ADLYXIN (lixisenatide)

ADLYXIN (lixisenatide) injection

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ADLYXIN (lixisenatide)

ADLYXIN contains lixisenatide ADLYXIN contains lixisenatide, which acts as a GLP-1 receptor agonist. Lixisenatide is a peptide containing 44 amino acids, which is amidated at the C-terminal amino acid (position 44). The order of the amino acids is given in the figure below. Its molecular weight is 4858.5 and its molecular formula is C215H347N61O65S.

ADLYXIN injection is a sterile, clear, colorless aqueous solution for subcutaneous administration. ADLYXIN is supplied in two single-patient use prefilled pens. Each green prefilled pen contains 3 mL solution and each mL contains 50 mcg lixisenatide. Each burgundy prefilled pen contains 3 mL solution, and each mL contains 100 mcg lixisenatide. Inactive ingredients for both prefilled pens are glycerol 85% (54 mg), sodium acetate trihydrate (10.5 mg), methionine (9.0 mg), metacresol (8.1 mg), and water for injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.

Indications and usage

ADLYXIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use:

  • ADLYXIN has not been studied in patients with chronic pancreatitis or a history of unexplained pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis
  • ADLYXIN is not a substitute for insulin. ADLYXIN is not indicated for use in patients with type 1 diabetes mellitus or for treatment of diabetic ketoacidosis.
  • The concurrent use of ADLYXIN with short acting insulin has not been studied and is not recommended.
  • ADLYXIN has not been studied in patients with gastroparesis and is not recommended in patients with gastroparesis.

Dosing Instructions

  • The starting dose of ADLYXIN is 10 mcg subcutaneously once daily for 14 days.
  • Increase the dose to the maintenance dose of 20 mcg once daily starting on Day 15.

Important Administration Instructions

  • Instruct patients and caregivers on the preparation and use of the pen prior to first use of ADLYXIN. Training should include a practice injection.
  • Inspect ADLYXIN visually before use. It should appear clear and colorless. Do not use ADLYXIN if particulate matter or coloration is seen.
  • Administer ADLYXIN by subcutaneous injection in the abdomen, thigh or upper arm once daily.
  • Rotate injections sites with each dose. Do not use the same site for each injection.
  • Instruct patients to administer an injection of ADLYXIN within one hour before the first meal of the day preferably the same meal each day. If a dose is missed, administer ADLYXIN within one hour prior to the next meal.
  • Instruct patients to protect the pen from light by keeping it in its original packaging and to discard pen 14 days after its first use.

Mechanism of Action

Lixisenatide is a GLP-1 receptor agonist. Lixisenatide increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying.

Pharmacodynamics

In a clinical pharmacology study in adults with type 2 diabetes mellitus, ADLYXIN reduced fasting plasma glucose and postprandial blood glucose AUC0-300min compared to placebo (-33.8 mg/dL and -387 mg*h/dL, respectively) following a standardized test meal. The effect on postprandial blood glucose AUC was most notable with the first meal, and the effect was attenuated with later meals in the day.

Glucagon secretion: Treatment with ADLYXIN 20 mcg once daily reduced postprandial glucagon levels (AUC0-300min) compared to placebo by -15.6 h*pmol/L after a standardized test meal in patients with type 2 diabetes.

Cardiac electrophysiology (Qtc): At a dose 1.5 times the recommended dose, ADLYXIN does not prolong the QTc interval to any clinically relevant extent.

Heart Rate: No increase in mean heart rate was seen in phase 3 placebo-controlled studies.

Pharmacokinetics

Absorption: Following subcutaneous administration in patients with type 2 diabetes, the median tmax is 1 to 3.5 hours. There are no clinically relevant differences in the rate of absorption when lixisenatide is administered subcutaneously in the abdomen, thigh, or arm.

Distribution: The apparent volume of distribution after subcutaneous administration of lixisenatide (Vz/F) is approximately 100 L.

Metabolism and Elimination: Lixisenatide is presumed to be eliminated through glomerular filtration, and proteolytic degradation.

After multiple dose administration in patients with type 2 diabetes, mean terminal half-life was approximately 3 hours and the mean apparent clearance (CL/F) about 35 L/h.

Contraindications

ADLYXIN is contraindicated in patients with known hypersensitivity to lixisenatide or to any component of ADLYXIN. Hypersensitivity reactions including anaphylaxis have occurred with ADLYXIN

Use in specific populations

Pregnancy: The limited available data with lixisenatide in pregnant women are not sufficient to inform a drug-associated risk of major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. Based on animal reproduction studies, there may be risks to the fetus from exposure to lixisenatide during pregnancy. ADLYXIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: There is no information regarding the presence of ADLYXIN in human milk, the effects on the breastfed infant, or the effects on milk production. However, lixisenatide is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lixisenatide and any potential adverse effects on the breastfed infant from lixisenatide or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness of ADLYXIN have not been established in pediatric patients below 18 years of age.

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Geriatric use: In Phase 2 and 3controlled clinical studies of ADLYXIN, a total of 1837 (25%) of the patients exposed to the study medication were 65 years of age and over and 288 (4%) were 75 years of age and over. No overall differences were observed in safety or effectiveness between these patients and younger patients, but individual sensitivity cannot be ruled out.

Renal Impairment: In patients with mild renal impairment (eGFR: 60-89 mL/min/1.73 m2) no dose adjustment is required but close monitoring for ADLYXIN related adverse reactions and for changes in renal function is recommended because a higher incidence of hypoglycemia, nausea and vomiting were observed in these patients.

Patients with Gastroparesis: ADLYXIN slows gastric emptying. Patients with preexisting gastroparesis were excluded from clinical trials of ADLYXIN. ADLYXIN should not be initiated in patients with severe gastroparesis.

Adverse reactions

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

Warnings and precautions

Anaphylaxis and Serious Hypersensitivity Reactions: In clinical trials of ADLYXIN, there have been cases of anaphylaxis determined to be related to ADLYXIN (frequency of 0.1% or 10 cases per 10,000 patient-years). Other serious hypersensitivity reactions including angioedema also occurred.

Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been reported postmarketing in patients treated with GLP-1 receptor agonists. In clinical trials of ADLYXIN, there were 21 cases of pancreatitis among ADLYXIN-treated patients and 14 cases in comparator-treated patients (incidence rate of 21 vs. 17 per 10,000 patient-years). ADLYXIN cases were reported as acute pancreatitis (n=3), pancreatitis (n=12), chronic pancreatitis (n=5), and edematous pancreatitis (n=1). Some patients had risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse.

Never Share ADLYXIN Pen Between Patients: ADLYXIN pens should never be shared between patients, even if the needle is changed. Pensharing poses a risk for transmission of blood-borne pathogens.

Hypoglycemia with Concomitant Use of Sulfonylurea or Basal Insulin: Patients receiving ADLYXIN in combination with basal insulin or a sulfonylurea have an increased risk of hypoglycemia. In patients receiving sulfonylurea with or without metformin, 14.5% patients on ADLYXIN reported symptomatic hypoglycemia compared to 10.6% for those on placebo.

In patients receiving basal insulin with or without metformin, 28.3% patients on ADLYXIN reported symptomatic hypoglycemia compared to 23.0% for those on placebo. In patients receiving basal insulin with sulfonylurea, 47.2% patients on ADLYXIN reported symptomatic hypoglycemia compared to 21.6% for those on placebo. Reduction in the dose of sulfonylurea or basal insulin may be necessary.

Acute Kidney Injury: Acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis has been reported postmarketing in patients treated with GLP-1 receptor agonists. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration.

Immunogenicity: Patients may develop antibodies to lixisenatide following treatment with ADLYXIN. A pooled analysis of studies of lixisenatide-treated patients showed that 70% were antibody positive at Week 24. 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.

Drug interactions

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

Overdosage

During clinical studies, doses up to 30 mcg of lixisenatide twice daily (3 times the daily recommended dose) were administered to type 2 diabetic patients in a 13-week study. The 30 mcg dose of lixisenatide is not an approved dose. An increased incidence of gastrointestinal disorders was observed.

In case of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

Storage and Handling

Prior to first use, ADLYXIN should be stored in a refrigerator, 36°–46°F (2°C–8°C). Do not freeze. Keep the prefilled pen in the original package to protect it from light.

After first use, store below 86°F (30°C). Replace the pen cap after each use to protect from light. Discard pen 14 days after first use.

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