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BYETTA®
(exenatide) Injection
BYETTA (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, alpha-glucosidase inhibitors, amylinomimetics and dipeptidyl peptidase-4 inhibitors.
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 for exenatide is shown below.
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu -Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
BYETTA (exenatide injection) is supplied for SC injection 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 antimicrobial preservative, 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 are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).
BYETTA (exenatide) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies].
BYETTA is not a substitute for insulin. BYETTA should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
The concurrent use of BYETTA with prandial insulin has not been studied and cannot be recommended.
Based on postmarketing data, BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYETTA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using BYETTA. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.
BYETTA should be initiated at 5 mcg administered twice daily (BID) at any time within the 60minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). BYETTA should not be administered after a meal. Based on clinical response, the dose of BYETTA can be increased to 10 mcg twice daily after 1 month of therapy. Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix BYETTA with insulin. Do not transfer BYETTA from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of BYETTA.
Use BYETTA only if it is clear, colorless, and contains no particles.
BYETTA injection is supplied as 250 mcg/mL exenatide in the following packages:
BYETTA (exenatide) is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide.
The following packages are available:
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
Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850. Revised: Feb 2020
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Table 1 summarizes the incidence and rate of hypoglycemia with BYETTA (exenatide injection) in five placebo-controlled clinical trials.
Table 1: Incidence (%) and Rate of Hypoglycemia When BYETTA (exenatide injection)
was Used as Monotherapy or With Concomitant Antidiabetic Therapy in Five Placebo-Controlled
Clinical Trials*
| BYETTA | |||
| Placebo twice daily | 5 mcg twice daily | 10 mcg twice daily | |
| Monotherapy (24 Weeks) | |||
| N | 77 | 77 | 78 |
| % Overall | 1.3% | 5.2% | 3.8% |
| Rate (episodes/patientÂyear) | 0.03 | 0.21 | 0.52 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With Metformin (30 Weeks) | |||
| N | 113 | 110 | 113 |
| % Overall | 5.3% | 4.5% | 5.3% |
| Rate(episodes/patientÂyear) | 0.12 | 0.13 | 0.12 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With a Sulfonylurea (30 Weeks) | |||
| N | 123 | 125 | 129 |
| % Overall | 3.3% | 14.4% | 35.7% |
| Rate (episodes/patientÂyear) | 0.07 | 0.64 | 1.61 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With Metformin and a Sulfonylurea (30 Weeks) | |||
| N | 247 | 245 | 241 |
| % Overall | 12.6% | 19.2% | 27.8% |
| Rate(episodes/patientÂyear) | 0.58 | 0.78 | 1.71 |
| % Severe | 0.0% | 0.4% | 0.0% |
| With a Thiazolidinedione (16 Weeks) | |||
| N | 112 | Dose not studied | 121 |
| % Overall | 7.1% | Dose not studied | 10.7% |
| Rate(episodes/patient-years) | 0.56 | Dose not studied | 0.98 |
| % Severe | 0.0% | Dose not studied | 0.0% |
| * For the 30-week trials, a hypoglycemia
episode was recorded if the patient reported symptoms consistent with
hypoglycemia and was recorded as severe if the subject required the assistance
of another person to treat the event. For the other trials, a hypoglycemic
episode was recorded if a patient reported signs or symptoms of hypoglycemia
or had a blood glucose value consistent with hypoglycemia regardless of
associated symptoms or treatment and was recorded as severe if the subject
required the assistance of another person to treat the event. The requirement
for assistance had to be accompanied by a blood glucose measurement of
< 50 mg/dL or prompt recovery after administration of oral carbohydrate.
N = The number of Intent-to-Treat subjects in each treatment group. |
|||
In the 30-week controlled trials of BYETTA (exenatide injection) add-on to metformin and/or sulfonylurea, 38% of patients had low titer antibodies to exenatide at 30 weeks. For this group, the level of glycemic control (hemoglobin A1c [HbA1c]) was generally comparable to that observed in those without antibody titers. An additional 6% of patients had higher titer antibodies at 30 weeks. In about half of this 6% (3% of the total patients given BYETTA (exenatide injection) in the 30-week controlled studies), the glycemic response to BYETTA (exenatide injection) was attenuated; the remainder had a glycemic response comparable to that of patients without antibodies.
In the 16-week trial of BYETTA (exenatide injection) add-on to thiazolidinediones, with or without metformin, 9% of patients had higher titer antibodies at 16 weeks. In the 24-week trial of BYETTA (exenatide injection) used as monotherapy, 3% of patients had higher titer antibodies at 24 weeks. Compared with patients who did not develop antibodies to BYETTA (exenatide injection) , on average the glycemic response in patients with higher titer antibodies was attenuated [see WARNINGS AND PRECAUTIONS].
For the 24-week placebo-controlled study of BYETTA (exenatide injection) used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥ 2% and occurring more frequently in BYETTA (exenatide injection) -treated patients compared with placebo-treated patients.
Table 2: Treatment-Emergent Adverse Reactions ≥ 2% Incidence
With BYETTA (exenatide injection) Used as Monotherapy (Excluding Hypoglycemia)*
| Monotherapy | Placebo BID N = 77 % |
All BYETTA (exenatide injection) BID N = 155 % |
| Nausea | 0 | 8 |
| Vomiting | 0 | 4 |
| Dyspepsia | 0 | 3 |
| * In a 24-week placebo-controlled trial.
BID = twice daily. |
||
Adverse reactions reported in ≥ 1.0 to < 2.0% of patients receiving BYETTA (exenatide injection) and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with BYETTA (exenatide injection) , nausea, occurred in a dose-dependent fashion.
Two of the 155 patients treated with BYETTA (exenatide injection) withdrew due to adverse reactions of headache and nausea. No placebo-treated patients withdrew due to adverse reactions.
Add-on to metformin and/or sulfonylurea
In the three 30-week controlled trials of BYETTA (exenatide injection) add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥ 2% and occurring more frequently in BYETTA (exenatide injection) -treated patients compared with placebo-treated patients [see WARNINGS AND PRECAUTIONS] are summarized in Table 3.
Table 3: Treatment-Emergent Adverse Reactions ≥ 2% Incidence
and Greater Incidence With BYETTA (exenatide injection) Treatment Used With Metformin and/or a Sulfonylurea
(Excluding Hypoglycemia)*
| Placebo BID N = 483 % |
All BYETTA (exenatide injection) BID N = 963 % |
|
| Nausea | 18 | 44 |
| Vomiting | 4 | 13 |
| Diarrhea | 6 | 13 |
| Feeling Jittery | 4 | 9 |
| Dizziness | 6 | 9 |
| Headache | 6 | 9 |
| Dyspepsia | 3 | 6 |
| Asthenia | 2 | 4 |
| Gastroesophageal Reflux Disease | 1 | 3 |
| Hyperhidrosis | 1 | 3 |
| * In three 30-week placebo-controlled clinical
trials. BID = twice daily. |
||
Adverse reactions reported in ≥ 1.0 to < 2.0% of patients receiving BYETTA (exenatide injection) and reported more frequently than with placebo included decreased appetite. Nausea was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials.
The most common adverse reactions leading to withdrawal for BYETTA (exenatide injection) -treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, < 1% withdrew due to nausea and none due to vomiting.
Add-on to thiazolidinedione with or without metformin
For the 16-week placebo-controlled study of BYETTA (exenatide injection) add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥ 2% and occurring more frequently in BYETTA (exenatide injection) -treated patients compared with placebo-treated patients.
Table 4: Treatment-Emergent Adverse Reactions ≥ 2% Incidence
With BYETTA (exenatide injection) Used With a Thiazolidinedione, With or Without Metformin (Excluding
Hypoglycemia)*
| With a TZD or TZD/MET | Placebo N = 112 % |
All BYETTA (exenatide injection) BID N = 121 % |
| Nausea | 15 | 40 |
| Vomiting | 1 | 13 |
| Dyspepsia | 1 | 7 |
| Diarrhea | 3 | 6 |
| Gastroesophageal Reflux Disease | 0 | 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 (exenatide injection) and reported more frequently than with placebo included decreased appetite. Chills (n = 4) and injection-site reactions (n = 2) occurred only in BYETTA (exenatide injection) -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 (exenatide injection) arm. No serious adverse events were reported in the placebo arm.
The most common adverse reactions leading to withdrawal for BYETTA (exenatide injection) -treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, < 1% withdrew due to nausea.
The following additional adverse reactions have been reported during post-approval use of BYETTA (exenatide injection) . Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction [see WARNINGS AND PRECAUTIONS].
Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding [see DRUG INTERACTIONS].
Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Limitations of Use and WARNINGS AND PRECAUTIONS].
Neurologic: dysgeusia; somnolence
Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction [see WARNINGS AND PRECAUTIONS].
Skin and Subcutaneous Tissue Disorders: alopecia
The effect of BYETTA (exenatide injection) to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. BYETTA (exenatide injection) should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption [see ADVERSE REACTIONS]. 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 (exenatide injection) injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when BYETTA is not administered [see CLINICAL PHARMACOLOGY].
There are postmarketing reports of increased INR sometimes associated with bleeding, with concomitant use of warfarin and BYETTA [see ADVERSE REACTIONS]. In a drug interaction study, BYETTA (exenatide injection) did not have a significant effect on INR [see CLINICAL PHARMACOLOGY]. In patients taking warfarin, prothrombin time should be monitored more frequently after initiation or alteration of BYETTA (exenatide injection) therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on warfarin.
Included as part of the "PRECAUTIONS" Section
BYETTA pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.
Based on postmarketing data, BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYETTA, and after 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 in patients with a history of pancreatitis.
The risk of hypoglycemia is increased when BYETTA is used in combination with a sulfonylurea. Therefore, patients receiving BYETTA and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia.
When BYETTA is used in combination with insulin, the dose of insulin should be evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of insulin [see ADVERSE REACTIONS]. The concurrent use of BYETTA with prandial insulin has not been studied and cannot be recommended. It is also possible that the use of BYETTA with other glucose-independent insulin secretagogues (e.g., meglitinides) could increase the risk of hypoglycemia.
For additional information on glucose-dependent effects see Mechanism Of Action.
There have been postmarketing reports of altered renal function with exenatide, including increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status, such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting, or diarrhea, with or without dehydration. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including 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 renal transplantation [see Use In Specific Populations]. 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 with moderate renal impairment (creatinine clearance 30-50 mL/min).
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 patients with severe gastrointestinal disease.
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 placebo-controlled 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 attenuated glycemic response. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered [see ADVERSE REACTIONS].
There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with BYETTA. If a hypersensitivity reaction occurs, the patient should discontinue BYETTA and other suspect medications and promptly seek medical advice. Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with BYETTA [see ADVERSE REACTIONS].
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].
See FDA-approved PATIENT INFORMATION.
Advise patients that they must never share a BYETTA pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens [see WARNINGS AND PRECAUTIONS].
Patients should be informed 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. Patients should be instructed to promptly discontinue BYETTA and contact their physician if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS].
The risk of hypoglycemia is increased when BYETTA is used in combination with a sulfonylurea. Therefore, patients receiving BYETTA and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia. Patients should be informed that it is also possible that the use of BYETTA with other glucose-independent insulin secretagogues (e.g., meglitinides) could increase the risk of hypoglycemia.
When BYETTA is used in combination with insulin, evaluate the dose of insulin. Consider reducing the dose of insulin in patients at increased risk of hypoglycemia [see ADVERSE REACTIONS]. Patients treated with BYETTA should be informed that the concurrent use of BYETTA with prandial insulin has not been studied and cannot be recommended.
The symptoms, treatment, and conditions that predispose to development of hypoglycemia should be explained to the patient. The patient's usual instructions for hypoglycemia management should be reviewed and reinforced when initiating BYETTA therapy, particularly when concomitantly administered with a sulfonylurea or insulin [see WARNINGS AND PRECAUTIONS].
Patients treated with BYETTA should be informed of the potential risk for worsening renal function and informed about associated signs and symptoms of renal dysfunction, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see WARNINGS AND PRECAUTIONS].
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].
Patients should be informed that serious hypersensitivity reactions have been reported during postmarketing use of BYETTA. If symptoms of hypersensitivity reactions occur, patients must stop taking BYETTA and seek medical advice promptly [see WARNINGS AND PRECAUTIONS].
Patients should be advised to inform their physicians if they are pregnant or intend to become pregnant.
Each dose of BYETTA should be administered 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 (or before the two main meals of the day, approximately 6 hours or more apart). BYETTA should not be administered after a meal. If a dose is missed, the treatment regimen should be resumed as prescribed with the next scheduled dose.
Patients should be advised that treatment with BYETTA may result in a reduction in appetite, food intake, and/or body weight, and that there is no need to modify the dosing regimen due to such effects. Treatment with BYETTA may also result in nausea, particularly upon initiation of therapy [see ADVERSE REACTIONS].
The patient should read the Medication Guide and the Pen User Manual before starting BYETTA therapy and review them each time the prescription is refilled. The patient should be instructed on proper use and storage of the pen, emphasizing how and when to set up a new pen and noting that only one setup step is necessary at initial use. The patient should be advised not to share the pen and needles.
Patients should be informed that pen needles are not included with the pen and must be purchased separately. Patients should be advised which needle length and gauge should be used.
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 were observed 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 systemic exposures of 5-, 22-, and 130-times, respectively, the human exposure resulting from the 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 administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic 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 and throughout 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.
Limited data with BYETTA in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with 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 the potential risk to the fetus.
Animal reproduction studies identified increased adverse fetal and neonatal outcomes from exposure to exenatide during pregnancy and lactation in association with maternal effects. In 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.
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.
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 fetal organogenesis, irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a dose yielding 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 through lactation 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.
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 was present 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 and health 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 the underlying maternal condition.
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.
Safety and effectiveness of BYETTA have not been established in pediatric patients.
Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see CLINICAL PHARMACOLOGY)]. BYETTA was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and 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.
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 with renal 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].
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].
In 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 and symptoms.
BYETTA is contraindicated in patients with:
Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. 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.
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 in both 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.
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.
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-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of BYETTA at therapeutic 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-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with BYETTA compared with saline (p<0.001 for both).
Figure 1: Mean (+SEM) Insulin Secretion Rate during Infusion of BYETTA or Saline in Patients with Type 2 Diabetes and during Infusion of Saline in Healthy Subjects
 |
In patients with type 2 diabetes, BYETTA moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.
BYETTA slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.
In both animals and humans, administration of exenatide has been shown to reduce food intake.
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, a Sulfonylurea, or Both (N=54)
 |
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 were significantly reduced with BYETTA compared with placebo (Figure 3).
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)
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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 upper bound 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 clinically meaningful prolongation of the QTc interval.
Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma 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.
The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA is 28.3 L.
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.
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 not significantly changed when acetaminophen was given 1 hour before BYETTA injection.
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 by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of digoxin was not changed.
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.
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 blood pressure.
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% and 27%, respectively, and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of 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 trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. 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 confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to BYETTA injection.
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 by approximately 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].
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 of subjects 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 with normal renal function [see Use In Specific Populations].
No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment [see Use In Specific Populations].
Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Use In Specific Population].
Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.
Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide.
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.
BYETTA 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.
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 in patients 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 at time 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
| Placebo BID | BYETTA 5 mcg BID | BYETTA 10 mcg* BID | |
| Intent-to-Treat Population (N) | 77 | 77 | 78 |
| HbA1c (%), Mean | |||
| Baseline | 7.8 | 7.9 | 7.8 |
| Change at Week 24† | −0.2 | −0.7 | −0.9 |
| Difference from placebo† (95% CI) | −0.5 [−0.9, −0.2]‡ | −0.7 [−1.0, −0.3] | |
| Proportion Achieving HbA1c <7% | 38% | 48% | 53% |
| Body Weight (kg), Mean | |||
| Baseline | 86.1 | 85.1 | 86.2 |
| Change at Week 24† | −1.5 | −2.7 | −2.9 |
| Difference from placebo† (95% CI) | −1.3 [−2.3, −0.2] | −1.5 [−2.5, −0.4] | |
| Fasting Serum Glucose§ (mg/dL), Mean | |||
| Baseline | 159 | 166 | 155 |
| Change at Week 24† | −5 | −17 | −19 |
| Difference from placebo† (95% CI) | −12 [−23.2, −1.3] | −14 [−24.5, −2.5] | |
| * BYETTA 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 5 months before the morning and 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.
Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy 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 to existing 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 to receive BYETTA 5 mcg BID, BYETTA 10 mcg BID, or placebo BID before the morning and evening 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. Patients assigned to placebo received placebo BID throughout the study. A total of 1446 patients were randomized 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 metformin. Randomization to BYETTA or placebo was stratified based on whether the patients were 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 morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 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 and placebo.
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 Agents
| Placebo BID | BYETTA 5 mcg BID | BYETTA 10 mcg* BID | |
| In Combination with Metformin (30 Weeks) | |||
| Intent-to-Treat Population (N) | 113 | 110 | 113 |
| HbA1c (%), Mean | |||
| Baseline | 8.2 | 8.3 | 8.2 |
| Change at Week 30† | −0.0 | −0.5 | −0.9 |
| Difference from placebo† (95% CI) | −0.5 [−0.7, −0.2]‡ | −0.9 [−1.1, −0.6]‡ | |
| Proportion Achieving HbA1c <7% | 12% | 32% | 40% |
| Body Weight (kg), Mean | |||
| Baseline | 99.9 | 100.0 | 100.9 |
| Change at Week 30† | −0.2 | −1.3 | −2.6 |
| Difference from placebo† (95% CI) | −1.1 [−2.2, −0.0] | −2.4 [−3.5, −1.3] | |
| Fasting Plasma Glucose§ (mg/dL), Mean | |||
| Baseline | 169 | 176 | 168 |
| Change at Week 30† | +14 | −5 | −10 |
| Difference from placebo† (95% CI) | −20 [−32, −7] | −24 [−37, −12] | |
| In Combination with a Sulfonylurea (30 Weeks) | |||
| Intent-to-Treat Population (N) | 123 | 125 | 129 |
| HbA1c (%), Mean | |||
| Baseline | 8.7 | 8.5 | 8.6 |
| Change at Week 30† | +0.1 | −0.5 | −0.9 |
| Difference from placebo† (95% CI) | −0.6 [−0.9, −0.3]‡ | −1.0 [−1.3, −0.7]‡ | |
| Proportion Achieving HbA1c <7% | 10% | 25% | 36% |
| Body Weight (kg), Mean | |||
| Baseline | 99.1 | 94.9 | 95.2 |
| Change at Week 30† | −0.8 | −1.1 | −1.6 |
| Difference from placebo† (95% CI) | −0.3 [−1.1, 0.6] | −0.9 [−1.7, −0.0] | |
| Fasting Plasma Glucose§ (mg/dL), Mean | |||
| Baseline | 194 | 180 | 178 |
| Change at Week 30† | +6 | −5 | −11 |
| Difference from placebo† (95% CI) | −11 [−25, 3] | −17 [−30, −3] | |
| In Combination with Metformin and a Sulfonylurea (30 Weeks) | |||
| Intent-to-Treat Population (N) | 247 | 245 | 241 |
| HbA1c (%), Mean | |||
| Baseline | 8.5 | 8.5 | 8.5 |
| Change at Week 30† | +0.1 | −0.7 | −0.9 |
| Difference from placebo† (95% CI) | −0.8 [−1.0, −0.6]‡ | −1.0 [−1.2, −0.8]‡ | |
| Proportion Achieving HbA1c <7% | 8% | 25% | 31% |
| Body Weight (kg), Mean | |||
| Baseline | 99.1 | 96.9 | 98.4 |
| Change at Week 30† | −0.9 | −1.6 | −1.6 |
| Difference from placebo† (95% CI) | −0.7 [−1.2, −0.2] | −0.7 [−1.3, −0.2] | |
| Fasting Plasma Glucose§ (mg/dL), Mean | |||
| Baseline | 181 | 182 | 178 |
| Change at Week 30† | +13 | −11 | −12 |
| Difference from placebo† (95% CI) | −24 [−33, −15] | −25 [−34, −16] | |
| In Combination with a Thiazolidinedione or a Thiazolidinedione plus Metformin (16 Weeks) | |||
| Intent-to-Treat Population (N) | 112 | Dose not studied | 121 |
| HbA1c (%), Mean | |||
| Baseline | 7.9 | Dose not studied | 7.9 |
| Change at Week 16† | +0.1 | Dose not studied | −0.7 |
| Difference from placebo† (95% CI) | Dose not studied | −0.9 [−1.1, −0.7]‡ | |
| Proportion Achieving HbA1c <7% | 15% | Dose not studied | 51% |
| Body Weight (kg), Mean | |||
| Baseline | 96.8 | Dose not studied | 97.5 |
| Change at Week 16† | −0.0 | Dose not studied | −1.5 |
| Difference from placebo† (95% CI) | Dose not studied | −1.5 [−2.2, −0.7] | |
| Fasting Serum Glucose§(mg/dL), Mean | |||
| Baseline | 159 | Dose not studied | 164 |
| Change at Week 16† | +4 | Dose not studied | −21 |
| Difference from placebo† (95% CI) | Dose not studied | −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 the dependent 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. | |||
The addition of BYETTA to a regimen of metformin, a sulfonylurea, or both, resulted in statistically 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 with patients receiving placebo (Table 7).
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).
A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of BYETTA (n=137) versus placebo (n=122) when added to titrated insulin glargine, with or 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, those patients assigned to BYETTA 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. 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 | BYETTA 10 mcg* BID + Titrated Insulin Glargine | |
| Intent-to-Treat Population (N) | 122 | 137 |
| HbA1c (%), Mean | ||
| Baseline | 8.5 | 8.3 |
| Change at Week 30† | −1.0 | −1.7 |
| Difference from placebo† (95% CI) | −0.7 [−1.0, −0.5]¶ | |
| Proportion Achieving HbA1c <7% | 30% | 57% |
| Body Weight (kg), Mean | ||
| Baseline | 93.8 | 95.4 |
| Change at Week 30‡ | 1.0 | −1.8 |
| Difference from placebo‡ (95% CI) | −2.7 [−3.7, −1.7]¶ | |
| Fasting Serum Glucose§ (mg/dL), Mean | ||
| Baseline | 133 | 132 |
| Change at Week 30‡ | −16 | −23 |
| Difference from placebo‡ (95% CI) | −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. ‡ 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) | Dose Change (U) |
| <56† | −4 |
| 56 to 72† | −2 |
| 73 to 99‡ | 0 |
| 100 to 119‡ | +2 |
| 120 to 139‡ | +4 |
| 140 to 179‡ | +6 |
| ≥180‡ | +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. | |
A 30 week, open-label, active comparator-controlled, noninferiority study was conducted to evaluate 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 to a 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%.
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 1/3 to 1/2 of the total daily insulin dose with the insulin glargine dose reduced accordingly. The insulin lispro dose was titrated 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 | BYETTA 10 mcg* BID + Titrated Insulin Glargine | |
| Intent-to-Treat Population (N) | 312 | 315 |
| HbA1c (%), Mean | ||
| Baseline | 8.2 | 8.3 |
| Change at Week 30†# | −1.1 | −1.1 |
| Difference from Insulin Lispro† # (95% CI) | −0.0 [−0.2, 0.1] | |
| Body Weight (kg), Mean | ||
| Baseline | 89.3 | 89.9 |
| Change at Week 30†# | 1.9 | −2.6 |
| Difference from Insulin Lispro† # (95% CI) | −4.5 [−5.2, −3.9] | |
| Fasting Serum Glucose‡ (mg/dL), Mean | ||
| Baseline | 126 | 129 |
| Change at Week 30† # | 5 | −7 |
| Difference from Insulin Lispro† # (95% CI) | −12 [−19, −4] | |
| * 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. | ||
BYETTA®
(bye-A-tuh)
(exenatide) injection, for subcutaneous use
Read this Medication Guide and the Pen User Manual that come with BYETTA before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have questions about BYETTAafter reading this information, ask your healthcare provider or pharmacist.
What is the most important information I should know about BYETTA?
What is BYETTA?
Who should not use BYETTA?
Do not use BYETTA if:
Symptoms of a severe allergic reaction with BYETTA may include:
Before taking BYETTA, tell your healthcare provider about all of your medical conditions, including if you:
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 other medicines may affect the way BYETTA works.
Especially tell your healthcare provider if you take:
How should I take BYETTA?
See the Pen User Manual that comes with BYETTA for instructions for using the BYETTA Pen and injecting BYETTA.
What are the possible side effects of BYETTA?
BYETTA may cause serious side effects, including:
Talk with your healthcare provider about how to treat low blood sugar.
The most common side effects of BYETTA include:
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?
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 have the 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.
PEN USER MANUAL
BYETTA®
exenatide injection 250 mcg/mL, 1.2 mL 5 mcg
5 mcg PEN USER MANUAL
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 PEN
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PEN USER MANUAL
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 in a 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 1-800- 236-9933.
IMPORTANT INFORMATION ABOUT YOUR BYETTA PEN
ABOUT PEN NEEDLES
What kinds of needles can be used with my BYETTA Pen?
Do I use a new needle for each injection?
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:
When your sharps disposal container is almost full, you will need to follow your community guidelines for the 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?
Keep your pen and needles out of the reach of children.
How long can I use a BYETTA Pen?
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?
See the complete BYETTA Medication Guide that comes with BYETTA. For more information, call toll free 1-800-236-9933 or visit www.BYETTA.com
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.
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ONE-TIME-ONLY NEW PEN SETUP
STEP A Check the Pen
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Note: Small air bubbles in the cartridge are normal.
STEP B Attach the Needle
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STEP C Dial the Dose
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Note: If you cannot turn the dose knob away from you to the 5, see Commonly Asked Questions, number 7, in Section 4 of this user manual.
STEP D Prepare the Pen
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PUSH & HOLD
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Note: If you do not see liquid after 4 times, see Commonly Asked Questions, number 3, in Section 4 of this user manual.
STEP E Complete New Pen Setup
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Go to Section 3, Step 3, for instructions on how to inject your first routine dose.
Note: If you cannot turn the dose knob, see Commonly Asked Questions, number 7, in Section 4 of user manual.
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
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Note: Small air bubbles will not harm you or affect your dose.
STEP 2 Attach the Needle
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STEP 3 Dial the Dose
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Note: If you cannot turn the dose knob away from you to the 5, see Commonly Asked Questions, number 7, in Section 4 of this user manual.
STEP 4 Inject the Dose
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Note: If you see several drops of BYETTA leaking from the needle after the injection, you may not have received a complete dose. See Commonly Asked Questions, number 4, in Section 4 of this user manual.
STEP 5 Reset the Pen
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Note: If you cannot turn the dose knob, or if your pen leaks, your full dose has not been delivered. See Commonly Asked Questions, numbers 4 and 7, in Section 4 of this user manual.
STEP 6 Remove and Dispose of the Needle
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STEP 7 Store Pen for Next Dose
Section 4 COMMONLY ASKED QUESTIONS
1. Do I need to do the One-Time-Only New Pen Setup before every dose?
2. Why are there air bubbles in the cartridge?
3. What should I do if BYETTA does not come out of the needle tip after four tries during One-Time- Only New Pen Setup?
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:
5. How can I tell when the injection is complete?
The injection is complete when:
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 the injection method explained to you by your healthcare provider.
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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:
If ↑is in the dose window and the dose knob will not turn:
If ↑and part of 5 are in the dose window and the dose knob cannot be pushed in:
If part of 5 and part of Δ are in the dose window and the dose knob cannot be pushed in:
If Δ is in the dose window and the dose knob will not turn:
See the complete BYETTA Medication Guide that comes with BYETTA. For more information, call toll free 1-800-236-9933 or visit www.BYETTA.com
PEN USER MANUAL
BYETTA®
exenatide injection 250 mcg/mL, 2.4 mL 10 mcg
10 mcg PEN USER MANUAL
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 PEN
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PEN USER MANUAL
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 in a 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 1-800- 236-9933.
IMPORTANT INFORMATION ABOUT YOUR BYETTA PEN
ABOUT PEN NEEDLES
What kinds of needles can be used with my BYETTA Pen?
Do I use a new needle for each injection?
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:
When your sharps disposal container is almost full, you will need to follow your community guidelines for the 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?
Keep your pen and needles out of the reach of children.
How long can I use a BYETTA Pen?
Date of First Use __________ Date to Throw Away Pen ___________
How do I clean my BYETTA Pen?
See the complete BYETTA Medication Guide that comes with BYETTA. For more information, call toll free 1-800-236-9933 or visit www.BYETTA.com
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.
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ONE-TIME-ONLY NEW PEN SETUP
STEP A Check the Pen
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Note: Small air bubbles in the cartridge are normal.
STEP B Attach the Needle
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STEP C Dial the Dose
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Note: If you cannot turn the dose knob away from you to the 10, see Commonly Asked Questions, number 7, in Section 4 of this user manual.
STEP D Prepare the Pen
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Note: If you do not see liquid after 4 times, see Commonly Asked Questions, number 3, in Section 4 of this user manual.
STEP E Complete New Pen Setup
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Note: If you cannot turn the dose knob, see Commonly Asked Questions, number 7, in Section 4 of user manual.
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.
STEP 2 Attach the Needle
 |
 |
 |
STEP 3 Dial the Dose
 |
 |
 |
Note: If you cannot turn the dose knob away from you to the 10, see Commonly Asked Questions, number 7, in Section 4 of this user manual.
STEP 4 Inject the Dose
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 |
 |
Note: If you see several drops of BYETTA leaking from the needle after the injection, you may not have received a complete dose. See Commonly Asked Questions, number 4, in Section 4 of this user manual.
STEP 5 Reset the Pen
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Note: If you cannot turn the dose knob, or if your pen leaks, your full dose has not been delivered. See Commonly Asked Questions, numbers 4 and 7, in Section 4 of this user manual.
STEP 6 Remove and Dispose of the Needle
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STEP 7 Store Pen for Next Dose
Section 4 COMMONLY ASKED QUESTIONS
1. Do I need to do the One-Time-Only New Pen Setup before every dose?
2. Why are there air bubbles in the cartridge?
3. What should I do if BYETTA does not come out of the needle tip after four tries during One-Time- Only New Pen Setup?
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:
5. How can I tell when the injection is complete?
The injection is complete when:
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 the injection 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:
If ↑ is in the dose window and the dose knob will not turn:
If ↑ and part of 10 are in the dose window and the dose knob cannot be pushed in:
If part of 10 and part of Δ are in the dose window and the dose knob cannot be pushed in:
If Δ is in the dose window and the dose knob will not turn:
See the complete BYETTA Medication Guide that comes with BYETTA. For more information, call toll free 1-800-236-9933 or visit www.BYETTA.com
This Medication Guide has been approved by the U.S. Food and Drug Administration
