WARNING: RISK OF THYROID C-CELL TUMORS

Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza^® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza^® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

• Victoza^® (liraglutide [rDNA origin] injection) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

• Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza^® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza^® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise
• Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been observed in patients treated with Victoza^®. Victoza^® has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Victoza^®. Other antidiabetic therapies should be considered in patients with a history of pancreatitis
• Victoza^® is not a substitute for insulin. Victoza^® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings
• Victoza^® has not been studied in combination with prandial insulin

WARNING: RISK OF THYROID C-CELL TUMORS

Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza^® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza^® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

• Do not use in patients with a prior serious hypersensitivity reaction to Victoza^® or to any of the product components

• Pancreatitis: Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been observed in patients treated with Victoza^®. After initiation of Victoza^®, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza^® should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Victoza^® should not be restarted. Consider antidiabetic therapies other than Victoza^® in patients with a history of pancreatitis
• Use with Medications Known to Cause Hypoglycemia: When Victoza^® is used with an insulin secretagogue (e.g. a sulfonylurea) or insulin serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia
• Renal Impairment: Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration, which may sometimes require hemodialysis. Use caution when initiating or escalating doses of Victoza^® in patients with renal impairment
• Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g. anaphylaxis and angioedema) have been reported during postmarketing use of Victoza^®. If symptoms of hypersensitivity reactions occur, patients must stop taking Victoza^® and seek medical advice promptly
• Macrovascular Outcomes: There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza^® or any other antidiabetic drug

• The most common adverse reactions, reported in ≥5% of patients treated with Victoza^® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, dyspepsia, constipation and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza^®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials

• Victoza^® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients

• There is limited data in patients with renal or hepatic impairment

In a 52-week monotherapy study (N=745) with a 52-week extension, the adverse reactions reported in ≥5% of patients treated with Victoza^® 1.8 mg, Victoza^® 1.2 mg, or glimepiride were constipation (11.8%, 8.4%, and 4.8%), diarrhea (19.5%, 17.5%, and 9.3%), flatulence (5.3%, 1.6%, and 2.0%), nausea (30.5%, 28.7%, and 8.5%), vomiting (10.2%, 13.1%, and 4.0%), fatigue (5.3%, 3.2%, and 3.6%), bronchitis (3.7%, 6.0%, and 4.4%), influenza (11.0%, 9.2%, and 8.5%), nasopharyngitis (6.5%, 9.2%, and 7.3%), sinusitis (7.3%, 8.4%, and 7.3%), upper respiratory tract infection (13.4%, 14.3%, and 8.9%), urinary tract infection (6.1%, 10.4%, and 5.2%), arthralgia (2.4%, 4.4%, and 6.0%), back pain (7.3%, 7.2%, and 6.9%), pain in extremity (6.1%, 3.6%, and 3.2%), dizziness (7.7%, 5.2%, and 5.2%), headache (7.3%, 11.2%, and 9.3%), depression (5.7%, 3.2%, and 2.0%), cough (5.7%, 2.0%, and 4.4%), and hypertension (4.5%, 5.6%, and 6.9%).

In a 52-week monotherapy study (N=745), the adverse reactions reported in ≥5% of patients treated with Victoza^® or ≥5% of patients treated with glimepiride were nausea (28.4% vs 8.5%), diarrhea (17.1% vs 8.9%), vomiting (10.9% vs 3.6%), constipation (9.9% vs 4.8%), upper respiratory tract infection (9.5% vs 5.6%), headache (9.1% vs 9.3%), influenza (7.4% vs 3.6%), urinary tract infection (6.0% vs 4.0%), dizziness (5.8% vs 5.2%), sinusitis (5.6% vs 6.0%), nasopharyngitis (5.2% vs 5.2%), back pain (5.0% vs 4.4%), and hypertension (3.0% vs 6.0%).

Adverse reactions reported in ≥5% of patients and occurring more frequently with Victoza^® compared to exenatide were diarrhea (12.3% vs 12.1%), dyspepsia (8.9% vs 4.7%), and constipation (5.1% vs 2.6%). Rates of gastrointestinal adverse reactions, including nausea, were similar.

In a 26-week study (N=323) of Victoza^® 1.8 mg and intensification with insulin detemir, the only adverse reaction reported in ≥5% of patients treated with Victoza^® 1.8 mg + metformin + insulin detemir and greater than in patients treated with Victoza^® 1.8 mg + metformin alone was diarrhea (11.7% vs 6.9%, respectively).

In a 26-week open-label study (N=665) comparing Victoza^® 1.2 mg, Victoza^® 1.8 mg, and sitagliptin 100 mg, all in combination with metformin, the adverse reactions reported in ≥5% of patients treated with Victoza^® were nausea (23.9% vs 4.6%), headache (10.3% vs 10.0%), diarrhea (9.3% vs 4.6%), and vomiting (8.7% vs 4.1%). 

In a 26-week open-label study (N=665) with a 26-week extension (n=497), the adverse reactions reported in ≥5% of patients treated with metformin in combination with Victoza^® 1.2 mg or Victoza^® 1.8 mg or sitagliptin 100 mg were nausea (21.7%, 27.5%, and 5.5%), vomiting (8.1%, 10.6%, and 5.0%), diarrhea (9.0%, 12.4%, and 6.4%), and headache (9.5%, 13.3%, and 12.3%). 

Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, or persistent hoarseness).

Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation.

Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza^®, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

After initiation of Victoza^®, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting).

In the eight clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 11 Victoza^®-treated patients and in two exenatide-treated patients. Of these 11 Victoza^®-treated patients, six patients were concomitantly using metformin and a sulfonylurea, one was concomitantly using a sulfonylurea, two were concomitantly using metformin and two were using Victoza^® as monotherapy. In the 26-week open-label trial comparing Victoza^® to sitagliptin, the incidence of hypoglycemic events was comparable among the treatment groups.

The incidence of withdrawal due to adverse events was 7.8% for Victoza^®-treated patients and 3.4% for comparator-treated patients in the 5 controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza^®-treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to withdrawal for Victoza^®-treated patients were nausea (2.8% vs 0% for comparator) and vomiting (1.5% vs 0.1% for comparator).

Victoza^® causes a delay in gastric emptying, and thereby has the potential to impact absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with Victoza^®.

Victoza^® slows gastric emptying. Victoza^® has not been studied in patients with pre-existing gastroparesis.

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