Byetta - Exenatide injection (Exenatide)

Warnings and Precautions, Pulmonary Aspiration During General Anesthesia or Deep Sedation (

BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

• •
  BYETTA contains exenatide. Coadministration with other exenatide-containing products is not recommended.

• •Initiate BYETTA at 5 mcg administered subcutaneously twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Do not administer after a meal.
• •Based on clinical response, the dose of BYETTA can be increased to 10 mcg twice daily which is recommended after 1 month of therapy, in order to reduce the risk of gastrointestinal adverse reactions
  [see

  5.5 Severe Gastrointestinal Adverse Reactions

  Use of GLP-1 receptor agonists, including BYETTA, has been associated with gastrointestinal adverse reactions, sometimes severe

  [see Adverse Reactions (6)]

  . BYETTA is not recommended in patients with severe gastroparesis.

  and

  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.

  Hypoglycemia

  Table 1 summarizes the incidence and rate of hypoglycemia with BYETTA in six placebo-controlled clinical trials.

  Table 1: Incidence (%) and Rate of Hypoglycemia when BYETTA was used as Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical TrialsA hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a documented blood glucose value <54 mg/dL or prompt recovery after treatment for hypoglycemia.

  	Placebo BID	BYETTA 5 mcg BID	BYETTA 10 mcg BID
  Monotherapy (24 Weeks)
  N	77	77	78
  % Overall	1.3%	5.2%	3.8%
  Rate (episodes/patient-year)	0.03	0.21	0.52
  % Severe	0.0%	0.0%	0.0%
  With Metformin (30 Weeks)
  N	113	110	113
  % Overall	5.3%	4.5%	5.3%
  Rate (episodes/patient-year)	0.12	0.13	0.12
  % Severe	0.0%	0.0%	0.0%
  With a Sulfonylurea (30 Weeks)
  N	123	125	129
  % Overall	3.3%	14.4%	35.7%
  Rate (episodes/patient-year)	0.07	0.64	1.61
  % Severe	0.0%	0.0%	0.0%
  With Metformin and a Sulfonylurea (30 Weeks)
  N	247	245	241
  % Overall	12.6%	19.2%	27.8%
  Rate (episodes/patient-year)	0.58	0.78	1.71
  % Severe	0.0%	0.4%	0.0%
  With a Thiazolidinedione (16 Weeks)
  N	112	not evaluated	121
  % Overall	7.1%	not evaluated	10.7%
  Rate (episodes/patient-years)	0.56	not evaluated	0.98
  % Severe	0.0%	not evaluated	0.0%
  With Insulin Glargine with or without Metformin and/or Thiazolidinedione (30 Weeks) When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by 20% in patients with an HbA1c≤8.0% to minimize the risk of hypoglycemia. See Table 9 for insulin dose titration algorithm.
  N	122	not evaluated	137
  % Overall	29.5%	not evaluated	24.8%
  Rate (episodes/patient-years)	1.58	not evaluated	1.61
  % Severe	0.8%	not evaluated	0.0%
  N = number of Intent-to-Treat subjects in each treatment group.

  Immunogenicity

  Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of BYETTA. In the 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer peaked at Week 6 and was reduced by 55% by Week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks. The level of glycemic control (HbA_1c) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks. Of these patients, 32 (3% overall) had an attenuated glycemic response to BYETTA; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies.

  In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. Of these patients, 4 (4% overall) had an attenuated glycemic response to BYETTA; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies.

  In the 24-week trial of BYETTA used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks. Of these patients, 1 (1% overall) had an attenuated glycemic response to BYETTA; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies.

  Antibodies to exenatide were not assessed in the 30-week placebo-controlled trial of BYETTA used in combination with insulin glargine.

  In the 30-week comparator-controlled trial of BYETTA used in combination with insulin glargine and metformin, 60 patients (20%) had low titer antibodies to exenatide at 30 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 234 patients (77%) without antibody titers. An additional 10 patients (3%) had higher titer antibodies at 30 weeks. Of these patients, 2 (1% overall) had an attenuated glycemic response to BYETTA; the remaining 8 (3% overall) had a glycemic response comparable to that of patients without antibodies.

  Two hundred and ten patients with antibodies to exenatide in the BYETTA 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

  Monotherapy

  For the 24-week placebo-controlled study of BYETTA used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.

  Table 2: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used as Monotherapy (excluding Hypoglycemia)In a 24-week placebo-controlled trial.

  Monotherapy	Placebo BID N=77 %	All BYETTA BID N=155 %
  Nausea	0	8
  Vomiting	0	4
  Dyspepsia	0	3
  BID = twice daily.

  Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with BYETTA, nausea, occurred in a dose-dependent fashion.

  Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of headache and nausea. No placebo-treated patients withdrew due to adverse reactions.

  Cholelithiasis and cholecystitis

  In a clinical study with exenatide, 1.9% of exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis.

  Combination Therapy

  Add-On to Metformin and/or Sulfonylurea

  In the three 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients are summarized in Table 3.

  Table 3: Treatment-Emergent Adverse Reactions ≥2% Incidence and Greater Incidence with BYETTA Treatment used with Metformin and/or a Sulfonylurea (excluding Hypoglycemia)In three 30-week placebo-controlled clinical trials.

  	Placebo BID N=483 %	All BYETTA BID N=963 %
  Nausea	18	44
  Vomiting	4	13
  Diarrhea	6	13
  Feeling Jittery	4	9
  Dizziness	6	9
  Headache	6	9
  Dyspepsia	3	6
  Asthenia	2	4
  Gastroesophageal Reflux Disease	1	3
  Hyperhidrosis	1	3
  BID = twice daily

  Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. Nausea was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials.

  The most common adverse reactions leading to withdrawal for BYETTA-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and none due to vomiting.

  Add-On to Thiazolidinedione with or without Metformin

  For the 16-week placebo-controlled study of BYETTA add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.

  Table 4: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used with a Thiazolidinedione (TZD), with or without Metformin (MET) (excluding Hypoglycemia)In a 16-week placebo-controlled clinical trial.

  With a TZD or TZD/MET	Placebo N=112 %	All BYETTA BID N=121 %
  Nausea	15	40
  Vomiting	1	13
  Dyspepsia	1	7
  Diarrhea	3	6
  Gastroesophageal Reflux Disease	0	3
  BID = twice daily.

  Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in BYETTA-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the BYETTA arm. No serious adverse events were reported in the placebo arm.

  The most common adverse reactions leading to withdrawal for BYETTA-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea.

  Add-On to Insulin Glargine with or without Metformin and/or Thiazolidinedione (Placebo-Controlled)

  For the 30-week placebo-controlled study of BYETTA as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.

  Table 5: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA used with Insulin Glargine with or without Oral Antihyperglycemic Medications (excluding Hypoglycemia)In a 30-week placebo-controlled clinical trial.

  With Insulin Glargine	Placebo N=122 %	All BYETTA BID N=137 %
  Nausea	8	41
  Vomiting	4	18
  Diarrhea	8	18
  Headache	4	14
  Constipation	2	10
  Dyspepsia	2	7
  Asthenia	1	5
  Abdominal Distension	1	4
  Decreased Appetite	0	3
  Flatulence	1	2
  Gastroesophageal Reflux Disease	1	2
  BID = twice daily.

  The most frequently reported adverse reactions leading to withdrawal for BYETTA-treated patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to nausea or vomiting.

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• •Administer as a subcutaneous injection in the thigh, abdomen, or upper arm.
• •Rotate injections sites with each dose. Do not use the same site for each injection.
• •Inspect visually for particulate matter and discoloration. Only use BYETTA if the solution appears clear, colorless, and contains no particles.
• •When using BYETTA with insulin, administer as separate injections and never mix. It is acceptable to inject BYETTA and insulin in the same body region, but the injections should not be adjacent to each other.
• •If a dose is missed, resume the treatment regimen as prescribed with the next scheduled dose.

BYETTA injection is a clear, colorless solution of exenatide supplied as follows:

• •5 mcg per dose in a single-patient-use prefilled pen containing 300 mcg/1.2 mL (250 mcg/mL), 60 doses.
• •10 mcg per dose in a single-patient-use prefilled pen containing 600 mcg/2.4 mL (250 mcg/mL), 60 doses.

No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of exenatide