.1%): Antibody formation^[Ref]

Ocular

Insulin:

Frequency not reported: Temporary worsening of diabetic retinopathy, transitory reversible ophthalmologic refraction disorder^[Ref]

Temporary worsening of diabetic retinopathy may occur with abrupt improvement in glycemic control; however, long-term improvement may decrease the risk of progression.^[Ref]

Oncologic

Pooled analysis of liraglutide clinical trials reveals the incidence rate for malignant neoplasms at 10.9, 6.3, and 7.2 per 1000 patient-years for liraglutide, placebo, and active comparator treated patients, respectively. Incidence rates were based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label studies. Seven cases of papillary thyroid carcinoma were in liraglutide-treated patients and 1 case in a comparator-treated patient. Most were less than 1 cm in greatest diameter and diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Seven malignant neoplasm events were reported beyond 1-year exposure to study medication: 4 colon, 1 prostate and 1 nasopharyngeal in liraglutide-treated patients with 1 (colon) reported in a comparator-treated patient.^[Ref]

Liraglutide:

Frequency not reported: Thyroid neoplasm, malignant neoplasms

Postmarketing: Medullary thyroid carcinoma^[Ref]

Renal

Liraglutide

Frequency not reported: Renal impairment, acute renal failure

Postmarketing reports: Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis^[Ref]

Hepatic

Liraglutide:

Common (1% to 10%): Elevated serum bilirubin, cholelithiasis

Uncommon (0.1% to 1%): Cholecystitis

Postmarketing: Cholestasis, hepatitis, elevated liver enzymes, hyperbilirubinemia^[Ref]

Cholelithiasis and cholecystitis have been reported in liraglutide trials. In doses of up to 3 mg, cholelithiasis and cholecystitis were reported in 1.5% (vs 0.5%) and 0.6% (vs 0.2%), respectively (compared to placebo). The majority of patients with cholelithiasis and cholecystitis required cholecystectomy. In the cardiovascular outcomes trial, liraglutide-treated patients reported an acute event of gallbladder disease such as cholelithiasis or cholecystitis more frequently than those receiving placebo (3.6% vs 1.9%). Most of these events required hospitalization or cholecystectomy.^[Ref]

Nervous system

Common (1% to 10%): Headache

Frequency not reported: Acute painful peripheral neuropathy^[Ref]

Acute painful peripheral neuropathy may occur with abrupt improvement in glycemic control; however, long-term improvement may decrease the risk of progression.^[Ref]

Respiratory

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