(ex EN a tide)
Type 2 diabetes mellitus: Treatment of type 2 diabetes mellitus (noninsulin dependent, NIDDM) to improve glycemic control as an adjunct to diet and exercise.
Limitations of use: Because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans, prescribe exenatide ER only to patients for whom the potential benefits are considered to outweigh the potential risks. Exenatide ER is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise.
Hypersensitivity to exenatide or any component of the formulation; history of or family history of medullary thyroid carcinoma (exenatide ER only); patients with multiple endocrine neoplasia syndrome type 2 (exenatide ER only)
Canadian labeling: Additional contraindications (not in US labeling):
Bydureon: End-stage renal disease (ESRD) or severe renal impairment (CrCl <30 mL/minute) including dialysis patients
Byetta: Diabetic ketoacidosis, diabetic coma/precoma or type 1 diabetes mellitus; end-stage renal disease (ESRD) or severe renal impairment (CrCl <30 mL/minute) including dialysis patients
Exenatide extended release (ER) causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared with controls. It is unknown whether exenatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of exenatide-ER-induced rodent thyroid C-cell tumors has not been determined.
Exenatide ER 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 exenatide ER and inform them of symptoms of thyroid tumors (eg, 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 exenatide ER.
Type 2 diabetes: SubQ:
Immediate release: Initial: 5 mcg twice daily within 60 minutes prior to a meal; after 1 month, may be increased to 10 mcg twice daily (based on response)
Extended release: 2 mg once weekly
Note: May administer a missed dose as soon as noticed if the next regularly scheduled dose is due in ≥3 days; resume normal schedule thereafter. To establish a new day of the week administration schedule, wait ≥3 days after last dose given, then administer next dose on new desired day of the week.
Conversion from immediate release to extended release: Initiate weekly administration of exenatide extended release the day after discontinuing exenatide immediate release. Note: May experience increased blood glucose levels for ~2 weeks after conversion. Pretreatment with immediate release exenatide is not required when initiating extended release exenatide.
Refer to adult dosing.
Mild impairment (CrCl ≥50 mL/minute): No dosage adjustment necessary.
Moderate impairment (CrCl 30 to 50 mL/minute): There are no dosage adjustments provided in the manufacturers labeling; use caution.
Severe impairment (CrCl <30 mL/minute):
US labeling: Use is not recommended.
Canadian labeling: Use is contraindicated.
End-stage renal disease (ESRD):
US labeling: Use is not recommended
Canadian labeling: Use is contraindicated.
Renal transplantation: Use with caution
US labeling: There are no dosage adjustments provided in the manufacturer 's labeling (has not been studied); however, hepatic dysfunction is not expected to affect exenatide pharmacokinetics.
Canadian labeling: No dosage adjustment necessary.
Bydureon: Reconstitute vial using provided diluent; use immediately.
SubQ:
Immediate release: Use only if clear, colorless, and free of particulate matter. Administer via injection in the upper arm, thigh, or abdomen. Administer within 60 minutes prior to morning and evening meal (or prior to the 2 main meals of the day, approximately ≥6 hours apart). Set up each new pen before the first use by priming it. See pen user manual for further details. Dial the dose into the dose window before each administration.
Extended release: Administer subcutaneously in the upper arm, thigh, or abdomen; rotate injection sites weekly. Administer immediately after reconstitution in diluent, the mixture should be white to off-white and cloudy. Do not substitute needles or any other components provided with the single-dose tray. May administer without regard to meals or time of day.
Bydureon: Store under refrigeration at 2 ‚ °C to 8 ‚ °C (36 ‚ °F to 46 ‚ °F); vials may be stored at ≤25 ‚ °C ( ≤77 ‚ °F) for up to 4 weeks. Do not freeze (discard if freezing occurs). Protect from light.
Byetta: Prior to initial use, store under refrigeration at 2 ‚ °C to 8 ‚ °C (36 ‚ °F to 46 ‚ °F); after initial use, may store at ≤25 ‚ °C ( ≤77 ‚ °F). Do not freeze (discard if freezing occurs). Protect from light. Pen should be discarded 30 days after initial use.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Pen-injector, Subcutaneous:
Bydureon: 2 mg (1 ea)
Solution Pen-injector, Subcutaneous:
Byetta 10 MCG Pen: 10 mcg/0.04 mL (2.4 mL) [contains metacresol]
Byetta 5 MCG Pen: 5 mcg/0.02 mL (1.2 mL) [contains metacresol]
Suspension Reconstituted ER, Subcutaneous:
Bydureon: 2 mg (1 ea)
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy
Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy
Contraceptives (Estrogens): Exenatide may decrease the serum concentration of Contraceptives (Estrogens). Management: Administer oral contraceptives at least one hour prior to exenatide. Consider therapy modification
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
Insulin: GLP-1 Agonists may enhance the hypoglycemic effect of Insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification
MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Oral Contraceptive (Progestins): Exenatide may decrease the serum concentration of Oral Contraceptive (Progestins). Management: Administer oral contraceptives at least one hour prior to exenatide. Consider therapy modification
Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Sulfonylureas: GLP-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Vitamin K Antagonists (eg, warfarin): Exenatide may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy
Serum glucose, hemoglobin A1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a]), renal function, signs/symptoms of pancreatitis
Combination therapy may include a sulfonylurea, a thiazolidinedione, insulin glargine, or a combination of oral agents unless otherwise specified.
>10%:
Central nervous system: Headache (8% to 14%)
Endocrine & metabolic: Hypoglycemia (combination therapy with a sulfonylurea: Byetta 14% to 36%, Bydureon 20%; combination therapy without a sulfonylurea ≤11%; monotherapy ≤5%; Bydureon with metformin 1% to 4%)
Gastrointestinal: Nausea (dose-dependent and usually decreases over time; Byetta combination therapy 40% to 44%, Bydureon combination therapy 9% to 24%, monotherapy 8% to 11%), diarrhea (combination therapy 6% to 20%, Bydureon monotherapy 11%, Byetta monotherapy 1% to <2%), vomiting (combination therapy 11% to 18%, Byetta monotherapy 4%)
Local: Injection site nodule (Bydureon 6% to 77%), injection site reaction (13% to 17%)
1% to 10%:
Cardiovascular: Increased heart rate* (Robinson 2013)
Central nervous system: Dizziness (Byetta combination therapy 9%, Byetta monotherapy 1% to <2%), fatigue (Bydureon combination therapy 6%), jitteriness (Byetta combination therapy 9%)
Dermatologic: Hyperhidrosis (Byetta combination therapy 3%)
Gastrointestinal: Constipation (6% to 10%), viral gastroenteritis (6% to 9%), dyspepsia (3% to 7%), decreased appetite (1% to 5%), abdominal distension (Byetta combination therapy 4%), gastroesophageal reflux disease (Byetta combination therapy 2% to 3%), flatulence (Byetta 2%)
Immunologic: Antibody development to exenatide (2% to 6%, associated with attenuated glycemic response)
Local: Itching at injection site (Bydureon ≥5%)
Neuromuscular & skeletal: Weakness (Byetta combination therapy 4% to 5%)
<1% (Limited to important or life-threatening; all products): Abscess at injection site, acute pancreatitis, acute renal failure, alopecia, anaphylaxis, angioedema, cellulitis at injection site, chest pain (Byetta combination therapy), drowsiness, exacerbation of renal failure, hemorrhagic pancreatitis, hypersensitivity pneumonitis (chronic; combination therapy), influenza, kidney transplant dysfunction, necrotizing pancreatitis (sometimes resulting in death), pain (stomach, side, or abdominal pain possibly radiating to the back), prolongation P-R Interval on ECG (Linnebjerg 2011), renal insufficiency, severe diarrhea, severe hypoglycemia (Byetta combination therapy with metformin and a sulfonylurea), severe nausea, severe vomiting, tissue necrosis at injection site, upper respiratory tract infection
In patients with mild to moderate renal impairment, exposure to exenatide was similar to that of patients with healthy renal function. Exposure to exenatide increased by 3.37-fold in patients with ESRD receiving dialysis. Exenatide ER has not been studied in patients with severe renal impairment or ESRD receiving dialysis. Population pharmacokinetic analysis of renally impaired patients receiving exenatide 2 mg ER indicated there is a 62% and 33% increase in exposure in moderate and mild renal impairment, respectively.
Concerns related to adverse effects:
- Anti-exenatide antibodies: Use may be associated with the development of anti-exenatide antibodies. Low titers are not associated with a loss of efficacy; however, high titers (observed in 6% to 12% of patients in clinical studies) may result in an attenuation of response.
- Hypersensitivity: Serious hypersensitivity reactions (eg, anaphylaxis, angioedema) have been reported; discontinue therapy in the event of a hypersensitivity reaction. Serious injection-site reactions (eg, abscess, cellulitis, and necrosis), with or without subcutaneous nodules have been reported with use. Isolated cases required surgical intervention.
- GI symptoms: Most common reactions are gastrointestinal related; these symptoms may be dose-related and may decrease in frequency/severity with gradual titration and continued use.
- Pancreatitis: Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities) have been reported; monitor for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain which may radiate to the back, and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue use. Do not resume unless an alternative etiology of pancreatitis is confirmed. Consider alternative antidiabetic therapy in patients with a history of pancreatitis.
- Thyroid tumors: Bydureon: [US Boxed Warning] Thyroid C-cell tumors have developed in animal studies with exenatide ER; it is not known if exenatide ER causes thyroid C-cell tumor, including medullary thyroid carcinoma (MTC) in humans. Patients should be counseled on the potential risk of MTC with the use of exenatide and informed of symptoms of thyroid tumors (eg, neck mass, dysphagia, dyspnea, persistent hoarseness). Use is contraindicated in patients with a personal or a family history of medullary thyroid cancer and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2). Consultation with an endocrinologist is recommended in patients who develop elevated calcitonin concentrations or have thyroid nodules detected during imaging studies or physical exam; routine monitoring of serum calcitonin or using thyroid ultrasound for early detection of MTC is of unknown value. Cases of MTC in humans have been reported with the GLP-1 agonist, liraglutide.
- Weight loss: Use may be associated with weight loss (due to reduced intake) independent of the change in hemoglobin A1c.
Disease-related concerns:
- Diabetes, type 1: Mechanism requires the presence of insulin, therefore use in type 1 diabetes (insulin dependent, IDDM) or diabetic ketoacidosis is not recommended (use is contraindicated in the Byetta Canadian labeling); it is not a substitute for insulin in insulin-requiring patients.
- Gastrointestinal disease: Not recommended to be used in patients with gastroparesis or severe gastrointestinal disease due to frequent gastrointestinal adverse effects associated with use.
- Renal impairment: Use not recommended in severe renal impairment (CrCl <30 mL/minute) or end-stage renal disease (ESRD) (use in these patients and in dialysis patients is contraindicated in the Canadian labeling). Patients with ESRD receiving dialysis may be more susceptible to GI effects (eg, nausea, vomiting) which may result in hypovolemia and further reductions in renal function. Use with caution in patients with renal transplantation or in patients with moderate renal impairment (CrCl 30-50 mL/minute), particularly when initiating or escalating doses with immediate release exenatide. Cases of acute renal failure and chronic renal failure exacerbation, including severe cases requiring hemodialysis, have been reported, predominately in patients with nausea/vomiting/diarrhea or dehydration; renal dysfunction was usually reversible with appropriate corrective measures, including discontinuation of exenatide. Risk may be increased in patients receiving concomitant medications affecting renal function and/or hydration status.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Duplicate therapy: Avoid concurrent use of extended release (weekly) and immediate release (daily) exenatide formulations.
Dosage form specific issues:
- Injection-site reactions: Bydureon: Serious injection-site reactions (eg, abscess, cellulitis, necrosis), with or without subcutaneous nodules, have been reported.
- Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC, 2012).
Other warnings/precautions:
- Appropriate use: Bydureon: Not recommended for first-line therapy in patients inadequately controlled on diet and exercise alone.
C
Adverse events were observed in some animal reproduction studies. Based on in vitro data, exenatide has a low potential to cross the placenta (Hiles 2003).
In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2015; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008). Other agents are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013). The Bydureon Canadian labeling recommends women of childbearing potential discontinue use at least 3 months prior to attempting to conceive.
Health care providers are encouraged to enroll women exposed to exenatide during pregnancy in the pregnancy registry (800-633-9081).
Exenatide is an analog of the hormone incretin (glucagon-like peptide 1 or GLP-1) which increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, increases B-cell growth/replication, slows gastric emptying, and decreases food intake. Exenatide administration results in decreases in hemoglobin A1c by approximately 0.5% to 1% (immediate release) or 1.5% to 1.9% (extended release).
Vd: 28.3 L
Minimal systemic metabolism; proteolytic degradation may occur following glomerular filtration
Urine (majority of dose)
SubQ:
Immediate release (daily) formulation: 2.1 hours
Extended release (weekly) formulation: Triphasic: Phase 1: 2-5 hours; Phase 2: ~2 weeks; Phase 3: ~7 weeks
Immediate release (daily) formulation: 2.4 hours
Extended release (weekly) formulation: ~2 weeks
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience weight loss, constipation, diarrhea, lack of appetite, nausea, vomiting, or loss of strength and energy. Have patient report immediately to prescriber signs of thyroid cancer (new lump or swelling in the neck, pain in the front of the neck, cough that does not go away, change in voice that does not go away like hoarseness, or trouble swallowing or breathing), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), severe dizziness, passing out, severe headache, urinary retention, change in amount of urine passed, or severe injection site pain or irritation (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.