Exenatide

Exenatide 5 microgram pre-filled pen dose contains 5 micrograms (μg) synthetic Exenatide in 20 microlitres (μl), (0.25 mg Exenatide per ml).

Exenatide 10 microgram pre-filled pen dose contains 10 micrograms (μg) synthetic Exenatide in 40 microlitres (μl), (0.25 mg Exenatide per ml).

This medicinal product contains less than 1 mmol sodium per dose, i.e. essentially "sodium-free".

Excipients/Inactive Ingredients: Metacresol, mannitol, glacial acetic acid, sodium acetate trihydrate, water for injections.

Exenatide 5 microgram pre-filled pen: Each dose contains 44 μg metacresol.

Exenatide 10 microgram pre-filled pen: Each dose contains 88 μg metacresol.

Exenatide is an extended-release formulation of Exenatide, administered as an injection once every 7 days (weekly).

Type 2 Diabetes Mellitus

Exenatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use

​Exenatide is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans. Prescribe Exenatide only to patients for whom the potential benefits are considered to outweigh the potential risk.

Exenatide is not a substitute for insulin. Exenatide should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of Exenatide with insulin has not been studied and cannot be recommended.

Exenatide and Exenatide® (Exenatide) injection both contain the same active ingredient, Exenatide, and therefore should not be used together.

Based on postmarketing data, Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Exenatide 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 Exenatide. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.

Exenatide is an injectable diabetes medicine that helps control blood sugar levels. This medication helps your pancreas produce insulin more efficiently. Exenatide is an extended-release form of Exenatide.

Exenatide is used to treat type 2 diabetes. Other diabetes medicines are sometimes used in combination with Exenatide if needed.

This medication guide provides information about the Exenatide brand of Exenatide. Exenatide is another brand of Exenatide that is not covered in this medication guide.

Exenatide may also be used for purposes not listed in this medication guide.

Recommended Dosing

Exenatide (Exenatide injection) should be initiated at 5 mcg administered twice daily 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). Exenatide (Exenatide injection) should not be administered after a meal. Based on clinical response, the dose of Exenatide (Exenatide injection) 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. No data are available on the safety or efficacy of intravenous or intramuscular injection of Exenatide (Exenatide injection).

Use Exenatide (Exenatide injection) only if it is clear, colorless and contains no particles.

How supplied

Dosage Forms And Strengths

Exenatide (Exenatide injection) is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL Exenatide in the following packages:

• 5 mcg per dose, 60 doses, 1.2 mL prefilled pen
• 10 mcg per dose, 60 doses, 2.4 mL prefilled pen

Exenatide (Exenatide injection) 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 66780-210-07

10 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 66780-212-01

Storage and Handling

Prior to first use, Exenatide (Exenatide injection) must be stored refrigerated at 36°F to 46°F (2°C to 8°C). After first use, Exenatide (Exenatide injection) can be kept at a temperature not to exceed 77°F (25°C). Do not freeze. Do not use Exenatide (Exenatide injection) if it has been frozen. Exenatide (Exenatide injection) should be protected from light. The pen should be discarded 30 days after first use, even if some drug remains in the pen. Exenatide (Exenatide injection) should not be used past the expiration date. Exenatide (Exenatide injection) pens are not to be shared with other patients.

Manufactured for Amylin Pharmaceuticals, Inc., San Diego, CA 92121. Marketed by Amylin Pharmaceuticals, Inc. and Eli Lilly and Company. 1-800-868-1190. http://www. Exenatide (Exenatide injection).com. Literature Revised September 2010.

See also:
What is the most important information I should know about Exenatide?

This medication guide provides information about the Exenatide brand of Exenatide. Exenatide is another brand of Exenatide that is not covered in this medication guide.

You should not use Exenatide if you have a personal or family history of thyroid cancer, or if you have multiple endocrine neoplasia type 2 (cancer that can affect the thyroid, parathryoid, and adrenal glands).

Do not use Exenatide to treat type 1 diabetes, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin). You should not use Exenatide if you have severe kidney disease (or if you are on dialysis), of if you have a severe stomach disorder that causes slow digestion.

In animal studies, Exenatide caused thyroid tumors. However, very high doses are used in animal studies. It is not known whether these effects would occur in people using doses recommended for human use. Ask your doctor about your personal risk.

You should not use Exenatide together with insulin. Do not use Exenatide together with Exenatide.

Exenatide is an extended-release form of Exenatide that can be given with or without food and given at any time of the day. Follow your doctor's instructions.

Stop using Exenatide and call your doctor at once if you have severe pain in your upper stomach spreading to your back, with nausea, vomiting, and a fast heart rate. These could be symptoms of pancreatitis.

Use Exenatide extended-release as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Exenatide extended-release comes with an extra patient information sheet called a Medication Guide and Instructions for Use. Read them carefully. Read them again each time you get Exenatide extended-release refilled.
• Use Exenatide extended-release with or without food once every 7 days (weekly).
• A health care provider will teach you how to use Exenatide extended-release. Be sure you understand how to use Exenatide extended-release. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.
• Before giving the injection, let this product stand in room temperature for at least 15 minutes. Do not heat this drug.
• Use Exenatide extended-release immediately after it has been mixed.
• Use the proper technique taught to you by your health care provider. Inject deep under the skin, in the stomach area (abdomen), upper leg (thigh), or upper arm, as directed by your doctor. Do NOT inject Exenatide extended-release into a vein or muscle.
• Do not use Exenatide extended-release if it contains particles, is discolored, or if the pen is cracked or damaged.
• Do not share Exenatide extended-release with another person even if the needle is changed. Sharing your pen may pass infections from one person to another. This includes infections you may not know you have.
• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• Use Exenatide extended-release on a regular schedule to get the most benefit from it.
• If you miss a dose of Exenatide extended-release, use it as soon as possible if your next scheduled dose is due at least 3 days later. If you miss a dose and your next scheduled dose is due 1 or 2 days later, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Exenatide extended-release.

Exenatide is used along with diet, exercise and other medicines to improve blood sugar control in adults with type-2 diabetes mellitus.

See also:
What other drugs will affect Exenatide?

The effect of Exenatide to slow gastric emptying may reduce the extent and rate of absorption of orally administered medicinal products. Patients receiving medicinal products of either a narrow therapeutic ratio or medicinal products that require careful clinical monitoring should be followed closely. These medicinal products should be taken in a standardised way in relation to Exenatide injection. If such medicinal products are to be administered with food, patients should be advised to, if possible, take them with a meal when Exenatide is not administered.

For oral medicinal products that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, patients should be advised to take those medicinal products at least 1 hour before Exenatide injection.

Gastroresistant formulations containing substances sensitive for degradation in the stomach, such as proton pump inhibitors, should be taken at least 1 hour before or more than 4 hours after Exenatide injection.

Digoxin, Lisinopril and Warfarin: A delay in t_max of about 2 h was observed when digoxin, lisinopril or warfarin was administered 30 min after Exenatide. No clinically relevant effects on C_max or AUC were observed. However, since market introduction, increased INR (International Normalized Ratio) has been reported during concomitant use of warfarin and Exenatide. INR should be closely monitored during initiation and dose increase of Exenatide therapy in patients on warfarin and/or cumarol derivatives.

Metformin or Sulphonylureas: Exenatide is not expected to have any clinically relevant effects on the pharmacokinetics of metformin or sulphonylureas. Hence no restriction in timing of intake of these medicinal products in relation to Exenatide injection are needed.

Paracetamol: Paracetamol was used as a model medicinal product to evaluate the effect of Exenatide on gastric emptying. When 1000 mg paracetamol was given with 10 mcg Exenatide (0 h) and 1 h, 2 h and 4 h after Exenatide injection, paracetamol AUCs were decreased by 21%, 23%, 24% and 14% respectively; C_max was decreased by 37%, 56%, 54% and 41%, respectively; T_max was increased from 0.6 h in the control period to 0.9 h, 4.2 h, 3.3 h, and 1.6 h, respectively. Paracetamol AUC, C_max and T_max were not significantly changed when paracetamol was given 1 hour before Exenatide injection. No adjustment to paracetamol dosing is required based on these study results.

Hydroxy Methyl Glutaryl Coenzyme A (HMG CoA) Reductase Inhibitors: Lovastatin AUC and C_max were decreased approximately 40% and 28%, respectively, and T_max was delayed about 4 h when Exenatide (10 mcg BID) was administered concomitantly with a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In the 30-week placebo-controlled clinical trials, concomitant use of Exenatide and HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles. Although no predetermined dose adjustment is required, one should be aware of possible changes in LDL-C or total cholesterol. Lipid profiles should be monitored regularly.

Ethinyl Estradiol and Levonorgestrel: Administration of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) one hour before Exenatide (10 mcg BID) did not alter the AUC, C_max or C_min of either ethinyl estradiol or levonorgestrel. Administration of the oral contraceptive 30 minutes after Exenatide did not affect AUC but resulted in a reduction of the C_max of ethinyl estradiol by 45%, and C_max of levonorgestrel by 27-41%, and a delay in T_max by 2-4 h due to delayed gastric emptying. The reduction in C_max is of limited clinical relevance and no adjustment of dosing of oral contraceptives is required.

See also:
What are the possible side effects of Exenatide?

Summary of the Safety Profile: The most frequent adverse reactions were mainly gastrointestinal related (nausea, vomiting and diarrhoea). The most frequently reported single adverse reaction was nausea which was associated with the initiation of treatment and decreased over time. Patients may experience hypoglycaemia when Exenatide is used with a sulphonylurea. Most adverse reactions associated with Exenatide were mild to moderate in intensity.

Acute pancreatitis and acute renal failure have been reported rarely since Exenatide twice daily has been marketed.

Tabulated List of Adverse Reactions: Table 2 lists adverse reactions reported from Phase 3 studies. The table presents adverse reactions that occurred with an incidence ≥5 % and more frequently among Exenatide-treated patients than insulin- or placebo-treated patients. The table also includes adverse reactions that occurred with an incidence ≥1 % and with a statistically significantly higher and/or ≥2X incidence among Exenatide-treated patients than insulin- or placebo-treated patients.

The reactions are listed below as MedDRA preferred term by system organ class and absolute frequency. Patient frequencies are defined as: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data), including isolated reports.

When Exenatide was used in combination with basal insulin therapy the incidence and types of other adverse events observed were similar to those seen in the controlled clinical trials with Exenatide as monotherapy, with metformin and/or sulphonylurea or a thiazolidinedione, with or without metformin.

Description of Selected Adverse Reactions: Hypoglycaemia: In studies in patients treated with Exenatide and a sulphonylurea (with or without metformin), the incidence of hypoglycaemia was increased compared to placebo (23.5% and 25.2% versus 12.6% and 3.3%) and appeared to be dependent on the doses of both Exenatide and the sulphonylurea.

There were no clinically relevant differences in incidence or severity of hypoglycaemia with Exenatide compared to placebo, in combination with a thiazolidinedione, with or without metformin. Hypoglycaemia was reported in 11% and 7% of patients treated with Exenatide and placebo respectively.

Most episodes of hypoglycaemia were mild to moderate in intensity, and resolved with oral administration of carbohydrate.

In a 30 week study, when Exenatide or placebo was added to existing basal insulin therapy(insulin glargine), the dose of basal insulin was decreased by 20% in patients with an HbA_1c ≤8.0%, per protocol design in order to minimize the risk of hypoglycaemia. Both treatment arms were titrated to achieve target fasting plasma glucose levels. There were no clinically significant differences in the incidence of hypoglycaemic episodes in the Exenatide compared to the placebo group (25% and 29% respectively). There were no episodes of major hypoglycaemia in the Exenatide arm.

In a 24 week study, where either insulin lispro protamine suspension or insulin glargine was added to existing therapy of Exenatide and metformin or metformin plus thiazolidinedione the incidence of patients with at least one minor hypoglycaemic episode was 18% and 9% respectively and one patient reported major hypoglycaemia. In patients where existing therapy also included a sulphonylurea the incidence of patients with at least one minor hypoglycaemic episode was 48% and 54% respectively and one patient reported major hypoglycaemia.

Nausea: The most frequently reported adverse reaction was nausea. In patients treated with 5 mcg or 10 mcg Exenatide, generally 40-50% reported at least one episode of nausea. Most episodes of nausea were mild to moderate and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased in most patients who initially experienced nausea.

The incidence of withdrawal due to adverse events was 8% for Exenatide-treated patients, 3% for placebo-treated and 1% for insulin-treated patients in the long-term controlled trials (16 weeks or longer). The most common adverse events leading to withdrawal for Exenatide-treated patients were nausea (4% of patients) and vomiting (1%). For placebo-treated or insulin-treated patients, <1% withdrew due to nausea or vomiting.

Exenatide-treated patients in the open-label extension studies at 82 weeks experienced similar types of adverse events observed in the controlled trials.

Injection Site Reactions: Injection site reactions have been reported in approximately 5.1% of subjects receiving Exenatide in long-term (16 weeks or longer) controlled trials. These reactions have usually been mild and usually did not result in discontinuation of Exenatide.

Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop anti-Exenatide antibodies following treatment with Exenatide. In most patients who develop antibodies, antibody titres diminish over time and remain low through 82 weeks.

Overall the percentage of antibody positive patients was consistent across clinical trials. Patients who develop antibodies to Exenatide tend to have more injection site reactions (for example: redness of skin and itching), but otherwise similar rates and types of adverse events as those with no anti-Exenatide antibodies. In the three placebo-controlled trials (n=963) 38% of patients had low titre anti-Exenatide antibodies at 30 weeks. For this group, the level of glycaemic control (HbA_1c) was generally comparable to that observed in those without antibody titres. An additional 6% of patients had higher titre antibodies at 30 weeks. About half of this 6% [3% of the total patients given Exenatide in the controlled studies], had no apparent glycaemic response to Exenatide. In two insulin-comparator controlled trials (n=475) comparable efficacy and adverse events were observed in Exenatide-treated patients regardless of antibody titre.

Examination of antibody-positive specimens from one long-term uncontrolled study revealed no significant cross-reactivity with similar endogenous peptides (glucagon or GLP-1).