ADLYXIN

ADLYXIN- lixisenatide
ADLYXIN- lixisenatide injection, solution
Sanofi-Aventis U.S. LLC

1 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 [see Warnings and Precautions (5.2)].
  • 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.

2 DOSAGE AND ADMINISTRATION

2.1 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.

2.2 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.

3 DOSAGE FORMS AND STRENGTHS

ADLYXIN is a clear solution for subcutaneous injection available as:

  • 50 mcg/mL in 3 mL solution in a green single-patient use prefilled pen (for 14 doses; 10 mcg/dose)
  • 100 mcg/mL in 3 mL solution in a burgundy single-patient use prefilled pen (for 14 doses; 20 mcg/dose)

4 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 [see Warnings and Precautions (5.1) and Adverse reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 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 [see Adverse Reactions (6.1)].

Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with ADLYXIN. ADLYXIN is contraindicated in patients with known hypersensitivity to lixisenatide [see Contraindications (4)]. If a hypersensitivity reaction occurs, the patient should discontinue ADLYXIN and promptly seek medical attention.

5.2 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.

After initiation of ADLYXIN, 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, promptly discontinue ADLYXIN and initiate appropriate management. If pancreatitis is confirmed, do not restart ADLYXIN. Consider antidiabetic therapies other than ADLYXIN in patients with a history of pancreatitis.

5.3 Never Share ADLYXIN Pen Between Patients

ADLYXIN pens should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.

5.4 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 [see Adverse Reactions (6.1) and Drug Interactions (7.2)].

5.5 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.

Monitor renal function when initiating or escalating doses of ADLYXIN in patients with renal impairment and in patients reporting severe gastrointestinal reactions. ADLYXIN is not recommended in patients with end stage renal disease [see Use in Specific Populations (8.6)].

5.6 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 [see Warnings and Precautions (5.1), Adverse Reactions (6.2)].

If there is worsening glycemic control or failure to achieve targeted glycemic control, significant injection site reactions or allergic reactions, alternative antidiabetic therapy should be considered [see Adverse Reactions (6.1)].

5.7 Macrovascular Outcomes

Clinical studies have not shown macrovascular risk reduction with ADLYXIN or any other antidiabetic drug [see Clinical Studies (14)].

6 ADVERSE REACTIONS

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

6.1 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 [see Clinical Studies (14)].

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
Adverse reaction Placebo(N=1639) ADLYXIN (N=2869)
*hypoglycemia is discussed separately
Nausea 6% 25%
Vomiting 2% 10%
Headache 6% 9%
Diarrhea 6% 8%
Dizziness 4% 7%

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
Background therapy Placebo ADLYXIN
*
12-week treatment duration
Monotherapy * N=122 N=239
Symptomatic (%) 2 2
Severe (%) 0 0
With Metformin N=432 N=946
Symptomatic (%) 1 3
Severe (%) 0 0
With Sulfonylurea +/- metformin N=377 N=656
Symptomatic (%) 11 15
Severe (%) 0 0.2
With Pioglitazone +/- metformin N=161 N=323
Symptomatic (%) 1 3
Severe (%) 0 0
With Basal insulin +/- metformin N=213 N=374
Symptomatic (%) 23 28
Severe (%) 0 1
With Basal insulin +/- sulfonylurea N=111 N=108
Symptomatic (%) 22 47
Severe (%) 0 0
With Insulin Glargine and metformin +/- thiazolidinedione N=223 N=223
Symptomatic (%) 14 22
Severe (%) 0 0.4

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%) [see Warnings and Precautions (5.1)].

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