Byetta Warnings & Precautions

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Byetta Warnings & Precautions
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WARNINGS

No information provided.
PRECAUTIONS
General

BYETTA is not a substitute for insulin in insulin-requiring patients. BYETTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Postmarketing cases of acute pancreatitis have been reported in patients treated with BYETTA. Patients should be informed that persistent severe abdominal pain, which may be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. If pancreatitis is suspected, BYETTA and other potentially suspect drugs should be discontinued, confirmatory tests performed and appropriate treatment initiated. Resuming treatment with BYETTA is not recommended if pancreatitis is confirmed and an alternative etiology for the pancreatitis has not been identified.

Patients may develop anti-exenatide antibodies following treatment with BYETTA, consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals. Patients receiving BYETTA should be observed for signs and symptoms of hypersensitivity reactions.

In a small proportion of patients, the formation of anti-exenatide antibodies at high titers could result in failure to achieve adequate improvement in glycemic control. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered.

The concurrent use of BYETTA with insulin, D-phenylalanine derivatives, meglitinides, or alpha-glucosidase inhibitors has notbeen studied.

BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min; see Pharmacokinetics, Special Populations). In patients with end-stage renal disease receiving dialysis, single doses of BYETTA 5 mcg were not well tolerated due to gastrointestinal side effects.

BYETTA has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Its use is commonly associated with gastrointestinal adverse effects, including nausea, vomiting, and diarrhea. Therefore, the use of BYETTA is not recommended in patients with severe gastrointestinal disease.
Hypoglycemia

In the 30-week controlled clinical trials with BYETTA, a hypoglycemia episode was recorded as an adverse event if the patient reported symptoms associated with hypoglycemia with an accompanying blood glucose < 60 mg/dL or if symptoms were reported without an accompanying blood glucose measurement. When BYETTA was used in combination with metformin, no increase in the incidence of hypoglycemia was observed over that of placebo in combination with metformin. In contrast, when BYETTA was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased over that of placebo in combination with a sulfonylurea. Therefore, patients receiving BYETTA in combination with a sulfonylurea may have an increased risk of hypoglycemia. Most episodes of hypoglycemia were mild to moderate in intensity, and all resolved with oral administration of carbohydrate. Hypoglycemia was rarely observed in patients treated with the combination of BYETTA and metformin and was similar in incidence to patients treated with placebo and metformin (Table 3). To reduce the risk of hypoglycemia associated with the use of a sulfonylurea, reduction in the dose of sulfonylurea may be considered (see DOSAGE AND ADMINISTRATION).

Table 3: Incidence (%) of Hypoglycemia* by Concomitant Antidiabetic Therapy

View Enlarged Table
BYETTA BYETTA BYETTA
Placebo BID 5 mcg BID 10 mcg BID Placebo BID 5 mcg BID 10 mcg BID Placebo BID 5 mcg BID 10 mcg BID
With Metformin With a Sulfonylurea With MET/SFU
N 113 110 113 123 125 129 247 245 241
Hypoglycemia 5.3% 4.5% 5.3% 3.3% 14.4% 35.7% 12.6% 19.2% 27.8%
*In three 30-week placebo-controlled clinical trials.
BYETTA and placebo were administered before the morning and evening meals. Abbreviations: BID, twice daily; MET/SFU, metformin and a sulfonylurea.

When used as add-on to a thiazolidinedione, with or without metformin, the incidence of symptomatic mild to moderate hypoglycemia with BYETTA was 11% compared to 7% with placebo.

BYETTA did not alter the counter-regulatory hormone responses to insulin-induced hypoglycemia in a randomized, double-blind, controlled study in healthy subjects.
Information for Patients

Patients should be informed of the potential risks of BYETTA. Patients should also be fully informed about self-management practices, including the importance of proper storage of BYETTA, injection technique, timing of dosage of BYETTA as well as concomitant oral drugs, adherence to meal planning, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.

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 SC 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.

The risk of hypoglycemia is increased when BYETTA is used in combination with an agent that induces hypoglycemia, such as a sulfonylurea. The symptoms, treatment, and conditions that predispose development of hypoglycemia should be explained to the patient. While the patient's usual instructions for hypoglycemia management do not need to be changed, these instructions should be reviewed and reinforced when initiating BYETTA therapy, particularly when concomitantly administered with a sulfonylurea (see PRECAUTIONS, Hypoglycemia).

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). Patients should be informed that persistent severe abdominal pain, which may be accompanied by vomiting, is the hallmark symptom of acute pancreatitis and be instructed to contact their physician if this symptom occurs (see PRECAUTIONS).

The patient should read the “Information for the Patient” insert 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.
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 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 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.
Pregnancy
Pregnancy Category C

Exenatide has been shown to cause reduced fetal and neonatal growth, and skeletal effects in mice at systemic exposures 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Exenatide has been shown to cause skeletal effects in rabbits at systemic exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. There are no adequate and well-controlled studies in pregnant women. BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths were observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Nursing Mothers

It is not known whether exenatide is excreted in human milk. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue producing milk for consumption or discontinue the drug, taking into account the importance of the drug to the lactating woman. Studies in lactating mice have demonstrated that exenatide is present at low concentrations in milk (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing). Caution should be exercised when BYETTA is administered to a nursing woman.
Pediatric Use

Safety and effectiveness of BYETTA have not been established in pediatric patients.
Geriatric Use

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.

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