Total Cost
Free shipping on all orders

Powered by GeniusRx

brand byetta 5 mcg dose pen inj

Out of Stock Manufacturer ASTRAZENECA 00310651201
Out of Stock

Uses

Diabetes Mellitus

Exenatide is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The drug is available as an injection for twice-daily administration (Byetta) and as an extended-release for injectable suspension formulation for once-weekly administration (Bydureon).

Exenatide has been used as monotherapy or in combination with metformin, a sulfonylurea, or a thiazolidinedione; in combination with metformin and a sulfonylurea or a thiazolidinedione; or in combination with insulin glargine with or without metformin and/or a thiazolidinedione. The extended-release formulation of exenatide has been used as monotherapy or in combination with metformin, a sulfonylurea, or a thiazolidinedione or in combination with metformin and a sulfonylurea or a thiazolidinedione. Current guidelines on the treatment of type 2 diabetes mellitus generally recommend the use of GLP-1 receptor agonists such as exenatide as second-line therapy (after first-line metformin therapy) and also as an option for first-line treatment. Because of the uncertain relevance to humans of thyroid C-cell tumors found in rodents given extended-release exenatide, this formulation of the drug is not recommended as first-line therapy for patients with inadequate glycemic control on diet and exercise alone.(See Risk of Thyroid C-cell Tumors with Extended-release Exenatide under Warnings/Precautions: Warnings, in Cautions.)

Safety and efficacy of exenatide or extended-release exenatide have not been established in patients with a history of pancreatitis; other antidiabetic agents should be considered in such patients.(See Pancreatitis and Pancreatic Precancerous Changes under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Exenatide or extended-release exenatide is not a substitute for insulin. The manufacturer states that exenatide or extended-release exenatide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis because the drug is not effective for these conditions. The safety and efficacy of exenatide in combination with prandial insulin or of extended-release exenatide in combination with insulin have not been established, and such concomitant use is not recommended.(See Use with Drugs Known to Cause Hypoglycemia under Cautions: Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Exenatide and extended-release exenatide contain the same active ingredient and should not be used concomitantly.

Exenatide

When given as monotherapy or add-on therapy, twice-daily exenatide improves glycemic control (e.g., as determined by changes in glycosylated hemoglobin [hemoglobin A1c, HbA1c]) more than placebo and similar to that of titrated insulin lispro or insulin aspart 70/30 therapy. In addition, therapy with GLP-1 receptor agonists such as exenatide generally is associated with weight loss compared with that observed with placebo and most other antidiabetic agents (e.g., sulfonylureas, thiazolidinediones, insulin).

Safety and efficacy of exenatide as monotherapy in patients with type 2 diabetes mellitus have been established in a 24-week, randomized, double-blind, placebo-controlled study. In this study, patients with baseline HbA1c concentrations of 6.5-10% (mean: 7.8-7.9%) received exenatide 5 or 10 mcg or placebo subcutaneously twice daily before the morning and evening meals. Patients assigned to receive exenatide 10 mcg twice daily received 5 mcg twice daily for 4 weeks, then 10 mcg twice daily. The primary study end point was the change in HbA1c concentration from baseline to week 24 (or the last value at time of early discontinuance of therapy). At week 24, therapy with exenatide 5 or 10 mcg twice daily resulted in mean reductions of 0.7 or 0.9%, respectively, in HbA1c compared with baseline. HbA1c concentrations below 7% were achieved in 48, 53, or 38% of patients receiving exenatide 5 mcg, exenatide 10 mcg, or placebo, respectively. Patients receiving exenatide also experienced greater weight reduction than those receiving placebo (-2.8, -3.1, or -1.4 kg with twice-daily dosages of exenatide 5 mcg, 10 mcg, or placebo, respectively).

In several studies of 30 weeks' duration in which exenatide (5 or 10 mcg twice daily) was given in combination with maximally effective dosages of metformin hydrochloride, a sulfonylurea (e.g., glipizide, glyburide, glimepiride, tolazamide, chlorpropamide), or metformin hydrochloride in combination with a sulfonylurea, combined therapy with subcutaneous exenatide and these oral antidiabetic agents or regimens resulted in a reduction from baseline in HbA1c and progressive weight loss compared with that achieved with existing oral antidiabetic therapy.

Safety and efficacy of exenatide as add-on therapy to other antidiabetic agents also have been established in other studies. In a 16-week, placebo-controlled study in patients who had not achieved adequate glycemic control with a thiazolidinedione with or without metformin, the addition of subcutaneous exenatide (5 or 10 mcg twice daily) to existing oral antidiabetic therapy resulted in a reduction from baseline in HbA1c at week 16 compared with that achieved with existing oral antidiabetic therapy. In a 30-week, placebo-controlled study in patients with type 2 diabetes mellitus who had inadequate glycemic control on titrated insulin glargine with or without metformin and/or a thiazolidinedione (i.e., pioglitazone), addition of exenatide (5 or 10 mcg twice daily) to existing antidiabetic therapy reduced HbA1c from baseline at week 30 compared with that achieved with existing antidiabetic therapy. In a 26-week randomized, open-label study in patients with type 2 diabetes mellitus receiving metformin therapy (baseline HbA1c 6.5-10%), addition of exenatide (5 mcg twice daily for 4 weeks, then 10 mcg twice daily) was noninferior to addition of titrated, premixed insulin aspart (70% long-acting insulin aspart protamine, 30% rapid-acting insulin aspart) in improving HbA1c (least-squares mean HbA1c reduction of 1 or 1.14% with exenatide or insulin aspart 70/30, respectively). In addition, exenatide therapy was associated with less hypoglycemia than insulin aspart and resulted in weight reduction while insulin aspart 70/30 caused weight gain.

Extended-release Exenatide

Clinical studies indicate that the once-weekly extended-release formulation of exenatide generally is as effective as conventional regimens of metformin or pioglitazone and more effective than sitagliptin, titrated insulin glargine, insulin detemir, or twice-daily exenatide in improving glycemic control. Improvements in glycemic control have been maintained during long-term therapy (e.g., up to 6 years) with extended-release exenatide. In addition, compared with twice-daily exenatide, once-weekly extended-release exenatide generally has been associated with a similar degree of weight loss and GI adverse effects.

Safety and efficacy of once-weekly subcutaneous extended-release exenatide as monotherapy or in combination with other antidiabetic agents have been established in several randomized, open-label or double-blind clinical studies generally of 24-30 weeks' duration (e.g., DURATION studies) in adults with type 2 diabetes mellitus. In the 6 DURATION studies, once-weekly therapy with subcutaneous extended-release exenatide was compared with subcutaneous insulin glargine, liraglutide, or twice-daily exenatide or with oral antidiabetic agents (metformin, sitagliptin, pioglitazone) in patients who had inadequate glycemic control (mean baseline HbA1c concentrations of 8.3-8.6%) with or without preexisting oral antidiabetic therapy. The primary efficacy end point in these studies was the mean change in HbA1c from baseline to the end of the study; extended-release exenatide reduced HbA1c by 1.3-1.9% compared with reductions of 0.9-1.5% for twice-daily exenatide, 1.2-1.6% for pioglitazone, 0.9-1.2% for sitagliptin, 1.5% for metformin, 1.3% for insulin glargine, and 1.5% for liraglutide. In general, extended-release exenatide was more effective than twice-daily exenatide overall in reducing HbA1c and fasting plasma glucose, while twice-daily exenatide had a greater effect on postprandial hyperglycemia. In addition, the proportion of patients achieving an HbA1c of less than 7% with extended-release exenatide in the DURATION studies generally was similar to that with pioglitazone and greater than that with sitagliptin or insulin glargine.

In the long-term therapy (up to 6 years) portions of the DURATION-1 study, improvements in glycemic control and weight generally were sustained in patients who continued once-weekly therapy with extended-release exenatide and sustained or enhanced in those whose therapy was switched from the twice-daily to the once-weekly formulation. Compared with insulin and most oral antidiabetic agents, therapy with subcutaneous extended-release exenatide resulted in slow but progressive weight loss, which was similar to that associated with twice-daily exenatide and sustained during long-term therapy. Extended-release exenatide therapy was well tolerated in these studies, with no major hypoglycemic episodes reported and a low risk of hypoglycemia compared with insulin and most other oral antidiabetic agent comparators; when hypoglycemic episodes occurred, patients generally were receiving concomitant sulfonylurea therapy.

Dosage and Administration

General

Patients should be monitored regularly (e.g., blood glucose determinations, HbA1c) to determine therapeutic response.

Administration

Exenatide and extended-release exenatide are intended for self-administration by the patient. Patients should be instructed by a healthcare professional in the preparation and use of exenatide or extended-release exenatide before first use.

Exenatide

Exenatide is administered by subcutaneous injection into the abdomen, thigh, or upper arm; safety and efficacy of IV or IM administration have not been established.

Exenatide is administered within 60 minutes before the morning and evening meals (or before the 2 main meals of the day, approximately 6 hours or more apart); it should not be administered after a meal.

If a dose of exenatide is missed, that dose should be omitted and the next dose taken at the regularly scheduled time.

Exenatide should not be transferred from the injection pen to a syringe or vial. Exenatide should not be mixed with insulin in the same injection pen or vial even if they are taken at the same time. Exenatide should be used only if the solution is clear, colorless, and contains no particles.

Exenatide injection pens should be stored in the original carton and protected from light at 2-8°C before first use and at room temperature not exceeding 25°C after first use. Exenatide pens should not be frozen; the pen should be discarded if it has been frozen. Injection pens should be discarded 30 days after first use, even if some drug remains in the pen.

The manufacturer's instructions for use should be consulted for additional details about preparation and administration of exenatide.

Extended-release Exenatide

Extended-release exenatide is administered by subcutaneous injection into the abdomen, thigh, or back of upper arm region; the drug must not be administered IV or IM. Patients should use a different injection site each week when administering extended-release exenatide in the same region.

Extended-release exenatide may be administered at any time during the dosing day, with or without a meal. The day of weekly administration of extended-release exenatide may be changed if necessary, provided the last dose was administered at least 3 days previously.

If a dose of extended-release exenatide is missed, the missed dose should be administered as soon as noticed provided there are at least 3 days until the next scheduled dose; the usual regimen of extended-release exenatide (once weekly) may then be resumed. If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, the missed dose should not be administered; instead, the next dose should be taken on the regularly scheduled day.

Extended-release exenatide should be stored at 2-8°C up to the expiration date or until preparation for use. If needed, the drug can be stored for up to 4 weeks at room temperature not to exceed 25°C. Extended-release exenatide should be protected from light and should not be frozen; the drug should be discarded if it has been frozen.

The manufacturer's instructions for use should be consulted for additional details about preparation and administration of extended-release exenatide.

Reconstitution

Extended-release exenatide is supplied as a sterile, white to off-white powder in prefilled single-use injection pens and in single-dose vials; the powder must be reconstituted before administration. If the injection pen has been stored in the refrigerator, the patient should allow the pen to stand at room temperature for at least 15 minutes before starting the reconstitution procedure.

The diluent is contained in one compartment of the injection pen with the extended-release exenatide powder in another compartment; the diluent for the vial is supplied in a prefilled syringe within each single-dose tray. The diluent should only be used if it is clear and free of visible particulate matter when viewed through the prefilled syringe or the injection window of the pen.

The needle provided by the manufacturer should be attached to the injection pen and twisted clockwise until tight; the needle cover should not be removed at this point. Needles other than those provided by the manufacturer should not be used with the extended-release exenatide injection pen.

The injection pen is reconstituted by holding the pen upright and slowly turning the white knob at the bottom of the pen until a click is heard and the green label disappears; this allows the diluent and the drug powder to mix. The pen should then be tapped firmly against the palm of the hand (refer to manufacturer's instructions for use for detailed illustration) until the suspension is uniformly cloudy with no clumps when viewed through the mixing window; if particles are visible in the suspension, it should not be used. The suspension should not be injected until it is well mixed or the full dose of extended-release exenatide will not be delivered.

The vial is reconstituted by tapping it several times against a hard surface to loosen the drug powder and attaching the orange vial connector to the vial. After removing the white cap on the syringe, the orange connector is twisted onto the syringe until it is snug. While pressing down on the plunger of the syringe with the thumb, the vial and attached syringe should be shaken hard until the diluent and drug powder are mixed well and the suspension is cloudy and without clumps. The vial and syringe are then inverted and the vial is tapped gently to drain the drug suspension into the syringe. The connector is then removed from the syringe and the needle is attached to the syringe. The manufacturer's instructions for use should be consulted for additional details about reconstitution and administration of extended-release exenatide.

The reconstituted suspension in the injection pen or vial contains 2 mg of extended-release exenatide in 0.65 mL of diluent. Extended-release exenatide must be administered immediately after reconstitution; it cannot be stored for later use.

Dosage

Exenatide

The recommended initial dosage of exenatide for the management of type 2 diabetes mellitus is 5 mcg subcutaneously twice daily. Based on clinical response, the dosage of exenatide may be increased to 10 mcg subcutaneously twice daily 1 month after treatment initiation.

Patients receiving exenatide in combination with a sulfonylurea may require a reduction in the dosage of the sulfonylurea to reduce the risk of hypoglycemia.(See Use with Drugs Known to Cause Hypoglycemia under Cautions: Warnings/Precautions.)

When exenatide is used in combination with insulin, the dosage of insulin should be evaluated. In patients at increased risk of hypoglycemia, a reduction in the dosage of insulin should be considered.(See Use with Drugs Known to Cause Hypoglycemia under Cautions: Warnings/Precautions.)

Extended-release Exenatide

The recommended dosage of extended-release exenatide for the management of type 2 diabetes mellitus is 2 mg subcutaneously once every 7 days (once weekly).

Patients receiving extended-release exenatide in combination with a sulfonylurea may require a reduction in the dosage of the sulfonylurea to reduce the risk of hypoglycemia.

Prior treatment with exenatide is not required when initiating extended-release exenatide therapy. If extended-release exenatide is initiated in an individual already receiving exenatide, exenatide should be discontinued. Patients changing from therapy with exenatide to extended-release exenatide may experience transient elevations (lasting approximately 2 weeks) in blood glucose concentrations.

Special Populations

No dosage adjustment of exenatide is required in patients with mild renal impairment (creatinine clearance 50-80 mL/minute). Caution should be used when initiating exenatide or increasing dosage from 5 mcg twice daily to 10 mcg twice daily in patients with moderate renal impairment (creatinine clearance 30-50 mL/minute). In a study of exenatide in patients with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.4-fold compared with that in patients with normal renal function. Extended-release exenatide has not been studied in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or in patients with end-stage renal disease receiving dialysis. However, population pharmacokinetic analysis of patients with renal impairment who received extended-release exenatide 2 mg indicates that exposure to the drug is increased by 62 or 33% in those with moderate or mild renal impairment, respectively. Exenatide and extended-release exenatide should not be used in patients with end-stage renal disease or severe renal impairment (creatinine clearance less than 30 mL/minute) and should be used with caution in patients with moderate renal impairment or in those who have undergone renal transplantation.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The pharmacokinetics of exenatide have not been studied in patients with acute or chronic hepatic impairment. However, since exenatide is eliminated principally by the kidney, dosage adjustments are not expected to be necessary in patients with hepatic impairment.

Careful dosage selection is recommended in geriatric patients due to possible age-related decrease in renal function and concomitant disease and drug therapy; however, dosage requirements generally are similar in geriatric patients and younger adults. Caution should be used when initiating extended-release exenatide in geriatric patients.

Population pharmacokinetic analysis suggests that body mass index has no clinically important effect on the pharmacokinetics of exenatide, and gender and race do not affect steady-state concentrations of exenatide following administration of extended-release exenatide.

Cautions

Contraindications

Known hypersensitivity to exenatide or any ingredient in the formulation.

Extended-release exenatide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).

Warnings/Precautions

Warnings

Risk of Thyroid C-cell Tumors with Extended-release Exenatide

Extended-release exenatide causes a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in male and female rats compared with controls. The manufacturer states the potential of extended-release exenatide to induce C-cell tumors in mice has not been established. Other glucagon-like peptide-1 (GLP-1) receptor agonists also have induced thyroid C-cell adenomas and carcinomas in male and female mice and rats at clinically relevant exposures. It is unknown whether extended-release exenatide causes thyroid C-cell tumors, including MTC, in humans. Serum calcitonin, a biologic marker of MTC, was not assessed in clinical trials evaluating the use of extended-release exenatide. Patients with MTC typically have serum calcitonin concentrations exceeding 50 ng/L. Patients receiving extended-release exenatide who have thyroid nodules noted on physical examination or neck imaging should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin or using thyroid ultrasound for early detection of MTC in patients receiving extended-release exenatide is of uncertain value, patients should also be referred to an endocrinologist for further evaluation if serum calcitonin is measured and found to be elevated.

Sensitivity Reactions

Generalized pruritus and/or urticaria, macular or papular rash, and angioedema have been reported during postmarketing experience with exenatide; anaphylactic reaction has been reported rarely. If a hypersensitivity reaction occurs, exenatide or extended-release exenatide and other suspect agents should be discontinued, and the patient should seek medical advice promptly.

Other Warnings and Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis requiring hospitalization, has been reported during postmarketing experience with exenatide. Persistent, severe abdominal pain, which may be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Most patients who have developed pancreatitis during exenatide therapy had at least one other risk factor for acute pancreatitis (e.g., gallstones, severe hypertriglyceridemia, alcohol use) and have required hospitalization. Some patients have developed serious complications including dehydration and renal failure, suspected ileus, phlegmon, and ascites. Acute or worsening pancreatitis has been associated temporally with an increase in exenatide dosage from 5 to 10 mcg twice daily, the maximum recommended dosage, in some patients. Symptoms of acute pancreatitis (e.g., nausea, vomiting, abdominal pain) recurred upon rechallenge with the drug in several patients; abdominal pain abated after permanent discontinuance of the drug in one patient. Most patients have improved upon discontinuance of exenatide.

FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cellular changes (pancreatic duct metaplasia) in patients with type 2 diabetes mellitus receiving incretin mimetics (exenatide, liraglutide, sitagliptin, saxagliptin, alogliptin, or linagliptin). These findings are based on examination of a small number of pancreatic tissue specimens taken from patients who died from unspecified causes while receiving an incretin mimetic. FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete, or when the agency has additional information to report.

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics. The manufacturer states that after initiation of exenatide or extended-release exenatide and after increases in dosage, patients should be observed carefully for signs and symptoms of acute pancreatitis (e.g., unexplained, persistent severe abdominal pain that may radiate to the back; nausea; vomiting; elevated serum amylase or lipase concentrations). If pancreatitis is suspected, therapy with exenatide or extended-release exenatide and other potentially suspect drugs should be promptly discontinued, confirmatory tests performed (e.g., serum amylase or lipase concentrations, radiologic imaging), and appropriate therapy initiated. Exenatide or extended-release exenatide should not be resumed if pancreatitis is confirmed.

Safety and efficacy of exenatide or extended-release exenatide have not been established in patients with a history of pancreatitis; other antidiabetic therapies should be considered in such patients.

Use with Drugs Known to Cause Hypoglycemia

The risk of hypoglycemia is increased when exenatide or extended-release exenatide is used in combination with a sulfonylurea. Therefore, patients receiving exenatide or extended-release exenatide in combination with a sulfonylurea may require a reduction in the dosage of the sulfonylurea to reduce the risk of hypoglycemia.

When exenatide is used in combination with insulin, the dosage of insulin should be evaluated. In a clinical trial in which exenatide was added to insulin glargine therapy, the dosage of insulin glargine was reduced by 20% in patients with HbA1c concentrations of 8% or less; however, some clinicians suggest that the relative safety and efficacy of this approach to dosage adjustment of basal insulin may not apply to patients with baseline HbA1c concentrations of less than 7%, those with a recent history of major hypoglycemia, or those receiving long-acting GLP-1 receptor agonists. In patients at increased risk of hypoglycemia, a reduction in the dosage of insulin should be considered.(See Dosage and Administration: Dosage.) The safety and efficacy of exenatide in combination with prandial insulin or of extended-release exenatide with any type of insulin have not been established, and such concomitant use is not recommended by the manufacturer.

The use of exenatide or extended-release exenatide in combination with other glucose-independent insulin secretagogues (e.g., meglitinides) also may increase the risk of hypoglycemia.

Renal Effects

Deterioration of renal function (e.g., increased serum creatinine concentrations, renal impairment/insufficiency, worsened chronic renal failure, acute renal failure sometimes requiring hemodialysis or kidney transplantation) has been reported rarely with exenatide. Some of these events occurred in patients experiencing nausea, vomiting, and/or diarrhea with or without dehydration; these adverse effects may have contributed to development of altered renal function in these patients. Some of these events also occurred in patients receiving exenatide in combination with other agents known to affect renal function or hydration status (e.g., angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory agents, diuretics).

Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies. Renal effects usually have been reversible with supportive treatment and discontinuance of potentially causative agents, including exenatide. Altered renal function may be a consequence of diabetes mellitus, independent of any risk associated with exenatide therapy. Because exenatide or extended-release exenatide may induce nausea and vomiting with transient hypovolemia, treatment with this drug may worsen renal function.

Clinicians should closely monitor patients receiving exenatide for signs and symptoms of renal dysfunction and consider discontinuance of the drug if renal dysfunction is suspected and cannot be explained by other causes.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

GI Effects

Data are lacking on the use of exenatide in patients with severe GI disease, including gastroparesis. Use of exenatide is commonly associated with adverse GI effects, including nausea, vomiting, and diarrhea. Nausea, vomiting, and/or diarrhea resulting in dehydration, abdominal distention, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, and hemorrhagic and necrotizing pancreatitis sometimes resulting in death have been reported during postmarketing experience with exenatide. Use of exenatide or extended-release exenatide is not recommended in patients with severe GI disease.

Immunogenicity

Antibodies to exenatide have developed in patients receiving exenatide or extended-release exenatide therapy. Antibodies to exenatide were assessed in 90% of patients in the 30-, 16-, and 24-week clinical trials of exenatide with or without other antidiabetic therapy. Patients in these trials who had low-titer (e.g., less than 625) antibodies to exenatide (38, 31, or 28% of patients assessed for antibodies in the 3 clinical trials at 30, 16, or 24 weeks, respectively) generally had glycemic control (based on glycosylated hemoglobin [HbA1c]) comparable to that of patients without antibodies. Of patients who had higher (e.g., 625 or higher) antibody titers (6, 9, or 2% of patients assessed for antibodies in the 3 clinical trials, respectively), 3, 4, or 1% of patients, respectively, appeared to have an attenuated glycemic response.

Anti-exenatide antibodies were measured in all patients who received extended-release exenatide in 5 comparator-controlled studies that ranged from 24-30 weeks in duration. In patients with low-titer antibodies (49% of patients at any time during the study and 45% of patients at study end point), the level of glycemic control was comparable to that observed in the 43% of patients without antibody titers. In addition, of patients with higher antibody titers at study end point (12% of patients), approximately half (6% of overall patients) treated with extended-release exenatide had an attenuated glycemic response. The remaining patients had a glycemic response comparable to that of patients without antibodies. If worsening glycemic control or failure to achieve targeted glycemic control occurs in patients receiving exenatide or extended-release exenatide therapy, alternative antidiabetic therapy should be considered.

Approximately 210 patients with anti-exenatide antibodies in clinical trials were evaluated for cross-reactive antibodies to GLP-1 and/or glucagon, and treatment-emergent cross-reactive antibodies were not observed across the range of titers.

Injection-site Reactions

Serious injection-site reactions (e.g., abscess, cellulitis, necrosis) with or without subcutaneous nodules have been reported during postmarketing experience in patients receiving extended-release exenatide; in isolated cases, surgical intervention was required. Injection-site reactions also have been reported with exenatide during postmarketing experience.

The incidence of injection-site reactions for patients treated with extended-release exenatide was similar for patients with antibodies to the drug and those without evidence of such antibody development (5.8 and 7%, respectively). In the 5 comparator-controlled clinical studies, injection site reactions were observed more frequently in patients treated with extended-release exenatide (17.1%) than in patients treated with exenatide (12.7%), titrated insulin glargine (1.8%), or in those patients who received placebo injections (sitagliptin [10.6%], pioglitazone [6.4%], and metformin [13%] treatment arms). For patients treated with extended-release exenatide, injection site reactions were more commonly observed in antibody-positive patients (14.2%) versus antibody-negative patients (3.1%), with a greater incidence in those with higher titer antibodies.

Macrovascular Outcomes

Evidence of macrovascular risk reduction with exenatide, extended-release exenatide, or any other antidiabetic agent has not been conclusively demonstrated in controlled clinical trials.

Risk Associated with Sharing of Injection Pens

Exenatide and extended-release exenatide injection pens must never be shared among patients, even if the needle has been changed. Sharing of injection pens poses a risk for transmission of blood-borne pathogens.

Specific Populations

Pregnancy

Category C. Pregnancy Registry at 800-633-9081.

Exenatide caused cleft palate, irregular skeletal ossification, and an increased number of neonatal deaths in animal developmental studies. Extended-release exenatide administered during the period of major organogenesis reduced fetal growth and produced skeletal ossification deficits in association with maternal effects (decreased food intake and decreased body weight gain) in rats. Extended-release exenatide was not teratogenic in rats. Exenatide or extended-release exenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Exenatide is distributed into milk in mice. It is not known whether exenatide is distributed into human milk. Because many drugs are distributed into human milk and because of the potential for tumorigenicity shown with extended-release exenatide in animal studies, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy of exenatide have not been established in patients younger than 17 years of age. Safety and efficacy of extended-release exenatide have not been established in pediatric patients, and the manufacturer states that use of the drug in this patient population is not recommended.

Geriatric Use

No substantial differences in safety and efficacy nor in pharmacokinetics have been observed in geriatric patients relative to younger adults. Because geriatric patients are more likely to have decreased renal function, caution should be used when initiating therapy with the drug in such patients.

Hepatic Impairment

Exenatide has not been studied in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared principally by the kidney, hepatic dysfunction is not expected to affect blood concentrations of the drug, and the manufacturer makes no specific dosage recommendations for patients with hepatic impairment.

Renal Impairment

Use of exenatide or extended-release exenatide is not recommended in patients with end-stage renal disease or severe renal impairment (creatinine clearance less than 30 mL/minute); the drug should be used with caution in patients who have undergone renal transplantation. In patients with end-stage renal disease receiving dialysis, mean exenatide clearance was reduced to 0.9 L/hour compared with 9.1 L/hour in patients without renal disease, and single 5-mcg doses of exenatide were not well tolerated in patients with end-stage renal disease because of adverse GI effects. Because exenatide or extended-release exenatide may induce nausea and vomiting with transient hypovolemia, treatment with this drug may worsen renal function.(See Renal Effects under Cautions: Warnings/Precautions.) Safety and efficacy of extended-release exenatide have not been established in patients with end-stage renal disease or severe renal impairment.

In patients with mild renal impairment (creatinine clearance 50-80 mL/minute), no adjustment of exenatide dosage is required. Caution should be used when initiating exenatide or increasing exenatide dosage from 5 mcg twice daily to 10 mcg twice daily in patients with moderate renal impairment (creatinine clearance 30-50 mL/minute). In patients with mild to moderate renal impairment (creatinine clearance 30-80 mL/minute), systemic exposure to exenatide was similar to that in individuals with normal renal function.(See Renal Effects under Cautions: Warnings/Precautions.)

Extended-release exenatide should be used with caution in patients with moderate renal impairment (creatinine clearance 30-50 mL/minute).

Common Adverse Effects

Hypoglycemia occurred in at least 5% of patients receiving exenatide in overall clinical trials and more frequently than with placebo. In individual clinical trials, hypoglycemia was reported in 5.2 or 3.8% of patients receiving exenatide 5 or 10 mcg twice daily, respectively, as monotherapy; in 4.5 or 5.3% of patients receiving exenatide 5 or 10 mcg twice daily, respectively, in combination with metformin; in 14.4 or 35.7% of patients receiving exenatide 5 or 10 mcg twice daily, respectively, in combination with a sulfonylurea; in 19.2 or 27.8% of patients receiving exenatide 5 or 10 mcg twice daily, respectively, in combination with metformin and a sulfonylurea; in 10.7% of patients receiving exenatide 10 mcg twice daily in combination with a thiazolidinedione; and in 24.8% of patients receiving exenatide 10 mcg twice daily in combination with insulin glargine.

Adverse effects other than hypoglycemia reported in at least 2% of patients receiving exenatide in combination with other oral antidiabetic agents in clinical trials and more frequently than with placebo include nausea, vomiting, diarrhea, jittery feeling, dizziness, headache, dyspepsia, asthenia, gastroesophageal reflux disease, hyperhidrosis, constipation, abdominal distention, decreased appetite, and flatulence.

There were no reported cases of major hypoglycemia in 5 comparator-controlled, 24- to 30-week clinical studies in patients receiving 2 mg of extended-release exenatide once weekly. In these studies, major hypoglycemia was defined as a glucose concentration of less than 54 mg/dL accompanied by loss of consciousness, seizure, or coma (or other mental status change consistent with neuroglycopenia in the judgment of the investigator or clinician) that resolved after the administration of glucagon or glucose or required third-party assistance to resolve because of severe impairment in consciousness or behavior. Minor hypoglycemia (defined as symptoms of hypoglycemia with a concomitant glucose concentration of less than 54 mg/dL and ability of the patient to self-treat) in these studies was reported in 2% of patients receiving extended-release exenatide as monotherapy; 1.3 or 3.7% of patients receiving extended-release exenatide in combination with metformin; and in 20% of patients receiving extended-release exenatide in combination with metformin and a sulfonylurea. Minor hypoglycemia occurred in 12.5 or 14.5% of patients receiving extended-release exenatide with metformin, a sulfonylurea, a thiazolidinedione, or a combination of these agents but was not reported in patients who received one of these same regimens without concomitant sulfonylurea therapy.

Adverse effects other than hypoglycemia reported in at least 5% of patients receiving extended-release exenatide as monotherapy or in combination with other oral antidiabetic agents (metformin, a sulfonylurea, a thiazolidinedione, or a combination of these drugs) include nausea, diarrhea, injection-site pruritus, vomiting, injection-site nodule, constipation, headache, viral gastroenteritis, gastroesophageal reflux disease, dyspepsia, injection-site erythema, fatigue, injection-site hematoma, and decreased appetite.

Drug Interactions

Effects on GI Absorption of Other Drugs

The effect of exenatide-induced slowing of gastric emptying may reduce the rate and extent of absorption of concomitantly administered oral drugs. Exenatide should be used with caution in patients receiving oral drugs that have a narrow therapeutic index or require rapid GI absorption. In patients receiving oral drugs for which efficacy depends on threshold concentrations, such as oral contraceptives and anti-infective agents, those drugs should be taken at least 1 hour before exenatide administration. If such drugs need to be administered with food, patients should take them with a meal or snack (e.g., lunch) at a time when exenatide is not administered.

Because of the potential for similar effects of extended-release exenatide on concomitant oral drug absorption, caution should be used with such concomitant use.

Acetaminophen

When acetaminophen (1 g) was administered simultaneously with subcutaneous exenatide (10 mcg) or 1, 2, or 4 hours following exenatide injection, acetaminophen area under the concentration-time curve (AUC) decreased by 21, 23, 24, or 14%, respectively; peak plasma concentrations decreased by 37, 56, 54, or 41%, respectively; and time to peak plasma concentrations increased from 0.6 hours to 0.9, 4.2, 3.3, or 1.6 hours, respectively; however, acetaminophen AUC, peak plasma concentration, and time to peak plasma concentration were not appreciably changed when acetaminophen was given 1 hour prior to exenatide.

When acetaminophen (1 g) was administered either with or without a meal following 14 weeks of therapy with subcutaneous extended-release exenatide (2 mg once weekly), no substantial changes in acetaminophen AUC were observed compared with control. Acetaminophen peak plasma concentration was reduced by 16% (fasting) and 5% (fed), and time to peak plasma concentration was increased from approximately 1 hour in the control period to 1.4 and 1.3 hours in the fasting and fed states, respectively.

Antidiabetic Agents

The risk of hypoglycemia is increased when exenatide or extended-release exenatide is used in combination with a sulfonylurea; patients receiving these exenatide formulations concomitantly with a sulfonylurea may require a reduction in the dosage of the sulfonylurea.

When exenatide is used in combination with insulin, the dosage of insulin should be evaluated; in patients at increased risk of hypoglycemia, a reduction in the dosage of insulin should be considered.(See Dosage and Administration: Dosage.) The safety and efficacy of exenatide in combination with prandial insulin or of extended-release exenatide in combination with any type of insulin have not been established, and such concomitant use is not recommended.

The use of exenatide or extended-release exenatide in combination with other glucose-independent insulin secretagogues (e.g., meglitinides) may increase the risk of hypoglycemia.

Anti-infective Agents

The effect of exenatide-induced slowing of gastric emptying may reduce the rate and extent of absorption of concomitantly administered oral anti-infective agents. Oral anti-infective agents should be taken at least 1 hour before exenatide administration.(See Drug Interactions: Effects on GI Absorption of Other Drugs.)

Digoxin

Administration of exenatide (10 mcg subcutaneously twice daily) 30 minutes before digoxin (0.25 mg orally once daily) decreased the peak plasma concentration of digoxin by 17% and delayed the time to peak plasma concentration of digoxin by approximately 2.5 hours; however, there was no change in the overall steady-state AUC and renal clearance of digoxin.

Lisinopril

In patients with mild to moderate hypertension receiving stable dosages of lisinopril (5-20 mg daily), exenatide (10 mcg subcutaneously twice daily) did not alter the steady-state AUC or peak plasma concentration of lisinopril or the 24-hour mean systolic and diastolic blood pressure. However, the steady-state time to peak plasma concentration of lisinopril was delayed by 2 hours.

Lovastatin

Administration of exenatide (10 mcg subcutaneously twice daily) 30 minutes before lovastatin (single 40-mg oral dose) decreased the lovastatin AUC and peak plasma concentration by approximately 40 and 28%, respectively, and delayed the time to peak plasma concentration of lovastatin by 4 hours. In clinical trials, the use of exenatide in patients already receiving HMG-CoA reductase inhibitors (statins) was not associated with consistent changes in lipid profiles compared to baseline.

Oral Contraceptives

In healthy women, repeated daily administration of a fixed-combination oral contraceptive (30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel) 30 minutes after subcutaneous injection of exenatide (10 mcg twice daily) decreased the peak plasma concentrations of ethinyl estradiol and levonorgestrel by 45 and 27%, respectively, and delayed the time to peak plasma concentrations of ethinyl estradiol and levonorgestrel by 3 and 3.5 hours, respectively. Repeated daily administration of the fixed-combination oral contraceptive 1 hour prior to administration of exenatide decreased the mean peak plasma concentration of ethinyl estradiol by 15%; however, the mean peak plasma concentration of levonorgestrel was not substantially changed. Exenatide did not alter the mean trough concentrations of levonorgestrel following repeated daily administration of the fixed-combination oral contraceptive for both regimens; however, the mean trough concentration of ethinyl estradiol increased by 20% when the fixed-combination oral contraceptive was administered 30 minutes after exenatide injection. In this study, the effect of exenatide on the pharmacokinetics of oral contraceptives was confounded by the possible effect of food on oral contraceptives. Therefore, oral contraceptives should be administered at least 1 hour prior to exenatide administration.(See Drug Interactions: Effects on GI Absorption of Other Drugs.)

Warfarin

Increases in international normalized ratio [INR], sometimes associated with bleeding, have been reported during postmarketing experience with concomitant use of exenatide and warfarin. In a drug interaction study, no clinically important changes in warfarin (S- or R-enantiomer) AUC, peak plasma concentrations, or therapeutic response (as indicated by INR) were observed when warfarin sodium (single 25-mg dose) was administered 35 minutes after exenatide (5 mcg subcutaneously twice daily for 2 days, then 10 mcg twice daily for 7 days); however, the time to peak warfarin concentration was delayed by approximately 2 hours. In patients receiving warfarin, prothrombin time should be monitored more frequently after initiating or altering exenatide therapy; once a stable prothrombin time has been achieved, prothrombin times may be monitored at intervals usually recommended for patients receiving warfarin therapy.

Data are lacking on the effects of concomitant therapy with warfarin and extended-release exenatide. After initiation of extended-release exenatide in patients receiving warfarin concomitantly, the INR should be monitored more frequently. Once a stable INR has been documented, the INR can be monitored at intervals generally recommended for patients receiving warfarin therapy.

Write Your Own Review

Your meds on autopilot. Forever.