BYDUREON (Page 3 of 6)

6.2 Post-Marketing Experience

BYETTA

The following additional adverse reactions have been reported during post-approval use of BYETTA. 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 (5.7)].

Drug Interactions: increased international normalized ratio (INR), sometimes associated with bleeding, with concomitant warfarin use [see Drug Interactions (7.2) ].

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 (1.2) and Warnings and Precautions (5.2)].

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 (5.4)].

Skin and Subcutaneous Tissue Disorders: alopecia

7 DRUG INTERACTIONS

7.1 Orally Administered Drugs

Exenatide slows gastric emptying. Therefore, BYDUREON has the potential to reduce the rate of absorption of orally administered drugs. Use caution when administering oral medications with BYDUREON [see Clinical Pharmacology (12.3)].

In patients with type 2 diabetes, BYDUREON did not affect the absorption of orally administered acetaminophen to any clinically relevant degree.

7.2 Warfarin

BYDUREON has not been studied with warfarin. However, in a drug interaction study, BYETTA did not have a significant effect on INR [see Clinical Pharmacology (12.3)]. There have been postmarketing reports for BYETTA of increased INR with concomitant use of warfarin, sometimes associated with bleeding [see Adverse Reactions (6.2)]. In patients taking warfarin, the INR should be monitored more frequently after initiating BYDUREON. Once a stable INR has been documented, the INR can be monitored at the intervals usually recommended for patients on warfarin.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of BYDUREON use in pregnant women. In rats, exenatide extended-release administered during the major period of organogenesis reduced fetal growth and produced skeletal ossification deficits in association with maternal effects; exenatide extended-release was not teratogenic in rats. In animal developmental studies, exenatide, the active ingredient of BYDUREON, caused cleft palate, irregular skeletal ossification and an increased number of neonatal deaths. BYDUREON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Fetuses from pregnant rats given subcutaneous doses of exenatide extended-release at 0.3, 1 or 3 mg/kg on gestation days 6, 9, 12 and 15 demonstrated reduced fetal growth at all doses and produced skeletal ossification deficits at 1 and 3 mg/kg in association with maternal effects (decreased food intake and decreased body weight gain). There was no evidence of malformations. Doses of 0.3, 1 and 3 mg/kg correspond to systemic exposures of 3, 7 and 17-times, respectively, the human exposure resulting from the recommended dose of 2 mg/week, based on area under the time-concentration curve (AUC) [see Nonclinical Toxicology (13.3)].

Female mice given subcutaneous doses of exenatide, the active ingredient of BYDUREON, at 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 148 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC [see Nonclinical Toxicology (13.3)].

In developmental toxicity studies, pregnant animals received exenatide, the active ingredient of BYDUREON, subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given subcutaneous doses of exenatide at 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 4 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC. Fetuses from pregnant mice given subcutaneous doses of exenatide at 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, cleft palate and skeletal effects at systemic exposure that is equivalent to the human exposure resulting from the recommended dose of 2 mg/week, based on AUC [see Nonclinical Toxicology (13.3)].

Lactating mice given subcutaneous doses of exenatide, the active ingredient of BYDUREON, at 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure that is equivalent to the human exposure resulting from the recommended dose of 2 mg/week, based on AUC [see Nonclinical Toxicology (13.3)].

Pregnancy Registry

Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling (800) 633-9081.

8.3 Nursing Mothers

Exenatide is present in the milk of lactating mice at concentrations less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing. It is not known whether exenatide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for exenatide extended-release in animal studies, a decision should be made whether to discontinue nursing or to discontinue BYDUREON, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of BYDUREON have not been established in pediatric patients. BYDUREON is not recommended for use in pediatric patients.

8.5 Geriatric Use

In the five comparator-controlled 24-30 week trials, BYDUREON was studied in 132 patients (16.6%) who were at least 65 years old and 20 patients who were at least 75 years old. No differences in safety (N = 152) and efficacy (N = 52) were observed between these patients and younger patients, but the small sample size for patients ≥75 years old limits conclusions.

In separate trials, BYETTA was studied in 282 patients at least 65 years old and in 16 patients at least 75 years old. No differences in safety and efficacy were observed between these patients and younger patients, but the small sample size for patients ≥75 years old limits conclusions.

Because elderly patients are more likely to have decreased renal function, use caution when initiating BYDUREON in the elderly.

8.6 Renal Impairment

BYDUREON 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. Use BYDUREON with caution in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ].

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 impairment is not expected to affect blood concentrations of exenatide [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There were no reports of overdose in the five comparator-controlled 24-30 week trials of BYDUREON. Effects of overdoses with BYETTA in clinical studies included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations, including severe hypoglycemia requiring parenteral glucose administration. In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

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