BYDUREON (Page 2 of 6)

5.4 Renal Impairment

BYDUREON should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation [see Use in Specific Populations (8.6)]. In patients with end-stage renal disease receiving dialysis, single doses of BYETTA 5 mcg were not well tolerated due to gastrointestinal side effects. Because BYDUREON may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Use BYDUREON with caution in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) [see Use in Specific Populations (8.6) Clinical Pharmacology (12.3)]. BYDUREON has not been studied in patients with end-stage renal disease or severe renal impairment.

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 exenatide. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

5.5 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.

5.6 Immunogenicity

Patients may develop antibodies to exenatide following treatment with BYDUREON. Anti-exenatide antibodies were measured in all BYDUREON-treated patients in the five comparator-controlled 24-30 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, alternative antidiabetic therapy should be considered [see Adverse Reactions (6.1)].

5.7 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 other suspect medications and promptly seek medical advice [see Adverse Reactions (6.2)].

5.8 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYDUREON or any other antidiabetic drug.

6 ADVERSE REACTIONS

6.1 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
Abbreviations: N = The number of intent-to-treat patients
Note: Percentages are based on the number of intent-to-treat patients in each treatment group.
*
Reported event that has symptoms consistent with hypoglycemia with a concomitant glucose <54 mg/dL and the patient was able to self-treat.
Insulin glargine was dosed to a target fasting glucose concentration of 72 to 100 mg/dL. The mean dose of insulin glargine was 10 Units/day at baseline and 31 Units/day at endpoint.
26-Week Monotherapy Trial
BYDUREON 2 mg (N = 248) 2.0% (0.05)
Sitagliptin 100 mg (N = 163) 0.0% (0.00)
Pioglitazone 45 mg (N = 163) 0.0% (0.00)
Metformin 2000 mg QD (N = 246) 0.0% (0.00)
26-Week Add-on to Metformin Trial
BYDUREON 2 mg (N = 160) 1.3% (0.03)
Sitagliptin 100 mg (N = 166) 3.0% (0.12)
Pioglitazone 45 mg (N = 165) 1.2% (0.03)
26-Week Add-on to Metformin or Metformin + Sulfonylurea Trial
With Concomitant Sulfonylurea Use (N = 136)
BYDUREON 2 mg (N = 70) 20.0% (1.11)
Titrated Insulin Glargine (N = 66) 43.9% (2.87)
Without Concomitant Sulfonylurea Use (N = 320)
BYDUREON 2 mg (N =163) 3.7% (0.11)
Titrated Insulin Glargine (N = 157) 19.1% (0.64)
24-Week Monotherapy or add-on to Metformin, a Sulfonylurea, a Thiazolidinedione or Combination of Oral Agents Trial
With Concomitant Sulfonylurea Use (N = 74)
BYDUREON 2 mg (N = 40) 12.5% (0.72)
BYETTA 10 mcg (N = 34) 11.8% (0.31)
Without Concomitant Sulfonylurea Use (N = 178)
BYDUREON 2 mg (N = 89) 0.0% (0.00)
BYETTA 10 mcg (N = 89) 0.0% (0.00)
30-Week Monotherapy or add-on to Metformin, a Sulfonylurea, a Thiazolidinedione or Combination of Oral Agents Trial
With Concomitant Sulfonylurea Use (N = 107)
BYDUREON 2 mg (N =55) 14.5% (0.55)
BYETTA 10 mcg (N = 52) 15.4% (0.37)
Without Concomitant Sulfonylurea Use (N = 186)
BYDUREON 2 mg (N = 93) 0.0% (0.00)
BYETTA 10 mcg (N = 93) 1.1% (0.02)

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 (5.6)]. 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
26-Week Monotherapy Trial
BYDUREON2 mgN = 248% Sitagliptin100 mgN = 163% Pioglitazone45 mgN = 163% Metformin2000 mgN = 246%
N = The number of intent-to-treat patients.
Note: Percentages are based on the number of intent-to-treat patients in each treatment group.
*
Patients in the sitagliptin, pioglitazone and metformin treatment groups received weekly placebo injections.
Nausea 11.3 3.7 4.3 6.9
Diarrhea 10.9 5.5 3.7 12.6
Injection Site Nodule * 10.5 6.7 3.7 10.2
Constipation 8.5 2.5 1.8 3.3
Headache 8.1 9.2 8.0 12.2
Dyspepsia 7.3 1.8 4.9 3.3
Table 3: Treatment-Emergent Adverse Reactions Reported in ≥5% of BYDUREON-Treated Patients in 24-30 week Add-on Combination Therapy Trials
N = The number of intent-to-treat patients.
Note: Percentages are based on the number of intent-to-treat patients in each treatment group.
*
Patients in the sitagliptin, pioglitazone and metformin treatment groups received weekly placebo injections.
26-Week Add-On to Metformin Trial
BYDUREON2 mg N = 160 % Sitagliptin100 mgN = 166 % Pioglitazone45 mgN = 165 %
Nausea 24.4 9.6 4.8
Diarrhea 20.0 9.6 7.3
Vomiting 11.3 2.4 3.0
Headache 9.4 9.0 5.5
Constipation 6.3 3.6 1.2
Fatigue 5.6 0.6 3.0
Dyspepsia 5.0 3.6 2.4
Decreased appetite 5.0 1.2 0.0
Injection Site Pruritus * 5.0 4.8 1.2
26-Week Add-on to Metformin or Metformin + Sulfonylurea Trial
BYDUREON2 mgN = 233 % Insulin glargineTitratedN = 223 %
Nausea 12.9 1.3
Headache 9.9 7.6
Diarrhea 9.4 4.0
Injection Site Nodule 6.0 0.0
30-Week Monotherapy or as Add-on to Metformin, a Sulfonylurea, a Thiazolidinedione or Combination of Oral Agents Trial
BYDUREON2 mgN = 148 % BYETTA10 mcgN = 145 %
Nausea 27.0 33.8
Diarrhea 16.2 12.4
Vomiting 10.8 18.6
Injection Site Pruritus 18.2 1.4
Constipation 10.1 6.2
Gastroenteritis viral 8.8 5.5
Gastroesophageal reflux disease 7.4 4.1
Dyspepsia 7.4 2.1
Injection site erythema 7.4 0.0
Fatigue 6.1 3.4
Headache 6.1 4.8
Injection site hematoma 5.4 11.0
24-Week Monotherapy or as Add-on to Metformin, a Sulfonylurea, a Thiazolidinedione or Combination of Oral Agents Trial
BYDUREON2 mgN = 129 % BYETTA10 mcgN = 123
Nausea 14.0 35.0
Diarrhea 9.3 4.1
Injection site erythema 5.4 2.4

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 (5.6)]. 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.

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