BYDUREON: Package Insert and Label Information

BYDUREON- exenatide injection, suspension, extended release
BYDUREON- exenatide
AstraZeneca Pharmaceuticals LP

WARNING: RISK OF THYROID C-CELL TUMORS

Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared to controls. It is unknown whether BYDUREON causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
BYDUREON is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of BYDUREON and inform them of symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for detection of MTC in patients treated with BYDUREON [see Contraindications (4) and Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14)].

Limitations of Use:

BYDUREON is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans [see Warnings and Precautions (5.1)].
BYDUREON is not a substitute for insulin. BYDUREON is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
The concurrent use of BYDUREON with prandial insulin has not been studied.
BYDUREON is an extended-release formulation of exenatide. BYDUREON should not be used with other products containing the active ingredient exenatide.
BYDUREON has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The recommended dose of BYDUREON is 2 mg subcutaneously once every 7 days (weekly). The dose can be administered at any time of day, with or without meals.

The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days before the new day of administration.

2.2 Missed Dose

If a dose is missed, administer the dose as soon as noticed, provided the next regularly scheduled dose is due at least 3 days later. Thereafter, patients can resume their usual dosing schedule of once every 7 days (weekly).

If a dose is missed and the next regularly scheduled dose is due 1 or 2 days later, do not administer the missed dose and instead resume BYDUREON with the next regularly scheduled dose.

2.3 Administration Instructions

There are two presentations of BYDUREON (i.e., a single dose tray and a single dose pen) [see How Supplied/Storage and Handling (16)]. The BYDUREON “Instructions for Use” for each presentation contains detailed instructions on the preparation and administration of BYDUREON [see Instructions for Use].
Each presentation of BYDUREON requires constitution prior to use to obtain a final concentration of 2 mg of exenatide per 0.65 mL of suspension.
BYDUREON is intended for patient self-administration. Prior to initiation, train patients on proper mixing and injection technique to ensure the product is adequately mixed and a full dose is delivered.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. The suspension should appear white to off-white and cloudy. (BYDUREON contains microspheres which appear as white to off-white particles). Do not use if foreign particulate matter is present or if discoloration is observed. Refer patients to the accompanying Instructions for Use for disposal information [see Instructions for Use].
Administer BYDUREON immediately after the dose is prepared as a subcutaneous injection in the abdomen, thigh, or upper arm region. Advise patients to use a different injection site each week when injecting in the same region.
When using BYDUREON with insulin, always administer BYDUREON and insulin as separate injections. Do not mix these medications together into a single injection. It is acceptable to inject BYDUREON and insulin in the same body region but the injections should not be adjacent to each other.
Do not administer BYDUREON intravenously or intramuscularly.
Refer patients to the accompanying Instructions for Use for complete administration instructions with illustrations [see Instructions for Use].

2.4 Initiating BYDUREON Therapy

Prior treatment with an immediate- or extended-release exenatide product is not required when initiating BYDUREON therapy. Discontinue an immediate- or extended-release exenatide product prior to initiation of BYDUREON.

Patients changing from immediate-release exenatide to BYDUREON may experience transient (approximately 2 to 4 weeks) elevations in blood glucose concentrations.

3 DOSAGE FORMS AND STRENGTHS

Extended-release for injectable suspension available as:

Single-dose tray which contains one single dose vial of 2 mg exenatide white to off-white powder, one vial connector, one prefilled diluent syringe, and two needles (one provided as a spare).
Single-dose pen which contains 2 mg of exenatide white to off-white powder, diluent, and includes one needle. Each carton contains one spare needle.

4 CONTRAINDICATIONS

BYDUREON is contraindicated in patients with:

A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
A prior serious hypersensitivity reaction to exenatide or to any of the product components. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with BYDUREON [see Warnings and Precautions (5.8)].
A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use [see Warnings and Precautions (5.9)].

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Thyroid C-cell Tumors

In both genders of rats, exenatide extended-release caused a dose-related and treatment-duration–dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures compared to controls [see Nonclinical Toxicology (13.1)]. A statistically significant increase in malignant thyroid C-cell carcinomas was observed in female rats receiving exenatide extended-release at 25-times clinical exposure compared to controls and higher incidences were noted in males above controls in all treated groups at ≥2-times clinical exposure. The potential of exenatide extended-release to induce C-cell tumors in mice has not been evaluated. Other GLP-1 receptor agonists have also induced thyroid C-cell adenomas and carcinomas in male and female mice and rats at clinically relevant exposures. It is unknown whether BYDUREON will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors has not been determined.

Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.

BYDUREON is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk of MTC with the use of BYDUREON and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with BYDUREON. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

5.2 Never Share a BYDUREON Pen Between Patients

BYDUREON pens must never be shared between patients. Pen-sharing poses a risk for transmission of blood-borne pathogens.

5.3 Acute Pancreatitis

Based on postmarketing data, exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYDUREON, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, BYDUREON should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, BYDUREON should not be restarted. Consider antidiabetic therapies other than BYDUREON in patients with a history of pancreatitis.

5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

The risk of hypoglycemia is increased when BYDUREON is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin to reduce the risk of hypoglycemia in this setting [see Adverse Reactions (6.1)].

5.5 Acute Kidney Injury

BYDUREON may induce nausea and vomiting with transient hypovolemia and may worsen renal function. There have been postmarketing reports of altered renal function with exenatide, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting or diarrhea, with or without dehydration. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including BYDUREON. BYDUREON is not recommended for use in patients with an eGFR below 45 mL/min/1.73 m2 [see Use in Specific Populations (8.6)].

5.6 Gastrointestinal Disease

Exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Because exenatide is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of BYDUREON is not recommended in patients with severe gastrointestinal disease.

5.7 Immunogenicity

Patients may develop antibodies to exenatide following treatment with BYDUREON. Anti-exenatide antibodies were measured in BYDUREON-treated patients in five of the six comparator-controlled 24- to 30-week studies of BYDUREON. In 6% of BYDUREON-treated patients, antibody formation was associated with an attenuated glycemic response. If there is worsening glycemic control or failure to achieve targeted glycemic control, consider alternative antidiabetic therapy [see Adverse Reactions (6.1) and (6.2)].

5.8 Hypersensitivity

There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with exenatide. If a hypersensitivity reaction occurs, the patient should discontinue BYDUREON and promptly seek medical advice [see Contraindications (4) and Adverse Reactions (6.3)]. 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 BYDUREON.

5.9 Drug-Induced Thrombocytopenia

Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported in the postmarketing setting with exenatide use. Drug-induced thrombocytopenia is an immune-mediated reaction, with exenatide-dependent anti-platelet antibodies. In the presence of exenatide, these antibodies cause platelet destruction. If drug-induced thrombocytopenia is suspected, discontinue BYDUREON immediately and do not re-expose the patient to exenatide. Upon discontinuation, thrombocytopenia can persist due to the prolonged exenatide exposure from BYDUREON (about 10 weeks) [see Adverse Reactions (6.3)].

5.10 Injection-Site Reactions

There have been postmarketing reports of serious injection-site reactions (e.g., abscess, cellulitis, and necrosis), with or without subcutaneous nodules, with the use of BYDUREON. Isolated cases required surgical intervention [see Adverse Reactions (6.1)].

5.11 Acute Gallbladder Disease

Acute events of gallbladder disease have been reported in GLP-1 receptor agonist trials. In the EXSCEL trial [see Clinical Studies (14.2)] , 1.9% of BYDUREON-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below or elsewhere in the prescribing information:
Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
Never Share a BYDUREON Pen Between Patients [see Warnings and Precautions (5.2)]
Acute Pancreatitis [see Warnings and Precautions (5.3)]
Hypoglycemia [see Warnings and Precautions (5.4)]
Acute Kidney Injury [see Warnings and Precautions (5.5)]
Gastrointestinal Disease [see Warnings and Precautions (5.6)]
Immunogenicity [see Warnings and Precautions (5.7)]
Hypersensitivity [see Warnings and Precautions (5.8)]
Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.9)]
Injection-Site Reactions [see Warnings and Precautions (5.10)]
Acute Gallbladder Disease [see Warnings and Precautions (5.11)]

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