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Full Prescribing Information with Medication Guide - PI

1. 17 4 Risk of Renal Impairment Patients treated with BYETTA should be informed of the potential risk for worsening renal function and informed about associated signs and symptoms of renal dysfunction as well as the possibility of dialysis as a medical intervention if renal failure occurs see Warnings and Precautions 5 4 17 5 Risk of Hypersensitivity Reactions Patients should be informed that serious hypersensitivity reactions have been reported during postmarketing use of BYETTA If symptoms of hypersensitivity reactions occur patients must stop taking BYETTA and seek medical advice promptly see Warnings and Precautions 5 7 17 6 Use in Pregnancy Patients should be advised to inform their physicians if they are pregnant or intend to become pregnant 17 7 Instructions Each dose of BYETTA should be administered as a SC injection in the thigh abdomen or upper arm 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 BYETTA should not be administered after a meal If a dose is missed the treatment regimen should be resumed as prescribed with the next scheduled dose Patients should be advised that treatment with BYETTA may result in a reduction in appetite food intake and or body weight and that there is no need to modify the dosing regimen due to such effects Treatment with BYETTA may also result in nausea particularly up
2. exenatide injection 10 e Inject your dose of BYETTA under the skin subcutaneous injection of your upper leg thigh stomach area abdomen or upper arm as instructed by your healthcare provider Do not inject into a vein or muscle e Do not mix BYETTA and insulin in the same syringe or vial even if you take them at the same time e BYETTA is injected two times each day at any time within the 60 minutes 1 hour before your morning and evening meals or before the two main meals of the day approximately 6 hours or more apart Do not take BYETTA after your meal e If you miss a dose of BYETTA skip that dose and take your next dose at the next prescribed time Do not take an extra dose or increase the amount of your next dose to make up for a missed dose e If you use too much BYETTA call your healthcare provider or poison control center at 1 800 222 1222 right away Too much BYETTA can cause your blood sugar to drop quickly and you may have symptoms of low blood sugar You may need medical treatment right away Too much BYETTA can also cause severe nausea and vomiting e Follow your healthcare provider s instructions for diet exercise and how often to test your blood sugar If you see your blood sugar increasing during treatment with BYETTA talk to your healthcare provider because you may need to adjust your current treatment plan for your diabetes e Talk to your healthcare provider about how to manage high bloo
3. Because BYETTA may induce nausea and vomiting with transient hypovolemia treatment may worsen renal function Caution should be applied when initiating or escalating doses of BYETTA from 5 to 10 mcg in patients with moderate renal impairment creatinine clearance 30 50 mL min There have been postmarketing reports of altered renal function including increased serum creatinine renal impairment worsened chronic renal failure and acute renal failure sometimes requiring hemodialysis or kidney transplantation Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status such as angiotensin converting enzyme inhibitors nonsteroidal anti inflammatory drugs or diuretics Some events occurred in patients who had been experiencing nausea vomiting or diarrhea with or without dehydration Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents including BYETTA Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies BYETTA exenatide injection 2 5 5 Gastrointestinal Disease BYETTA has not been studied in patients with severe gastrointestinal disease including gastroparesis Because BYETTA is commonly associated with gastrointestinal adverse reactions including nausea vomiting and diarrhea the use of BYETTA is not recommended in patients wi
4. exenatide injection 9 e It is not known if BYETTA is safe and effective in children e BYETTA has not been studied in people who have pancreatitis e BYETTA should not be used in people who have severe kidney problems Who should not use BYETTA Do not use BYETTA if e you have had an allergic reaction to exenatide or any of the other ingredients in BYETTA See the end of this Medication Guide for a complete list of ingredients in BYETTA Symptoms of a severe allergic reaction with BYETTA may include e swelling of your face lips tongue or throat e problems breathing or swallowing e severe rash or itching e fainting or feeling dizzy e very rapid heartbeat What should I tell my healthcare provider before using BYETTA Before taking BYETTA tell your healthcare provider if you e have or have had pancreatitis stones in your gallbladder gallstones a history of alcoholism or high blood triglyceride levels e have severe problems with your stomach such as delayed emptying of your stomach gastroparesis or problems with digesting food e have or have had kidney problems or have had a kidney transplant e have any other medical conditions e are pregnant or plan to become pregnant It is not known if BYETTA will harm your unborn baby Pregnancy Registry A registry has been implemented for women who take BYETTA during pregnancy The purpose of this registry is to collect information about the heal
5. 6 5 h discontinued at time t 30 min to normalize plasma glucose concentrations and a continuous IV infusion of either BYETTA or saline for 5 h beginning 3 h prior to an IV bolus of glucose 0 3 g kg over 30 sec at t 0 min Glucagon Secretion In patients with type 2 diabetes BYETTA moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand Gastric Emptying BYETTA slows gastric emptying thereby reducing the rate at which meal derived glucose appears in the circulation Food Intake In both animals and humans administration of exenatide has been shown to reduce food intake Postprandial Glucose HW sg with type 2 diabetes BYETTA reduces postprandial plasma glucose concentrations igure 2 Figure 2 Mean SEM Postprandial Plasma Glucose Concentrations on Day 1 of BYETTA Treatment in Patients with Type 2 Diabetes Treated with Metformin a Sulfonylurea or Both N 54 350 SC Injection TT Standardized Breakfast ke 5 300 250 200 5 amp 150 A 100 30 0 30 60 90 120 150 180 210 240 Time min m BYETIA N 26 Placebo N 28 a Mean dose 7 8 mcg based on body weight was administered by subcutaneous SC injection Fasting Glucose In a single dose crossover study in patients with type 2 diabetes and fasting hyperglycemia
6. BYETTA exenatide injection 8 16 2 Storage and Handling Prior to first use BYETTA must be stored refrigerated at 36 F to 46 F 2 C to 8 C After first use BYETTA can be kept at a temperature not to exceed 77 F 25 C Do not freeze Do not use BYETTA if it has been frozen BYETTA should be protected from light The pen should be discarded 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 BYETTA should not be used past the expiration date 17 PATIENT COUNSELING INFORMATION See FDA approved Medication Guide Patients should be informed of the potential risks and benefits of BYETTA and of alternative modes of therapy Patients should also be fully informed about self management practices including the importance of proper storage of BYETTA injection technique timing of dosage of BYETTA and concomitant oral drugs adherence to meal planning regular physical activity periodic blood glucose monitoring and HbA testing recognition and management of hypoglycemia and hyperglycemia and assessment for diabetes complications 17 1 Never Share a BYETTA Pen Between Patients Advise patients that they must never share a BYETTA pen with another person even if the needle is changed because doing so carries a risk for transmission of blood borne pathogens 17 2 Risk of Pancreatitis Patients should be informed that persistent sever
7. BYETTA treated patients were nausea 5 1 and vomiting 2 9 No placebo treated patients withdrew due to nausea or vomiting 6 2 Postmarketing Experience The following additional adverse reactions have been reported during postapproval 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 International normalized ratio INR increased with concomitant warfarin use sometimes associated with bleeding 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 Indications and Usage 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
8. Glargine Titrated Insulin Glargine Intent to Treat Population N 312 315 HbA Mean Baseline 8 2 8 3 Change at Week 30t 1 1 1 1 Difference from Insulin Lispro 0 0 0 2 0 1 95 CI Body Weight kg Mean Baseline 89 3 89 9 Change at Week 30t 1 9 2 6 Difference from Insulin Lispro 4 5 5 2 3 9 95 Cl Fasting Serum Glucose mg dL Mean Baseline 126 129 Change at Week 30t 5 7 Difference from Insulin Lisprot 12 19 4 95 CI BYETTA 5 mcg BID for 1 month followed by 10 mcg BID for 5 months for the 30 week trial t Least squares means are based on a mixed model adjusting for treatment country prior use of sulfonylurea yes no visit corresponding baseline and treatment by visit interaction where subject is treated as a random effect Data at 30 weeks are available from 88 and 84 of the intent to treat subjects in the Lispro and BYETTA groups respectively Patients titrated insulin glargine or insulin lispro dose to achieve prespecified target fasting and preprandial glucose concentrations BID twice daily TID three times daily 16 HOW SUPPLIED STORAGE AND HANDLING 16 1 How Supplied BYETTA exenatide 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 0310 6512 01 10 mcg per dose 60 doses 2 4 mL prefilled pen NDC 0310 6524 01
9. Tissue Disorders alopecia 7 DRUG INTERACTIONS 7 1 Orally Administered Drugs The effect of BYETTA to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs BYETTA should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption see Adverse Reactions 6 2 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 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 see Clinical Pharmacology 12 3 7 2 Warfarin There are postmarketing reports of increased INR sometimes associated with bleeding with concomitant use of warfarin and BYETTA see Adverse Reactions 6 2 In a drug interaction study BYETTA did not have a significant effect on INR see Clinical Pharmacology 12 3 In patients taking warfarin prothrombin time should be monitored more frequently after initiation or alteration of BYETTA therapy Once a stable prothrombin time has been documented prothrombin times 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 BYETTA use in
10. as a subcutaneous SC injection in the thigh abdomen or upper arm Do not mix BYETTA with insulin Do not transfer BYETTA from the pen to a syringe or a vial No data are available on the safety or efficacy of intravenous or intramuscular injection of BYETTA Use BYETTA only if it is clear colorless and contains no particles 3 DOSAGE FORMS AND STRENGTHS BYETTA is supplied as a sterile solution for subcutaneous injection containing 250 mcg mL exenatide in the following packages e 5 mcg per dose 60 doses 1 2 mL prefilled pen e 10 mcg per dose 60 doses 2 4 mL prefilled pen 4 CONTRAINDICATIONS 4 1 Hypersensitivity BYETTA is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components 5 WARNINGS AND PRECAUTIONS 5 1 Never Share a BYETTA Pen Between Patients BYETTA pens must never be shared between patients even if the needle is changed Pen sharing poses a risk for transmission of blood borne pathogens 5 2 Acute Pancreatitis Based on postmarketing data BYETTA has been associated with acute pancreatitis including fatal and non fatal hemorrhagic or necrotizing pancreatitis After initiation of BYETTA and after dose increases observe patients carefully for signs and symptoms of pancreatitis including persistent severe abdominal pain sometimes radiating to the back which may or may not be accompanied by vomiting If pancreatitis is suspected BYETTA should promptl
11. immediate insulin release followed injection of BYETTA Plasma glucose concentrations were significantly reduced with BYETTA compared with placebo Figure 3 BYETTA exenatide injection 5 Figure 3 Mean SEM Serum Insulin and Plasma Glucose Concentrations Following a One Time Injection of BYETTA or Placebo in Fasting Patients with Type 2 Diabetes N 12 40 Injection 354 7 30 25 Serum Insulin U mL 1 0 1 2 3 4 5 6 7 Time h oo 240 Injection 220 200 180 160 140 120 100 1 0 1 2 3 4 5 6 7 8 Time h BYETTA O Placebo a BYETTA administration was based on body weight at baseline mean dose was 9 1 mcg Plasma Glucose mg dL Cardiac Electrophysiology The effect of exenatide 10 ug subcutaneously on QTc interval was evaluated in a randomized placebo and active controlled moxifloxacin 400 mg crossover thorough QTc study in 62 healthy subjects In this study with demonstrated ability to detect small effects the upper bound of the 90 confidence interval for the largest placebo adjusted baseline corrected QTc was below 10 msec Thus BYETTA 10 mcg single dose was not associated with clinically meaningful prolongation of the QTc interval 12 3 Pharmacokinetics Absorption Following SC administration to patients with type 2 diabetes exenatide reaches median peak plasma concentrations in 2 1 hours The mean peak exenatide concentration Cna was 211 pg mL and overall mean area under the tim
12. manual window e The pen is now ready to reset STEP 5 Reset the Pen e Turn dose knob away from you until it stops and the is in the dose window Note If you cannot turn the dose knob or if your pen leaks your full dose has not been delivered See Commonly Asked Questions numbers 4 and 7 in Section 4 of this user manual Unscrew the needle e Carefully put the outer needle shield back over the needle e Remove the needle after each injection STEP 7 Store Pen for Next Dose e Replace Blue Pen Cap on pen before storage e Store your BYETTA Pen at a temperature between 36 F to 77 F 2 C to 25 C See Storing Your BYETTA Pen in Section 1 of this user manual for complete storage information e When it is time for your next routine dose go to Section 3 Step 1 and repeat Steps 1 7 Section 4 Throw away needles in a puncture resistant container Or as recommended by your healthcare provider COMMONLY ASKED QUESTIONS 1 Do I need to do the One Time Only New Pen Setup before every dose e No The One Time Only New Pen Setup is done only once just before each new pen is used for the first time e The purpose of the setup is to make sure that your BYETTA Pen is ready to use for the next 30 days e If you repeat the One Time Only New Pen Setup before each routine dose you will not have enough BYETTA for 30 days The small amount of BYETTA used in the new pen setup will not affect the 30 day supply of B
13. may be state and local laws about how you should throw away used pens and needles e Do not throw the disposal container in the household trash Do not recycle e Always keep the puncture proof container out of reach of children Do not share your BYETTA Pen with other people even if the needle has been changed You may give other people a serious infection or get a serious infection from them STORING YOUR BYETTA PEN How do I store my BYETTA Pen e Prior to first use store your unused BYETTA Pen in the original carton in a refrigerator at 36 F to 46 F 2 C to 8 C e After first use your BYETTA Pen can be kept at a temperature not to exceed 77 F 25 C e Do not freeze Do not use BYETTA if it has been frozen BYETTA should be protected from light e When carrying the pen away from home store the pen at a temperature between 36 F to 77 F 2 C to 25 C and keep dry e Do not store the pen with the needle attached If the needle is left on the pen BYETTA may leak from the pen and air bubbles may form in the cartridge Keep your pen and needles out of the reach of children How long can I use a BYETTA Pen e You can use your BYETTA Pen for up to 30 days after setting up a new pen for first use After 30 days throw away the BYETTA Pen even if it is not completely empty e Mark the date when you first used your pen and the date 30 days later in the spaces below Date of First Use Date to Throw Away Pen e BYETTA should not
14. not harm you or affect your dose Pull off inner needle shield and throw away A small drop of liquid may appear This is normal Turn dose knob away from you until it stops at 10 Make sure that the 10 with the line under it is in the center of the dose window Note If you cannot turn the dose knob away from you to the 10 see Commonly Asked Questions number 7 in Section 4 of this user manual BYETTA exenatide injection 22 STEP 4 Inject the Dose SS wey N a y 3 p IE VAA P ma Me Pal i ae e y e Grip pen firmly PUSH amp HOLD e Injection is complete when the e Insert needle into skin e Use thumb to firmly push 4 is in the center of the dose using the under the skin injection button in until it window subcutaneous injection stops Continue holding in the The pen is now ready to reset method explained by your injection button while slowly P y healthcare provider counting to 5 to get a full dose e Remove needle from skin Note If you see several drops of BYETTA leaking from the needle after the injection you may not have received a complete dose See Commonly Asked Questions number 4 in Section 4 of this user manual STEP 5 Reset the Pen e Turn dose knob away Note If you cannot turn the dose knob from you until it stops or if your pen leaks your full dose has not been delivered See Commonly shart Is In the dose Asked Questions numbers 4 and 7 in Section 4
15. of this user manual e Carefully put the outer needle e Unscrew the needle e Throw away needles in a Shield back over the needle puncture resistant container e Remove the needle after or as recommended by your each injection healthcare provider STEP 7 Store Pen for Next Dose e Replace Blue Pen Cap on pen before storage e Store your BYETTA Pen at a temperature between 36 F to 77 F 2 C to 25 C See Storing Your BYETTA Pen in Section 1 of this user manual for complete storage information e When it is time for your next routine dose go to Section 3 Step 1 and repeat Steps 1 7 Section 4 COMMONLY ASKED QUESTIONS 1 Do I need to do the One Time Only New Pen Setup before every dose e No The One Time Only New Pen Setup is done only once just before each new pen is used for the first time e The purpose of the setup is to make sure that your BYETTA Pen is ready to use for the next 30 days e If you repeat the One Time Only New Pen Setup before each routine dose you will not have enough BYETTA for 30 days The small amount of BYETTA used in the new pen setup will not affect the 30 day supply of BYETTA 2 Why are there air bubbles in the cartridge e A small air bubble is normal It will not harm you or affect your dose e Ifthe pen is stored with a needle attached air bubbles may form in the cartridge Do not store the pen with the needle attached 3 What should I do if BYETTA does not come out of the needle tip after fo
16. pregnant women In animal studies exenatide caused cleft palate irregular skeletal ossification and an increased number of neonatal deaths BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus Female mice given SC doses of 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 390 times the human exposure resulting from the maximum recommended dose of 20 mcg day based on AUC see Nonclinical Toxicology 13 3 In developmental toxicity studies pregnant animals received exenatide subcutaneously during organogenesis Specifically fetuses from pregnant rabbits given SC doses of 0 2 2 22 156 or 260 mcg kg day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum BYETTA exenatide injection 4 recommended dose of 20 mcg day based on AUC Moreover fetuses from pregnant mice given SC doses of 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 3 times the human exposure resulting from the maximum recommended dose of 20 mcg day based on AUC see Nonclinical Toxicology 13 3 Lactating mice given SC doses of 6 68 or 760 mcg kg day from gestati
17. site reaction had high titers of antibodies to exenatide Two serious adverse events chest pain and chronic hypersensitivity pneumonitis were reported in the BYETTA arm No serious adverse events were reported in the placebo arm The most common adverse reactions leading to withdrawal for BYETTA treated patients were nausea 9 and vomiting 5 For placebo treated patients lt 1 withdrew due to nausea Add On to Insulin Glargine with or without Metformin and or Thiazolidinedione Placebo Controlled For the 30 week placebo controlled study of BYETTA as add on to insulin glargine with or without oral antihyperglycemic medications Table 5 summarizes adverse reactions excluding hypoglycemia occurring with an incidence gt 2 and occurring more frequently in BYETTA treated patients compared with placebo treated patients BYETTA exenatide injection Table 5 Treatment Emergent Adverse Reactions gt 2 Incidence with BYETTA used with Insulin Glargine with or without Oral Antihyperglycemic Medications excluding Hypoglycemia With Insulin Glargine Placebo All BYETTA BID N 122 N 137 Nausea 8 4 Vomiting 4 18 Diarrhea 8 18 Headache 4 14 Constipation 2 10 Dyspepsia 2 7 Asthenia 1 5 Abdominal Distension 1 4 Decreased Appetite 0 3 Flatulence 1 2 Gastroesophageal Reflux Disease 1 2 In a 30 week placebo controlled clinical trial BID twice daily The most frequently reported adverse reactions leading to withdrawal for
18. stable upon initiation or alteration of BYETTA therapy 6 2 7 2 e Pregnancy Based on animal data BYETTA may cause fetal harm BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus To report drug exposure during pregnancy call 1 800 633 9081 8 1 e Nursing Mothers Caution should be exercised when BYETTA is administered to a nursing woman 8 3 See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised 2 2015 8 5 Geriatric Use 8 6 Renal Impairment 8 7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12 1 Mechanism of Action 12 2 Pharmacodynamics 12 3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis Impairment of Fertility 13 3 Reproductive and Developmental Toxicology 14 CLINICAL STUDIES 14 1 Monotherapy 14 2 Combination Therapy with Oral Antihyperglycemic Medicines 14 3 Combination with Insulin Glargine 16 HOW SUPPLIED STORAGE AND HANDLING 16 1 How Supplied 16 2 Storage and Handling 17 PATIENT COUNSELING INFORMATION 17 1 Never Share a BYETTA Pen Between Patients 17 2 Risk of Pancreatitis 17 3 Risk of Hypoglycemia 17 4 Risk of Renal Impairment 17 5 Risk of Hypersensitivity Reactions 17 6 Use in Pregnancy 17 7 Instructions Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1 1 Type 2 Diabetes Mellitus
19. treated as a random effect Least squares means are based on a mixed model adjusting for treatment pooled investigator visit baseline HbA stratum baseline value of the dependent variable where applicable and treatment by visit where subject is treated as a random effect Patients in both groups titrated insulin glargine dose to achieve optimal fasting glucose concentrations p lt 0 01 treatment vs placebo BID twice daily BYETTA exenatide injection Table 9 Dosing Algorithm for Titration of Insulin Glargine Fasting Plasma Glucose Values Dose Change mg dL U lt 56 4 56 to 72t 2 73 to 99 0 100 to 119 2 120 to 139 4 140 to 179 6 gt 180 8 Abbreviations U units Adapted from Riddle et al 2003 t Value for at least 1 fasting plasma glucose measurement since the last assessment Based on the average of fasting plasma glucose measurements taken over the prior 3 to 7 days The increase in the total daily dose should not have exceeded more than 10 units per day or 10 of the current total daily dose whichever was greater 30 Week Comparator Controlled Noninferiority Trial A 30 week open label active comparator controlled noninferiority study was conducted to evaluate the safety and efficacy of BYETTA n 315 versus titrated insulin lispro n 312 on a background of optimized basal insulin glargine and metformin in patients with type 2 diabetes with inadequate glycemic control Fol
20. 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 treated patients were nausea 3 of patients and vomiting 1 For placebo treated patients lt 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 add on to a thiazolidinedione with or without metformin Table 4 summarizes the adverse reactions excluding hypoglycemia with an incidence of gt 2 and occurring more frequently in BYETTA treated patients compared with placebo treated patients Table 4 Treatment Emergent Adverse Reactions gt 2 Incidence with BYETTA used with a Thiazolidinedione TZD with or without Metformin MET excluding Hypoglycemia With a TZD or TZD MET Placebo All BYETTA BID N 112 N 121 Nausea 15 40 Vomiting 1 13 Dyspepsia 1 7 Diarrhea 3 6 Gastroesophageal Reflux Disease 0 3 In a 16 week placebo controlled clinical trial BID twice daily Adverse reactions reported in 21 0 to lt 2 0 of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite Chills n 4 and injection site reactions n 2 occurred only in BYETTA treated patients The two patients who reported an injection
21. 1 hour before BYETTA injection Digoxin Administration of repeated doses of BYETTA 10 mcg BID 30 minutes before oral digoxin 0 25 mg once daily decreased the Crax of digoxin by 17 and delayed the Tna Of digoxin by approximately 2 5 hours however the overall steady state pharmacokinetic exposure e g AUC of digoxin was not changed Lovastatin Administration of BYETTA 10 mcg BID 30 minutes before a single oral dose of lovastatin 40 mg decreased the AUC and Cna of lovastatin by approximately 40 and 28 respectively and delayed the Tma by about 4 hours compared with lovastatin administered alone In the 30 week controlled clinical trials of BYETTA the use of BYETTA in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline BYETTA exenatide injection Lisinopril In patients with mild to moderate hypertension stabilized on lisinopril 5 20 mg day BYETTA 10 mcg BID did not alter steady state Cna or AUC of lisinopril Lisinopril steady state Tnax Was delayed by 2 hours There were no changes in 24 hour mean systolic and diastolic blood pressure Oral Contraceptives The effect of BYETTA 10 mcg BID on single and on multiple doses of a combination oral contraceptive 30 mcg ethinyl estradiol plus 150 mcg levonorgestrel was studied in healthy female subjects Repeated daily doses of the oral contraceptive OC given 30 minutes after BYETTA a
22. 3107019 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BYETTA safely and effectively See full prescribing information for BYETTA BYETTA exenatide Injection Initial U S Approval 2005 BYETTA exenatide 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 1 14 Important Limitations of Use e Nota substitute for insulin BYETTA should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis 1 2 e Concurrent use with prandial insulin has not been studied and cannot be recommended 1 2 e Has not been studied in patients with a history of pancreatitis Consider other antidiabetic therapies in patients with a history of pancreatitis 1 2 e 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 e initiate at 5 mcg per dose twice daily increase to 10 mcg twice daily after 1 month based on clinical response 2 1 DOSAGE FORMS AND STRENGTHS BYETTA is supplied as 250 mcg mL exenatide in e 5 mcg per dose 60 doses 1 2 mL prefilled pen e 10 mcg per dose 60 doses 2 4 mL prefilled pen e Never share a BYETIA pen between patients even if the needle is changed 5 1 e Pancreatitis Postmarketing repo
23. 8 Dose not studied 97 5 Change at Week 16t 0 0 Dose not studied 1 5 Difference from placebot 95 Cl Fasting Serum Glucose mg dL Mean Baseline 159 Change at Week 16t 4 Dose not studied 21 Difference from placebo 95 Cl Dose not studied 25 33 16 BYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 6 months for the 30 week trials or 10 mcg BID for 3 months in the 16 week trial before the morning and evening meals t Least squares means are adjusted for baseline HbA strata or value investigator site baseline value of the dependent variable if applicable and background antihyperglycemic therapy if applicable p lt 0 01 treatment vs placebo Measured using the hexokinase based glucose method BID twice daily Dose not studied 1 5 2 2 0 7 Dose not studied 164 BYETTA exenatide injection 7 HbA The addition of BYETTA to a regimen of metformin a sulfonylurea or both resulted in statistically significant reductions from baseline in HbA compared with patients receiving placebo added to these agents in the three controlled trials Table 7 In the 16 week trial of BYETTA add on to thiazolidinediones with or without metformin BYETTA resulted in statistically significant reductions from baseline in HbA compared with patients receiving placebo Table 7 Postprandial Glucose Postprandial glucose was measured after a mixed meal tolerance test in 9 5 of patients participat
24. 9 Difference from placebot 95 Cl 0 6 0 9 0 3 1 0 1 3 0 7 Proportion Achieving HbA lt 7 10 20 36 Body Weight kg Mean Baseline 99 1 94 9 95 2 Change at Week 30 0 8 1 1 1 6 Difference from placebot 95 Cl Fasting Plasma Glucose mg dL Mean 0 3 1 1 0 6 0 9 1 7 0 0 Baseline 194 180 178 Change at Week 30t 6 5 11 Difference from placebot 95 CI 11 25 3 17 30 3 In Combination with Metformin and a Sulfonylurea 30 Weeks Intent to Treat Population N 247 245 241 HbA Mean Baseline 8 5 8 5 8 5 Change at Week 30 0 1 0 7 0 9 Difference from placebot 95 Cl 0 8 1 0 0 6 1 0 1 2 0 8 Proportion Achieving HbA lt 7 8 25 31 Body Weight kg Mean Baseline 99 1 96 9 98 4 Change at Week 30t 0 9 1 6 1 6 Difference from placebot 95 Cl Fasting Plasma Glucose mg dL Mean 0 7 1 2 0 2 0 7 1 3 0 2 Baseline 181 182 178 Change at Week 30t 13 11 12 Difference from placebot 95 CI 24 33 15 25 34 16 In Combination with a Thiazolidinedione or a Thiazolidinedione plus Metformin 16 Weeks Intent to Treat Population N 112 Dose not studied 121 HbA Mean Baseline 7 9 Dose not studied 7 9 Change at Week 16t 0 1 Dose not studied 0 7 Difference from placebot 95 Cl Dose not studied 0 9 1 1 0 7 Proportion Achieving HbA lt 7 15 Dose not studied 51 Body Weight kg Mean Baseline 96
25. BYETTA exenatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus see Clinical Studies 14 1 2 Important Limitations of Use BYETTA is not a substitute for insulin BYETTA should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis as it would not be effective in these settings The concurrent use of BYETTA with prandial insulin has not been studied and cannot be recommended Based on postmarketing data BYETTA has been associated with acute pancreatitis including fatal and non fatal hemorrhagic or necrotizing pancreatitis BYETTA 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 BYETTA Other antidiabetic therapies should be considered in patients with a history of pancreatitis 2 DOSAGE AND ADMINISTRATION 2 1 Recommended Dosing BYETTA should be initiated at 5 mcg administered twice daily BID 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 BYETTA should not be administered after a meal Based on clinical response the dose of BYETTA 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
26. BYETTA Pen to a syringe or vial e Do not mix BYETTA and insulin in the same syringe or vial even if you take them at the same time e If any part of your pen appears broken or damaged do not use the pen e This BYETTA Pen is not recommended for use by people who are blind or have vision problems without the help of a person trained in the proper use of the pen e Follow the injection method explained to you by your healthcare provider e Follow Section 2 only to set up a new pen before first use e Section 3 of this manual should be used for every injection ABOUT PEN NEEDLES What kinds of needles can be used with my BYETTA Pen e Pen needles are not included with your pen You may need a prescription to get them from your pharmacist e Use 29 thin 30 or 31 thinner gauge disposable pen needles with your BYETTA Pen Ask your healthcare provider which needle gauge and length is best for you Do I use a new needle for each injection e Yes Do not reuse or share your needles with other people You may give other people a serious infection or get a serious infection from them e Remove the needle from the pen immediately after you complete each injection This will help prevent leakage of BYETTA keep out air bubbles reduce needle clogs and decrease the risk of infection e Do not push the injection button on your pen unless a needle is attached to the pen BYETTA exenatide injection 13 How do I throw away my needles e Do n
27. BYETTA add on to thiazolidinediones with or without metformin 36 patients 31 had low titer antibodies to exenatide at 16 weeks The level of glycemic control in these patients was generally comparable to that observed in the 69 patients 60 without antibody titer An additional 10 patients 9 had higher titer antibodies at 16 weeks Of these patients 4 4 overall had an attenuated glycemic response to BYETTA the remaining 6 5 overall had a glycemic response comparable to that of patients without antibodies see Warnings and Precautions 5 6 In the 24 week trial of BYETTA used as monotherapy 40 patients 28 had low titer antibodies to exenatide at 24 weeks The level of glycemic control in these patients was generally comparable to that observed in the 101 patients 70 without antibody titers An additional 3 patients 2 had higher titer antibodies at 24 weeks Of these patients 1 1 overall had an attenuated glycemic response to BYETTA the remaining 2 1 overall had a glycemic response comparable to that of patients without antibodies see Warnings and Precautions 5 6 Antibodies to exenatide were not assessed in the 30 week placebo controlled trial of BYETTA used in combination with insulin glargine In the 30 week comparator controlled trial of BYETTA used in combination with insulin glargine and metformin 60 patients 20 had low titer antibodies to exenatide at 30 weeks The level of glycemic control in these patie
28. YETTA 2 Why are there air bubbles in the cartridge e A small air bubble is normal It will not harm you or affect your dose e Ifthe pen is stored with a needle attached air bubbles may form in the cartridge Do not store the pen with the needle attached 3 What should I do if BYETTA does not come out of the needle tip after four tries during One Time Only New Pen Setup e Carefully put the outer needle shield back over the needle Remove the needle by unscrewing it Throw away the needle properly e Attach a new needle and repeat One Time Only New Pen Setup Steps B E in Section 2 of this user manual Once you see several drops or a stream of liquid coming out of the tip of the needle the setup is complete BYETTA exenatide injection 17 4 Why do I see BYETTA leaking from my needle after I have finished my injection It is normal for a single drop to remain on the tip of your needle after your injection is complete If you see more than one drop e You may not have received your full dose Do not inject another dose Talk with your healthcare provider about what to do about a partial dose e To make sure that you get your full dose when you take your injections firmly push and hold the injection button in and slowly count to 5 see Section 3 Step 4 Inject the Dose 5 How can I tell when the injection is complete The injection is complete when e You have firmly pushed the injection button in all the way until it stops and e
29. You have slowly counted to 5 while you are still holding the injection button in and the needle is still in your skin and e The 4 is in the center of the dose window If you hear a click sound from your BYETTA Pen ignore it You must follow all the steps listed above to make sure your injection is complete 6 Where should I inject BYETTA Front Back Inject BYETTA into your abdomen thigh or upper arm using the injection method explained to you by your healthcare provider 7 What if I cannot pull turn or push the dose knob Check the symbol in the dose window Follow the steps next to the matching symbol If is in the dose window e Pull the dose knob out until appears If is in the dose window and the dose knob will not turn e The cartridge in your BYETTA Pen may not have enough medicine to deliver a full dose A small amount of BYETTA will always stay in the cartridge If the cartridge contains a small amount and the dose knob will not turn your pen does not have enough BYETTA and will not deliver any more doses Obtain a new BYETTA Pen If and part of are in the dose window and the dose knob cannot be pushed in e The dose knob was not turned all the way Continue turning the dose knob away from you until 5 is in the center of the dose window If part of 5 and part of are in the dose window and the dose knob cannot be pushed in e The needle may be clogged bent or incorrectly attached e Attach a new need
30. You may give other people a serious infection or get a serious infection from them Section 1 Read this section completely before you begin Then move on to Section 2 Getting Started WHAT YOU NEED TO KNOW ABOUT YOUR BYETTA PEN PEN USER MANUAL Read these instructions carefully BEFORE using your BYETTA Pen For complete dosing and safety information also read the BYETTA Medication Guide that comes with the BYETTA Pen carton It is important that you use your pen correctly Failure to follow these instructions completely may result in a wrong dose a broken pen or an infection These instructions do not take the place of talking with your healthcare provider about your medical condition or your treatment If you are having problems using your BYETTA Pen call toll free 1 800 236 9933 IMPORTANT INFORMATION ABOUT YOUR BYETTA PEN e Each BYETTA Pen contains enough medicine for injection two times each day for 30 days You do not have to measure any doses the pen measures each dose for you e Do not transfer the medicine in the BYETTA Pen to a syringe or vial e Do not mix BYETTA and insulin in the same syringe or vial even if you take them at the same time e If any part of your pen appears broken or damaged do not use the pen e This BYETTA Pen is not recommended for use by people who are blind or have vision problems without the help of a person trained in the proper use of the pen e Follow the injection method explained to you b
31. ake it with a meal or snack where you do not also take BYETTA e warfarin sodium Coumadin Jantoven e a blood pressure medicine e a water pill diuretic e apain medicine e lovastatin Altoprev Mevacor Advicor Ask your healthcare provider if you are not sure if your medicine is listed above Know the medicines you take Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine How should I use BYETTA See the Pen User Manual that comes with BYETTA for instructions for using the BYETTA Pen and injecting BYETTA e Your healthcare provider may prescribe BYETTA alone or with certain other medicines to help control your blood sugar e BYETTA comes in a prefilled pen e Use BYETTA exactly as prescribed by your healthcare provider Do not change your dose unless your healthcare provider has told you to change your dose e Your healthcare provider must teach you how to inject BYETTA before you use it for the first time If you have questions or do not understand the instructions talk to your healthcare provider or pharmacist e Pen needles are not included You may need a prescription to purchase pen needles from your pharmacist Ask your healthcare provider which needle length and gauge is best for you Do not reuse or share your needles with other people You may give other people a serious infection or get a serious infection from them BYETTA
32. as been changed You may give other people a serious infection or get a serious infection from them Serious side effects can happen in people who take BYETTA including inflammation of the pancreas pancreatitis which may be severe and lead to death Before taking BYETTA tell your healthcare provider if you have had e pancreatitis e stones in your gallbladder gallstones e a history of alcoholism e high blood triglyceride levels These medical conditions can make you more likely to get pancreatitis in general It is not known if having these conditions will lead to a higher chance of getting pancreatitis while taking BYETTA While taking BYETTA Call your healthcare provider right away if you have pain in your stomach area abdomen that is severe and will not go away The pain may happen with or without vomiting The pain may be felt going from your abdomen through to your back These may be symptoms of pancreatitis What is BYETTA e BYETTA is an injectable prescription medicine that may improve blood sugar glucose control in adults with type 2 diabetes mellitus when used with a diet and exercise program e BYETTA is not insulin e You should not take BYETTA instead of insulin e The use of BYETTA with short acting insulin is not recommended e The use of BYETTA with rapid acting insulin is not recommended e BYETTA is not for people with type 1 diabetes or people with diabetic ketoacidosis BYETTA
33. be used after the expiration date printed on the pen label How do I clean my BYETTA Pen e Wipe the outside of the pen with a clean damp cloth e White particles may appear on the outside tip of the cartridge during normal use You may remove them with an alcohol wipe or alcohol swab See the complete BYETTA Medication Guide that comes with BYETTA For more information call toll free 1 800 236 9933 or visit www BYETTA com Section 2 Read and follow the directions in this section only after you ve read Section 1 What You Need To Know About Your BYETTA Pen GETTING STARTED Set up your new pen just before you use it the first time For routine use do not repeat this one time only new pen setup If you do you will run out of BYETTA before 30 days of use iy Blue Pen Cap Cartridge BYETTA Label Dose Dose Injection Liquid Window Knob Button Pen Needles Not Included ready to pull dose knob out a Ready to turn to dose position ready to inject 10 mcg Outer Inner Needle Paper 4 dose knob pushed in and Needle Needle Tab ready to reset Shield Shield BYETTA exenatide injection 20 ONE TIME ONLY NEW PEN SETUP STEP A Check the Pen Note A small air bubble in the cartridge is normal e Wash hands prior to use e Check BYETTA in the cartridge e Check pen label to make sure it is The liquid should be clear your 10 mcg pen colorless and free of particles e Pull off the bl
34. ciated with BYETTA nausea occurred in a dose dependent fashion Two of the 155 patients treated with BYETTA 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 add on to metformin and or sulfonylurea adverse reactions excluding hypoglycemia with an incidence gt 2 and occurring more frequently in BYETTA treated patients compared with placebo treated patients see Warnings and Precautions 5 3 are summarized in Table 3 BYETTA exenatide injection 3 Table 3 Treatment Emergent Adverse Reactions gt 2 Incidence and Greater Incidence with BYETTA Treatment used with Metformin and or a Sulfonylurea excluding Hypoglycemia Placebo BID All BYETTA BID N 483 N 963 Nausea 18 44 Vomiting 4 13 Diarrhea 6 13 Feeling Jittery 4 9 Dizziness 6 9 Headache 6 9 Dyspepsia 3 6 Asthenia 2 4 Gastroesophageal Reflux Disease 1 3 Hyperhidrosis 1 3 In three 30 week placebo controlled clinical trials BID twice daily Adverse reactions reported in 21 0 to lt 2 0 of patients receiving BYETTA 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
35. d sugar hyperglycemia and low blood sugar hypoglycemia and how to recognize problems that can happen with your diabetes e Do not share your BYETTA Pen with other people even if the needle has been changed You may give other people a serious infection or get a serious infection from them What are the possible side effects of BYETTA BYETTA can cause serious side effects See What is the most important information I should know about BYETTA It is not known whether BYETTA or other anti diabetes medications increase your risk of a heart attack or stroke e Low blood sugar hypoglycemia Your risk for getting low blood sugar is higher if you take BYETTA with another medicine that can cause low blood sugar such as a sulfonylurea or insulin The dose of your sulfonylurea or BYETTA exenatide injection insulin medicine may need to be lowered while you use BYETTA Signs and symptoms of low blood sugar may include e headache e dizziness e drowsiness e confusion e weakness e irritability e hunger e sweating e fast heart beat e feeling jittery Talk with your healthcare provider about how to treat low blood sugar e Kidney problems BYETTA may cause new or worse problems with kidney function including kidney failure Dialysis or kidney transplant may be needed e While taking BYETTA Call your healthcare provider right away if you have nausea vomiting or diarrhea that will not go away or if you ca
36. dle tip BYETTA exenatide injection 21 STEP E Complete New Pen Setup e For routine use do not repeat this one time only new pen setup If you do i you will run out of BYETTA before 30 days of use e Turn dose knob away from you until it stops and the is in the dose window You are now ready for your first dose of BYETTA Go to Section 3 Step 3 for instructions on how to inject your first routine dose Note If you cannot turn the dose knob see Commonly Asked Questions number 7 in Section 4 of user manual Section 3 STEP 1 Check the Pen Check BYETTA in the cartridge The liquid should be clear colorless and free of particles If it is not do not use e Wash hands prior to use e Check pen label to make sure it 0 is your 10 mcg pen e Pull off the blue pen cap STEP 2 Attach the Needle Pull off outer needle shield Do not throw away e Remove paper tab from outer needle shield e Push outer needle shield containing the needle straight onto pen then screw needle on until secure STEP 3 Dial the Dose Pull dose knob out until it stops and the is in the dose window e Check that the is in the dose window If not turn dose knob away from you clockwise until it stops and the is in the dose window Now that you have done the one time only new pen setup follow Section 3 for all of your injections ROUTINE USE Note A small air bubble will
37. dministration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45 and 27 respectively and delayed the Tma of ethinyl estradiol and levonorgestrel by 3 0 hours and 3 5 hours respectively as compared to the oral contraceptive administered alone Administration of repeated daily doses of the OC one hour prior to BYETTA administration decreased the mean Cmax Of ethinyl estradiol by 15 but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone BYETTA did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens However the mean trough concentration of ethinyl estradiol was increased by 20 when the OC was administered 30 minutes after BYETTA administration injection as compared to when the OC was given alone The effect of BYETTA on OC pharmacokinetics is confounded by the possible food effect on OC in this study Therefore OC products should be administered at least one hour prior to BYETTA injection Warfarin Administration of warfarin 25 mg 35 minutes after repeated doses of BYETTA 5 mcg BID on days 1 2 and 10 mcg BID on days 3 9 in healthy volunteers delayed warfarin Tmax by approximately 2 hours No clinically relevant effects on Cma or AUC of S and R enantiomers of warfarin were observed BYETTA did not significantly alter the pharmacodynamic properties e g international normalized ratio of warfarin s
38. e abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting is the hallmark symptom of acute pancreatitis Patients should be instructed to promptly discontinue BYETTA and contact their physician if persistent severe abdominal pain occurs see Warnings and Precautions 5 2 17 3 Risk of Hypoglycemia The risk of hypoglycemia is increased when BYETTA is used in combination with a sulfonylurea Therefore patients receiving BYETTA and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia Patients should be informed that it is also possible that the use of BYETTA with other glucose independent insulin secretagogues e g meglitinides could increase the risk of hypoglycemia When BYETTA is used in combination with insulin evaluate the dose of insulin Consider reducing the dose of insulin in patients at increased risk of hypoglycemia see Adverse Reactions 6 1 Patients treated with BYETTA should be informed that the concurrent use of BYETTA with prandial insulin has not been studied and cannot be recommended The symptoms treatment and conditions that predispose to development of hypoglycemia should be explained to the patient The patient s usual instructions for hypoglycemia management should be reviewed and reinforced when initiating BYETTA therapy particularly when concomitantly administered with a sulfonylurea or insulin see Warnings and Precautions 5 3
39. e concentration curve AUC was 1036 pgeh mL following SC administration of a 10 mcg dose of BYETTA Exenatide exposure AUC increased proportionally over the therapeutic dose range of 5 to 10 mcg The Cmax values increased less than proportionally over the same range Similar exposure is achieved with SC administration of BYETTA in the abdomen thigh or upper arm Distribution The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA is 28 3 L Metabolism and Elimination Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation The mean apparent clearance of exenatide in humans is 9 1 L hour and the mean terminal half life is 2 4 hours These pharmacokinetic characteristics of exenatide are independent of the dose In most individuals exenatide concentrations are measurable for approximately 10 hours post dose Drug Interactions Acetaminophen When 1000 mg acetaminophen elixir was given with 10 mcg BYETTA 0 hour and 1 hour 2 hours and 4 hours after BYETTA injection acetaminophen AUCs were decreased by 21 23 24 and 14 respectively Cmax was decreased by 37 56 54 and 41 respectively Tax Was increased from 0 6 hour in the control period to 0 9 hour 4 2 hours 3 3 hours and 1 6 hours respectively Acetaminophen AUC Crna and Tmax were not significantly changed when acetaminophen was given
40. edle Needle Tab ready to reset Shield Shield STEP A Check the Pen BYETTA exenatide injection 14 ONE TIME ONLY NEW PEN SETUP Wash hands prior to use Check pen label to make sure it is your 5 mcg pen Pull off the blue pen cap STEP B Attach the Needle Remove paper tab from outer needle shield Push outer needle shield containing the needle straight onto the pen then screw needle on until secure STEP C Dial the Dose Check that the L is in the dose window If not turn dose knob away from you clockwise until it stops and the is in the dose window Note If you cannot turn the dose knob away from you to the 5 see Commonly Asked Questions number 7 in Section 4 of this user manual STEP D Prepare the Pen Point the needle of the pen up and away from you Check BYETTA in the cartridge The liquid should be clear colorless and free of particles If not do not use Pull off outer needle shield Do not throw away Pull dose knob out until it stops and the is in the dose window PUSH amp HOLD Use thumb to firmly push Injection button in until it stops then continue holding the injection button in while slowly counting to 5 If you do not see a stream or several drops come from the needle tip repeat Steps C amp D Note A small air bubble in the cartridge is normal Pull off inner needle shield and throw away A small drop of liquid may appear This i
41. edle is left on medicine may leak from the BYETTA Pen or air bubbles may form in the cartridge e See the BYETTA Pen User Manual for instructions about the right way to throw away your BYETTA Pen e Do not reuse or share your needles with other people You may give other people a serious infection or get a serious infection from them e Keep your BYETTA Pen pen needles and all medicines out of the reach of children General information about BYETTA Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide Do not use BYETTA for a condition for which it was not prescribed Do not give BYETTA to other people even if they have the same symptoms you have It may harm them This Medication Guide includes the most important information you should know about using BYETTA If you would like more information talk with your healthcare provider You can ask your healthcare provider or pharmacist for information about BYETTA that is written for health professionals For more information about BYETTA go to www BYETTA com or call BYETTA Customer Service at 1 800 236 9933 What are the ingredients in BYETTA Active Ingredient exenatide Inactive Ingredients metacresol mannitol glacial acetic acid and sodium acetate trihydrate in water for injection This Medication Guide has been approved by the U S Food and Drug Administration BYETTA is a registered trademark of the AstraZeneca group
42. ee Drug Interactions 7 2 Specific Populations Renal Impairment Pharmacokinetics of exenatide was studied in subjects with normal mild or moderate renal impairment and subjects with end stage renal disease In subjects with mild to moderate renal impairment creatinine clearance 30 80 mL min exenatide exposure was similar to that of subjects with normal renal function However in subjects with end stage renal disease receiving dialysis mean exenatide exposure increased by 3 37 fold compared to that of subjects with normal renal function see Use in Specific Populations 8 6 Hepatic Impairment No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment see Use in Specific Populations 8 7 Age Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide see Use in Specific Population 8 5 Gender Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide Race Population pharmacokinetic analysis of samples from Caucasian Hispanic Asian and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide Body Mass Index Population pharmacokinetic analysis of patients with body mass indices BMI gt 30 kg m and lt 30 kg m suggests
43. eedle shield Pull off inner needle shield e Remove paper tab from outer o needle shield Do not throw away and throw away A small drop e Push outer needle shield containing of liquid may appear This is the needle straight onto pen then normal screw needle on until secure STEP 3 Dial the Dose Checkthatihe l isinthe e Pull dose knob out until e Turn dose knob away from dose window If not turn it stops and the is in the you until it stops at 5 dose knob away from you dose window Make sure that the 5 with the clockwise until it stops and line under it is in the center of the ZJ is in the dose window the dose window Note If you cannot turn the dose knob away from you to the 5 see Commonly Asked Questions number 7 in Section 4 of this user manual BYETTA exenatide injection 16 STEP 4 Inject the Dose g da e Grip pen firmly PUSH amp HOLD e Injection is complete when the e Insert needle into skin e Use thumb to firmly push 4 is in the center of the dose using the under the skin subcutaneous injection method explained by your healthcare provider injection button in until it stops Continue holding in the injection button while slowly counting to 5 to get a full dose e Remove needle from skin Note If you see several drops of BYETTA leaking from the needle after the injection you may not have received a complete dose See Commonly Asked Questions number 4 in Section 4 of this user
44. er about what to do about a partial dose e Follow these steps to reset your pen for your next injection e Firmly push the injection button in all the way until it stops Keep holding the injection button in and slowly count to 5 Then release the injection button and turn the dose knob away from you until appears in the dose window e If you cannot turn the dose knob the needle may be clogged Replace the needle and repeat the step above e For your next dose be sure to firmly push and hold the injection button in and slowly count to 5 before removing needle from skin See the complete BYETTA Medication Guide that comes with BYETTA For more information call toll free 1 800 236 9933 or visit www BYETTA com Distributed by AstraZeneca Pharmaceuticals LP Wilmington DE 19850 BYETTA is a registered trademark of the AstraZeneca group of companies 3107019 3 15 Revised February 2015
45. es 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 appropriate supportive treatment should be initiated according to the patient s clinical signs and symptoms 11 DESCRIPTION BYETTA exenatide is a synthetic peptide that was originally identified in the lizard Heloderma suspectum Exenatide differs in chemical structure and pharmacological action from insulin sulfonylureas including D phenylalanine derivatives and meglitinides biguanides thiazolidinediones alpha glucosidase inhibitors amylinomimetics and dipeptidy peptidase 4 inhibitors Exenatide is a 39 amino acid peptide amide Exenatide has the empirical formula C H N5 90 09 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 GIn Met Glu Glu Glu Ala Val Arg Leu Phe lle Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser NH BYETTA is supplied for SC injection 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 2 2 mg metacresol as an antimicrobial preservative mannitol as a tonicity adjusting agent and glacial acetic acid and s
46. f elevated glucose concentrations This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia However BYETTA does not impair the normal glucagon response to hypoglycemia First Phase Insulin Response In healthy individuals robust insulin secretion occurs during the first 10 minutes following intravenous IV glucose administration This secretion known as the first phase insulin response is characteristically absent in patients with type 2 diabetes The loss of the first phase insulin response is an early beta cell defect in type 2 diabetes Administration of BYETTA at therapeutic plasma concentrations restored first phase insulin response to an IV bolus of glucose in patients with type 2 diabetes Figure 1 Both first phase insulin secretion and second phase insulin secretion were significantly increased in patients with type 2 diabetes treated with BYETTA compared with saline p lt 0 001 for both Figure 1 Mean SEM Insulin Secretion Rate during Infusion of BYETTA or Saline in Patients with Type 2 Diabetes and during Infusion of Saline in Healthy Subjects First Phase Second Phase Insulin Response Insulin Response lt a N N wo O a O Oo O Insulin Secretion Rate pmolekg emin Sp 30 0 30 60 90 120 VGI Time min Bolle BYETTA Type 2 Diabetes N 13 Saline Type 2 Diabetes N 13 Saline Healthy N 12 Patients received an IV infusion of insulin for
47. g until gestation day 7 No adverse effect on fertility was observed at 760 mcg kg day a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg day based on AUC 13 3 Reproductive and Developmental Toxicology In female mice given SC doses of 6 68 or 760 mcg kg day beginning 2 weeks prior to and throughout mating until gestation day 7 there were no adverse fetal effects at doses up to 760 mcg kg day systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg day based on AUC In pregnant mice given SC doses of 6 68 460 or 760 mcg kg day from gestation day 6 through 15 organogenesis cleft palate some with holes and irregular fetal skeletal ossification of BYETTA exenatide injection 6 rib and skull bones were observed at 6 mcg kg day a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg day based on AUC In pregnant rabbits given SC doses of 0 2 2 22 156 or 260 mcg kg day from gestation day 6 through 18 organogenesis irregular fetal skeletal ossifications were observed at 2 mcg kg day a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg day based on AUC In pregnant mice given SC doses of 6 68 or 760 mcg kg day from gestation day 6 through lactation day 20 weaning an increased number of neonatal deaths was observed on postpar
48. ients with renal transplantation Caution should be applied when initiating BYETTA or escalating the dose of BYETTA in patients with moderate renal failure 5 4 8 6 12 3 e Severe Gastrointestinal Disease Use of BYETTA is not recommended in patients with severe gastrointestinal disease e g gastroparesis 5 5 e Hypersensitivity Postmarketing reports with exenatide of hypersensitivity reactions e g anaphylaxis and angioedema The patient should discontinue BYETTA and other suspect medications and promptly seek medical advice 5 7 e Macrovascular outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYETTA or any other antidiabetic drug 5 8 e Most common 25 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 e Postmarketing reports with exenatide of increased international normalized ratio INR with concomitant use of warfarin sometimes with bleeding 6 2 7 2 To report SUSPECTED ADVERSE REACTIONS contact AstraZeneca at 1 800 236 9933 and www byetta com or FDA at 1 800 FDA 1088 or www fda gov medwatch e May impact absorption of orally administered medications 7 1 12 3 e Warfarin Postmarketing reports of increased INR sometimes associated with bleeding Monitor INR frequently until
49. incidence and rate of hypoglycemia with BYETTA in six placebo controlled clinical trials Table 1 Incidence and Rate of Hypoglycemia when BYETTA was used as Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo Controlled Clinical Trials Placebo BYETTA BYETTA BID 5 mcg BID 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 45 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 def
50. ined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a documented blood glucose value lt 54 mg dL or prompt recovery after treatment for hypoglycemia t When BYETTA was initiated in combination with insulin glargine the dose of insulin glargine was decreased by 20 in patients with an HbA lt 8 0 to minimize the risk of hypoglycemia See Table 9 for insulin dose titration algorithm N number of Intent to Treat subjects in each treatment group BYETTA exenatide injection Immunogenicity Antibodies were assessed in 90 of subjects in the 30 week 24 week and 16 week studies of BYETTA In the 30 week controlled trials of BYETTA 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 lt 625 to exenatide at 30 weeks The level of glycemic control HbA in these patients was generally comparable to that observed in the 534 patients 56 without antibody titers An additional 59 patients 6 had higher titer antibodies gt 625 at 30 weeks Of these patients 32 3 overall had an attenuated glycemic response to BYETTA the remaining 27 3 overall had a glycemic response comparable to that of patients without antibodies see Warnings and Precautions 5 6 In the 16 week trial of
51. ing in the 30 week add on to metformin add on to sulfonylurea and add on to metformin in combination with sulfonylurea clinical trials In this pooled subset of patients BYETTA reduced postprandial plasma glucose concentrations in a dose dependent manner The mean SD change in 2 hour postprandial glucose concentration following administration of BYETTA at Week 30 relative to baseline was 63 65 mg dL for 5 mcg BID n 42 71 73 mg dL for 10 mcg BID n 52 and 11 69 mg dL for placebo BID n 44 14 3 Combination with Insulin Glargine 30 Week Placebo Controlled Trial A 30 week double blind placebo controlled trial was conducted to evaluate the efficacy and safety of BYETTA n 137 versus placebo n 122 when added to titrated insulin glargine with or without metformin and or thiazolidinedione in patients with type 2 diabetes with inadequate glycemic control All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks After 4 weeks those patients assigned to BYETTA had their dose increased to 10 mcg BID Patients assigned to placebo received placebo BID throughout the trial BYETTA or placebo was injected subcutaneously before the morning and evening meals Patients with an HbA lt 8 0 decreased their prestudy dose of insulin glargine by 20 and patients with an HbA 28 1 maintained their current dose of insulin glargine Five weeks after initiating randomized treatment insulin doses were titrated with guidance fro
52. ject BYETTA Front Back Inject BYETTA into your abdomen thigh or upper arm using the injection method explained to you by your healthcare provider 7 What if I cannot pull turn or push the dose knob Check the symbol in the dose window Follow the steps next to the matching symbol If is in the dose window e Pull the dose knob out until appears If is in the dose window and the dose knob will not turn e The cartridge in your BYETTA Pen may not have enough medicine to deliver a full dose A small amount of BYETTA will always stay in the cartridge If the cartridge contains a small amount and the dose knob will not turn your pen does not have enough BYETTA and will not deliver any more doses Obtain a new BYETTA Pen If and part of are in the dose window and the dose knob cannot be pushed in e The dose knob was not turned all the way Continue turning the dose knob away from you until is in the center of the dose window If part of and part of 4 are in the dose window and the dose knob cannot be pushed in e The needle may be clogged bent or incorrectly attached e Attach a new needle Make sure needle is on straight and screwed on all the way e Firmly push the injection button in all the way BYETTA should come from needle tip If is in the dose window and the dose knob will not turn e The injection button was not pushed in all the way and a complete dose was not delivered Talk with your healthcare provid
53. le Make sure needle is on straight and screwed on all the way e Firmly push the injection button in all the way BYETTA should come from needle tip If 4 is in the dose window and the dose knob will not turn e The injection button was not pushed in all the way and a complete dose was not delivered Talk with your healthcare provider about what to do about a partial dose e Follow these steps to reset your pen for your next injection e Firmly push the injection button in all the way until it stops Keep holding the injection button in and slowly count to 5 Then release the injection button and turn the dose knob away from you until appears in the dose window e If you cannot turn the dose knob the needle may be clogged Replace the needle and repeat the step above e For your next dose be sure to firmly push and hold the injection button in and slowly count to 5 before removing needle from skin See the complete BYETTA Medication Guide that comes with BYETTA For more information call toll free 1 800 236 9933 or visit www BYETTA com Distributed by AstraZeneca Pharmaceuticals LP Wilmington DE 19850 BYETTA is a registered trademark of the AstraZeneca group of companies 3107019 3 15 Revised February 2015 BYETTA exenatide injection 18 PEN USER MANUAL BYETTA exenatide injection 250 mcg mL 2 4 mL 10 mcg 10 mcg PEN USER MANUAL Do not share your BYETTA Pen with other people even if the needle has been changed
54. lowing a 12 week basal insulin optimization BIO phase subjects with an HbA c gt 7 0 entered a 30 week intervention phase and were randomized to add either BYETTA or insulin lispro to their existing regimen of insulin glargine and metformin Insulin glargine was titrated to a target fasting plasma glucose of 72 to 100 mg dL All patients assigned to BYETTA initially received 5 mcg BID for four weeks After four weeks their dose was increased to 10 mcg BID Patients in the BYETTA treated arm with an HbA c lt 8 0 at the end of the BIO phase decreased their insulin glargine dose by at least 10 All patients assigned to insulin lispro three times daily TID maintained their prior total daily insulin dose at baseline however the initial insulin lispro dose was 1 to 1 2 of the total daily insulin dose with the insulin glargine dose reduced accordingly The insulin lispro dose was titrated based on preprandial glucose values The majority of patients 87 were Caucasian 7 American Indian or Alaska Native 5 Asian and lt 1 African American The primary endpoint was the change in HbAic from baseline to Week 30 Both BYETTA 10 mcg BID and titrated lispro provided a mean reduction in HbA at Week 30 that met the pre specified non inferiority margin of 0 4 Table 10 30 Week Comparator Controlled Trial of BYETTA used in Combination with Insulin Glargine and Metformin Titrated Insulin Lispro TID BYETTA 10 mcg BID Titrated Insulin
55. lts of 24 Week Placebo Controlled Trial of BYETTA used as Monotherapy Placebo BYETTA BYETTA BID 5 mcg 10 mcg BID BID Intent to Treat Population N T1 T1 78 HbA Mean Baseline 7 8 7 9 7 8 Change at Week 24 0 2 0 7 0 9 Difference from placebot 95 Cl 0 5 0 9 0 2 0 7 1 0 0 3 Proportion Achieving HbA lt 7 38 48 53 Body Weight kg Mean Baseline 86 1 85 1 86 2 Change at Week 24 1 5 2 1 2 9 Difference from placebot 95 Cl Fasting Serum Glucose mg dL Mean Baseline 159 166 155 Change at Week 24 5 17 19 Difference from placebot 95 CI 12 23 2 1 3 14 24 5 2 5 BYETTA 5 mcg twice daily BID for 1 month followed by 10 mcg BID for 5 months before the morning and evening meals t Least squares means are adjusted for screening HbA strata and baseline value of the dependent variable p lt 0 01 treatment vs placebo Measured using the hexokinase based glucose method BID twice daily 1 3 2 3 0 2 1 5 2 5 0 4 On average there were no adverse effects of exenatide on blood pressure or lipids 14 2 Combination Therapy with Oral Antihyperglycemic Medicines Three 30 week double blind placebo controlled trials were conducted to evaluate the safety and efficacy of BYETTA in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone a sulfonylurea alone or metformin in combination with a sulfonylurea In addition a 16 week placebo co
56. m the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9 The majority of patients 78 were Caucasian 10 American Indian or Alaska Native 9 Black 3 Asian and 0 8 of multiple origins The primary endpoint was the change in HbA from baseline to Week 30 Compared to placebo BYETTA 10 mcg BID resulted in statistically significant reductions in HbA from baseline at Week 30 Table 8 in patients receiving titrated insulin glargine Table 8 30 Week Placebo Controlled Trial of BYETTA Used in Combination with Insulin Glargine with or without Metformin and or Thiazolidinediones Placebo BID BYETTA Titrated 10 mcg BID Titrated Insulin Glargine Insulin Glargine Intent to Treat Population N 122 137 HbA Mean Baseline 8 5 8 3 Change at Week 30t 1 0 1 7 Difference from placebot 95 CI 0 7 1 0 0 5 1 Proportion Achieving HbA lt 7 30 57 Body Weight kg Mean Baseline 93 8 95 4 Change at Week 30 1 0 1 8 Difference from placebot 95 CI 2 7 3 7 1 7 1 Fasting Serum Glucose mg dL Mean Baseline 133 132 Change at Week 30 16 23 Difference from placebo 95 Cl 7 18 3 BYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 5 months for the 30 week trial t Least squares means are based on a mixed model adjusting for treatment pooled investigator visit baseline HbA value and treatment by visit where subject is
57. nnot take liquids by mouth You may be at increased risk for kidney problems e Severe allergic reactions Severe allergic reactions can happen with BYETTA Stop taking BYETTA and get medical help right away if you have any symptom of a severe allergic reaction See Who should not use BYETTA The most common side effects with BYETTA include e nausea Nausea most commonly happens when first starting BYETTA but may become less over time e vomiting e headache e diarrhea e acid stomach e feeling jittery e constipation e dizziness e weakness Talk to your healthcare provider about any side effect that bothers you or that does not go away These are not all the side effects with BYETTA Call your doctor for medical advice about side effects You may report side effects to FDA at 1 800 FDA 1088 How should I store BYETTA e Store your new unused BYETTA Pen in the Original carton in a refrigerator at 36 F to 46 F 2 C to 8 C e After first use keep your BYETTA Pen at a temperature cooler than 77 F 25 C e Do not freeze your BYETTA Pen Do not use BYETTA if it has been frozen e Protect BYETTA from light BYETTA exenatide injection 11 e Use a BYETTA Pen for only 30 days Throw away a used BYETTA Pen after 30 days even if there is some medicine left in the pen e Do not use BYETTA after the expiration date printed on the label e Do not store the BYETTA Pen with the needle attached If the ne
58. ntrolled trial was conducted where BYETTA was added to existing thiazolidinedione pioglitazone or rosiglitazone treatment with or without metformin in patients with type 2 diabetes with inadequate glycemic control In the 30 week trials after a 4 week placebo lead in period patients were randomly assigned to receive BYETTA 5 mcg BID BYETTA 10 mcg BID or placebo BID before the morning and evening meals in addition to their existing oral antidiabetic agent All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks After 4 weeks those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID Patients assigned to placebo received placebo BID throughout the study A total of 1446 patients were randomized in the three 30 week trials 991 69 were Caucasian 224 16 Hispanic and 174 12 Black Mean HbA values at baseline for the trials ranged from 8 2 to 8 7 In the placebo controlled trial of 16 weeks duration BYETTA n 121 or placebo n 112 was added to existing thiazolidinedione pioglitazone or rosiglitazone treatment with or without metformin Randomization to BYETTA or placebo was stratified based on whether the patients were receiving metformin BYETTA treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks Patients assigned to placebo received placebo BID throughout the study BYETTA or placebo was injected subcutaneously bef
59. nts was generally comparable to that observed in the 234 patients 77 without antibody titers An additional 10 patients 3 had higher titer antibodies at 30 weeks Of these patients 2 1 overall had an attenuated glycemic response to BYETTA the remaining 8 3 overall had a glycemic response comparable to that of patients without antibodies see Warnings and Precautions 5 5 Two hundred and ten patients with antibodies to exenatide in the BYETTA clinical trials were tested for the presence of cross reactive antibodies to GLP 1 and or glucagon No treatment emergent cross reactive antibodies were observed across the range of titers Other Adverse Reactions Monotherapy For the 24 week placebo controlled study of BYETTA used as a monotherapy Table 2 summarizes adverse reactions excluding hypoglycemia occurring with an incidence gt 2 and occurring more frequently in BYETTA treated patients compared with placebo treated patients Table 2 Treatment Emergent Adverse Reactions gt 2 Incidence with BYETTA used as Monotherapy excluding Hypoglycemia Monotherapy Placebo BID All BYETTA BID N 77 N 155 Nausea 0 8 Vomiting 0 4 Dyspepsia 0 3 In a 24 week placebo controlled trial BID twice daily Adverse reactions reported in gt 1 0 to lt 2 0 of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite diarrhea and dizziness The most frequently reported adverse reaction asso
60. odium 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 or 10 mcg Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration BID 12 CLINICAL PHARMACOLOGY 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 BYETTA 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 BYETTA exenatide injection BYETTA improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below 12 2 Pharmacodynamics Glucose Dependent Insulin Secretion BYETTA has acute effects on pancreatic beta cell responsiveness to glucose leading to insulin release predominantly in the presence o
61. of companies All other trademarks are the trademarks of their respective owners Distributed by AstraZeneca Pharmaceuticals LP Wilmington DE 19850 3107019 3 15 Revised February 2015 BYETTA exenatide injection 12 PEN USER MANUAL BYETTA exenatide injection 250 mcg mL 1 2 mL 5 mcg 5 mcg PEN USER MANUAL Do not share your BYETTA Pen with other people even if the needle has been changed You may give other people a serious infection or get a serious infection from them Section 1 Read this section completely before you begin Then move on to Section 2 Getting Started WHAT YOU NEED TO KNOW ABOUT YOUR BYETTA PEN PEN USER MANUAL Read these instructions carefully BEFORE using your BYETTA Pen For complete dosing and safety information also read the BYETTA Medication Guide that comes with the BYETTA Pen carton It is important that you use your pen correctly Failure to follow these instructions completely may result in a wrong dose a broken pen or an infection These instructions do not take the place of talking with your healthcare provider about your medical condition or your treatment If you are having problems using your BYETTA Pen call toll free 1 800 236 9933 IMPORTANT INFORMATION ABOUT YOUR BYETTA PEN e Each BYETTA Pen contains enough medicine for injection two times each day for 30 days You do not have to measure any doses the pen measures each dose for you e Do not transfer the medicine in the
62. on day 6 through lactation day 20 weaning experienced an increased number of neonatal deaths Deaths were observed on postpartum days 2 to 4 in dams given 6 mcg kg day a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg day based on AUC see Nonclinical Toxicology 13 3 Pregnancy Registry A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy Physicians are encouraged to register patients by Calling 1 800 633 9081 8 3 Nursing Mothers It is not known whether exenatide is excreted in human milk However exenatide is present at low concentrations less than or equal to 2 5 of the concentration in maternal plasma following subcutaneous dosing in the milk of lactating mice Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide a decision should be made whether to discontinue nursing or discontinue the drug taking into account these potential risks against the glycemic benefits to the lactating woman Caution should be exercised when BYETTA is administered to a nursing woman 8 4 Pediatric Use Safety and effectiveness of BYETTA have not been established in pediatric patients 8 5 Geriatric Use Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic pro
63. on initiation of therapy see Adverse Reactions 6 The patient should read the Medication Guide and the Pen User Manual before starting BYETTA therapy and review them each time the prescription is refilled The patient should be instructed on proper use and storage of the pen emphasizing how and when to set up a new pen and noting that only one setup step is necessary at initial use The patient should be advised not to share the pen and needles Patients should be informed that pen needles are not included with the pen and must be purchased separately Patients should be advised which needle length and gauge should be used Distributed by AstraZeneca Pharmaceuticals LP Wilmington DE 19850 BYETTA is a registered trademark of the AstraZeneca group of companies 3107019 3 15 Revised February 2015 BYETTA exenatide injection MEDICATION GUIDE BYETTA bye A tuh exenatide Injection Read this Medication Guide and the Pen User Manual that come with BYETTA before you start using it and each time you get a refill There may be new information This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment If you have questions about BYETTA after reading this information ask your healthcare provider or pharmacist What is the most important information I should know about BYETTA Do not share your BYETTA Pen with other people even if the needle h
64. ore the morning and evening meals In this trial 79 of patients were taking a thiazolidinedione and metformin and 21 were taking a thiazolidinedione alone The majority of patients 84 were BYETTA exenatide injection Caucasian 8 Hispanic and 3 Black The mean baseline HbA values were 7 9 for BYETTA and placebo The primary endpoint in each study was the mean change in HbA from baseline to study end or early discontinuation Table 7 summarizes the study results for the 30 and 16 week clinical trials Table 7 Results of 30 Week and 16 Week Placebo Controlled Trials of BYETTA used in Combination with Oral Antidiabetic Agents Placebo BYETTA BYETTA BID 5 mcg BID 10 mcg BID In Combination with Metformin 30 Weeks Intent to Treat Population N 113 110 113 HbA Mean Baseline 8 2 8 3 8 2 Change at Week 30t 0 0 0 5 0 9 Difference from placebot 95 Cl 0 5 0 7 0 2 0 9 1 1 0 6 Proportion Achieving HbA lt 7 12 32 40 Body Weight kg Mean Baseline 99 9 100 0 100 9 Change at Week 30t 0 2 1 3 2 6 Difference from placebot 95 Cl Fasting Plasma Glucose mg dL Mean 1 1 2 2 0 0 2 4 3 5 1 3 Baseline 169 176 168 Change at Week 30 14 5 10 Difference from placebot 95 Cl 20 32 7 24 37 12 In Combination with a Sulfonylurea 30 Weeks Intent to Treat Population N 123 125 129 HbA Mean Baseline 8 7 8 5 8 6 Change at Week 30 0 1 0 5 0
65. ot throw away the pen with a needle attached e Place used needles in a closeable puncture resistant container You may use a sharps container such as a red biohazard container a hard plastic container such as a detergent bottle or a metal container such as an empty coffee can Ask your healthcare provider for instructions on the right way to throw away dispose of your used pens and the container There may be state and local laws about how you should throw away used pens and needles e Do not throw the disposal container in the household trash Do not recycle e Always keep the puncture proof container out of reach of children Do not share your BYETTA Pen with other people even if the needle has been changed You may give other people a serious infection or get a serious infection from them STORING YOUR BYETTA PEN How do I store my BYETTA Pen e Prior to first use store your unused BYETTA Pen in the original carton in a refrigerator at 36 F to 46 F 2 C to 8 C e After first use your BYETTA Pen can be kept at a temperature not to exceed 77 F 25 C e Do not freeze Do not use BYETTA if it has been frozen BYETTA should be protected from light ee oe le the pen away from home store the pen at a temperature between 36 F to 77 F 2 C to 25 C and eep dry e Do not store the pen with the needle attached If the needle is left on the pen BYETTA may leak from the pen and air bubbles may form in the cartridge Kee
66. p your pen and needles out of the reach of children How long can I use a BYETTA Pen e You can use your BYETTA Pen for up to 30 days after setting up a new pen for first use After 30 days throw away the BYETTA Pen even if it is not completely empty e Mark the date when you first used your pen and the date 30 days later in the spaces below Date of First Use Date to Throw Away Pen e BYETTA should not be used after the expiration date printed on the pen label How do I clean my BYETTA Pen e Wipe the outside of the pen with a clean damp cloth e White particles may appear on the outside tip of the cartridge during normal use You may remove them with an alcohol wipe or alcohol swab See the complete BYETTA Medication Guide that comes with BYETTA For more information call toll free 1 800 236 9933 or visit www BYETTA com Section 2 Read and follow the directions in this section only after you ve read Section 1 What You Need To Know About Your BYETTA Pen GETTING STARTED Set up your new pen just before you use it the first time For routine use do not repeat this one time only new pen setup If you do you will run out of BYETTA before 30 days of use Blue Pen Cap Cartridge BYETTA Label Dose Dose Injection Liquid Window Knob Button Pen Needles Not Included ready to pull dose knob out EF Ready to turn to dose position 5 ready to inject 5 mcg Outer Inner Needle Paper 4 dose knob pushed in and Ne
67. perties of exenatide see Clinical Pharmacology 12 3 BYETTA was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older No differences in safety or effectiveness were observed between these patients and younger patients Because elderly patients are more likely to have decreased renal function care should be taken in dose selection in the elderly based on renal function 8 6 Renal Impairment BYETTA is not recommended for use in patients with end stage renal disease or severe renal impairment creatinine clearance lt 30 mL min and should be used with caution in patients with renal transplantation No dosage adjustment of BYETTA is required in patients with mild renal impairment creatinine clearance 50 80 mL min Caution should be applied when initiating or escalating doses of BYETTA from 5 to 10 mcg in patients with moderate renal impairment creatinine clearance 30 50 mL min see 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 dysfunction is not expected to affect blood concentrations of exenatide see Clinical Pharmacology 12 3 10 OVERDOSAGE In a Clinical study of BYETTA three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC 10 times the maximum recommended dose Effects of the overdos
68. rts with exenatide including fatal and non fatal hemorrhagic or necrotizing pancreatitis Discontinue BYETTA promptly BYETTA should not be restarted Consider other antidiabetic therapies in patients with a history of pancreatitis 5 2 e Hypoglycemia Increased risk when BYETTA is used in combination with medications known to cause hypoglycemia e g insulin or insulin secretagogue Consider reducing the dose of insulin or insulin secretagogue 5 3 FULL PRESCRIBING INFORMATION CONTENTS 1 INDICATIONS AND USAGE 1 1 Type 2 Diabetes Mellitus 1 2 Important Limitations of Use 2 DOSAGE AND ADMINISTRATION 2 1 Recommended Dosing 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4 1 Hypersensitivity 5 WARNINGS AND PRECAUTIONS 5 1 Never Share a BYETTA Pen Between Patients 5 2 Acute Pancreatitis 5 3 Use with Medications Known to Cause Hypoglycemia 5 4 Renal Impairment 5 0 Gastrointestinal Disease 5 6 Immunogenicity 5 7 Hypersensitivity 5 8 Macrovascular Outcomes 6 ADVERSE REACTIONS 6 1 Clinical Trial Experience 6 2 Postmarketing Experience 7 DRUG INTERACTIONS 7 1 Orally Administered Drugs 7 2 Warfarin 8 USE IN SPECIFIC POPULATIONS 8 1 Pregnancy 8 3 Nursing Mothers 8 4 Pediatric Use e Renal Impairment Postmarketing reports with exenatide sometimes requiring hemodialysis and kidney transplantation BYETTA should not be used in patients with severe renal impairment or end stage renal disease and should be used with caution in pat
69. s normal Turn dose knob away from you until it stops at 5 Make sure that the 5 with the line under it is in the center of the dose window Pen preparation is complete when the 4 is in the center of the dose window AND you have seen a stream or several drops come from the needle tip Note If you do not see liquid after 4 times see Commonly Asked Questions number 3 in Section 4 of this user manual BYETTA exenatide injection 15 STEP E Complete New Pen Setup e For routine use do not e You are now ready for your first repeat this one time only dose of BYETTA new pen setup If you do e Go to Section 3 Step 3 for you will run out of BYETTA instructions on how to inject S N 2 before 30 days of use your first routine dose e Turn dose knob away from you until it stops and the is in the dose window Note If you cannot turn the dose knob see Commonly Asked Questions number 7 in Section 4 of user manual Section 3 Now that you have done the one time only new pen setup follow Section 3 for all of your injections ROUTINE USE STEP 1 Check the Pen Note A small air bubble will not harm you or affect your dose e Wash hands prior to use e Check BYETTA in the cartridge e Check pen label to make sure it e The liquid should be clear is your 5 mcg pen colorless and free of particles e Pull off the blue pen cap If it is not do not use STEP 2 Attach the Needle Pull off outer n
70. th of you and your baby If you take BYETTA at any time during pregnancy you may enroll in this registry by calling 1 800 633 9081 e are breastfeeding or plan to breast feed It is not known if BYETTA passes into your breast milk You and your healthcare provider should decide if you will take BYETTA or breast feed You should not do both without talking with your healthcare provider first Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines vitamins and herbal supplements BYETTA slows stomach emptying and BYETTA exenatide injection can affect medicines that need to pass through the stomach quickly BYETTA may affect the way some medicines work and some other medicines may affect the way BYETTA works Especially tell your healthcare provider if you take e other anti diabetes medicines especially sulfonylurea medicines or insulin e birth control pills that are taken by mouth oral contraceptives BYETTA may lower the amount of the medicine in your blood from your birth control pills and they may not work as well to prevent pregnancy Take your birth control pills at least one hour before your injection of BYETTA If you must take your birth control pills with food take it with a meal or snack where you do not also take BYETTA e an antibiotic Take antibiotic medicines at least one hour before taking BYETTA If you must take your antibiotic with food t
71. th severe gastrointestinal disease 5 6 Immunogenicity Patients may develop antibodies to exenatide following treatment with BYETTA Antibody levels were measured in 90 of subjects in the 30 week 24 week and 16 week placebo controlled Studies and the 30 week comparator controlled study of BYETTA In 3 4 1 and 1 of these patients respectively antibody formation was associated with an attenuated glycemic response If there is worsening glycemic control or failure to achieve targeted glycemic control alternative antidiabetic therapy should be considered see Adverse Reactions 6 1 5 7 Hypersensitivity There have been postmarketing reports of serious hypersensitivity reactions e g anaphylaxis and angioedema in patients treated with BYETTA If a hypersensitivity reaction occurs the patient should discontinue BYETTA and other suspect medications and promptly seek medical advice see Adverse Reactions 6 2 5 8 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYETTA or any other antidiabetic drug 6 ADVERSE REACTIONS 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
72. that BMI has no significant effect on the pharmacokinetics of exenatide 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis Impairment of Fertility A 104 week carcinogenicity study was conducted in male and female rats at doses of 18 70 or 250 mcg kg day administered by bolus SC injection Benign thyroid C cell adenomas were observed in female rats at all exenatide doses The incidences in female rats were 8 and 5 in the two control groups and 14 11 and 23 in the low medium and high dose groups with systemic exposures of 5 22 and 130 times respectively the human exposure resulting from the maximum recommended dose of 20 mcg day based on plasma area under the curve AUC In a 104 week carcinogenicity study in mice at doses of 18 70 or 250 mcg kg day administered by bolus SC injection no evidence of tumors was observed at doses up to 250 mcg kg day a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg day based on AUC Exenatide was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells Exenatide was negative in the in vivo mouse micronucleus assay In mouse fertility studies with SC doses of 6 68 or 760 mcg kg day males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout matin
73. tum days 2 4 in dams given 6 mcg kg day a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg day based on AUC 14 CLINICAL STUDIES BYETTA has been studied as monotherapy and in combination with metformin a sulfonylurea a thiazolidinedione a combination of metformin and a sulfonylurea a combination of metformin and a thiazolidinedione or in combination with insulin glargine with or without metformin and or thiazolidinedione 14 1 Monotherapy In a randomized double blind placebo controlled trial of 24 weeks duration BYETTA 5 mcg BID n 77 BYETTA 10 mcg BID n 78 or placebo BID n 77 was used as monotherapy in patients with entry HbA ranging from 6 5 to 10 All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks After 4 weeks those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID Patients assigned to placebo received placebo BID throughout the trial BYETTA or placebo was injected subcutaneously before the morning and evening meals The majority of patients 68 were Caucasian 26 West Asian 3 Hispanic 3 Black and 0 4 East Asian The primary endpoint was the change in HbA from baseline to Week 24 or the last value at time of early discontinuation Compared to placebo BYETTA 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA from baseline at Week 24 Table 6 Table 6 Resu
74. ue pen cap If not do not use STEP B Attach the Needle e Remove paper tab from outer e Pull off outer needle shield e Pull off inner needle shield needle shield Do not throw away and throw away A small drop e Push outer needle shield of mle may appear This is normal containing the needle straight onto the pen then screw needle on until secure STEP C Dial the Dose s Checletharthes l eine e Pull dose knob out until it e Turn dose knob away from dose window If not turn stops and the is in the you until it stops at 10 dose knob away from you dose window Make sure that the 10 with clockwise until it stops and the line under it is in the the is in the dose window center of the dose window Note If you cannot turn the dose knob away from you to the 10 see Commonly Asked Questions number 7 in Section 4 of this user manual STEP D Prepare the Pen e Point the needle of the pen up PUSH amp HOLD e Pen preparation is complete and away from you e Use thumb to firmly push when the 4 is in the center injection button in until it of the dose window AND you stops then continue holding the have seen a stream or several injection button in while slowly counting to 5 e If you do not see a stream or several drops come from the needle tip repeat Steps C amp D Note If you do not see liquid after 4 times see Commonly Asked Questions number 3 in Section 4 of this user manual drops come from the nee
75. ur tries during One Time Only New Pen Setup e Carefully put the outer needle shield back over the needle Remove the needle by unscrewing it Throw away the needle properly e Attach a new needle and repeat One Time Only New Pen Setup Steps B E in Section 2 of this user manual Once you see several drops or a stream of liquid coming out of the tip of the needle the setup is complete BYETTA exenatide injection 23 4 Why do I see BYETTA leaking from my needle after I have finished my injection It is normal for a single drop to remain on the tip of your needle after your injection is complete If you see more than one drop e You may not have received your full dose Do not inject another dose Talk with your healthcare provider about what to do about a partial dose e To make sure that you get your full dose when you take your injections firmly push and hold the injection button in and slowly count to 5 see Section 3 Step 4 Inject the Dose 5 How can I tell when the injection is complete The injection is complete when e You have firmly pushed the injection button in all the way until it stops and e You have slowly counted to 5 while you are still holding the injection button in and the needle is still in your skin and e The 4 is in the center of the dose window If you hear a click sound from your BYETTA Pen ignore it You must follow all the steps listed above to make sure your injection is complete 6 Where should I in
76. y be discontinued and appropriate management should be initiated If pancreatitis is confirmed BYETTA should not be restarted Consider antidiabetic therapies other than BYETTA in patients with a history of pancreatitis 5 3 Use with Medications Known to Cause Hypoglycemia The risk of hypoglycemia is increased when BYETTA is used in combination with a sulfonylurea Therefore patients receiving BYETTA and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia When BYETTA is used in combination with insulin the dose of insulin should be evaluated In patients at increased risk of hypoglycemia consider reducing the dose of insulin see Adverse Reactions 6 1 The concurrent use of BYETTA with prandial insulin has not been studied and cannot be recommended It is also possible that the use of BYETTA with other glucose independent insulin secretagogues e g meglitinides could increase the risk of hypoglycemia For additional information on glucose dependent effects see Mechanism of Action 12 1 5 4 Renal Impairment BYETTA should not be used in patients with severe renal impairment creatinine clearance lt 30 mL min or end stage renal disease and should be used with caution in patients with renal transplantation see Use in Specific Populations 8 6 In patients with end stage renal disease receiving dialysis single doses of BYETTA 5 mcg were not well tolerated due to gastrointestinal side effects
77. y your healthcare provider e Follow Section 2 only to set up a new pen before first use e Section 3 of this manual should be used for every injection ABOUT PEN NEEDLES What kinds of needles can be used with my BYETTA Pen e Pen needles are not included with your pen You may need a prescription to get them from your pharmacist e Use 29 thin 30 or 31 thinner gauge disposable pen needles with your BYETTA Pen Ask your healthcare provider which needle gauge and length is best for you Do I use a new needle for each injection e Yes Do not reuse or share your needles with other people You may give other people a serious infection or get a serious infection from them e Remove the needle from the pen immediately after you complete each injection This will help prevent leakage of BYETTA keep out air bubbles reduce needle clogs and decrease the risk of infection e Do not push the injection button on your pen unless a needle is attached to the pen BYETTA exenatide injection 19 How do I throw away my needles e Do not throw away the pen with a needle attached e Place used needles in a closeable puncture resistant container You may use a sharps container such as a red biohazard container a hard plastic container such as a detergent bottle or a metal container such as an empty coffee can Ask your healthcare provider for instructions on the right way to throw away dispose of your used pens and the container There

Full Prescribing Information with Medication Guide - PI

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