Side Effects of Byetta (exenatide)

Byetta (exenatide) is an incretin mimetic given by injection that reduces the level of sugar (glucose) in the blood and is used to treat type 2 diabetes. 

Incretin mimetics mimic the effects of incretins. Incretins, such as human-glucagon-like peptide-1 (GLP-1), are hormones that are produced and released into the blood by the intestine in response to food. 

GLP-1 increases the secretion of insulin from the pancreas, slows absorption of glucose from the gut, and reduces the action of glucagon. (Glucagon is a hormone that increases glucose production by the liver.) All three of these actions reduce levels of glucose in the blood. 

In addition, GLP-1 reduces appetite. Byetta is a synthetic (man-made) hormone that resembles and acts like GLP-1. In studies, Byetta-treated patients achieved lower blood glucose levels and experienced weight loss.

Common side effects of Byetta include

• nausea,
• excessively low blood glucose (hypoglycemia),
• vomiting,
• diarrhea,
• headache,
• nervousness and
• stomach discomfort.

Other important side effects Byetta include

• decreased appetite,
• acid reflux, and
• increased sweating.

Serious side effects of Byetta include acute pancreatitis (symptoms include severe, persistent abdominal pain).

Drug interactions of Byetta include drugs that are taken orally because Byetta slows down the transit of food and drugs through the intestine and, therefore, can reduce the absorption of drugs that are taken orally. To avoid this interaction, administer oral medications one hour before Byetta is administered. 

There are no adequate studies of Byetta in pregnant women. Most experts agree insulin is the drug of choice in pregnant women with diabetes. 

There are no adequate studies of Byetta in nursing mothers, and it is unknown if Byetta is excreted in breast milk. Consult your doctor before breastfeeding.

The most common side effects of exenatide are:

• nausea (nausea from exenatide is more common with the higher doses and decreases over time.)
• hypoglycemia (excessively low blood glucose),
• vomiting,
• diarrhea,
• headache,
• nervousness and,
• stomach discomfort.

Other important side effects include:

• decreased appetite,
• acid reflux, and
• increased sweating.

There have been reports of acute pancreatitis associated with the use of exenatide. Patients developing severe, persistent abdominal pain should seek prompt medical attention. If pancreatitis is suspected, exenatide should be discontinued and not started again until pancreatitis has been excluded.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypoglycemia

Table 1 summarizes the incidence and rate of hypoglycemia with Byetta (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*

Immunogenicity

• 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.

Other Adverse Reactions

Monotherapy

• 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)*

• 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.

Combination Therapy

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 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)*

• 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)*

• 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.

Post-Marketing Experience

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.
• Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding.
• 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.
• 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.
• Skin and Subcutaneous Tissue Disorders: alopecia

Orally Administered Drugs

• 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.
• 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.

Warfarin

• There are postmarketing reports of increased INR sometimes associated with bleeding, with concomitant use of warfarin and Byetta.
• In a drug interaction study, Byetta (exenatide injection) did not have a significant effect on INR.
• 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.