Exenatide

1 INDICATIONS AND USAGE Exenatide injection is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Exenatide injection is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 , 14 ) Limitations of Use Co-administration with other exenatide-containing products is not recommended. ( 1 ) Limitations of Use Exenatide injection contains exenatide. Co-administration with other exenatide-containing products is not recommended.

2 DOSAGE AND ADMINISTRATION Inject subcutaneously within 60 minutes prior to morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). ( 2.1 ) Initiate at 5 mcg per dose twice daily; increase to 10 mcg twice daily after 1 month based on clinical response. ( 2.1 ) 2.1 Recommended Dosing Initiate exenatide injection at 5 mcg administered subcutaneously 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). Do not administer after a meal. Based on clinical response, the dose of exenatide injection can be increased to 10 mcg twice daily which is recommended after 1 month of therapy, in order to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] . Administer as a subcutaneous injection in the thigh, abdomen, or upper arm. Rotate injections sites with each dose. Do not use the same site for each injection. Inspect visually for particulate matter and discoloration. Only use exenatide injection if the solution appears clear, colorless and contains no particles. When using exenatide injection with insulin, administer as separate injections and never mix. It is acceptable to inject exenatide injection and insulin in the same body region, but the injections should not be adjacent to each other. If a dose is missed, resume the treatment regimen as prescribed with the next scheduled dose.

3 DOSAGE FORMS AND STRENGTHS Exenatide Injection, USP is a clear, colorless sterile solution for subcutaneous injection containing 250 mcg/mL exenatide, USP supplied as follows: 5 mcg per dose in a single-patient-use prefilled pen containing 300 mcg/1.2 mL (250mcg/mL), 60 doses. 10 mcg per dose in a single-patient-use prefilled pen containing 600 mcg/2.4 mL (250mcg/mL), 60 doses. Exenatide injection is supplied as: 5 mcg per dose, in a single-patient-use prefilled pen containing 300 mcg/1.2 mL (250 mcg/mL), 60 doses. 10 mcg per dose, in a single-patient-use prefilled pen containing 600 mcg/2.4 mL (250 mcg/mL), 60 doses.

4 CONTRAINDICATIONS Exenatide injection is contraindicated in patients with: A prior severe hypersensitivity reaction to exenatide or to any of the excipients in exenatide injection. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with exenatide injection [see Warnings and Precautions (5.7) ] . A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use [see Warnings and Precautions (5.8) ]. History of severe hypersensitivity to exenatide or any of the excipients in exenatide injection. ( 4 ) History of drug-induced immune-mediated thrombocytopenia from exenatide products. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Acute Pancreatitis [see Warnings and Precautions (5.1) ] Never Share an Exenatide Pen Between Patients [see Warnings and Precautions (5.2) ] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3) ] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.4) ] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.5) ] Immunogenicity [see Warnings and Precautions (5.6) ] Hypersensitivity [see Warnings and Precautions (5.7) ] Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.8) ] Acute Gallbladder Disease [see Warnings and Precautions (5.9) ] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10) ] Most common (≥ 5%) and occurring more frequently than placebo in clinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia, constipation, asthenia. Nausea usually decreases over time. ( 5.3 , 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 exenatide in six placebo-controlled clinical trials. Table 1: Incidence (%) and Rate of Hypoglycemia when Exenatide was used as Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials * Placebo BID Exenatide 5 mcg BID Exenatide 10 mcg BID Monotherapy (24 Weeks) N 77 77 78 % Overall 1.3% 5.2% 3.8% Rate (episodes/patient-year) 0.03 0.21 0.52 % Severe 0.0% 0.0% 0.0% With Metformin (30 Weeks) N 113 110 113 % Overall 5.3% 4.5% 5.3% Rate (episodes/patient-year) 0.12 0.13 0.12 % Severe 0.0% 0.0% 0.0% With a Sulfonylurea (30 Weeks) N 123 125 129 % Overall 3.3% 14.4% 35.7% Rate (episodes/patient-year) 0.07 0.64 1.61 % Severe 0.0% 0.0% 0.0% With Metformin and a Sulfonylurea (30 Weeks) N 247 245 241 % Overall 12.6% 19.2% 27.8% Rate (episodes/patient-year) 0.58 0.78 1.71 % Severe 0.0% 0.4% 0.0% With a Thiazolidinedione (16 Weeks) N 112 not evaluated 121 % Overall 7.1% not evaluated 10.7% Rate (episodes/patient-years) 0.56 not evaluated 0.98 % Severe 0.0% not evaluated 0.0% With Insulin Glargine with or without Metformin and/or Thiazolidinedione (30 Weeks) † N 122 not evaluated 137 % Overall 29.5% not evaluated 24.8% Rate (episodes/patient-years) 1.58 not evaluated 1.61 % Severe 0.8% not evaluated 0.0% * A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a documented blood glucose value < 54 mg/dL or prompt recovery after treatment for hypoglycemia. † When exenatide was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by 20% in patients with an HbA 1c ≤ 8.0% to minimize the risk of hypoglycemia. See Table 10 for insulin dose titration algorithm. N = number of Intent-to-Treat subjects in each treatment group. Immunogenicity Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of exenatide. In the 30-week controlled trials of exenatide add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer peaked at Week 6 and was reduced by 55% by Week 30. Three hundred and sixty patients (38%) had low titer antibodies (< 625 …

7 DRUG INTERACTIONS Table 6: Clinically Relevant Interactions with Exenatide Concomitant Use of Insulin Secretagogues or Insulin Clinical Impact Exenatide promotes insulin release from pancreatic beta-cells in the presence of elevated glucose concentrations. The risk of hypoglycemia is increased when exenatide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin [see Warnings and Precautions (5.3) and Adverse Reactions (6) ] . Intervention When initiating exenatide, consider reducing the dose of concomitantly administered insulin secretagogue or insulin to reduce the risk of hypoglycemia. Warfarin Clinical Impact In a drug interaction study, exenatide did not have a significant effect on INR [see Clinical Pharmacology (12.3) ] . There have been post-marketing reports for exenatide of increased INR with concomitant use of warfarin, sometimes associated with bleeding [see Adverse Reactions (6.2) ] . Intervention In patients taking warfarin, the prothrombin time should be monitored more frequently after initiation or alteration of exenatide therapy. Once a stable prothrombin time has been documented, the prothrombin time can be monitored at the intervals recommended for patients taking warfarin. Orally Administered Drugs (e.g., acetaminophen) Clinical Impact Exenatide slows gastric emptying. Therefore, exenatide has the potential to reduce the rate of absorption of orally administered drugs [see Clinical Pharmacology (12.3) ]. Intervention Use caution when administering oral medications with exenatide where a slower rate of oral absorption may be clinically meaningful. 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 exenatide injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when exenatide is not administered [see Clinical Pharmacology (12.3) ] . May impact absorption of orally administered medications. ( 7 ) Warfarin: Post-marketing reports of increased INR sometimes associated with bleeding. Monitor INR frequently until stable upon initiation or alteration of exenatide therapy. ( 7 )

8 USE IN SPECIFIC POPULATIONS Pregnancy: Use during pregnancy only if the potential benefit justifies the risk to the fetus. ( 8.1 ) 8.1 Pregnancy Risk Summary Limited data with exenatide in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations) . Based on animal reproduction studies, there may be risks to the fetus from exposure to exenatide during pregnancy. Exenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies identified increased adverse fetal and neonatal outcomes from exposure to exenatide during pregnancy and lactation in association with maternal effects. In mice, exenatide administered during gestation and lactation caused increased neonatal deaths at systemic exposure 3-times the human exposure resulting from the maximum recommended human dose (MRHD) of 20 mcg/day for exenatide (see Data) . The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with an HbA 1c > 7 and has been reported to be as high as 20% to 25% in women with HbA 1c > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryofetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data In studies evaluating reproduction and development in pregnant mice and rabbits, maternal animals were administered exenatide, the active ingredient in exenatide injection, by subcutaneous injection twice a day. In pregnant mice given 6, 68, 460, or 760 mcg/kg/day exenatide during fetal organogenesis, skeletal variations associated with slowed fetal growth, including changes in number of rib pairs or vertebral ossifications sites, and wavy ribs were observed at 760 mcg/kg/day, a dose that produced maternal toxicity and yielded systemic exposure 390-times the human exposure resulting from the MRHD of exenatide based on AUC comparison. In pregnant rabbits given 0.2, 2, 22, 156, or 260 mcg/kg/day exenatide during fetal organogenesis, irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a dose yielding systemic exposure up to 12-times the human exposure from the MRHD of exenatide based on AUC comparison. In maternal mice given 6, 68, or 760 mcg/kg/day exenatide from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a dose yielding a systemic exposure 3-times the human exposure from the MRHD of exenatide based on AUC comparison. 8.2 Lactation Risk Summary There is no information regarding the presence of exenatide, in human milk, the effects of exenatide on the breastfed infant, or the effects of exenatide on milk production. Exenatide was present in the milk of lactating mice. However, due to species-specific differences in lactation physiology, the clinical relevance of these data is not clear (see Data) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for exenatide and any potential adverse effects on the breastfed child from exenatide or from the underlying maternal condition. Data In lactating mice subcutaneously injected twice a day with exenatide, the concentration of exenatide in milk was up to 2.5% of the concentration in materna …

12.1 Mechanism of Action Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro . This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

11 DESCRIPTION Exenatide is a synthetic peptide, GLP-1 receptor agonist, that was originally identified in the lizard Heloderma suspectum . Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C 184 H 282 N 50 O 60 S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below. H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 Exenatide injection, USP is supplied for subcutaneous administration as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, USP; 2.2 mg metacresol as an antimicrobial preservative; mannitol as a tonicity-adjusting agent; and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg per dose or 10 mcg per dose. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID). Each prefilled device is filled with volume to allow delivery of 1.2 mL or 2.4 mL. Each device contains additional volume to allow for troubleshooting the device 4 times.

10 OVERDOSAGE In a clinical study of exenatide, three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC (10-times the maximum recommended dose). Effects of the overdoses included severe nausea, severe vomiting and rapidly declining blood glucose concentrations. One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Initiate appropriate supportive treatment according to the patient’s clinical signs and symptoms.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Exenatide Injection, USP is supplied as a clear, colorless sterile solution for subcutaneous injection containing 250 mcg/mL exenatide, USP. The following packages are available: 5 mcg per dose, in a single-patient-use prefilled pen containing 300 mcg/1.2 mL (250mcg/mL), 60 doses: NDC 70121-1685-1 10 mcg per dose, in a single-patient-use prefilled pen containing 600 mcg/2.4 mL (250mcg/mL), 60 doses: NDC 70121-1686-1 16.2 Storage and Handling Store exenatide injection in the refrigerator at 36 ○ to 46 ○ F (2 ○ to 8 ○ C). After first use, exenatide injection can be kept at a temperature not to exceed 77 ○ F (25 ○ C). Do not freeze. Do not use exenatide injection if it has been frozen. Protect exenatide injection from light. Discard the pen 30 days after first use, even if some drug remains in the pen. Use a puncture-resistant container to discard the needles. Do not reuse or share needles.