Adlyxin

Name: Adlyxin

What is the most important information I should know about lixisenatide?

Stop using this medicine and call your doctor at once if you have nausea and vomiting with severe pain in your upper stomach spreading to your back.

What should I discuss with my healthcare provider before using lixisenatide?

You should not use lixisenatide if you are allergic to it.

To make sure lixisenatide is safe for you, tell your doctor if you have:

  • a history of pancreatitis or gall stones;

  • problems with digestion;

  • kidney disease;

  • a history of alcoholism; or

  • diabetic ketoacidosis (call your doctor for treatment with insulin).

Follow your doctor's instructions about using lixisenatide if you are pregnant or breast-feeding a baby. Blood sugar control is very important during pregnancy, and your dose needs may be different during each trimester of pregnancy. Your dose needs may also be different while you are breast-feeding.

Lixisenatide can make birth control pills less effective. Ask your doctor about using a nonhormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy.

Lixisenatide is not approved for use by anyone younger than 18 years old.

What should I avoid while using lixisenatide?

Lixisenatide can slow your digestion, and it may take longer for your body to absorb any medicines you take by mouth.

  • If you also take acetaminophen (Tylenol), take it at least 1 hour before you use lixisenatide.

  • If you also take any type of antibiotic, take it at least 1 hour before you use lixisenatide.

  • If you also take a birth control pill, take it at least 1 hour before or 11 hours after you use lixisenatide.

Commonly used brand name(s)

In the U.S.

  • Adlyxin

Available Dosage Forms:

  • Solution

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Glucagon-Like Peptide-1 Receptor Agonist

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about Adlyxin, please talk with the doctor, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Adlyxin. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Adlyxin.

Review Date: October 4, 2017

Adlyxin Dosage and Administration

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.

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)

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 [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.

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.

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.

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)].

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)].

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)].

Macrovascular Outcomes

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

Adverse Reactions

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

  • Anaphylaxis and Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
  • Pancreatitis [see Warnings and Precautions (5.2)]
  • Hypoglycemia with Concomitant Use of Sulfonylurea or Basal Insulin [see Warnings and Precautions (5.4)]
  • Renal Failure [see Warnings and Precautions (5.5)]
  • Immunogenicity [see Warnings and Precautions (5.6)]

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)].

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. [see Warnings and Precautions (5.6)]

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.

Adlyxin Overview

Adlyxin is a brand name medication included in a group of medications called Other blood glucose lowering drugs, excl. insulins. For more information about Adlyxin see its generic Lixisenatide

Adverse Effects

>10%

Nausea (25%)

Hypoglycemia

  • Coadministered with basal insulin +/- sulfonylurea (47.2%)
  • Coadministered with basal insulin +/- metformin (28.3%)
  • Coadministered with insulin glargine and metformin +/- thiazolidinedione (22%)
  • Coadministered with sulfonylurea +/- metformin (14.5%)

1-10%

Vomiting (10%)

Headache (9%)

Diarrhea (8%)

Dizziness (7%)

Injection site reactions (4%)

Dyspepsia (3.2%)

Constipation (2.8%)

Attenuated glycemic response with high antibodies (ie, >100 nmol/L) (2.4%)

Abdominal distension (2.2%)

Upper abdominal pain (2.2%)

Abdominal pain (2%)

<1%

Anaphylaxis (0.1%)

Acute pancreatitis

Lixisenatide Breastfeeding Warnings

Use is not recommended Excreted into human milk: Unknown Excreted into animal milk: Yes

In lactating rats, milk transfer of this drug and its metabolites was low (9.4%) and levels of unchanged drug in the gastric contents of weaning offspring was negligible (0.01%). There is no information on its presence in human milk, the effects on the breastfed infant, or the effects on milk production.

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