Adlyxin (lixisenatide) Side Effects, Warnings, and Drug Interactions

Adlyxin (lixisenatide) is an incretin mimetic that reduces the level of sugar (glucose) in the blood. It is used along with diet and exercise to treat type 2 diabetes. Adlyxin should not be used for the treatment of diabetic ketoacidosis or type 1 diabetes.

Common side effects of Adlyxin include

• nausea,
• vomiting, 
• diarrhea, 
• headache, 
• dizziness, 
• low blood sugar (hypoglycemia - when combined with insulin or sulfonyrea), 
• indigestion, 
• constipation, 
• abdominal distension, 
• abdominal pain, and 
• injection site reactions (pain, redness, itching).

Serious side effects of Adlyxin include 

• severe allergic reactions (anaphylaxis, hives), 
• pancreatitis, 
• acute kidney failure, and 
• antibodies to Adlyxin.

Drugs that may cause harmful interactions with or affect the functioning of Adlyxin include other drugs taken by mouth at the same time.  Other drugs that may interact with Adlyxin are insulin or drugs that stimulate release of insulin. 

There are no adequate studies of Adlyxin in pregnant women. Most experts agree that insulin is the drug of choice in pregnant women with diabetes. 

There are no adequate studies of Adlyxin in nursing mothers, and it is not known whether this drug is excreted in human breast milk. Consult your doctor before breastfeeding.

Common side effects of include:

• Nausea
• Vomiting
• Diarrhea
• Headache
• Diarrhea
• Dizziness
• Hypoglycemia (when combined with insulin or sulfonyrea)

Other possible side effects of include:

• Indigestion (dyspepsia)
• Constipation
• Upper abdominal pain
• Abdominal distension
• Abdominal pain
• Injection site reactions (pain, redness, itching)

Possible serious side effects of include:

• Severe allergic reactions (anaphylaxis, angioedema [hives])
• Pancreatitis
• Acute kidney failure
• Antibodies to lixisenatide

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  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 cross-reactive 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.

Delayed Gastric Emptying Effects on Oral Medications

Adlyxin delays gastric emptying which may reduce the rate of absorption of orally administered medications. Use caution when coadministering oral medications that have a narrow therapeutic ratio or that require careful clinical monitoring. These medications should be adequately monitored when concomitantly administered with Adlyxin. If such medications are to be administered with food, patients should be advised to take them with a meal or snack when Adlyxin is not administered.

Oral medications that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, or medications for which a delay in effect is undesirable, such as acetaminophen, should be administered at least 1 hour before Adlyxin injection.

Patients taking oral contraceptives should be advised to take them at least 1 hour before Adlyxin administration or at least 11 hours after the dose of Adlyxin.

Dosage Adjustment of Sulfonylurea or Basal Insulin with Concomitant Use with Adlyxin

When Adlyxin is added to a sulfonylurea or basal insulin, there is a potential risk of hypoglycemia. A reduction of the concomitantly administered sulfonylurea or basal insulin may be necessary.