ADLYXIN SIDE EFFECTS

SIDE EFFECTS

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

• Anaphylaxis and Serious Hypersensitivity Reactions.
• Pancreatitis.
• Hypoglycemia with Concomitant Use of Sulfonylurea or Basal Insulin.
• Renal Failure.
• Immunogenicity.

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 trials of another drug and may not reflect the rates observed in practice.

Pool Of Placebo-Controlled Trials

The data in Table 1 are derived from the placebo-controlled trials.

These data reflect exposure of 2869 patients to ADLYXIN and a mean duration of exposure to ADLYXIN of 21.7 weeks. Across the treatment arms, the mean age of patients was 56.1 years, 2.3% were 75 years or older and 48.2% were male. The population in these studies was 63.7% White, 2.6% Black or African American, 32.0% Asian; 18.9% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean HbA1c of 8.1%. At baseline, 11.2% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m²) in 95.3% of the pooled study populations.

Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of ADLYXIN in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on ADLYXIN than on placebo, and occurred in at least 5% of patients treated with ADLYXIN.

Table 1: Adverse Reactions Reported in ≥5% of ADLYXIN-Treated Patients with Type 2 Diabetes Mellitus and Occurring More Frequently Compared to Placebo

Gastrointestinal Adverse Reactions

In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving ADLYXIN than placebo (placebo 18.4%, ADLYXIN 39.7%). More patients receiving ADLYXIN (4.3%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.5%). Investigators graded the severity of gastrointestinal adverse reactions occurring on ADLYXIN as “mild” in 64.2% of cases, “moderate” in 32.3% of cases, or “severe” in 3.5% of cases. The majority of these adverse reactions occurred during the first 3 weeks after starting treatment.

In addition to the reactions in Table 1, the following adverse reactions were reported in >2% of patients and more frequently in ADLYXIN-treated patients than placebo (frequencies listed, respectively, as: placebo; ADLYXIN): dyspepsia (0.2%, 3.2%), constipation (1.8%, 2.8%), abdominal distension (0.9%, 2.2%), abdominal pain upper (0.9%, 2.2%), abdominal pain (1.5%, 2.0%).

Hypoglycemia

Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose <60 mg/dL or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose value was available.

Severe symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia in which the patient required the assistance of another person, associated with a plasma glucose level below 36 mg/dL or, associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose was available.

Table 2 summarizes the incidence of symptomatic hypoglycemia and severe hypoglycemia in seven placebo-controlled efficacy/safety studies.

Table 2: Incidence (%) of Symptomatic Hypoglycemia and Severe Hypoglycemia in Patients with Type 2 Diabetes Mellitus During the 24-week Main Treatment Period

Injection Site Reactions

Injections site reactions (e.g., pain, pruritus and erythema) were reported more frequently in ADLYXIN-treated patients (4%) than placebo treated patients (2 %).

Anaphylaxis And Hypersensitivity

In the ADLYXIN development program anaphylaxis cases were adjudicated. Anaphylaxis was defined as a skin or mucosal lesion of acute onset associated with at least 1 other organ system involvement. Symptoms such as hypotension, laryngeal edema or severe bronchospasm could be present but were not required for the case definition. More cases adjudicated as meeting the definition for anaphylaxis occurred in ADLYXIN-treated patients (incidence rate of 0.2% or 16 cases per 10,000 patient years) than placebo treated patient (incidence rate of 0.1% or 7 cases per 10,000 patient years).

Allergic reactions (such as anaphylactic reaction, angioedema and urticaria) adjudicated as possibly related to the study medication were observed more frequently in ADLYXIN-treated patients (0.4%) than placebo-treated patient (0.2%).

Immunogenicity

In the pool of 9 placebo-controlled studies, 70% of patients exposed to lixisenatide tested positive for anti-lixisenatide antibodies during the trials. In the subset of patients (2.4%) with the highest antibody concentrations (>100 nmol/L), an attenuated glycemic response was observed. A higher incidence of allergic reactions and injection site reactions occurred in antibody positive patients.

Anti-lixisenatide antibody characterization studies have demonstrated the potential for development of antibodies crossreactive with endogenous GLP-1 and glucagon, but their incidence has not been fully determined and the clinical significance of these antibodies is not currently known.

No information regarding the presence of neutralizing antibodies is currently available.

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 lixisenatide cannot be directly compared with the incidence of antibodies with other products.