Use with metformin and/or a sulfonylurea

In the three 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, adverse events with an incidence ≥ 5% (excluding hypoglycemia; see Table 3) that occurred more frequently in BYETTA-treated patients compared with placebo-treated patients are summarized in Table 4.

Table 4: Frequent Treatment-Emergent Adverse Events ( ≥ 5% Incidence and Greater Incidence With BYETTA Treatment) Excluding Hypoglycemia*

The adverse events associated with BYETTA generally were mild to moderate in intensity. The most frequently reported adverse event, mild to moderate nausea, 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. Adverse events reported in ≥ 1.0 to < 5.0% of patients receiving BYETTA and reported more frequently than with placebo included asthenia (mostly reported as weakness), decreased appetite, gastroesophageal reflux disease, and hyperhidrosis. Patients in the extension studies at 52 weeks experienced similar types of adverse events observed in the 30-week controlled trials.

The incidence of withdrawal due to adverse events was 7% for BYETTA-treated patients and 3% for placebo-treated patients. The most common adverse events leading to withdrawal for BYETTA-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, < 1% withdrew due to nausea and 0% due to vomiting.

Use with a thiazolidinedione

In the 16-week placebo-controlled study of BYETTA add-on to a thiazolidinedione, with or without metformin, the incidence and type of other adverse events observed were similar to those seen in the 30-week controlled clinical trials with metformin and/or a sulfonylurea. No serious adverse events were reported in the placebo arm. Two serious adverse events, namely chest pain (leading to withdrawal) and chronic hypersensitivity pneumonitis, were reported in the BYETTA arm.

The incidence of withdrawal due to adverse events was 16% (19/121) for BYETTA-treated patients and 2% (2/112) for placebo-treated patients. The most common adverse events leading to withdrawal for BYETTA-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, < 1% withdrew due to nausea. Chills (n = 4) and injection-site reactions (n = 2) occurred only in BYETTA-treated patients. The two patients who reported an injection-site reaction had high titers of anti-exenatide antibody.

Spontaneous Data

Since market introduction of BYETTA, the following additional adverse reactions have been reported. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: injection-site reactions; dysgeusia; somnolence, INR increased with concomitant warfarin use (some reports associated with bleeding).

Allergy/Hypersensitivity: generalized pruritus and/or urticaria, macular or papular rash, angioedema; rare reports of anaphylactic reaction.

Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration with some reports associated with increased serum creatinine/acute renal failure that may be reversible if treated appropriately; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis (see PRECAUTIONS).

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop anti-exenatide antibodies following treatment with BYETTA. In most patients who develop antibodies, antibody titers diminish over time.

In the 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, 38% of patients had low titer anti-exenatide antibodies at 30 weeks. For this group, the level of glycemic control (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 in the 30-week controlled studies), the glycemic response to BYETTA was attenuated; the remainder had a glycemic response comparable to that of patients without antibodies.

In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, 9% of patients had higher titer antibodies at 16 weeks. Compared with patients who did not develop antibodies to BYETTA, on average the glycemic response in patients with higher titer antibodies was attenuated.

The patient's glycemic response to BYETTA should be monitored. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered.

The effect of BYETTA to slow gastric emptying may reduce the extent and rate of absorption of orally administered drugs. BYETTA should be used with caution in patients receiving oral medications that 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 h before BYETTA 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. The effect of BYETTA on the absorption and effectiveness of oral contraceptives has not been characterized.

Warfarin

In a controlled clinical pharmacology study in healthy volunteers, a delay in warfarin Tmax of about 2 h was observed when warfarin was administered 30 min after BYETTA. No clinically relevant effects on Cmax or AUC were observed. However, since market introduction there have been some spontaneously reported cases of increased INR (International Normalized Ratio) with concomitant use of warfarin and BYETTA, sometimes associated with bleeding.

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