Clinical Trial 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.

The safety of BYDUREON was assessed in five comparator-controlled trials, in patients who entered the studies not achieving adequate glycemic control on their current therapy. In a double-blind 26 week trial, patients on diet and exercise were treated with BYDUREON 2 mg once every seven days (weekly), sitagliptin 100 mg daily, pioglitazone 45 mg daily, or metformin 2000 mg daily. In a double-blind 26 week trial, patients on metformin were treated with BYDUREON 2 mg once every seven days (weekly), sitagliptin 100 mg daily, or pioglitazone 45 mg daily. In an open-label 26 week trial, patients on metformin or metformin plus sulfonylurea were treated with BYDUREON 2 mg once every seven days (weekly) or optimized insulin glargine. In two open-label 24 to 30 week studies, patients on diet and exercise or metformin, a sulfonylurea, a thiazolidinedione or combination of oral agents were treated with BYDUREON 2 mg once every seven days (weekly) or BYETTA 10 mcg twice daily.

Withdrawals

The incidence of withdrawal due to adverse events was 4.9% (N=45) for BYDUREON-treated patients, 4.9% (N=13) for BYETTA-treated patients and 2.0% (N=23) for other comparator-treated patients in the five comparator-controlled 24-30 week trials. The most common adverse reactions leading to withdrawal for BYDUREON-treated patients were nausea 0.5% (N=5) versus 1.5% (N=4) for BYETTA and 0.3 % (N=3) for other comparators, injection site nodule 0.5% (N=5) versus 0.0% for BYETTA and 0.0% for other comparators, diarrhea 0.3% (N=3) versus 0.4% (N=1) for BYETTA and 0.3% (N=3) for other comparators, injection site reaction 0.2% (N=2) versus 0.0% for BYETTA and 0.0% for other comparators and headache 0.2% (N=2) versus 0.0% for BYETTA and 0.0% for other comparators.

Hypoglycemia

Table 1 summarizes the incidence and rate of minor hypoglycemia in the five comparator-controlled 24-30 week trials of BYDUREON used as monotherapy or as add-on to metformin, a sulfonylurea, a thiazolidinedione or combination of these oral antidiabetic agents. In these trials, an event was classified as minor hypoglycemia if there were symptoms of hypoglycemia with a concomitant glucose < 54 mg/dL and the patient was able to self-treat.

Table 1: Incidence (% of subjects) and Rate (episodes/subject year) of Minor^† Hypoglycemia in the Monotherapy Trial and in the Combination Therapy Trials

There were no reported events of major hypoglycemia in these five comparator-controlled 24-30 week trials. Major hypoglycemia was defined as loss of consciousness, seizure or coma (or other mental status change consistent with neuroglycopenia in the judgment of the investigator or physician) which resolved after administration of glucagon or glucose or required third party assistance to resolve because of severe impairment in consciousness or behavior. Patients were to have a concomitant glucose < 54 mg/dL.

Immunogenicity

Anti-exenatide antibodies were measured at prespecified intervals (4-14 weeks) in all BYDUREON-treated patients (N=918) in the five comparator-controlled studies of BYDUREON. In these five trials, 452 BYDUREON-treated patients (49%) had low titer antibodies ( ≤ 125) to exenatide at any time during the trials and 405 BYDUREON-treated patients (45%) had low titer antibodies to exenatide at study endpoint (24-30 weeks). The level of glycemic control in these patients was generally comparable to that observed in the 379 BYDUREON-treated patients (43%) without antibody titers. An additional 107 BYDUREON-treated patients (12%) had higher titer antibodies at endpoint. Of these patients, 50 (6% overall) had an attenuated glycemic response to BYDUREON ( < 0.7% reduction in HbA1c); the remaining 57 (6% overall) had a glycemic response comparable to that of patients without antibodies [see WARNINGS AND PRECAUTIONS]. In the 30-week trial in which anti-exenatide antibody assessments were performed at baseline and at 4-week intervals from week 6 to week 30, the mean anti-exenatide antibody titer in the BYDUREON-treated patients peaked at week 6 then declined by 56% from this peak by week 30.

A total of 246 patients with antibodies to exenatide in the BYETTA and BYDUREON clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No treatment-emergent cross reactive antibodies were observed across the range of titers.

Other Adverse Reactions

BYDUREON

Tables 2 and 3 summarize adverse reactions with an incidence ≥ 5% reported in the five comparator controlled 24-30 week trials of BYDUREON used as monotherapy or as add-on to metformin, a sulfonylurea, a thiazolidinedione or combination of these oral antidiabetic agents.

Table 2: Treatment-Emergent Adverse Reactions Reported in ≥ 5% of BYDUREON-Treated Patients in Monotherapy Trial

Table 3: Treatment-Emergent Adverse Reactions Reported in ≥ 5% of BYDUREON-Treated Patients in 24-30 week Add-on Combination Therapy Trials

Nausea was the most common adverse reaction associated with initiation of treatment with BYDUREON, and usually decreased over time.

Injection Site Reactions

In the five comparator-controlled 24-30 week trials, injection site reactions were observed more frequently in patients treated with BYDUREON (17.1%) than in patients treated with BYETTA (12.7%), titrated insulin glargine (1.8%) or those patients who received placebo injections (sitagliptin (10.6%), pioglitazone (6.4%), and metformin (13.0%) treatment groups). These reactions for patients treated with BYDUREON were more commonly observed in antibody-positive patients (14.2%) compared with antibody-negative patients (3.1%), with a greater incidence in those with higher titer antibodies [see WARNINGS AND PRECAUTIONS]. Incidence of injection site reactions for patients treated with BYETTA was similar for antibody positive patients (5.8%) and antibody negative patients (7.0%). One percent of patients treated with BYDUREON withdrew due to injection site adverse reactions (injection site mass, injection site nodule, injection site pruritus, and injection site reaction).

Small, asymptomatic subcutaneous injection site nodules are seen with the use of BYDUREON. In a separate 15-week study in which information on nodules were collected and analyzed, 24 out of 31 subjects (77%) experienced at least one injection site nodule during treatment; 2 subjects (6.5%) reported accompanying localized symptoms. The mean duration of events was 27 days. The formation of nodules is consistent with the known properties of the microspheres used in BYDUREON.

BYETTA

In three 30-week controlled trials of BYETTA (N=963) add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence of ≥ 1% and reported more frequently than with placebo included nausea (44% BYETTA, 18% placebo), vomiting (13% BYETTA, 4% placebo), diarrhea (13% BYETTA, 6% placebo), feeling jittery (9% BYETTA, 4% placebo), dizziness (9% BYETTA, 6% placebo), headache (9% BYETTA, 6% placebo), dyspepsia (6% BYETTA, 3% placebo), asthenia (4% BYETTA, 2% placebo), gastroesophageal reflux (3% BYETTA, 1% placebo), hyperhidrosis (3% BYETTA, 1% placebo) and decreased appetite (1% BYETTA, < 1% placebo). Similar types of adverse reactions were observed in 24-week and 16-week controlled trials of BYETTA used as monotherapy or as add-on to a thiazolidinedione, with or without metformin, respectively.

Post-Marketing Experience

BYETTA

The following additional adverse reactions have been reported during post-approval use of BYETTA. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema; anaphylactic reaction [see WARNINGS AND PRECAUTIONS].

Drug Interactions: increased international normalized ratio (INR), sometimes associated with bleeding, with concomitant warfarin use [see DRUG INTERACTIONS].

Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Limitations of Use and WARNINGS AND PRECAUTIONS].

Neurologic: dysgeusia; somnolence

Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction [see WARNINGS AND PRECAUTIONS].

Skin and Subcutaneous Tissue Disorders: alopecia

Read the Bydureon (exenatide) Side Effects Center for a complete guide to possible side effects »

Orally Administered Drugs

Exenatide slows gastric emptying. Therefore, BYDUREON has the potential to reduce the rate of absorption of orally administered drugs. Use caution when administering oral medications with BYDUREON [see CLINICAL PHARMACOLOGY].

In patients with type 2 diabetes, BYDUREON did not affect the absorption of orally administered acetaminophen to any clinically relevant degree.

Warfarin

BYDUREON has not been studied with warfarin. However, in a drug interaction study, BYETTA did not have a significant effect on INR [see CLINICAL PHARMACOLOGY]. There have been postmarketing reports for BYETTA of increased INR with concomitant use of warfarin, sometimes associated with bleeding [see ADVERSE REACTIONS]. In patients taking warfarin, the INR should be monitored more frequently after initiating BYDUREON. Once a stable INR has been documented, the INR can be monitored at the intervals usually recommended for patients on warfarin.

Last reviewed on RxList: 2/2/2012
This monograph has been modified to include the generic and brand name in many instances.