HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
BYETTA safely and effectively. See full prescribing information for
BYETTA.

BYETTA® (exenatide) injection, for subcutaneous use
Initial U.S. Approval: 2005
-------------------------- RECENT MAJOR CHANGES -------------------------Warnings and Precautions, Acute Gallbladder Disease (5.9)
06/2022--------------------------- INDICATIONS AND USAGE -------------------------BYETTA (exenatide) is a glucagon-like peptide-1 (GLP-1) receptor agonist
indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus. (1, 14)
Limitations of Use
 Should not be used for the treatment of type 1 diabetes. (1) Has not been studied in patients with a history of pancreatitis. Consider
other antidiabetic therapies in patients with a history of pancreatitis. (1)---------------------- DOSAGE AND ADMINISTRATION --------------------- Inject subcutaneously within 60 minutes prior to morning and evening
meals (or before the two main meals of the day, approximately 6 hours ormore apart). (2.1)
 Initiate at 5 mcg per dose twice daily; increase to 10 mcg twice daily after
1 month based on clinical response. (2.1)

risk of hypoglycemia, including severe hypoglycemia. Reduction in thedose of insulin secretagogues or insulin may be necessary. (5.3)
Acute Kidney Injury: Postmarketing reports with exenatide, sometimes
requiring hemodialysis and kidney transplantation. BYETTA should not be
used in patients with severe renal impairment or end-stage renal disease
and should be used with caution in patients with renal transplantation.
Caution should be applied when initiating BYETTA or escalating the doseof BYETTA in patients with moderate renal failure. (5.4, 8.6, 12.3)
Severe Gastrointestinal Disease: Use of BYETTA is not recommended inpatients with severe gastrointestinal disease (e.g., gastroparesis). (5.5)
Immunogenicity: Patients may develop antibodies to exenatide. If there isworsening glycemic control or failure to achieve target glycemic control,
consider alternative antidiabetic therapy. (5.6)
Hypersensitivity: Serious hypersensitivity reactions (e.g., anaphylaxis andangioedema) have been reported. Discontinue BYETTA and promptly
seek medical advice. (5.7)
Drug-induced Immune-mediated Thrombocytopenia: Serious bleedingwhich may be fatal has been reported. Discontinue BYETTA promptly andavoid re-exposure to exenatide. (5.8)
Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected,
gallbladder studies are indicated. (5.9)------------------------------ ADVERSE REACTIONS ---------------------------- Most common (≥5%) and occurring more frequently than placebo inclinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery,dizziness, headache, dyspepsia, constipation, asthenia. Nausea usually
decreases over time. (5.3, 6)
 Postmarketing reports with exenatide of increased international normalized
ratio (INR) with concomitant use of warfarin, sometimes with bleeding.
(6.2, 7.3)--------------------- DOSAGE FORMS AND STRENGTHS -------------------BYETTA injection is supplied as 250 mcg/mL exenatide in: 5 mcg per dose, 60 doses, 1.2 mL single-patient-use prefilled pen 10 mcg per dose, 60 doses, 2.4 mL single-patient-use prefilled pen

To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------ CONTRAINDICATIONS ---------------------------- History of severe hypersensitivity to exenatide or any of the excipients in
BYETTA. (4) History of drug-induced immune-mediated thrombocytopenia fromexenatide products. (4)------------------------------ DRUG INTERACTIONS ---------------------------- May impact absorption of orally administered medications. (7.1, 12.3)
 Warfarin: Postmarketing reports of increased INR sometimes associatedwith bleeding. Monitor INR frequently until stable upon initiation oralteration of BYETTA therapy. (6.2, 7.3)----------------------- WARNINGS AND PRECAUTIONS --------------------- Never share a BYETTA pen between patients, even if the needle is----------------------- USE IN SPECIFIC POPULATIONS ---------------------changed. (5.1)
 Pregnancy: Use during pregnancy only if the potential benefit justifies the Acute Pancreatitis: Postmarketing reports with exenatide, including fatalrisk to the fetus. (8.1)
and non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue
BYETTA promptly. BYETTA should not be restarted. Consider otherSee 17 for PATIENT COUNSELING INFORMATION and Medication
antidiabetic therapies in patients with a history of pancreatitis. (5.2)
Guide.
 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin:
Revised: 12/2022
Patients taking an insulin secretagogue or insulin may have an increased
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
8USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosing
8.2
Lactation
8.4
Pediatric Use
3
DOSAGE FORMS AND STRENGTHS
8.5
Geriatric Use
4
CONTRAINDICATIONS
8.6
Renal Impairment
5
WARNINGS AND PRECAUTIONS
5.1
Never Share a BYETTA Pen Between Patients
8.7
Hepatic Impairment
5.2
Acute Pancreatitis
10
OVERDOSAGE
5.3
Hypoglycemia with Concomitant Use of Insulin Secretagogues or
11
DESCRIPTION
Insulin12
CLINICAL PHARMACOLOGY
5.4
Acute Kidney Injury
12.1
Mechanism of Action
5.5
Gastrointestinal Disease
12.2
Pharmacodynamics
5.6
Immunogenicity
12.3
Pharmacokinetics
5.7
Hypersensitivity
13
NONCLINICAL TOXICOLOGY
5.8
Drug-Induced Thrombocytopenia
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
5.9
Acute Gallbladder Disease
14
CLINICAL STUDIES
14.1
Monotherapy
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
14.2
Combination Therapy with Oral Antihyperglycemic Medicines
6.2
Postmarketing Experience
14.3
Combination with Insulin Glargine
7
DRUG INTERACTIONS
16
HOW SUPPLIED/STORAGE AND HANDLING
7.1
Orally Administered Drugs
16.1
How Supplied
7.2
Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea)
16.2
Storage and Handlingor with Insulin
17
PATIENT COUNSELING INFORMATION
7.3
Warfarin*Sections or subsections omitted from the full prescribing information are not listed.

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FULL PRESCRIBING INFORMATION
1

INDICATIONS AND USAGEBYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults
with type 2 diabetes mellitus [see Clinical Studies (14)].
Limitations of Use

BYETTA is not indicated for use in patients with type 1 diabetes.
BYETTA contains exenatide and should not be used with other products containing theactive ingredient exenatide.
BYETTA has not been studied in patients with a history of pancreatitis. Consider otherantidiabetic therapies in patients with a history of pancreatitis [see Warnings andPrecautions (5.2)].

2

DOSAGE AND ADMINISTRATION

2.1

Recommended Dosing








3

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
after 1 month of therapy.
Administer as a subcutaneous injection in the thigh, abdomen, or upper arm.
Inspect visually for particulate matter and discoloration. Only use BYETTA if thesolution appears clear, colorless, and contains no particles.
Do not mix BYETTA with insulin. Do not transfer BYETTA from the pen to a syringe ora vial.
If a dose is missed, resume the treatment regimen as prescribed with the next scheduled
dose.
DOSAGE FORMS AND STRENGTHSBYETTA injection is a clear, colorless solution of 250 mcg/mL exenatide supplied as follows:
4

5 mcg per dose in a 1.2 mL single-patient-use prefilled pen (60 doses)
10 mcg per dose in a 2.4 mL single-patient-use prefilled pen (60 doses)
CONTRAINDICATIONSBYETTA is contraindicated in patients with:2

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



A prior severe hypersensitivity reaction to exenatide or to any of the excipients in
BYETTA. Serious hypersensitivity reactions including anaphylaxis and angioedema havebeen reported with BYETTA [see Warnings and Precautions (5.7)].
A history of drug-induced immune-mediated thrombocytopenia from exenatide products.
Serious bleeding, which may be fatal, from drug-induced immune-mediatedthrombocytopenia has been reported with exenatide use [see Warnings and Precautions(5.8)].

5

WARNINGS AND PRECAUTIONS

5.1

Never Share a BYETTA Pen Between Patients

BYETTA pens must never be shared between patients, even if the needle is changed. Pensharing poses a risk for transmission of blood-borne pathogens.
5.2

Acute Pancreatitis

Based on postmarketing data, BYETTA has been associated with acute pancreatitis, including
fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYETTA, andafter dose increases, observe patients carefully for signs and symptoms of pancreatitis (including
persistent severe abdominal pain, sometimes radiating to the back, which may or may not be
accompanied by vomiting). If pancreatitis is suspected, BYETTA should promptly be
discontinued and appropriate management should be initiated. If pancreatitis is confirmed,
BYETTA should not be restarted. Consider antidiabetic therapies other than BYETTA inpatients with a history of pancreatitis.
5.3

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Patients receiving BYETTA in combination with an insulin secretagogue (e.g., sulfonylurea) or
insulin may have an increased risk of hypoglycemia including severe hypoglycemia [see Adverse
Reactions (6) and Drug Interactions (7.2)].
The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or otherconcomitantly administered insulin secretagogue) or insulin. Inform patients using these
concomitant medications of the risk of hypoglycemia and educate them on the signs andsymptoms of hypoglycemia.
5.4

Acute Kidney Injury

There have been postmarketing reports of altered renal function with BYETTA, including
increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal
failure, sometimes requiring hemodialysis or kidney transplantation. Some of these eventsoccurred in patients receiving one or more pharmacologic agents known to affect renal function
or hydration status, such as angiotensin converting enzyme inhibitors, nonsteroidal antiinflammatory drugs, or diuretics. Some events occurred in patients who had been experiencing
3

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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 potentiallycausative agents, including BYETTA. Exenatide has not been found to be directly nephrotoxic in
preclinical or clinical studies.
BYETTA is not recommended 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 renaltransplantation [see Use in Specific Populations (8.6)]. Because BYETTA may induce nausea
and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should
be applied when initiating or escalating doses of BYETTA from 5 to 10 mcg in patients withmoderate renal impairment (creatinine clearance 30-50 mL/min).
5.5

Gastrointestinal Disease

BYETTA has not been studied in patients with severe gastrointestinal disease, including
gastroparesis. Because BYETTA is commonly associated with gastrointestinal adverse reactions,
including nausea, vomiting, and diarrhea, the use of BYETTA is not recommended in patientswith severe gastrointestinal disease.
5.6

Immunogenicity

Patients may develop antibodies to exenatide following treatment with BYETTA. Antibody
levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week placebocontrolled studies and the 30-week comparator-controlled study of BYETTA. In 3%, 4%, 1%,
and 1% of these patients, respectively, antibody formation was associated with an attenuatedglycemic 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 BYETTA. If a hypersensitivity reaction occurs, thepatient should discontinue BYETTA and other suspect medications and promptly seek medical
advice. Inform and closely monitor patients with a history of anaphylaxis or angioedema withanother GLP-1 receptor agonist for allergic reactions, because it is unknown whether suchpatients will be predisposed to anaphylaxis with BYETTA [see Adverse Reactions (6.2)].
5.8

Drug-Induced Thrombocytopenia

Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia
has been reported in the postmarketing setting with exenatide use. Drug-induced
thrombocytopenia is an immune-mediated reaction, with exenatide-dependent anti-platelet
antibodies. In the presence of exenatide, these antibodies cause platelet destruction. If
drug-induced thrombocytopenia is suspected, discontinue BYETTA immediately and do not
re-expose the patient to exenatide [see Adverse Reactions (6.2)].
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5.9

Acute Gallbladder Disease

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in
GLP-1 receptor agonist trials and postmarketing. In a clinical study with exenatide, 1.9% of
exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event ofgallbladder disease, such as cholelithiasis or cholecystitis. If cholelithiasis is suspected,
gallbladder studies and appropriate clinical follow-up are indicated.
6

ADVERSE REACTIONS

The following serious adverse reactions are described below or elsewhere in the prescribing
information:










Never Share a BYETTA Pen Between Patients [see Warnings and Precautions (5.1)]
Acute Pancreatitis [see Warnings and Precautions (5.2)]
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings andPrecautions (5.3)]
Acute Kidney Injury [see Warnings and Precautions (5.4)]
Gastrointestinal Disease [see Warnings and Precautions (5.5)]
Immunogenicity [see Warnings and Precautions (5.6)]
Hypersensitivity [see Warnings and Precautions (5.7)]
Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.8)]
Acute Gallbladder Disease [see Warnings and Precautions (5.9)]

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 trialsof 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 placebocontrolled clinical trials.

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Table 1: Incidence (%) and Rate of Hypoglycemia when BYETTA was used as
Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled
Clinical Trials*
Placebo
BID
Monotherapy (24 Weeks)N
77% Overall
1.3%
Rate (episodes/patient-year)
0.03% Severe
0.0%With Metformin (30 Weeks)N
113% Overall
5.3%
Rate (episodes/patient-year)
0.12% Severe
0.0%With a Sulfonylurea (30 Weeks)N
123% Overall
3.3%
Rate (episodes/patient-year)
0.07% Severe
0.0%With Metformin and a Sulfonylurea (30 Weeks)N
247% Overall
12.6%
Rate (episodes/patient-year)
0.58% Severe
0.0%With a Thiazolidinedione (16 Weeks)N112% Overall
7.1%
Rate (episodes/patient-years)
0.56% Severe
0.0%

6Reference ID: 5098195

BYETTA
5 mcg BIDBYETTA
10 mcg BID

77
5.2%
0.21
0.0%

78
3.8%
0.52
0.0%

110
4.5%
0.13
0.0%

113
5.3%
0.12
0.0%

125
14.4%
0.64
0.0%

129
35.7%
1.61
0.0%

245
19.2%
0.78
0.4%

241
27.8%
1.71
0.0%

not evaluated
not evaluated
not evaluated
not evaluated

121
10.7%
0.98
0.0%

With Insulin Glargine with or without Metformin and/or Thiazolidinedione (30 Weeks)†N
122
not evaluated137% Overall
29.5%
not evaluated
24.8%
Rate (episodes/patient-years)
1.58
not evaluated
1.61% Severe
0.8%
not evaluated0.0%* A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without ablood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event withsymptoms consistent with hypoglycemia requiring the assistance of another person and associated with eithera documented blood glucose value <54 mg/dL or prompt recovery after treatment for hypoglycemia.
† When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine wasdecreased by 20% in patients with an HbA1c ≤8.0% to minimize the risk of hypoglycemia. See Table 9 forinsulin dose titration algorithm.
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 peakedat 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 (HbA1c) inthese 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 titerantibodies to exenatide at 24 weeks. The level of glycemic control in these patients was generallycomparable 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 anattenuated 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.
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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 titerantibodies 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 treatmentemergent 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% andoccurring 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)*
Monotherapy
NauseaVomiting
Dyspepsia

Placebo BID
N=77
%
0
0
0

All BYETTA BID
N=155
%
8
4
3

* In a 24-week placebo-controlled trial.
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 mostfrequently reported adverse reaction associated with BYETTA, nausea, occurred in a dosedependent fashion.
Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of headacheand 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-treatedpatients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis.
Combination Therapy
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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 summarizedin 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)*

NauseaVomiting
Diarrhea
Feeling Jittery
Dizziness
HeadacheDyspepsia
Asthenia
Gastroesophageal Reflux Disease
Hyperhidrosis

Placebo BID
N=483
%
18
4
6
4
6
6
3
2
1
1

All BYETTA BID
N=963
%
44
13
13
9
9
9
6
4
3
3

* In three 30-week placebo-controlled clinical trials.
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, thefrequency 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 tonausea 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 orwithout metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with anincidence of ≥2% and occurring more frequently in BYETTA-treated patients compared withplacebo-treated patients.

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Table 4: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA
used with a Thiazolidinedione (TZD), with or without Metformin (MET) (excluding
Hypoglycemia)*
With a TZD or TZD/MET

Placebo
N=112
%
15
1
1
3
0

NauseaVomiting
Dyspepsia
Diarrhea
Gastroesophageal Reflux Disease

All BYETTA BID
N=121
%
40
13
7
6
3

* In a 16-week placebo-controlled clinical trial.
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 (PlaceboControlled)
For the 30-week placebo-controlled study of BYETTA as add-on to insulin glargine with orwithout oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding
hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in BYETTAtreated 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)*
With Insulin Glargine

Placebo
N=122
%
8
4
8
4
2
2
1

NauseaVomiting
Diarrhea
HeadacheConstipation
Dyspepsia
Asthenia

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All BYETTA BID
N=137
%
41
18
18
14
10
7
5

Table 5: Treatment-Emergent Adverse Reactions ≥2% Incidence with BYETTA
used with Insulin Glargine with or without Oral Antihyperglycemic Medications(excluding Hypoglycemia)*
With Insulin Glargine

Placebo
N=122
%
1
0
1
1

Abdominal Distension
Decreased Appetite
Flatulence
Gastroesophageal Reflux Disease

All BYETTA BID
N=137
%
4
3
2
2

* In a 30-week placebo-controlled clinical trial.
BID = twice daily.

The most frequently reported adverse reactions leading to withdrawal for BYETTA-treatedpatients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due tonausea or vomiting.
6.2

Postmarketing Experience

The following additional adverse reactions have been reported during post-approval use of
BYETTA or other exenatide formulations. 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, macularor papular rash, angioedema, anaphylactic reaction.
Blood and Lymphatic Systems: drug-induced thrombocytopenia.
Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use
sometimes associated with bleeding [see Drug Interactions (7.3)].
Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal
distension, abdominal pain, eructation, constipation, flatulence, ileus, acute pancreatitis,hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Indications andUsage (1)].
Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy.
Metabolic: Severe hypoglycemia with concomitant use of sulfonylurea or insulin.
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.
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Skin and Subcutaneous Tissue Disorders: alopecia
7

DRUG INTERACTIONS

7.1

Orally Administered Drugs

The effect of BYETTA to slow gastric emptying can reduce the extent and rate of absorption oforally administered drugs. BYETTA should be used with caution in patients receiving oral
medications that have narrow therapeutic index or require rapid gastrointestinal absorption [seeAdverse Reactions (6.2)]. For oral medications that are dependent on threshold concentrations
for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs
at least 1 hour before BYETTA injection. If such drugs are to be administered with food, patientsshould be advised to take them with a meal or snack when BYETTA is not administered [seeClinical Pharmacology (12.3)].
7.2

Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When initiating BYETTA, consider reducing the dose of concomitantly administered insulin
secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [seeWarnings and Precautions (5.3) and Adverse Reactions (6)].
7.3

Warfarin

There are postmarketing reports of increased INR sometimes associated with bleeding, withconcomitant use of warfarin and BYETTA [see Adverse Reactions (6.2)]. In a drug interaction
study, BYETTA did not have a significant effect on INR [see Clinical Pharmacology (12.3)]. In
patients taking warfarin, prothrombin time should be monitored more frequently after initiationor alteration of BYETTA therapy. Once a stable prothrombin time has been documented,
prothrombin times can be monitored at the intervals usually recommended for patients on
warfarin.
8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary
Limited data with BYETTA in pregnant women are not sufficient to determine a drug-associatedrisk for major birth defects or miscarriage. There are risks to the mother and fetus associatedwith poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal
reproduction studies, there may be risks to the fetus from exposure to BYETTA during
pregnancy. BYETTA should be used during pregnancy only if the potential benefit justifies thepotential risk to the fetus.
Animal reproduction studies identified increased adverse fetal and neonatal outcomes fromexposure to exenatide during pregnancy and lactation in association with maternal effects. In
12Reference ID: 5098195

mice, exenatide administered during gestation and lactation caused increased neonatal deaths at
systemic exposure 3-times the human exposure resulting from the maximum recommended
human dose (MRHD) of 20 mcg/day for BYETTA (see Data).
The estimated background risk of major birth defects is 6-10% in women with pre-gestational
diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with
HbA1c >10. The estimated background risk of miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryofetal risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis,
preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly
controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia
related morbidity.
Data
Animal Data
In studies evaluating reproduction and development in pregnant mice and rabbits, maternal
animals were administered exenatide, the active ingredient in BYETTA, by subcutaneous
injection twice a day.
In pregnant mice given 6, 68, 460, or 760 mcg/kg/day exenatide during fetal organogenesis,
skeletal variations associated with slowed fetal growth, including changes in number of rib pairs
or vertebral ossifications sites, and wavy ribs were observed at 760 mcg/kg/day, a dose that
produced maternal toxicity and yielded systemic exposure 390-times the human exposure
resulting from the MRHD of BYETTA based on AUC comparison.
In pregnant rabbits given 0.2, 2, 22, 156, or 260 mcg/kg/day exenatide during fetalorganogenesis, irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a doseyielding systemic exposure up to 12-times the human exposure from the MRHD of BYETTA
based on AUC comparison.
In maternal mice given 6, 68, or 760 mcg/kg/day exenatide from gestation day 6 throughlactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum
days 2 to 4 in dams given 6 mcg/kg/day, a dose yielding a systemic exposure 3-times the human
exposure from the MRHD of BYETTA based on AUC comparison.

13

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8.2

Lactation

Risk Summary
There is no information regarding the presence of BYETTA, in human milk, the effects of
BYETTA on the breastfed infant, or the effects of BYETTA on milk production. Exenatide waspresent in the milk of lactating mice. However, due to species-specific differences in lactation
physiology, the clinical relevance of these data is not clear (see Data). The developmental andhealth benefits of breastfeeding should be considered along with the mother’s clinical need for
BYETTA and any potential adverse effects on the breastfed child from BYETTA or from theunderlying maternal condition.
Data
In lactating mice subcutaneously injected twice a day with exenatide, the concentration of
exenatide in milk was up to 2.5% of the concentration in maternal plasma.
8.4

Pediatric Use

The safety and effectiveness of BYETTA have not been established in pediatric patients.
Effectiveness of BYETTA was not demonstrated in a randomized, double-blind, placebocontrolled study conducted in 120 pediatric patients (78 received BYETTA and 42 received
placebo) aged 10 to 17 years with type 2 diabetes mellitus.
8.5

Geriatric Use

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests thatage does not influence the pharmacokinetic properties of exenatide [see Clinical Pharmacology(12.3)]. BYETTA was studied in 282 patients 65 years of age or older and in 16 patients 75 yearsof age or older. No differences in safety or effectiveness were observed between these patientsand younger patients. Because elderly patients are more likely to have decreased renal function,
care should be taken in dose selection in the elderly based on renal function.
8.6

Renal Impairment

BYETTA is not recommended for use in patients with end-stage renal disease or severe renal
impairment (creatinine clearance <30 mL/min) and should be used with caution in patients withrenal transplantation. In patients with end-stage renal disease receiving dialysis, single doses of
BYETTA 5 mcg were not well-tolerated due to gastrointestinal side effects. No dosage
adjustment of BYETTA is required in patients with mild renal impairment (creatinine clearance
50-80 mL/min). Caution should be applied when initiating or escalating doses of BYETTA from
5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min)[see Clinical Pharmacology (12.3)].

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8.7

Hepatic Impairment

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 [see Clinical Pharmacology (12.3)].
10

OVERDOSAGEIn a clinical study of BYETTA, three patients with type 2 diabetes each experienced a single
overdose of 100 mcg SC (10-times the maximum recommended dose). Effects of the overdoses
included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations.
One of the three patients experienced severe hypoglycemia requiring parenteral glucose
administration. The three patients recovered without complication. In the event of overdose,
appropriate supportive treatment should be initiated according to the patient's clinical signs andsymptoms.
11

DESCRIPTIONBYETTA (exenatide) is a synthetic peptide, glucagon-like peptide-1 (GLP-1) receptor agonist,that was originally identified in the lizard Heloderma suspectum.
Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula
C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence forexenatide is shown below.
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-ArgLeu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
BYETTA injection is supplied for subcutaneous administration as a sterile, preserved isotonic
solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL)contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobialpreservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate
trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens areavailable to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses toprovide for 30 days of twice daily administration (BID).
12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretionand exhibit other antihyperglycemic actions following their release into the circulation from thegut. BYETTA is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by
the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows
gastric emptying.
15

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The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has
been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase inboth glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta
cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
BYETTA improves glycemic control by reducing fasting and postprandial glucose
concentrations in patients with type 2 diabetes through the actions described below.
12.2

Pharmacodynamics

Glucose-Dependent Insulin Secretion
BYETTA has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin
release predominantly in the presence of elevated glucose concentrations. This insulin secretion
subsides as blood glucose concentrations decrease and approach euglycemia. However,BYETTA does not impair the normal glucagon response to hypoglycemia.
First-Phase Insulin Response
In healthy individuals, robust insulin secretion occurs during the first 10 minutes following
intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin
response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phaseinsulin response is an early beta-cell defect in type 2 diabetes. Administration of BYETTA attherapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose
in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phaseinsulin secretion were significantly increased in patients with type 2 diabetes treated with
BYETTA compared with saline (p<0.001 for both).

16

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Figure 1: Mean (+SEM) Insulin Secretion Rate during Infusion of BYETTA or Saline inPatients with Type 2 Diabetes and during Infusion of Saline in Healthy Subjects

Glucagon Secretion
In patients with type 2 diabetes, BYETTA moderates glucagon secretion and lowers serum
glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations leadto decreased hepatic glucose output and decreased insulin demand.
Gastric Emptying
BYETTA slows gastric emptying, thereby reducing the rate at which meal-derived glucose
appears in the circulation.
Food Intake
In both animals and humans, administration of exenatide has been shown to reduce food intake.

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Postprandial Glucose
In patients with type 2 diabetes, BYETTA reduces postprandial plasma glucose concentrations(Figure 2).
Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of
BYETTAa Treatment in Patients with Type 2 Diabetes Treated with Metformin, aSulfonylurea, or Both (N=54)

Fasting Glucose
In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia,
immediate insulin release followed injection of BYETTA. Plasma glucose concentrations weresignificantly reduced with BYETTA compared with placebo (Figure 3).

18

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Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a
One-Time Injection of BYETTAa or Placebo in Fasting Patients with Type 2 Diabetes(N=12)

Cardiac Electrophysiology
The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized,
placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in
62 healthy subjects. In this study with demonstrated ability to detect small effects, the upperbound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc
was below 10 msec. Thus, BYETTA (10 mcg single dose) was not associated with clinicallymeaningful prolongation of the QTc interval.

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12.3

Pharmacokinetics

Absorption
Following SC administration to patients with type 2 diabetes, exenatide reaches median peakplasma concentrations in 2.1 hours. The mean peak exenatide concentration (Cmax) was
211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was
1036 pg∙h/mL following SC administration of a 10-mcg dose of BYETTA. Exenatide exposure(AUC) increased proportionally over the therapeutic dose range of 5 to 10 mcg. The Cmax values
increased less than proportionally over the same range. Similar exposure is achieved with SC
administration of BYETTA in the abdomen, thigh, or upper arm.
Distribution
The mean apparent volume of distribution of exenatide following SC administration of a single
dose of BYETTA is 28.3 L.
Metabolism and Elimination
Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular
filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in
humans is 9.1 L/hour and the mean terminal half-life is 2.4 hours. These pharmacokinetic
characteristics of exenatide are independent of the dose. In most individuals, exenatide
concentrations are measurable for approximately 10 hours post-dose.
Drug Interactions
Acetaminophen
When 1000 mg acetaminophen elixir was given with 10 mcg BYETTA (0 hour) and 1 hour,
2 hours, and 4 hours after BYETTA injection, acetaminophen AUCs were decreased by 21%,23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%,
respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours,
3.3 hours, and 1.6 hours, respectively. Acetaminophen AUC, Cmax and Tmax were notsignificantly changed when acetaminophen was given 1 hour before BYETTA injection.
Digoxin
Administration of repeated doses of BYETTA (10 mcg BID) 30 minutes before oral digoxin(0.25 mg once daily) decreased the Cmax of digoxin by 17% and delayed the Tmax of digoxin byapproximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g.,
AUC) of digoxin was not changed.

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Lovastatin
Administration of BYETTA (10 mcg BID) 30 minutes before a single oral dose of lovastatin(40 mg) decreased the AUC and Cmax of lovastatin by approximately 40% and 28%, respectively,
and delayed the Tmax by about 4 hours compared with lovastatin administered alone. In the
30-week controlled clinical trials of BYETTA, the use of BYETTA in patients already receiving
HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles
compared to baseline.
Lisinopril
In patients with mild to moderate hypertension stabilized on lisinopril (5-20 mg/day), BYETTA(10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. Lisinopril steady-state Tmax
was delayed by 2 hours. There were no changes in 24-hour mean systolic and diastolic bloodpressure.
Oral Contraceptives
The effect of BYETTA (10 mcg BID) on single and on multiple doses of a combination oral
contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy
female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after
BYETTA administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and27%, respectively, and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administrationof repeated daily doses of the OC one hour prior to BYETTA administration decreased the mean
Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly
changed as compared to when the OC was given alone. BYETTA did not alter the mean troughconcentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for bothregimens. However, the mean trough concentration of ethinyl estradiol was increased by 20%
when the OC was administered 30 minutes after BYETTA administration injection as compared
to when the OC was given alone. The effect of BYETTA on OC pharmacokinetics is confoundedby the possible food effect on OC in this study. Therefore, OC products should be administeredat least one hour prior to BYETTA injection.
Warfarin
Administration of warfarin (25 mg) 35 minutes after repeated doses of BYETTA (5 mcg BID on
Days 1-2 and 10 mcg BID on Days 3-9) in healthy volunteers delayed warfarin Tmax byapproximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of
warfarin were observed. BYETTA did not significantly alter the pharmacodynamic properties(e.g., international normalized ratio) of warfarin [see Drug Interactions (7.3)].

21

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Specific Populations
Renal Impairment
Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal
impairment and subjects with end-stage renal disease. In subjects with mild to moderate renal
impairment (creatinine clearance 30-80 mL/min), exenatide exposure was similar to that ofsubjects with normal renal function. However, in subjects with end-stage renal disease receiving
dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects withnormal renal function [see Use in Specific Populations (8.6)].
Hepatic Impairment
No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic
hepatic impairment [see Use in Specific Populations (8.7)].
Age
Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests thatage does not influence the pharmacokinetic properties of exenatide [see Use in Specific
Population (8.5)].
GenderPopulation pharmacokinetic analysis of male and female patients suggests that gender does not
influence the distribution and elimination of exenatide.
Race
Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Blackpatients suggests that race has no significant influence on the pharmacokinetics of exenatide.
Body Mass Index
Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m2 and<30 kg/m2 suggests that BMI has no significant effect on the pharmacokinetics of exenatide.
13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or
250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas wereobserved in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in
the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with

22

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systemic exposures of 5-, 22-, and 130-times, respectively, the human exposure resulting fromthe maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).
In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administeredby bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, asystemic exposure up to 95-times the human exposure resulting from the maximum
recommended dose of 20 mcg/day, based on AUC.
Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames
bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells.
Exenatide was negative in the in vivo mouse micronucleus assay.
In mouse fertility studies with SC doses of 6, 68, or 760 mcg/kg/day, males were treated for
4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating andthroughout mating until gestation day 7. No adverse effect on fertility was observed at
760 mcg/kg/day, a systemic exposure 390-times the human exposure resulting from the
maximum recommended dose of 20 mcg/day, based on AUC.
14

CLINICAL STUDIESBYETTA has been studied as monotherapy and in combination with metformin, a sulfonylurea,
a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of metformin
and a thiazolidinedione, or in combination with insulin glargine with or without metformin
and/or thiazolidinedione.
14.1

Monotherapy

In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, BYETTA 5 mcg
BID (n=77), BYETTA 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy inpatients with entry HbA1c ranging from 6.5% to 10%. All patients assigned to BYETTA initially
received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive
BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo
received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously
before the morning and evening meals. The majority of patients (68%) were Caucasian, 26%West Asian, 3% Hispanic, 3% Black, and 0.4% East Asian.
The primary endpoint was the change in HbA1c from baseline to Week 24 (or the last value attime of early discontinuation). Compared to placebo, BYETTA 5 mcg BID and 10 mcg BID
resulted in statistically significant reductions in HbA1c from baseline at Week 24 (Table 6).
Table 6: Results of 24-Week Placebo-Controlled Trial of BYETTA used as
Monotherapy
Intent-to-Treat Population (N)Placebo
BID
77

BYETTA 5 mcg BID
77

23

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BYETTA 10 mcg*
BID
78

Table 6: Results of 24-Week Placebo-Controlled Trial of BYETTA used as
Monotherapy
Placebo
BID

BYETTA 5 mcg BID

BYETTA 10 mcg*
BID

7.9
−0.7
−0.5 [−0.9, −0.2]‡
48%

7.8
−0.9
−0.7 [−1.0, −0.3]
53%

85.1
−2.7
−1.3 [−2.3, −0.2]

86.2
−2.9
−1.5 [−2.5, −0.4]

166−17−12 [−23.2, −1.3]

155−19−14 [−24.5, −2.5]

HbA1c (%), Mean
Baseline
7.8
Change at Week 24†−0.2
Difference from placebo† (95% CI)
38%
Proportion Achieving HbA1c <7%
Body Weight (kg), Mean
Baseline
86.1
Change at Week 24†−1.5
Difference from placebo† (95% CI)
Fasting Serum Glucose§ (mg/dL), Mean
Baseline
159
Change at Week 24†−5
Difference from placebo† (95% CI)* BYETTA 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 5 months before the morningand evening meals.
†
Least squares means are adjusted for screening HbA1c strata and baseline value of the dependent variable.
‡
p <0.01, treatment vs. placebo.
§
Measured using the hexokinase-based glucose method.
BID = twice daily.

On average, there were no adverse effects of exenatide on blood pressure or lipids.
14.2

Combination Therapy with Oral Antihyperglycemic Medicines

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety andefficacy of BYETTA in patients with type 2 diabetes whose glycemic control was inadequate
with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In
addition, a 16-week, placebo-controlled trial was conducted where BYETTA was added toexisting thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin,in patients with type 2 diabetes with inadequate glycemic control.
In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned toreceive BYETTA 5 mcg BID, BYETTA 10 mcg BID, or placebo BID before the morning andevening meals, in addition to their existing oral antidiabetic agent. All patients assigned to
BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either
continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patientsassigned to placebo received placebo BID throughout the study. A total of 1446 patients wererandomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) Hispanic, and 174(12%) Black. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%.
In the placebo-controlled trial of 16 weeks duration, BYETTA (n=121) or placebo (n=112) was
added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without
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metformin. Randomization to BYETTA or placebo was stratified based on whether the patientswere receiving metformin. BYETTA treatment was initiated at a dose of 5 mcg BID for 4 weeks
then increased to 10 mcg BID for 12 more weeks. Patients assigned to placebo received placebo
BID throughout the study. BYETTA or placebo was injected subcutaneously before the morningand evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metforminand 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian,
8% Hispanic, and 3% Black. The mean baseline HbA1c values were 7.9% for BYETTA andplacebo.
The primary endpoint in each study was the mean change in HbA1c from baseline to study end(or early discontinuation). Table 7 summarizes the study results for the 30- and 16-week clinical
trials.
Table 7: Results of 30-Week and 16-Week Placebo-Controlled Trials of BYETTA used in
Combination with Oral Antidiabetic AgentsPlaceboBID
113
Intent-to-Treat Population(N)
HbA1c (%), Mean
Baseline
8.2
Change at Week 30†−0.0
Difference from placebo†(95% CI)12%
Proportion Achieving HbA1c<7%
Body Weight (kg), Mean
Baseline
99.9
Change at Week 30†−0.2
Difference from placebo†(95% CI)
Fasting Plasma Glucose§ (mg/dL), Mean
Baseline
169
Change at Week 30†+14
Difference from placebo†(95% CI)
Intent-to-Treat Population(N)
HbA1c (%), Mean
Baseline
Change at Week 30†
Difference from placebo†(95% CI)

123
8.7
+0.1

BYETTA 5 mcg
BYETTA 10 mcg*
BID
BID
In Combination with Metformin (30 Weeks)
110
113
8.3
−0.5
−0.5 [−0.7, −0.2]‡

8.2
−0.9
−0.9 [−1.1, −0.6]‡

32%

40%

100.0
−1.3
−1.1 [−2.2, −0.0]

100.9
−2.6
−2.4 [−3.5, −1.3]

176−5−20 [−32, −7]168−10−24 [−37, −12]

In Combination with a Sulfonylurea (30 Weeks)
125
129
8.5
−0.5
−0.6 [−0.9, −0.3]‡25

Reference ID: 5098195

8.6
−0.9
−1.0 [−1.3, −0.7]‡

Table 7: Results of 30-Week and 16-Week Placebo-Controlled Trials of BYETTA used in
Combination with Oral Antidiabetic AgentsPlacebo
BID
10%

BYETTA 5 mcg
BID
25%

BYETTA 10 mcg*
BID
36%

Proportion Achieving HbA1c<7%
Body Weight (kg), Mean
Baseline
99.1
94.9
95.2
Change at Week 30†
−0.8
−1.1
−1.6
Difference from placebo†−0.3 [−1.1, 0.6]
−0.9 [−1.7, −0.0](95% CI)
Fasting Plasma Glucose§ (mg/dL), Mean
Baseline
194
180
178
†
Change at Week 30
+6
−5
−11
Difference from placebo†−11 [−25, 3]−17 [−30, −3](95% CI)In Combination with Metformin and a Sulfonylurea (30 Weeks)
247
245
241
Intent-to-Treat Population(N)
HbA1c (%), Mean
Baseline
8.5
8.5
8.5
†
Change at Week 30
+0.1
−0.7
−0.9
Difference from placebo†−0.8 [−1.0, −0.6]‡−1.0 [−1.2, −0.8]‡(95% CI)8%25%
31%
Proportion Achieving HbA1c<7%
Body Weight (kg), Mean
Baseline
99.1
96.9
98.4
Change at Week 30†
−0.9
−1.6
−1.6
Difference from placebo†−0.7 [−1.2, −0.2]−0.7 [−1.3, −0.2](95% CI)
Fasting Plasma Glucose§ (mg/dL), Mean
Baseline
181
182
178
†
Change at Week 30
+13
−11
−12
Difference from placebo†−24 [−33, −15]
−25 [−34, −16]
(95% CI)In Combination with a Thiazolidinedione or a Thiazolidinedione
plus Metformin (16 Weeks)
112
Dose not studied
121
Intent-to-Treat Population(N)
HbA1c (%), Mean
Baseline
7.9
Dose not studied
7.9
Change at Week 16†+0.1
Dose not studied−0.7
Difference from placebo†
Dose not studied−0.9 [−1.1, −0.7]‡(95% CI)
15%
Dose not studied
51%
Proportion Achieving HbA1c<7%
Body Weight (kg), Mean

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Table 7: Results of 30-Week and 16-Week Placebo-Controlled Trials of BYETTA used in
Combination with Oral Antidiabetic AgentsPlacebo
BID
96.8
−0.0

Baseline
Change at Week 16†
Difference from placebo†(95% CI)
Fasting Serum Glucose§ (mg/dL), Mean
Baseline
159
Change at Week 16†+4
Difference from placebo†(95% CI)

BYETTA 5 mcg
BID
Dose not studied
Dose not studied
Dose not studied

BYETTA 10 mcg*
BID
97.5
−1.5
−1.5 [−2.2, −0.7]

Dose not studied
Dose not studied
Dose not studied

164−21−25 [−33, −16]

* BYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 6 months for the 30-week trials or 10 mcg
BID for 3 months in the 16-week trial before the morning and evening meals.
†
Least squares means are adjusted for baseline HbA1c strata or value, investigator site, baseline value of thedependent variable (if applicable), and background antihyperglycemic therapy (if applicable).
‡p <0.01, treatment vs. placebo.
§
Measured using the hexokinase-based glucose method.
BID = twice daily.

HbA1c
The addition of BYETTA to a regimen of metformin, a sulfonylurea, or both, resulted instatistically significant reductions from baseline in HbA1c compared with patients receiving
placebo added to these agents in the three controlled trials (Table 7).
In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin,
BYETTA resulted in statistically significant reductions from baseline in HbA1c compared withpatients receiving placebo (Table 7).
Postprandial Glucose
Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients
participating in the 30-week add-on to metformin, add-on to sulfonylurea, and add-on to
metformin in combination with sulfonylurea clinical trials. In this pooled subset of patients,
BYETTA reduced postprandial plasma glucose concentrations in a dose-dependent manner. The
mean (SD) change in 2-hour postprandial glucose concentration following administration of
BYETTA at Week 30 relative to baseline was −63 (65) mg/dL for 5 mcg BID(n=42), -71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44).

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14.3

Combination with Insulin Glargine

30-Week Placebo-Controlled Trial
A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy andsafety of BYETTA (n=137) versus placebo (n=122) when added to titrated insulin glargine, withor without metformin and/or thiazolidinedione, in patients with type 2 diabetes with inadequate
glycemic control.
All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, thosepatients assigned to BYETTA had their dose increased to 10 mcg BID. Patients assigned toplacebo received placebo BID throughout the trial. BYETTA or placebo was injectedsubcutaneously before the morning and evening meals. Patients with an HbA1c ≤8.0% decreased
their prestudy dose of insulin glargine by 20% and patients with an HbA1c ≥8.1% maintained
their current dose of insulin glargine. Five weeks after initiating randomized treatment, insulin
doses were titrated with guidance from the investigator toward predefined fasting glucose targets
according to the dose titration algorithm provided in Table 9. The majority of patients (78%)
were Caucasian, 10% American Indian or Alaska Native, 9% Black, 3% Asian, and 0.8% of
multiple origins.
The primary endpoint was the change in HbA1c from baseline to Week 30. Compared to placebo,
BYETTA 10 mcg BID resulted in statistically significant reductions in HbA1c from baseline at
Week 30 (Table 8) in patients receiving titrated insulin glargine.
Table 8: 30-Week Placebo-Controlled Trial of BYETTA Used in Combination with
Insulin Glargine with or without Metformin and/or Thiazolidinediones
Placebo BID+
Titrated Insulin Glargine
122

BYETTA 10 mcg* BID+
Titrated Insulin Glargine
137

8.5
−1.0

8.3
−1.7
−0.7 [−1.0, −0.5]¶
56%

Intent-to-Treat Population (N)HbA1c (%), Mean
Baseline
Change at Week 30†
Difference from placebo† (95% CI)
Proportion Achieving HbA1c <7%
Body Weight (kg), Mean
Baseline
Change at Week 30‡
Difference from placebo‡ (95% CI)
Fasting Serum Glucose§ (mg/dL), Mean
Baseline
Change at Week 30‡
Difference from placebo‡ (95% CI)

29%
93.8
1.0

95.4
−1.8
−2.7 [−3.7, −1.7]¶

133
−16

132
−23
−7 [−18, 3]* BYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 5 months for the 30-week trial.
†
Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline
HbA1c value, and treatment by visit, where subject is treated as a random effect.

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Table 8: 30-Week Placebo-Controlled Trial of BYETTA Used in Combination with
Insulin Glargine with or without Metformin and/or Thiazolidinediones
Placebo BID+
Titrated Insulin Glargine

BYETTA 10 mcg* BID+
Titrated Insulin Glargine‡

Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline
HbA1c stratum, baseline value of the dependent variable (where applicable), and treatment by visit, where
subject is treated as a random effect.
§
Patients in both groups titrated insulin glargine dose to achieve optimal fasting glucose concentrations.
¶p <0.01, treatment vs. placebo.
BID = twice daily.

Table 9: Dosing Algorithm for Titration of Insulin Glargine*
Fasting Plasma Glucose Values(mg/dL)<56†
56 to 72†
73 to 99‡
100 to 119‡120 to 139‡
140 to 179‡
≥180‡

Dose Change
(U)
−4
−2
0
+2
+4
+6
+8

Abbreviations: U = units.
* Adapted from Riddle et al. 2003.
†
Value for at least 1 fasting plasma glucose measurement since the last assessment.
‡
Based on the average of fasting plasma glucose measurements taken over the prior 3 to 7 days. The
increase in the total daily dose should not have exceeded more than 10 units per day or 10% of the current
total daily dose, whichever was greater.

30-Week Comparator-Controlled Noninferiority Trial
A 30 week, open-label, active comparator-controlled, noninferiority study was conducted toevaluate the safety and efficacy of BYETTA (n=315) versus titrated insulin lispro (n=312) on a
background of optimized basal insulin glargine and metformin in patients with type 2 diabetes
with inadequate glycemic control.
Following a 12-week basal insulin optimization (BIO) phase, subjects with an HbA1c >7.0%
entered a 30-week intervention phase and were randomized to add either BYETTA or insulin
lispro to their existing regimen of insulin glargine and metformin. Insulin glargine was titrated toa target fasting plasma glucose of 72 to 100 mg/dL.
All patients assigned to BYETTA initially received 5 mcg BID for four weeks. After four weeks,
their dose was increased to 10 mcg BID. Patients in the BYETTA-treated arm with an HbA1c≤8.0% at the end of the BIO phase decreased their insulin glargine dose by at least 10%.

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All patients assigned to insulin lispro three times daily (TID) maintained their prior total daily
insulin dose at baseline; however, the initial insulin lispro dose was ⅓ to ½ of the total daily
insulin dose with the insulin glargine dose reduced accordingly. The insulin lispro dose wastitrated based on preprandial glucose values.
The majority of patients (87%) were Caucasian, 7% American Indian or Alaska Native, 5%Asian, and <1% African American.
The primary endpoint was the change in HbA1c from baseline to Week 30. Both BYETTA
10 mcg BID and titrated lispro provided a mean reduction in HbA1c at Week 30 that met the prespecified non-inferiority margin of 0.4%.
Table 10: 30-Week Comparator-Controlled Trial of BYETTA used in Combination with
Insulin Glargine and Metformin
Titrated Insulin Lispro TID+
Titrated Insulin Glargine
312

BYETTA 10 mcg* BID+
Titrated Insulin Glargine
315

8.2
−1.1

8.3
−1.1
−0.0 [−0.2, 0.1]

89.3
1.9

89.9
−2.6
−4.5 [−5.2, −3.9]

126
5

130
−7
−12 [−19, −4]

Intent-to-Treat Population (N)HbA1c (%), Mean
Baseline
Change at Week 30† #Difference from Insulin Lispro† #(95% CI)
Body Weight (kg), Mean
Baseline
Change at Week 30† #Difference from Insulin Lispro† #(95% CI)
Fasting Serum Glucose‡ (mg/dL), Mean
Baseline
Change at Week 30† #Difference from Insulin Lispro† #(95% CI)*

BYETTA 5 mcg BID for 1 month followed by 10 mcg BID for 5 months for the 30-week trial.
Least squares means are based on a mixed model adjusting for treatment, country, prior use of sulfonylurea(yes/no), visit, corresponding baseline, and treatment by visit interaction, where subject is treated as a random
effect.
#Data at 30 weeks are available from 88% and 84% of the intent-to-treat subjects in the Lispro and BYETTA
groups, respectively.
‡
Patients titrated insulin glargine or insulin lispro dose to achieve prespecified target fasting and preprandial
glucose concentrations.
BID = twice daily.
TID = three times daily.
†

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16

HOW SUPPLIED/STORAGE AND HANDLING

16.1

How Supplied

BYETTA (exenatide) 250 mcg/mL is a clear, colorless solution supplied as:

5 mcg per dose, 60 doses, 1.2 mL prefilled pen, NDC 0310-6512-01

10 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 0310-6524-01

16.2






17

Storage and HandlingStore BYETTA in the refrigerator at 36°F to 46°F (2°C to 8°C).
After first use, BYETTA can be kept at a temperature not to exceed 77°F (25°C).
Do not freeze. Do not use BYETTA if it has been frozen.
Protect BYETTA from light.
Discard the pen 30 days after first use, even if some drug remains in the pen.
Use a puncture-resistant container to discard the needles. Do not reuse or share needles.
PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions
for Use).
Never Share a BYETTA Pen Between Patients
Advise patients that they must never share a BYETTA pen with another person, even if theneedle is changed, because doing so carries a risk for transmission of blood-borne pathogens [seeWarnings and Precautions (5.1)].
Acute Pancreatitis
Inform patients that persistent severe abdominal pain that may radiate to the back and which may
or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instructpatients to promptly discontinue BYETTA and contact their physician if persistent severe
abdominal pain occurs [see Warnings and Precautions (5.2)].
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
Inform patients that the risk of hypoglycemia is increased when BYETTA is used in combination
with an agent that induces hypoglycemia, such as a sulfonylurea or insulin. Educate patients on
the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.3)].
Acute Kidney Injury

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Inform patients treated with BYETTA of the potential risk for worsening renal function andabout associated signs and symptoms of renal dysfunction, as well as the possibility of dialysis asa medical intervention if renal failure occurs [see Warnings and Precautions (5.4)].
Drug-Induced Thrombocytopenia
Inform patients that drug-induced immune-mediated thrombocytopenia has been reported during
use of exenatide. Inform patients that if symptoms of thrombocytopenia occur, stop taking
BYETTA and seek medical advice promptly [see Warnings and Precautions (5.8)].
Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions have been reported during postmarketinguse of BYETTA. If symptoms of hypersensitivity reactions occur, instruct patients to stop taking
BYETTA and seek medical advice promptly [see Warnings and Precautions (5.7)].
Acute Gallbladder Disease
Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact
their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up[see Warnings and Precautions (5.9)].
Pregnancy
Advise patients to inform their physicians if they are pregnant or intend to become pregnant.
Instructions
Instruct patients to administer BYETTA as a subcutaneous injection in the thigh, abdomen, or
upper arm at any time within the 60-minute period before the morning and evening meals (orbefore the two main meals of the day, approximately 6 hours or more apart). Do not administer
BYETTA after a meal. If a dose is missed, resume the treatment regimen as prescribed with thenext scheduled dose.
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
BYETTA® is a registered trademark of the AstraZeneca group of companies.

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MEDICATION GUIDEBYETTA® (bye-A-tuh)(exenatide)
injection, for subcutaneous use
Read this Medication Guide and the Instructions for Use that comes with BYETTA before you start using it andeach time you get a refill. There may be new information. This Medication Guide does not take the place oftalking with your healthcare provider about your medical condition or your treatment. If you have questions about
BYETTA after reading this information, ask your healthcare provider or pharmacist.
What is the most important information I should know about BYETTA?
 Do not share your BYETTA Pen with other people, even if the needle has been changed. You may giveother people a serious infection or get a serious infection from them.
 Serious side effects can happen in people who take BYETTA, including inflammation of the pancreas(pancreatitis) which may be severe and lead to death. Stop using BYETTA and call your healthcare
provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with orwithout vomiting. You may feel the pain from your abdomen to your back. These may be symptoms ofpancreatitis.
What is BYETTA?
 BYETTA is an injectable prescription medicine that may improve blood sugar (glucose) control in adults with
type 2 diabetes mellitus, when used with a diet and exercise program.
 BYETTA is not insulin.
 BYETTA is not a substitute for insulin.
 The use of BYETTA with short acting insulin is not recommended.
 The use of BYETTA with rapid acting insulin is not recommended.
 BYETTA is not for people with type 1 diabetes or people with diabetic ketoacidosis.
 It is not known if BYETTA can be used in people who have had pancreatitis.
 It is not known if BYETTA is safe and effective in children.
 BYETTA should not be used in people who have severe kidney problems.
Who should not use BYETTA?
Do not use BYETTA if: you have had a severe allergic reaction to exenatide or any of the other ingredients in BYETTA. See the endof this Medication Guide for a complete list of ingredients in BYETTA.
Symptoms of a severe allergic reaction with BYETTA may include:oswelling of your face, lips, tongue, or throatofainting or feeling dizzyoproblems breathing or swallowingovery rapid heartbeatosevere rash or itching you have a history of low blood platelet count from using exenatide medicines (drug-induced
thrombocytopenia).
Before taking BYETTA, tell your healthcare provider about all of your medical conditions, including ifyou: have or have had problems with your pancreas.
 have severe problems with your stomach, such as delayed emptying of your stomach (gastroparesis) or
problems with digesting food.
 have or have had kidney problems, or have had a kidney transplant.
 are pregnant or plan to become pregnant. It is not known if BYETTA will harm your unborn baby. Tell yourhealthcare provider if you become pregnant while taking BYETTA. Talk to your healthcare provider about thebest way to control your blood sugar if you plan to become pregnant or while you are pregnant.
 are breastfeeding or plan to breastfeed. It is not known if BYETTA passes into your breast milk. You should
talk with your healthcare provider about the best way to feed your baby while taking BYETTA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. BYETTA may affect the way some medicines work and some othermedicines may affect the way BYETTA works.
Especially tell your healthcare provider if you take: other anti-diabetes medicines, especially sulfonylurea medicines or insulin.

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

birth control pills that are taken by mouth (oral contraceptives). BYETTA may lower the amount of the
medicine in your blood from your birth control pills and they may not work as well to prevent pregnancy. Take
your birth control pills at least one hour before your injection of BYETTA. If you must take your birth control
pills with food, take it with a meal or snack at a time when you do not also take BYETTA.
 an antibiotic. Take antibiotic medicines at least one hour before taking BYETTA. If you must take yourantibiotic with food, take it with a meal or snack at a time when you do not also take BYETTA.
 warfarin sodium (Coumadin®, Jantoven®).
 a blood pressure medicine.
 a water pill (diuretic).
 a pain medicine.
 lovastatin (Altoprev®, Mevacor®, Advicor®).
How should I take BYETTA?
See the Instructions for Use that comes with BYETTA for instructions for using the BYETTA Pen and injecting
BYETTA.
 Your healthcare provider may prescribe BYETTA alone or with certain other medicines to help control yourblood sugar.
 Use BYETTA exactly as your healthcare provider tells you to.
 Your healthcare provider should teach you how to inject BYETTA before you use it for the first time.
 Inject your dose of BYETTA under the skin (subcutaneous injection) of your upper leg (thigh), stomach area
(abdomen), or upper arm as instructed by your healthcare provider. Do not inject into a vein or muscle.
 Do not mix BYETTA and insulin in the same syringe or vial even if you take them at the same time.
 BYETTA is injected two times each day, at any time within 60 minutes (1 hour) before your morning andevening meals (or before the two main meals of the day, approximately 6 hours or more apart). Do not take
BYETTA after your meal.
 If you miss a dose of BYETTA, skip that dose and take your next dose at the next prescribed time. Do nottake an extra dose or increase the amount of your next dose to make up for a missed dose.
 If you use too much BYETTA, call your healthcare provider. Too much BYETTA can cause your blood sugar
to drop quickly and you may have symptoms of low blood sugar. You may need medical treatment right away.
Too much BYETTA can also cause severe nausea and vomiting.
 If you see your blood sugar increasing during treatment with BYETTA, talk to your healthcare provider
because you may need to adjust your current treatment plan for your diabetes.
What are the possible side effects of BYETTA?
BYETTA may cause serious side effects, including: See "What is the most important information I should know about BYETTA?" Low blood sugar (hypoglycemia). Your risk for getting low blood sugar is higher if you take BYETTA withanother medicine that can cause low blood sugar, such as a sulfonylurea or insulin. The dose of yoursulfonylurea or insulin medicine may need to be lowered while you use BYETTA. Signs and symptoms of low
blood sugar may include: headache hunger confusion
 feeling jittery drowsiness fast heart beat anxiety, irritability or blurred visionmood change weakness
 dizziness sweating
 slurred speech
Talk with your healthcare provider about how to treat low blood sugar.
 Kidney problems. BYETTA may cause new or worse problems with kidney function, including kidney failure.
Dialysis or kidney transplant may be needed.
o While taking BYETTA: Call your healthcare provider right away if you have nausea, vomiting, or
diarrhea that will not go away, or if you cannot take liquids by mouth. You may be at increased risk
for kidney problems.
 Stomach problems. Other medicines like BYETTA may cause severe stomach problems. It is not known if
BYETTA causes stomach problems or will cause your stomach problems to worsen.
 Low blood platelet count (drug-induced thrombocytopenia). BYETTA may cause the number of platelets
in your blood to be reduced. When your platelet count is too low, your body cannot form blood clots. You

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could have serious bleeding that could lead to death. Stop using BYETTA and call your healthcare
provider right away if you have unusual bleeding or bruising.
 Severe allergic reactions. Severe allergic reactions can happen with BYETTA. Stop taking BYETTA andget medical help right away if you have any symptom of a severe allergic reaction. See "Who should not
use BYETTA?" Gallbladder problems. Gallbladder problems have happened in some people who take BYETTA. Tell yourhealthcare provider right away if you get symptoms of gallbladder problems, which may include:o pain in your upper stomach (abdomen)
o yellowing of skin or eyes (jaundice)o clay-colored stoolso fever
The most common side effects of BYETTA include: nausea feeling jittery indigestion
 vomiting
 dizziness constipation
 diarrhea
 headache weakness
Nausea is most common when you first start using BYETTA but may decrease over time.
Talk to your healthcare provider about any side effect that bothers you or that does not go away. These are not
all the possible side effects of BYETTA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store BYETTA?
 Store your new, unused BYETTA Pen in the original carton in a refrigerator at 36°F to 46°F (2°C to 8°C).
 After first use, keep your BYETTA Pen at a temperature cooler than 77°F (25°C).
 Do not freeze your BYETTA Pen. Do not use BYETTA if it has been frozen.
 Protect BYETTA from light.
 Use a BYETTA Pen for only 30 days. Throw away a used BYETTA Pen after 30 days, even if there is somemedicine left in the pen.
 Do not use BYETTA after the expiration date printed on the label.
 Keep your BYETTA Pen, pen needles, and all medicines out of the reach of children.
General information about the safe and effective use of BYETTA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
BYETTA for a condition for which it was not prescribed. Do not give BYETTA to other people, even if they havethe same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for
information about BYETTA that is written for health professionals.
What are the ingredients in BYETTA?
Active ingredient: exenatide
Inactive ingredients: metacresol, mannitol, glacial acetic acid, and sodium acetate trihydrate in water for
injection.
BYETTA® is a registered trademark of the AstraZeneca group of companies. All other trademarks are the trademarks of their respective owners.
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
For more information, call 1-800-236-9933.
This Medication Guide has been approved by the U.S. Food and Drug Administration

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Revised 06/2022

INSTRUCTIONS FOR USE
BYETTA® (bye-A-tuh)(exenatide) injection
for subcutaneous use
250 mcg/mL, 1.2 mL
Do not share your BYETTA Pen with other people, even if the needle has been changed. You may
give other people a serious infection or get a serious infection from them.
Section 1

Read this section completely before you begin. Then, move on to Section
2–Getting Started.

WHAT YOU NEED TO KNOW ABOUT YOUR BYETTA PENINSTRUCTIONS FOR USE
Read these instructions carefully BEFORE using your BYETTA Pen. For complete dosing and safety
information, also read the BYETTA Medication Guide that comes with the BYETTA Pen carton.
It is important that you use your pen correctly. Failure to follow these instructions completely may result ina wrong dose, a broken pen or an infection.
These instructions do not take the place of talking with your healthcare provider about your medical
condition or your treatment. If you are having problems using your BYETTA Pen, call toll free 1-800236-9933.
IMPORTANT INFORMATION ABOUT YOUR BYETTA PEN









Each BYETTA Pen contains enough medicine for injection two times each day for 30 days. You do nothave to measure any doses, the pen measures each dose for you.
Do not transfer the medicine in the BYETTA Pen to a syringe or vial.
Do not mix BYETTA and insulin in the same syringe or vial even if you take them at the same time.
If any part of your pen appears broken or damaged, do not use the pen.
This BYETTA Pen is not recommended for use by people who are blind or have vision problems without
the help of a person trained in the proper use of the pen.
Follow the injection method explained to you by your healthcare provider.
Follow Section 2 only to set up a new pen before first use.
Section 3 of these Instructions for Use should be used for every injection.

ABOUT PEN NEEDLES

1Reference ID: 5098195

What kinds of needles can be used with my BYETTA Pen?


Pen needles are not included with your pen. You may need a prescription to get them from yourpharmacist.
Use 29 (thin), 30, or 31 (thinner) gauge disposable pen needles with your BYETTA Pen. Ask yourhealthcare provider which needle gauge and length is best for you.

Do I use a new needle for each injection?
Yes. Do not reuse or share your needles with other people. You may give other people a serious
infection or get a serious infection from them.
Remove the needle from the pen immediately after you complete each injection. This will help prevent
leakage of BYETTA, keep out air bubbles, reduce needle clogs, and decrease the risk of infection.
Do not push the injection button on your pen unless a needle is attached to the pen.

How do I throw away my needles?
Put your used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away
(dispose of) loose needles and syringes in your household trash. If you do not have a FDA-cleared sharps
disposal container, you may use a household container that is:






Made of a heavy-duty plastic,
Can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
Upright and stable during use,
Leak-resistant, andProperly labeled to warn of hazardous waste inside the container.

When your sharps disposal container is almost full, you will need to follow your community guidelines forthe right way to dispose of your sharps disposal container. There may be state or local laws about how you
should throw away used needles and syringes.
Do not share your BYETTA Pen with other people, even if the needle has been changed. You may
give other people a serious infection or get a serious infection from them.
STORING YOUR BYETTA PEN
How do I store my BYETTA Pen?






Prior to first use, store your unused BYETTA Pen in the original carton in a refrigerator at 36°F to 46°F
(2°C to 8°C).
After first use, your BYETTA Pen can be kept at a temperature cooler than 77°F (25°C).
Do not freeze your BYETTA Pen. Do not use BYETTA if it has been frozen. BYETTA should beprotected from light.
When carrying the pen away from home, store the pen at a temperature between 36°F to 77°F (2°C to25°C) and keep dry.
Do not store the pen with the needle attached. If the needle is left on the pen, BYETTA may leak fromthe pen and air bubbles may form in the cartridge.

Keep your pen and needles out of the reach of children.
How long can I use a BYETTA Pen?

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

You can use your BYETTA Pen for up to 30 days after setting up a new pen for first use. After 30 days,
throw away the BYETTA Pen in a FDA-cleared sharps disposal container, even if it is notcompletely empty.
Mark the date when you first used your pen and the date 30 days later in the spaces below:

Date of First UseDate to Throw Away Pen

BYETTA should not be used after the expiration date printed on the pen label.

How do I clean my BYETTA Pen?


Wipe the outside of the pen with a clean, damp cloth.
White particles may appear on the outside tip of the cartridge during normal use. You may remove themwith an alcohol wipe or alcohol swab.

See the complete BYETTA Medication Guide that comes with BYETTA. For more information, calltoll free 1-800-236-9933.

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Section 2

Read and follow the directions in this section only after you've read Section
1—What You Need To Know About Your BYETTA Pen.
GETTING STARTED

Set up your new pen just before you use it the first time. For routine use, do not repeat this one-time-only
new pen setup. If you do, you will run out of BYETTA before 30 days of use.

ONE-TIME-ONLY NEW PEN SETUP
STEP A Check the Pen
Note: Small air bubbles in the
cartridge are normal.



Wash hands prior to use.
Check pen label to makesure it is your 5 mcg pen.
Pull off the blue pen cap.

Check BYETTA in the
cartridge. The liquid should
be clear, colorless, and freeof particles. If not, do notuse.

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STEP B Attach the NeedleRemove paper tab from outerneedle shield.
Push outer needle shieldcontaining the needle
straight onto the pen, thenscrew needle on until secure.

Pull off outer needle
shield. Do not throw
away.



Pull off inner needle shield
and throw away. A small
drop of liquid may appear.
This is normal.

Pull dose knob out until itTurn dose knob awayfrom you until it stops at

STEP C Dial the Dose

Check that theis in thedose window. If not, turndose knob away from you(clockwise) until it stops
and thewindow.



stops and thedose window.

is in theis in the dose

Note: If you cannot turn the dose knob away from you to thenumber 7, in Section 4 of these Instructions for Use.

5

Reference ID: 5098195. Make sure that the 5with the line under it is in
the center of the dose
window.
, see Commonly Asked Questions,

STEP D Prepare the Pen



Point the needle of the pen
up and away from you.





PUSH & HOLD
Use thumb to firmly pushinjection button in until it
stops, then continue holding
the injection button in whileslowly counting to 5.
If you do not see a stream
or several drops comefrom the needle tip, repeat
Steps C & D.

Pen preparation is complete
when theis in thecenter of the dose window
and you have seen a
stream or several drops
come from the needle tip.

Note: If you do not see liquid after 4 times, see Commonly Asked Questions, number 3, in Section 4 ofthese Instructions for Use.
STEP E Complete New Pen Setup

For routine use, do notrepeat this one-time-only
new pen setup. If you do,
you will run out of BYETTA
before 30 days of use.

Turn dose knob awayfrom you until it stops and

You are now ready for yourfirst dose of BYETTA.
Go to Section 3, Step 3,
for instructions on how toinject your first routine
dose.

the
is in the dose
window.
Note: If you cannot turn the dose knob, see Commonly Asked Questions, number 7, in Section 4 of these
Instructions for Use.

6

Reference ID: 5098195

Section 3

Now that you have done the one-time-only new pen setup, follow Section 3
for all of your injections.
ROUTINE USE

STEP 1 Check the Pen
Note: Small air bubbles will notharm you or affect your dose.



Wash hands prior to use.
Check pen label to makesure it is your 5 mcg pen.
Pull off the blue pen cap.

Check BYETTA in the
cartridge.
The liquid should be clear,colorless, and free ofparticles. If it is not, do not
use.

STEP 2 Attach the Needle

Remove paper tab fromouter needle shield.
Push outer needle shieldcontaining the needle
straight onto pen, thenscrew needle on until
secure.



Pull off outer needle shield.
Do not throw away.



Pull off inner needle shield
and throw away. A small
drop of liquid may appear.
This is normal.

Pull dose knob out until itTurn dose knob awayfrom you until it stops at

STEP 3 Dial the Dose

Check that theis in thedose window. If not, turndose knob away from you(clockwise) until it stops
and thewindow.

stops and thedose window.

is in theis in the dose

Note: If you cannot turn the dose knob away from you to thenumber 7, in Section 4 of these Instructions for Use.
STEP 4 Inject the Dose7

Reference ID: 5098195. Make sure that the 5with the line under it is in
the center of the dose
window.
, see Commonly Asked Questions,Grip pen firmly.
Insert needle into skin using
the under-the-skin(subcutaneous) injection
method explained by yourhealthcare provider.

PUSH & HOLD

Use thumb to firmly pushinjection button in until it
stops. Continue holding in
the injection button whileslowly counting to 5 to geta full dose.
Remove needle from skin.



Injection is complete when
theis in the center ofthe dose window.
The pen is now ready toreset.

Note: If you see several drops of BYETTA leaking from the needle after the injection, you may not havereceived a complete dose. See Commonly Asked Questions, number 4, in Section 4 of these Instructions
for Use.
STEP 5 Reset the Pen
Turn dose knob away fromyou until it stops and theis in the dose window.

Note: If you cannot turn thedose knob, or if your pen leaks,
your full dose has not beendelivered. See Commonly
Asked Questions, numbers 4
and 7, in Section 4 of these
Instructions for Use.

STEP 6 Remove and Dispose of the Needle

Carefully put the outerneedle shield back over theneedle.
Remove the needle after
each injection.



Unscrew the needle.



Throw away needles in a
FDA-cleared sharps
disposal container (Seeabove “How do I throw
away my needles?”) or asrecommended by yourhealthcare provider.

STEP 7 Store Pen for Next Dose

Replace Blue Pen Cap on pen before storage.
Store your BYETTA Pen at a temperature between 36°F to 77°F (2°C to 25°C). (See Storing YourBYETTA Pen in Section 1 of these Instructions for Use for complete storage information.)
When it is time for your next routine dose, go to Section 3, Step 1, and repeat Steps 1–7.

Section 4

COMMONLY ASKED QUESTIONS

1. Do I need to do the One-Time-Only New Pen Setup before every dose?

8

Reference ID: 5098195

No. The One-Time-Only New Pen Setup is done only once, just before each new pen is used forthe first time.
The purpose of the setup is to make sure that your BYETTA Pen is ready to use for the next 30 days.
If you repeat the One-Time-Only New Pen Setup before each routine dose, you will not haveenough BYETTA for 30 days. The small amount of BYETTA used in the new pen setup will not affectthe 30-day supply of BYETTA.

2. Why are there air bubbles in the cartridge?


A small air bubble is normal. It will not harm you or affect your dose.
If the pen is stored with a needle attached, air bubbles may form in the cartridge. Do not store the pen
with the needle attached.

3. What should I do if BYETTA does not come out of the needle tip after four tries during One-TimeOnly New Pen Setup?


Carefully put the outer needle shield back over the needle. Remove the needle by unscrewing it. Throw
away the needle properly.
Attach a new needle and repeat One-Time-Only New Pen Setup, Steps B–E, in Section 2 of these
Instructions for Use. Once you see several drops or a stream of liquid coming out of the tip of theneedle, the setup is complete.

4. Why do I see BYETTA leaking from my needle after I have finished my injection?
It is normal for a single drop to remain on the tip of your needle after your injection is complete. If you see
more than one drop:You may not have received your full dose. Do not inject another dose. Talk with your healthcare
provider about what to do about a partial dose.
To make sure that you get your full dose, when you take your injections, firmly push and hold theinjection button in and slowly count to 5 (see Section 3, Step 4: Inject the Dose).

5. How can I tell when the injection is complete?
The injection is complete when:You have firmly pushed the injection button in all the way until it stops
andYou have slowly counted to 5 while you are still holding the injection button in and the needle is stillin your skin
and



The

is in the center of the dose window.

If you hear a click sound from your BYETTA Pen, ignore it. You must follow all the steps listed above to
make sure your injection is complete.

9

Reference ID: 5098195

6. Where should I inject BYETTA?
Inject BYETTA into your abdomen, thigh, or upper arm using theinjection method explained to you by your healthcare provider.

7. What if I cannot pull, turn, or push the dose knob?
Check the symbol in the dose window. Follow the steps next to the matching symbol.
If

is in the dose window:Pull the dose knob out until

is in the dose window and the dose knob will not turn:If

The cartridge in your BYETTA Pen may not have enough medicine to deliver a full dose. A small
amount of BYETTA will always stay in the cartridge. If the cartridge contains a small amount and thedose knob will not turn, your pen does not have enough BYETTA and will not deliver any more doses.
Get a new BYETTA Pen.
and part of

If




and part ofisare in the dose window and the dose knob cannot be pushed in:

The needle may be clogged, bent, or incorrectly attached.
Attach a new needle. Make sure needle is on straight and screwed on all the way.
Firmly push the injection button in all the way. BYETTA should come from needle tip.
is in the dose window and the dose knob will not turn:Ifare in the dose window and the dose knob cannot be pushed in:

The dose knob was not turned all the way. Continue turning the dose knob away from you untilin the center of the dose window.

If part of

appears.

The injection button was not pushed in all the way and a complete dose was not delivered. Talk withyour healthcare provider about what to do about a partial dose.
Follow these steps to reset your pen for your next injection:

10

Reference ID: 5098195



Firmly push the injection button in all the way until it stops. Keep holding the injection button
in and slowly count to 5. Then release the injection button and turn the dose knob away fromyou until
appears in the dose window.
If you cannot turn the dose knob, the needle may be clogged. Replace the needle and repeat
the step above.
For your next dose, be sure to firmly push and hold the injection button in and slowly count to 5
before removing needle from skin.


See the complete BYETTA Medication Guide that comes with BYETTA. For more information, calltoll free 1-800-236-9933.

Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
BYETTA® is a registered trademark of the AstraZeneca group of companies.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Revised: December 2022

11

Reference ID: 5098195

INSTRUCTIONS FOR USE
BYETTA® (bye-A-tuh)(exenatide) injection
for subcutaneous use
250 mcg/mL, 2.4 mL
Do not share your BYETTA Pen with other people, even if the needle has been changed. You may
give other people a serious infection or get a serious infection from them.
Section 1

Read this section completely before you begin. Then, move on to Section
2−Getting Started.

WHAT YOU NEED TO KNOW ABOUT YOUR BYETTA PENINSTRUCTIONS FOR USE
Read these instructions carefully BEFORE using your BYETTA Pen. For complete dosing and safety
information, also read the BYETTA Medication Guide that comes with the BYETTA Pen carton.
It is important that you use your pen correctly. Failure to follow these instructions completely may result ina wrong dose, a broken pen or an infection.
These instructions do not take the place of talking with your healthcare provider about your medical
condition or your treatment. If you are having problems using your BYETTA Pen, call toll free 1-800236-9933.
IMPORTANT INFORMATION ABOUT YOUR BYETTA PEN









Each BYETTA Pen contains enough medicine for injection two times each day for 30 days. You do nothave to measure any doses, the pen measures each dose for you.
Do not transfer the medicine in the BYETTA Pen to a syringe or vial.
Do not mix BYETTA and insulin in the same syringe or vial even if you take them at the same time.
If any part of your pen appears broken or damaged, do not use the pen.
This BYETTA Pen is not recommended for use by people who are blind or have vision problems without
the help of a person trained in the proper use of the pen.
Follow the injection method explained to you by your healthcare provider.
Follow Section 2 only to set up a new pen before first use.
Section 3 of these Instructions for Use should be used for every injection.

ABOUT PEN NEEDLES

1Reference ID: 5098195

What kinds of needles can be used with my BYETTA Pen?


Pen needles are not included with your pen. You may need a prescription to get them from yourpharmacist.
Use 29 (thin), 30, or 31 (thinner) gauge disposable pen needles with your BYETTA Pen. Ask yourhealthcare provider which needle gauge and length is best for you.

Do I use a new needle for each injection?
Yes. Do not reuse or share your needles with other people. You may give other people a serious
infection or get a serious infection from them.
Remove the needle from the pen immediately after you complete each injection. This will help prevent
leakage of BYETTA, keep out air bubbles, reduce needle clogs, and decrease the risk of infection.
Do not push the injection button on your pen unless a needle is attached to the pen.

How do I throw away my needles?
Put your used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away
(dispose of) loose needles and syringes in your household trash. If you do not have a FDA-cleared sharps
disposal container, you may use a household container that is:






Made of a heavy-duty plastic,
Can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
Upright and stable during use,
Leak-resistant, andProperly labeled to warn of hazardous waste inside the container.

When your sharps disposal container is almost full, you will need to follow your community guidelines forthe right way to dispose of your sharps disposal container. There may be state or local laws about how you
should throw away used needles and syringes.
Do not share your BYETTA Pen with other people, even if the needle has been changed. You may
give other people a serious infection or get a serious infection from them.
STORING YOUR BYETTA PEN
How do I store my BYETTA Pen?






Prior to first use, store your unused BYETTA Pen in the original carton in a refrigerator at 36°F to 46°F
(2°C to 8°C).
After first use, your BYETTA Pen can be kept at a temperature cooler than 77°F (25°C).
Do not freeze your BYETTA Pen. Do not use BYETTA if it has been frozen. BYETTA should beprotected from light.
When carrying the pen away from home, store the pen at a temperature between 36°F to 77°F (2°C to25°C) and keep dry.
Do not store the pen with the needle attached. If the needle is left on the pen, BYETTA may leak fromthe pen and air bubbles may form in the cartridge.

Keep your pen and needles out of the reach of children.
How long can I use a BYETTA Pen?

2

Reference ID: 5098195



You can use your BYETTA Pen for up to 30 days after setting up a new pen for first use. After 30 days,
throw away the BYETTA Pen in a FDA-cleared sharps disposal container, even if it is notcompletely empty.
Mark the date when you first used your pen and the date 30 days later in the spaces below:

Date of First UseDate to Throw Away Pen

BYETTA should not be used after the expiration date printed on the pen label.

How do I clean my BYETTA Pen?


Wipe the outside of the pen with a clean, damp cloth.
White particles may appear on the outside tip of the cartridge during normal use. You may remove themwith an alcohol wipe or alcohol swab.

See the complete BYETTA Medication Guide that comes with BYETTA. For more information, calltoll free 1-800-236-9933.

3

Reference ID: 5098195

Section 2

Read and follow the directions in this section only after you've read Section
1—What You Need To Know About Your BYETTA Pen.

GETTING STARTED
Set up your new pen just before you use it the first time. For routine use, do not repeat this one-time-only
new pen setup. If you do, you will run out of BYETTA before 30 days of use.

ONE-TIME-ONLY NEW PEN SETUP
STEP A Check the Pen
Note: Small air bubbles in
the cartridge are normal.



Wash hands prior to use.
Check pen label to make sure
it is your 10 mcg pen.
Pull off the blue pen cap.

Check BYETTA in the
cartridge. The liquid should
be clear, colorless, and freeof particles. If not, do notuse.

4

Reference ID: 5098195

STEP B Attach the NeedlePull off outer needle
shield. Do not throw
away.



Pull off inner needle shield
and throw away. A small
drop of liquid may appear.
This is normal.

Pull dose knob out untilTurn dose knob away fromRemove paper tab from outerneedle shield.
Push outer needle shieldcontaining the needle straightonto the pen, then screw
needle on until secure.

STEP C Dial the Dose

Check that theis in thedose window. If not, turn doseknob away from you(clockwise) until it stops andtheit stops and thethe dose window.

you until it stops at .
Make sure that the 10 withthe line under it is in thecenter of the dose window.

is in

is in the dose window.

Note: If you cannot turn the dose knob away from you to thenumber 7, in Section 4 of these Instructions for Use.

, see Commonly Asked Questions,

STEP D Prepare the Pen



Point the needle of the pen
up and away from you.

PUSH & HOLD

Use thumb to firmly pushinjection button in until it
stops, then continue
holding the injection button
in while slowly counting to5.
If you do not see a stream
or several drops comefrom the needle tip, repeat
Steps C & D.

Pen preparation is complete
when theis in thecenter of the dose window
and you have seen a
stream or several drops
come from the needle tip.

Note: If you do not see liquid after 4 times, see Commonly Asked Questions, number 3, in Section 4 ofthese Instructions for Use.

5

Reference ID: 5098195

STEP E Complete New Pen Setup

For routine use, do notrepeat this one-time-only
new pen setup. If you do,
you will run out of BYETTA
before 30 days of use.

Turn dose knob away from

You are now ready foryour first dose of
BYETTA.
Go to Section 3, Step 3,
for instructions on how
to inject your firstroutine dose.

you until it stops and theis in the dose window.
Note: If you cannot turn the dose knob, see Commonly Asked Questions, number 7, in Section 4 of these
Instructions for Use.
Section 3
Now that you have done the one-time-only new pen setup, follow Section 3 for all of
your injections.
ROUTINE USE
STEP 1 Check the Pen
Note: Small air bubbles will
not harm you or affect your
dose.





Wash hands prior to use.
Check pen label to makesure it is your 10 mcg pen.
Pull off the blue pen cap.

Check BYETTA in the
cartridge.
The liquid should be clear,colorless, and free ofparticles. If it is not, do not
use.

STEP 2 Attach the Needle

Remove paper tab fromouter needle shield.
Push outer needle shieldcontaining the needle
straight onto pen, thenscrew needle on until
secure.



Pull off outer needle shield.
Do not throw away.

STEP 3 Dial the Dose6

Reference ID: 5098195

Pull off inner needle shield
and throw away. A small
drop of liquid may appear.
This is normal.



Check that theis in thedose window. If not, turndose knob away from you(clockwise) until it stops
and thewindow.



Pull dose knob out until it
stops and thedose window.

is in theis in the dose

Note: If you cannot turn the dose knob away from you to thenumber 7, in Section 4 of these Instructions for Use.



Turn dose knob away fromyou until it stops at.
Make sure that the 10 withthe line under it is in thecenter of the dose window.

, see Commonly Asked Questions,

STEP 4 Inject the Dose

PUSH & HOLD Injection is complete when
Use thumb to firmly pushtheis in the center of
injection button in until it
the dose window.
stops. Continue holding in The pen is now ready tothe injection button while
reset.
slowly counting to 5 to geta full dose.
 Remove needle from skin.
Note: If you see several drops of BYETTA leaking from the needle after the injection, you may not havereceived a complete dose. See Commonly Asked Questions, number 4, in Section 4 of these
Instructions for Use.
Grip pen firmly.
Insert needle into skin using
the under-the-skin(subcutaneous) injection
method explained by yourhealthcare provider.



STEP 5 Reset the Pen
Turn dose knob awayfrom you until it stops andtheis in the dose
window.

STEP 6 Remove and Dispose of the Needle

7

Reference ID: 5098195

Note: If you cannot turn thedose knob, or if your pen leaks,
your full dose has not beendelivered. See Commonly
Asked Questions, numbers 4
and 7, in Section 4 of these
Instructions for Use.



Carefully put the outerneedle shield back over theneedle.
Remove the needle after
each injection.



Unscrew the needle.



Throw away needles in a
FDA-cleared sharps
disposal container (Seeabove “How do I throw
away my needles?”) or asrecommended by yourhealthcare provider.

STEP 7 Store Pen for Next Dose

Replace Blue Pen Cap on pen before storage.
Store your BYETTA Pen at a temperature between 36°F to 77°F (2°C to 25°C). (See Storing YourBYETTA Pen in Section 1 of these Instructions for Use for complete storage information.)
When it is time for your next routine dose, go to Section 3, Step 1, and repeat Steps 1–7.

Section 4

COMMONLY ASKED QUESTIONS

1. Do I need to do the One-Time-Only New Pen Setup before every dose?


No. The One-Time-Only New Pen Setup is done only once, just before each new pen is used forthe first time.
The purpose of the setup is to make sure that your BYETTA Pen is ready to use for the next 30 days.
If you repeat the One-Time-Only New Pen Setup before each routine dose, you will not haveenough BYETTA for 30 days. The small amount of BYETTA used in the new pen setup will not affectthe 30-day supply of BYETTA.

2. Why are there air bubbles in the cartridge?


A small air bubble is normal. It will not harm you or affect your dose.
If the pen is stored with a needle attached, air bubbles may form in the cartridge. Do not store the pen
with the needle attached.

3. What should I do if BYETTA does not come out of the needle tip after four tries during One-TimeOnly New Pen Setup?


Carefully put the outer needle shield back over the needle. Remove the needle by unscrewing it. Throw
away the needle properly.
Attach a new needle and repeat One-Time-Only New Pen Setup, Steps B–E, in Section 2 of these
Instructions for Use. Once you see several drops or a stream of liquid coming out of the tip of theneedle, the setup is complete.

8

Reference ID: 5098195

4. Why do I see BYETTA leaking from my needle after I have finished my injection?
It is normal for a single drop to remain on the tip of your needle after your injection is complete. If you see
more than one drop:You may not have received your full dose. Do not inject another dose. Talk with your healthcare
provider about what to do about a partial dose.
To make sure that you get your full dose, when you take your injections, firmly push and hold theinjection button in and slowly count to 5 (see Section 3, Step 4: Inject the Dose).

5. How can I tell when the injection is complete?
The injection is complete when:You have firmly pushed the injection button in all the way until it stops
andYou have slowly counted to 5 while you are still holding the injection button in and the needle is stillin your skin
and



The

is in the center of the dose window.

If you hear a click sound from your BYETTA Pen, ignore it. You must follow all the steps listed above to
make sure your injection is complete.
6. Where should I inject BYETTA?
Inject BYETTA into your abdomen, thigh, or upper arm using theinjection method explained to you by your healthcare provider.

7. What if I cannot pull, turn, or push the dose knob?
Check the symbol in the dose window. Follow the steps next to the matching symbol.
If

is in the dose window:Pull the dose knob out until

If

appears.

is in the dose window and the dose knob will not turn:

9

Reference ID: 5098195



The cartridge in your BYETTA Pen may not have enough medicine to deliver a full dose. A small amountof BYETTA will always stay in the cartridge. If the cartridge contains a small amount and the dose knob
will not turn, your pen does not have enough BYETTA and will not deliver any more doses. Obtain a
new BYETTA Pen.
and part ofIfThe dose knob was not turned all the way. Continue turning the dose knob away from you untilin the center of the dose window.

If part of






and part ofisare in the dose window and the dose knob cannot be pushed in:

The needle may be clogged, bent, or incorrectly attached.
Attach a new needle. Make sure needle is on straight and screwed on all the way.
Firmly push the injection button in all the way. BYETTA should come from needle tip.
is in the dose window and the dose knob will not turn:Ifare in the dose window and the dose knob cannot be pushed in:

The injection button was not pushed in all the way and a complete dose was not delivered. Talk withyour healthcare provider about what to do about a partial dose.
Follow these steps to reset your pen for your next injection:
 Firmly push the injection button in all the way until it stops. Keep holding the injection button
in and slowly count to 5. Then release the injection button and turn the dose knob away fromappears in the dose window.
you until
If you cannot turn the dose knob, the needle may be clogged. Replace the needle and repeat
the step above.
For your next dose, be sure to firmly push and hold the injection button in and slowly count to 5
before removing needle from skin.


See the complete BYETTA Medication Guide that comes with BYETTA. For more information, calltoll free 1-800-236-9933.

Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
BYETTA® is a registered trademark of the AstraZeneca group of companies.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Revised: December 2022

10

Reference ID: 5098195