SAXENDA SIDE EFFECTS

SIDE EFFECTS

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Risk of Thyroid C-Cell Tumors
• Acute Pancreatitis
• Acute Gallbladder Disease
• Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy
• Heart Rate Increase
• Renal Impairment
• Hypersensitivity Reactions
• Suicidal Behavior and Ideation

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Saxenda was evaluated for safety in 5 double-blind, placebo controlled trials that included 3384 patients with overweight (excess weight) or obesity treated with Saxenda for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), and 32 weeks (1 trial). All patients received study drug in addition to diet and exercise counseling. In these trials, patients received Saxenda for a mean treatment duration of 46 weeks (median, 56 weeks). Baseline characteristics included a mean age of 47 years, 71% women, 85% white, 39% with hypertension, 15% with type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m², and 9% with cardiovascular disease. In one of the 56-week trials, a subset of patients (with abnormal glucose measurements at randomization) were enrolled for a placebo-controlled 160-week period instead, followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients received Saxenda for a mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was initiated and increased weekly to reach the 3 mg dose.

In clinical trials, 9.8% of patients treated with Saxenda and 4.3% of patients treated with placebo prematurely discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (2.9% versus 0.2% for Saxenda and placebo, respectively), vomiting (1.7% versus less than 0.1%), and diarrhea (1.4% versus 0%).

Adverse reactions reported in greater than or equal to 2% of Saxenda-treated patients and more frequently than in placebo-treated patients are shown in Table 1.

Table 1. Adverse Reactions Reported in Greater Than or Equal to 2% of Saxenda-treated Patients and More Frequently than with Placebo*

Hypoglycemia

Patients with Type 2 Diabetes

In a clinical trial in patients with type 2 diabetes mellitus and overweight (excess weight) or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 Saxendatreated patients (all taking a sulfonylurea) and in none of the 212 placebo-treated patients. In this trial, among patients taking a sulfonylurea, hypoglycemia defined as a plasma glucose less than 54 mg/dL with or without symptoms occurred in 31 (28.2%) of 110 Saxenda-treated patients and 7 (12.7%) of 55 placebo-treated patients. Because Saxenda can lower blood glucose, the doses of sulfonylureas were reduced by 50% at the beginning of the trial per protocol. The frequency of hypoglycemia may be higher if the dose of sulfonylurea is not reduced. Among patients not taking a sulfonylurea, blood glucose less than 54 mg/dL with or without symptoms occurred in 22 (7.1%) of 312 Saxenda-treated patients and 7 (4.5%) of 157 placebo-treated patients.

In a Saxenda clinical trial in patients with overweight (excess weight) or obesity with type 2 diabetes mellitus treated with basal insulin and Saxenda in combination with a reduced-calorie diet and increased physical activity and up to 2 oral anti-diabetes medications, severe hypoglycemia was reported by 3 (1.5%) of 195 Saxenda-treated patients and 2 (1.0%) of 197 placebo-treated patients. No meaningful difference in hypoglycemia, defined as blood glucose less than 54 mg/dL with or without symptoms, was reported between groups.

Patients without Type 2 Diabetes

In Saxenda clinical trials involving patients without type 2 diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia, as patients were not provided with blood glucose meters or hypoglycemia diaries. Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 46 (1.6%) of 2962 Saxenda-treated patients and 19 (1.1%) of 1729 placebo-treated patients. Fasting plasma glucose values obtained at routine clinic visits less than 54 mg/dL, irrespective of hypoglycemic symptoms, were reported as “hypoglycemia” in 2 (0.1%) Saxenda-treated patients and 1 (0.1%) placebo-treated patients.

Gastrointestinal Adverse Reactions

In the clinical trials, approximately 68% of Saxenda-treated patients and 39% of placebo-treated patients reported gastrointestinal disorders; the most frequently reported was nausea (39% and 14% of patients treated with Saxenda and placebo, respectively). The percentage of patients reporting nausea declined as treatment continued. Other common adverse reactions that occurred at a higher incidence among Saxenda-treated patients included diarrhea, constipation, vomiting, dyspepsia, abdominal pain, dry mouth, gastritis, gastroesophageal reflux disease, flatulence, eructation and abdominal distension. Most episodes of gastrointestinal events were mild or moderate and did not lead to discontinuation of therapy (6.2% with Saxenda versus 0.8% with placebo discontinued treatment as a result of gastrointestinal adverse reactions). There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and renal impairment.

Asthenia, Fatigue, Malaise, Dysgeusia And Dizziness

Events of asthenia, fatigue, malaise, dysgeusia and dizziness were mainly reported within the first 12 weeks of treatment with Saxenda and were often co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea.

Immunogenicity

Patients treated with Saxenda may develop anti-liraglutide antibodies. Anti-liraglutide antibodies were detected in 42 (2.8%) of 1505 Saxenda-treated patients with a post-baseline assessment. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1505 Saxenda-treated patients. Presence of antibodies may be associated with a higher incidence of injection site reactions and reports of low blood glucose. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to Saxenda cannot be directly compared with the incidence of antibodies of other products.

Allergic Reactions

Urticaria was reported in 0.7% of Saxenda-treated patients and 0.5% of placebo-treated patients. Anaphylactic reactions, asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal swelling, facial swelling, angioedema, pharyngeal edema, type IV hypersensitivity reactions have been reported in patients treated with liraglutide in clinical trials. Cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnea, and edema have been reported with marketed use of liraglutide. Anaphylactic reactions may potentially be life-threatening.

Injection Site Reactions

Injection site reactions were reported in approximately 13.9% of Saxenda-treated patients and 10.5% of placebo-treated patients. The most common reactions, each reported by 1% to 2.5% of Saxenda-treated patients and more commonly than by placebo-treated patients, included erythema, pruritus, and rash at the injection site. 0.6% of Saxenda-treated patients and 0.5% of placebo-treated patients discontinued treatment due to injection site reactions.

Breast Cancer

In Saxenda clinical trials, breast cancer confirmed by adjudication was reported in 17 (0.7%) of 2379 Saxendatreated women compared with 3 (0.2%) of 1300 placebo-treated women, including invasive cancer (13 Saxenda- and 2 placebo-treated women) and ductal carcinoma in situ (4 Saxenda- and 1 placebo-treated woman). The majority of cancers were estrogen- and progesterone-receptor positive. There were too few cases to determine whether these cases were related to Saxenda. In addition, there are insufficient data to determine whether Saxenda has an effect on pre-existing breast neoplasia.

Papillary Thyroid Cancer

In Saxenda clinical trials, papillary thyroid carcinoma confirmed by adjudication was reported in 8 (0.2%) of 3291 Saxenda-treated patients compared with no cases among 1843 placebo-treated patients. Four of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and 4 were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings identified prior to treatment.

Colorectal Neoplasms

In Saxenda clinical trials, benign colorectal neoplasms (mostly colon adenomas) confirmed by adjudication were reported in 20 (0.6%) of 3291 Saxenda-treated patients compared with 7 (0.4%) of 1843 placebo-treated patients. Six positively adjudicated cases of malignant colorectal neoplasms were reported in 5 Saxenda-treated patients (0.2%, mostly adenocarcinomas) and 1 in a placebo-treated patient (0.1%, neuroendocrine tumor of the rectum).

Cardiac Conduction Disorders

In Saxenda clinical trials, 11 (0.3%) of 3384 Saxenda-treated patients compared with none of the 1941 placebotreated patients had a cardiac conduction disorder, reported as first degree atrioventricular block, right bundle branch block, or left bundle branch block.

Hypotension

Adverse reactions related to hypotension (that is, reports of hypotension, orthostatic hypotension, circulatory collapse, and decreased blood pressure) were reported more frequently with Saxenda (1.1%) compared with placebo (0.5%) in Saxenda clinical trials. Systolic blood pressure decreases to less than 80 mmHg were observed in 4 (0.1%) Saxenda-treated patients compared with no placebo-treated patients. One of the Saxendatreated patients had hypotension associated with gastrointestinal adverse reactions and renal failure.

Laboratory Abnormalities

Liver Enzymes

Increases in alanine aminotransferase (ALT) greater than or equal to 10 times the upper limit of normal were observed in 5 (0.15%) Saxenda-treated patients (two of whom had ALT greater than 20 and 40 times the upper limit of normal) compared with 1 (0.05%) placebo-treated patient during the Saxenda clinical trials. Because clinical evaluation to exclude alternative causes of ALT and aspartate aminotransferase (AST) increases was not done in most cases, the relationship to Saxenda is uncertain. Some increases in ALT and AST were associated with other confounding factors (such as gallstones).

Serum Calcitonin

Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. More patients treated with Saxenda in the clinical trials were observed to have high calcitonin values during treatment, compared with placebo. The proportion of patients with calcitonin greater than or equal to 2 times the upper limit of normal at the end of the trial was 1.2% in Saxenda-treated patients and 0.6% in placebo-treated patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in 0.5% of Saxenda-treated patients and 0.2% of placebo-treated patients; among patients with pretreatment serum calcitonin less than 20 ng/L, none had calcitonin elevations to greater than 50 ng/L at the end of the trial.

Serum Lipase and Amylase

Serum lipase and amylase were routinely measured in the Saxenda clinical trials. Among Saxenda-treated patients, 2.1% had a lipase value at anytime during treatment of greater than or equal to 3 times the upper limit of normal compared with 1.0% of placebo-treated patients. 0.1% of Saxenda-treated patients had an amylase value at anytime in the trial of greater than or equal to 3 times the upper limit of normal versus 0.1% of placebotreated patients. The clinical significance of elevations in lipase or amylase with Saxenda is unknown in the absence of other signs and symptoms of pancreatitis.Postmarketing Experience

The following adverse reactions have been reported during post-approval use of liraglutide, the active ingredient of Saxenda. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Neoplasms

Medullary thyroid carcinoma

Gastrointestinal Disorders

Acute pancreatitis, hemorrhagic and necrotizing pancreatitis, sometimes resulting in death

Metabolism And Nutrition Disorders

Dehydration resulting from nausea, vomiting and diarrhea

Renal And Urinary Disorders

Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis

General Disorders And Administration Site Conditions

Allergic reactions: rash and pruritus

Immune System Disorders

Angioedema and anaphylactic reactions

Hepatobiliary Disorders

Elevations of liver enzymes, hyperbilirubinemia, cholestasis and hepatitis.

SRC: NLM .