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Apidra (insulin glulisine)

1. General As with all insulin preparations the time course of APIDRA action may vary in different individuals or at different times in the same individual and is dependent on site of injection blood supply temperature and physical activity Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan Hypokalemia is among the potential clinical adverse effect associated with the use of all insulin therapies particularly when given intravenously e g treatment of diabetic ketoacidosis This potential clinical adverse effect may be more relevant in patients who are on potassium lowering drugs losing potassium through other means e g diarrhea or treated for diabetic ketoacidosis As with other insulins additional caution should be exercised in patients with a long history of diabetes on insulin who might be prone to develop hypoglycemia and in patients with a previous history of cardiac ischemic disorders who might be prone to develop cardiac adverse events Stress or concomitant illness especially infectious and febrile conditions may change insulin requirements Thiazolidinediones TZDs alone or in combination with other antidiabetic agents including insulin can cause heart failure and edema The combination of TZD with insulin is not indicated for the treatment of Type 2 Diabetes Mellitus Please refer to the respective TZD product monograph WARNINGS AND PRECAUTIONS i
2. WARNINGS AND PRECAUTIONS Serious Warnings and Precautions Hypoglycemia is the most common adverse effect of insulin therapy including APIDRA see WARNINGS AND PRECAUTIONS Endocrine and Metabolism Hypoglycemia As with all insulins the timing of hypoglycemia may differ among various insulin formulations Glucose monitoring is recommended for all patients with diabetes Uncorrected hypoglycemic or hyperglycemic reactions can cause loss of consciousness coma or death Any change of insulin should be made cautiously and only under medical supervision APIDRA differs from regular human insulin by its rapid onset of action and shorter duration of action When used as a meal time insulin the dose of APIDRA should be given within Page 4 of 61 15 minutes before or within 20 minutes after starting a meal see ACTION AND CLINICAL PHARMACOLOGY APIDRA given by subcutaneous injection should generally be used in regimens with an intermediate or long acting insulin APIDRA can also be used alone in insulin infusion pump therapy to maintain adequate glucose control APIDRA can be mixed with NPH human insulin except when administered with pump see DOSAGE AND ADMINISTRATION Continuous Subcutaneous Insulin Infusion pump This insulin product shall not be used if it is not water clear and colourless or if it has formed a deposit of solid particles on the wall of the vial or cartridge see DOSAGE AND ADMINISTRATION
3. increases in effect as common to short and rapid acting insulins Table 6 Pharmacokinetic and Pharmacodynamic Results in Type 1 Diabetes Mellitus subjects treated with s c insulin glulisine Pharmacokinetic Parameters Values in bold font represent the geometric means all others are based on the mean amp standard deviation unless denoted with to indicate the median minimum amp maximum range Dose 0 075 U kg 0 15 U kg 0 3 U kg AUCo 2h 3792 6676 12992 uU min mL 3855 677 6832 1461 13237 2599 AUC ena 5341 11196 24891 uU min mL 5372 589 11284 1456 25076 3209 Cmax 42 72 140 uU mL 43 9 73 16 142 25 MRT min 115 121 134 122 50 125 34 136 28 Tmax 47 57 72 Min 34 99 44 93 50 112 T10 AUG 26 31 39 Min 18 53 24 52 28 64 Tose 149 205 242 Min 116 260 141 295 169 345 Tare min 64 33 55417 56 17 Volume of 1075 362 986 274 930 216 Distribution mL kg Glucose Infusion Rate Pharmacodynamic Parameters GIR AUC 0 2h 314 156 491 167 536 153 mg kg GIR AUC 0 end 499 233 1090 271 1476 300 mg kg The table below compares pharmacokinetic and pharmacodynamic parameters for APIDRA s c from a study in patients with Type I diabetes n 18 with historical data for Huminsulin Normal 100 s c from a study in healthy adult subjects n 24 see Table 7 Page 23 of 61 Table 7
4. tingling in your hands feet lips or tongue tremor shaking unsteady gait walking dizziness light headedness or drowsiness headache blurred vision slurred speech palpitations rapid heartbeat cold sweat pale skin nightmares or trouble sleeping nausea hunger Mild to moderate hypoglycemia can be treated by consuming foods or drinks that contain sugar Patients should always carry a quick source of sugar such as candy juice or glucose tablets prominently labelled for rescuers Contact your health professional about appropriate proportions of carbohydrates Signs of severe hypoglycemia can include e disorientation e convulsions e loss of consciousness e seizures Severe hypoglycemia may require the assistance of another person Patients who are unable to take sugar orally or who are unconscious may require an injection of glucagon or should be treated with intravenous administration of glucose by medical personnel Without immediate medical help serious reactions or even death could occur The early warning symptoms of hypoglycemia may be changed be less pronounced or be absent as for example in patients whose sugar levels are markedly improved in elderly patients in patients with diabetic nerve disease in patients with a long history of diabetes or in patients receiving concurrent treatment with certain other drugs Such situations may result in severe hypoglycemia and possibly loss of consc
5. wheezing trouble breathing a fast pulse sweating low blood pressure Possible reactions on the skin at the injection site Injecting insulin can cause the following reactions on the skin at the injection site e a little depression in the skin lipoatrophy e skin thickening lipohypertrophy e redness itching swelling or hemorrhage at injection site In some instances these reactions may be related to factors other than insulin such as irritants in the skin Page 60 of 61 cleansing agent or poor injection technique You can reduce the chance of getting an injection site reaction if you change the injection site each time If you have local injection site reactions contact your health professional This is not a complete list of side effects For any unexpected effects while taking APIDRA contact your health professional HOW TO STORE IT Unopened SoloSTAR Unopened APIDRA SoloSTAR should be stored in a refrigerator between 2 C 8 C Keep APIDRA SoloSTAR away from direct heat and light APIDRA SoloSTAR should not be stored in the freezer and should not be allowed to freeze If APIDRA SoloSTAR freezes or overheats discard it Opened In Use SoloSTAR Opened APIDRA SoloSTAR in use must be kept unrefrigerated 15 25 C for up to 28 days away from direct heat and light as long as the temperature is not greater than 25 C If the APIDRA SoloSTAR overheats or if there is any remaining insulin after 28 da
6. Hyperglycemia The use of too low insulin dosages or discontinuation of treatment especially in Type 1 diabetes may lead to hyperglycemia and diabetic ketoacidosis Uncorrected hyperglycemic reactions can cause loss of consciousness coma or death Immune Injection Site and Local Allergic Reactions As with any insulin therapy lipodystrophy may occur at the injection site and delay insulin absorption Other injection site reactions with insulin therapy include redness pain itching at the injection site hives swelling and inflammation Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions Most minor reactions to insulins usually resolve in a few days to a few weeks They may occur if the injection is not properly made irritants in the skin cleansing agent or poor injection technique or if the patient is allergic to the insulin or any excipients Rarely SC administration of insulin products can result in lipoatrophy depression in the skin or lipohypertrophy enlargement or thickening of tissue Patients should be advised to consult their doctor if they notice any of these conditions Systemic allergic reactions Immediate type allergic reactions are rare Such reactions to insulin including insulin glulisine or the excipients may for example be associated with generalized skin reactions angioedema bronchospasm hypotension anaphylactic reaction or shock and may be life
7. If the blood glucose is below your normal fasting glucose you should consider eating or drinking sugar containing foods to treat your hypoglycemia If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the symptoms you should consult your health professional to discuss possible changes in therapy meal plans and or exercise programs to help you avoid hypoglycemia Hyperglycemia Hyperglycemia too much glucose in the blood may develop if your body has too little insulin Hyperglycemia can be brought about by e intercurrent conditions illness stress or emotional disturbances e not taking your insulin or taking less than recommended by your health professional e malfunction and or misuse of medical devices e eating significantly more than your meal plan suggests e anew insulin type or schedule e some new medications including prescriptions over the counter medications herbs vitamins and street drugs Symptoms of hyperglycemia include e confusion or drowsiness increased thirst decreased appetite nausea or vomiting rapid heart rate increased urination and dehydration too little fluid in your body blurred vision e flushed dry skin e acetone odour of breath Hyperglycemia can be mild or severe It can progress to high glucose levels diabetic ketoacidosis DKA and result in unconsciousness and death Diabetic ketoacidosis DKA The first symptoms of diabetic k
8. insulin glulisine injection DNA origin is an antidiabetic agent short acting recombinant human insulin analogue used to reduce high blood sugar in adults and children 6 years or older with diabetes mellitus What it does Insulin is a hormone produced by the pancreas a large gland that lies near the stomach This hormone is necessary for the body s correct use of food especially sugar Diabetes occurs when the pancreas does not make enough insulin to meet your body s needs or when your body cannot use properly the insulin you normally produce When your body does not make enough insulin you need an external source of insulin That is why you must take insulin injections APIDRA is similar to the insulin made by your body APIDRA has a rapid onset of action and a short duration of about 4 hours APIDRA should normally be used with a longer acting insulin to maintain adequate blood sugar APIDRA can also be used with oral drugs to reduce blood sugar You have been instructed to test your blood and or your urine regularly for glucose sugar it is especially important to test even more often when changing insulins or dosing schedule If your blood tests consistently show above or below normal glucose levels or your urine tests consistently show the presence of glucose your diabetes is not properly controlled and you must let your health professional know When it should not be used You should not take APIDRA if you
9. insulin you normally produce When your body does not make enough insulin you need an external source of insulin That is why you must take insulin injections APIDRA is similar to the insulin made by your body APIDRA has a rapid onset of action and a short duration of about 4 hours APIDRA should normally be used with a longer acting insulin to maintain adequate blood sugar APIDRA can also be used with oral drugs to reduce blood sugar You have been instructed to test your blood and or your urine regularly for glucose sugar it is especially important to test even more often when changing insulins or dosing schedule If your blood tests consistently show above or below normal glucose levels or your urine tests consistently show the presence of glucose your diabetes is not properly controlled and you must let your health professional know When it should not be used You should not take APIDRA if you are allergic to this drug or to any ingredient in the formulation or component of the container What the medicinal ingredient is The active ingredient in APIDRA is insulin glulisine rDNA origin What the nonmedicinal ingredients are The nonmedicinal ingredients are m cresol polysorbate 20 sodium chloride trometamol water and hydrochloric acid and sodium hydroxide for pH adjustment What dosage forms it comes in APIDRA is a solution for injection 100 U mL available in the following package size 10
10. syringe 13 Before removing the needle from the vial check your syringe for air bubbles If bubbles are present hold the syringe straight up and tap its side until the bubbles float to the top Push them out with the plunger and withdraw the correct dose 14 Remove the needle from the vial Do not let the needle touch anything prior to injection 15 An empty vial must never be reused and must be properly discarded Mixing of APIDRA with NPH human insulin 1 APIDRA should be mixed with NPH human insulin only on the advice of your doctor 2 Before withdrawing insulin from the vials for the first time remove the plastic protective cap but DO NOT remove the stopper 3 Wipe the top of the vials with an alcohol swab 4 Draw back the plunger of the syringe to the number of NPH human insulin units you need Put the syringe into the NPH human insulin vial and press the plunger down This injects air into the vial Remove the needle from the vial without taking insulin out 5 Draw back the plunger of the syringe to the number of APIDRA units you need Put the syringe into the APIDRA vial and press the plunger down This injects air into the vial Do not withdraw the needle 6 Turn the vial and syringe upside down Hold the vial with one hand and the syringe with the other Pull back the plunger to five units past your dose 7 If you get an air bubble flick the syringe so the bubble rises to the top Then push the air back
11. to prevent hypoglycemia you must eat more food and monitor your blood sugar For information on the treatment of hypoglycemia see Side Effects and What To Do About Them below Hypoglycemia may occur as a result of an excess of insulin relative to food intake energy expenditure or both In severe cases coma seizure and brain disorders may be seen and treated with glucagon injected in the muscle or subcutaneous tissue or glucose injected in the vein You should continue checking your blood sugar even if you feel better because hypoglycemia may recur In case of drug overdose contact a health professional hospital emergency department or regional Poison Control Centre immediately even if there are no symptoms INSTRUCTIONS FOR USE Your doctor has recommended the type of insulin that he she believes is best for you DO NOT USE ANY OTHER INSULIN EXCEPT ON THE ADVICE AND DIRECTION OF YOUR DOCTOR The instructions for using the APIDRA in the injection pen must be followed carefully It is important to use the APIDRA cartridge only with ClikSTAR AllStar Pro and JuniorSTAR pens Using the cartridge in any other injection pen not suitable for the APIDRA cartridge could lead to a mistake in dosing and cause medical problems for you such as a blood glucose level that is too low or too high JuniorSTAR delivers APIDRA in 0 5 unit dose increments ClikSTAR and AllStar Pro delivers APIDRA in 1 unit dose in
12. C for up to 28 days away from direct heat and light as long as the temperature is not greater than 25 C Opened APIDRA vials whether or not refrigerated must be discarded after 28 days even if they contain insulin Opened APIDRA vials should not be stored in the freezer and should not be allowed to freeze If a vial freezes or overheats discard it Cartridges Unopened Cartridge Unopened APIDRA cartridges should be stored in a refrigerator between 2 C 8 C Keep APIDRA away from direct heat and light APIDRA should not be stored in the freezer and should not be allowed to freeze If APIDRA freezes or overheats discard it Opened In Use Cartridge The opened cartridge in use must be kept unrefrigerated 15 25 C for up to 28 days away from direct heat and light as long as the temperature is not greater than 25 C If the cartridge overheats or if there is any remaining insulin after 28 days discard it The opened cartridge in use must never be removed from and reinserted into the injection pen SoloSTAR Unopened SoloSTAR Unopened APIDRA SoloSTAR should be stored in a refrigerator between 2 C 8 C Keep APIDRA away from direct heat and light APIDRA should not be stored in the freezer and should not be allowed to freeze If APIDRA freezes or overheats discard it Opened In Use SoloSTAR Opened APIDRA SoloSTAR in use must be kept unrefrigerated 15 25 C for up to 28 days away from direct heat and light as long
13. DOSAGE AND ADMINISTRATION Continuous Subcutaneous Insulin Infusion Pump When used in an external insulin pump for subcutaneous infusion APIDRA should not be mixed with any other insulin or diluted with any other solution The infusion set and reservoir used with APIDRA must be changed at least every 48 hours using aseptic technique It is important that patients follow these instructions even if they differ from the general pump manual instructions Failure to follow the instruction above pump or infusion set malfunctions handling errors or insulin degradation can lead to hyperglycemia ketosis and diabetic ketoacidosis in a short time This is especially pertinent for rapid acting insulin analogues that are more rapidly absorbed and have a shorter duration of action Prompt identification and correction of the cause of hyperglycemia or ketosis or diabetic ketoacidosis is necessary Interim subcutaneous injection with APIDRA may be required Patients using continuous subcutaneous insulin infusion CSII pump therapy must be trained to administer insulin by injection and have alternate insulin delivery system available in case of pump failure see DOSAGE AND ADMINISTRATION Continuous Subcutaneous Insulin Infusion Pump CONSUMER INFORMATION Vials Continuous Subcutaneous Insulin Infusion Pump STORAGE AND STABILITY Page 8 of 61 Renal Hepatic Biliary Pancreatic impairment The pharmacokinetic properties of APIDRA were generally mainta
14. Pharmacokinetic and Pharmacodynamic Results for s c Apidra and Huminsulin Normal 100 APIDRA Huminsulin Normal 100 N 18 N 24 Dose 0 3 U kg 0 3 IU kg Pharmacokinetic Parameters AUCo ena 25076 3209 17417 2348 uU min mL 1 Cmax 142 25 56 16 uU mL 1 MRT min 136 28 229 41 Tmax 72 120 Min 50 112 60 240 T10 AUC 39 58 Min 28 64 45 81 T 90 AUC 242 448 Min 169 345 321 590 Ta min 56 17 64 287 Volume of Distribution 930 216 2375 963 mL kg Glucose Infusion Rate Pharmacodynamic Parameter GIR AUC 0 end 1476 300 3032 743 mg kg Values represent mean and standard deviation unless denoted with to indicate the median minimum amp maximum range 1 Historical data and different radioimmunoassay from Apidra study Type 1 Diabetes patients 3 Healthy adult subjects 4 N 23 Absorption and bioavailability Pharmacokinetic profiles in healthy volunteers and diabetes patients Type 1 or 2 demonstrated that absorption of insulin glulisine was up to twice as fast with a peak concentration approximately up to twice as high compared to regular human insulin In a study in patients with type 1 diabetes n 20 after subcutaneous administration of 0 15 U kg the median time to maximum concentration Tmax was 55 minutes range 34 to 91 minutes and the peak concentration Cmax was 82 uU mL range 42 to 134 uU mL for i
15. amp Post Natal Development Including Maternal Function Species Route Dosage Duration No of Findings Strain Animals Group Sprague Subcutaneous Dose levels 0 1 Groups of 23 e Administration of both insulin glulisine Dawley 3 15 or 8 U kg mated females and HR1799 caused clinical signs and rats body weight of mortality in the Fo animals at the daily insulin glulisine or dose of 8 U kg body weight when HR1799 at the administered during embryo and dose levels of 1 or fetogenesis and during lactation in 8 U kg body Sprague Dawley rats There were no weight once daily specific effects on birth parameters or as a solution in lactation of the Fo animals and on placebo from day postnatal development fertility or 6 of gestation until pregnancy of the F animals day 21 post e With regard to the present study the partum No Observable Adverse Effect Level is at the daily dose of 3 15 U insulin glulisine kg body weight and at the daily dose of 1 0 U HR1799 kg body weight HR1799 Reference compound human insulin Page 39 of 61 REFERENCES 1 2 Barnett AH Owens DR Insulin Analogues Lancet 1997 349 47 51 Davidson JK Galloway JA Chance RE Insulin therapy In Davidson JK Clinical Diabetes Mellitus A Problem Oriented Approach New York Thieme Medical Publishers Inc 1991 266 332 Pickup JC Williams G EDITOR The pharmacokinetics of insulin In Pickup JC Williams G Textbook of Diabetes Oxfor
16. are allergic to this drug or to any ingredient in the formulation or component of the container What the medicinal ingredient is The active ingredient in APIDRA is insulin glulisine rDNA origin What the nonmedicinal ingredients are The nonmedicinal ingredients are m cresol polysorbate 20 sodium chloride trometamol water and hydrochloric acid and sodium hydroxide for pH adjustment What dosage forms it comes in APIDRA is a solution for injection 100 U mL available in the following package size 3 mL Cartridges package of 5 for use only with ClikSTAR AllStar Pro and JuniorSTAR pens It is also available in 10 mL vials 3 mL SoloSTAR pre filled disposable pen package of 5 WARNINGS AND PRECAUTIONS Serious Warnings and Precautions e Hypoglycemia low blood sugar is the most common adverse effect of insulin including APIDRA e Blood glucose monitoring is recommended for all patients with diabetes e Uncorrected hypoglycemic low blood sugar or hyperglycemic high blood sugar reactions can cause loss of consciousness coma or death e Any change of insulin should be made cautiously and only under medical supervision This may result in dosage adjustment e When used as a meal time insulin the dose of APIDRA should be given within 15 minutes before or within 20 minutes after starting a meal e APIDRA given by subcutaneous injection should generally be used in regimens with
17. as the basal insulin in both groups Before start of the study there was a 4 week run in period combining insulin lispro and insulin glargine followed by randomization Glycemic control and the rates of hypoglycemia requiring intervention from a third party were comparable for the two treatment regimens The number of daily insulin injections and the total daily doses of APIDRA and insulin lispro were similar The decrease in Alc was observed in patients treated with APIDRA without an increase in the basal insulin dose see Table 8 Table 8 Type 1 Diabetes Mellitus Adult Treatment duration 26 weeks Treatment in combination with following basal LANTUS insulin insulin glargine APIDRA Insulin lispro Number of subjects treated 339 333 A1C Endstudy mean 7 46 7 45 Adjusted mean change from baseline 0 14 0 14 APIDRA Insulin lispro 0 00 95 Cl for treatment difference 0 09 0 10 Basal insulin dose U day Endstudy mean 24 16 26 43 Adjusted mean change from baseline 0 12 1 82 Short acting insulin dose U day Endstudy mean 29 03 30 12 Adjusted mean change from baseline 1 07 0 81 Severe hypoglycemia Number of subjects 16 335 4 8 13 326 4 0 Rate events month patient 0 02 0 02 Mean number of short acting insulin injections per 3 36 3 42 day Events requiring assistance from third party during the last 3 months of the study CI Confidence Interval Page 30 of 61 Type 1 Diabetes Pe
18. as the temperature is not greater than 25 C If the APIDRA SoloSTAR overheats or if there is any remaining insulin after 28 days discard it Page 27 of 61 Opened APIDRA SoloSTAR should not be stored in the freezer and should not be allowed to freeze If APIDRA SoloSTAR freezes discard it As with all medications and devices keep out of reach of children Infusion sets Infusion sets reservoirs tubing and catheters and the APIDRA in the reservoir must be discarded after no more than 2 days of use or after exposure to temperatures that exceed 37 C SPECIAL HANDLING INSTRUCTIONS See also PART II CONSUMER INFORMATION and refer patients to the APIDRA Information for the Patient circular for APIDRA VIAL APIDRA CARTRIDGE and APIDRA SoloSTAR for additional information Refer patients to the Instructions for Use for ClikSTAR AllStar Pro and JuniorSTAR or to the User Manual for APIDRA SoloSTAR for additional information on use of the pens DOSAGE FORMS COMPOSITION AND PACKAGING The vials cartridges and SoloSTAR contain a sterile solution of insulin glulisine for use as an injection APIDRA Insulin glulisine injection rDNA origin consists of insulin glulisine dissolved in a clear aqueous solution Each milliliter of APIDRA contains insulin glulisine 100 units It also contains excipients m cresol trometamol sodium chloride polysorbate 20 and water for injection APIDRA has a pH of approximately 7 3 and is adjuste
19. dose levels Clinical observations and pathological findings obtained in these studies were similar or comparable to those in human beings observed after hyperinsulinemia hypoglycemia In some cases excessive hypoglycemia caused the deaths of animals These findings in healthy non diabetic animals are not indicative of any specific toxicity on insulin glulisine in patients where it is used for controlled glucose lowering effects at therapeutic doses Page 34 of 61 Carcinogenesis In Sprague Dawley rats a 12 month repeat dose toxicity study was conducted with insulin glulisine at doses of 2 5 5 20 or 50 U kg twice daily dose resulting in an exposure equivalent to approximately 26 54 258 662 times the human Cmax at the average human dose respectively The incidence of mortality increased dose dependently in 2x20 and 2x50 U kg insulin glulisine or IU kg human insulin treated groups respectively Generally males were more severely affected than females and mortality at the comparable dose levels was always higher in the human insulin treated groups In this study the effects of insulin glulisine on cellular proliferation in mammary glands were evaluated using Ki 67 immunohistochemistry There were no significant differences in mammary cell proliferation between insulin glulisine regular human insulin and control groups Table 12 Insulin glulisine Incidence of female SD rats with mammary tumors in a 12 month toxicity study 30 ra
20. for rescuers Contact your health professional about appropriate proportions of carbohydrates Signs of severe hypoglycemia can include e disorientation e convulsions e loss of consciousness e seizures Severe hypoglycemia may require the assistance of another person Patients who are unable to take sugar orally or who are unconscious may require an injection of glucagon or should be treated with intravenous administration of glucose by medical personnel Without immediate medical help serious reactions or even death could occur The early warning symptoms of hypoglycemia may be changed be less pronounced or be absent as for example in patients whose sugar levels are markedly improved in elderly patients in patients with diabetic nerve disease in patients with a long history of diabetes or in patients receiving concurrent treatment with certain other drugs Such situations may result in severe hypoglycemia and possibly loss of consciousness before a patient has symptoms Some people may not recognize when their blood sugar drops low Without recognition of early warning symptoms you may not be able to take steps to avoid more serious hypoglycemia Be alert for all of the various types of symptoms that may indicate hypoglycemia Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose frequently especially prior to activities such as driving a car or use mechanical equipment
21. mL vials It is also available in 3 mL Cartridges package of 5 for use only with ClikSTAR AllStar Pro and JuniorSTAR pens 3 mL SoloSTAR pre filled disposable pen package of 5 WARNINGS AND PRECAUTIONS Serious Warnings and Precautions e Hypoglycemia low blood sugar is the most common adverse effect of insulin including APIDRA e Blood glucose blood sugar monitoring is recommended for all patients with diabetes e Uncorrected hypoglycemic low blood sugar or hyperglycemic high blood sugar reactions can cause loss of consciousness coma or death e Any change of insulin should be made cautiously and only under medical supervision This may result in dosage adjustment e When used as a meal time insulin the dose of APIDRA should be given within 15 minutes before or within 20 minutes after starting a meal e APIDRA given by subcutaneous injection should Page 41 of 61 generally be used in regimens with an intermediate or long acting insulin APIDRA can also be used alone in insulin infusion pump therapy to maintain adequate glucose control e APIDRA can be mixed with NPH human insulin except when administered with pump e Insulin products shall not be used if it is not water clear and colourless or if it has formed a deposit of solid particles on the wall of the vial or cartridge Insulin injections play an important role in keeping your diabetes under control But the
22. opened vial can be kept refrigerated or unrefrigerated 15 25 C for up to 28 days away from direct heat and light as long as the temperature is not greater than 25 C Opened APIDRA vials whether or not refrigerated must be discarded after 28 days even if they contain insulin Opened APIDRA vials should not be stored in the freezer and should not be allowed to freeze If a vial freezes or overheats discard it Do not use a vial of APIDRA after the expiration date stamped on the label or if it is cloudy or if you see particles Infusion sets when used with Continuous Subcutaneous Insulin Infusion pump Infusion sets reservoirs tubing and catheters and the APIDRA in the reservoir must be discarded after no more than 48 hours of use or after exposure to temperatures that exceed 37 C As with all medications and devices keep out of reach of children REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways e Report online at www healthcanada gc ca medeffect e Call toll free at 1 866 234 2345 e Complete a Canada Vigilance Reporting Form and Fax toll free to 1 866 678 6789 or Mail to Canada Vigilance Program Health Canada Postal Locator 0701E Ottawa ON KIA 0K9 Postage paid labels Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on
23. pen is for single patient use Do not share it with anyone including other family members even if the needle on the injection pen is changed Do not use on multiple patients Preparing the Dose 1 To avoid medication errors check the label on the SoloSTAR pen to make sure you have the correct insulin The APIDRA SoloSTAR is blue 2 Inspect the insulin APIDRA should be a clear and colorless solution with no visible particles Do not use it if you notice anything unusual in the Page 58 of 61 appearance of the solution Do not use the insulin after the expiry date on the label 3 Make sure the insulin is at room temperature to minimize local irritation at the injection site Wash your hands 5 It is not necessary to shake or rotate the SoloSTAR before use 6 Remove the protective cap 7 Follow the SoloSTAR directions for attaching and changing the needle 8 Check the SoloSTAR for air bubbles If bubbles are present remove them as instructed in the SoloSTAR directions 9 Follow the SoloSTAR directions for performing the Safety Test 10 Set the SoloSTAR to the correct APIDRA dose as instructed in the SoloSTAR directions 11 There is no relevant difference in absorption of APIDRA between abdominal thigh buttock or upper arm subcutaneous injection areas However injection sites within an injection area abdomen thigh buttock or upper arm must be rotated from one injection to the next 12 Cleanse the
24. period postprandial blood glucose levels in the APIDRA group were lower than in the regular human insulin group The rates of hypoglycemia requiring intervention from a third party were comparable for the two treatment regimens No differences between APIDRA and regular human insulin groups were seen in the number of daily injections or basal or short acting insulin doses see Table 10 Table 10 Type 2 Diabetes Mellitus Adult Treatment duration 26 weeks Treatment in combination with following basal NPH human insulin insulin APIDRA Regular Human Insulin Number of subjects treated 435 441 A1C Endstudy mean 7 11 7 22 Adjusted mean change from baseline 0 46 0 30 APIDRA Regular Human Insulin 0 16 95 Cl for Treatment difference 0 26 0 05 Basal insulin dose U day Endstudy mean 65 34 63 05 Adjusted mean change from baseline 5 73 6 03 Short acting insulin dose U day Endstudy mean 35 99 36 16 Adjusted mean change from baseline 3 69 5 00 Severe hypoglycemia Number of subjects 6 416 1 4 5 420 1 2 Rate events month patient 0 00 0 00 Mean number of short acting insulin injections per 2 27 2 24 day Events requiring assistance from third party during the last 3 months of the study CI Confidence Interval Page 32 of 61 Pre and Post Meal Administration Type 1 Diabetes A 12 week randomized open label active control study n 860 was conducted in patients with Type 1 di
25. psychiatric medications including MAO inhibitors or antidepressants and anti anxiety medications Substances including beta blockers used for conditions including blood pressure heart arrhythmias palpitations and headache and alcohol may enhance or weaken the blood glucose lowering effect of insulins and signs of hypoglycemia may be reduced or absent Exercise If your exercise routine changes discuss with your health professional the possible need to adjust your insulin regimen Exercise may lower your body s need for insulin during and for some time after the activity As for all insulins the rate of absorption and consequently the onset and duration of action may be affected by exercise and other variables Travel Consult your health professional concerning possible adjustments in your insulin schedule if you will be traveling across time zones You may want to take along extra insulin and supplies whenever you travel Missed dose If you have missed a dose of APIDRA or if you have not injected enough insulin your blood sugar level may become too high hyperglycemia Check your blood sugar frequently For information on the treatment of hyperglycemia see Side Effects and What To Do About Them below Do not take a double dose to make up for a forgotten dose Overdose If you have injected too much APIDRA your blood sugar level may become too low hypoglycemia Check your blood sugar frequently In general
26. see WARNINGS AND PRECAUTIONS Endocrine and Metabolism Hypoglycemia In the elderly progressive deterioration of renal function may lead to steady decrease in insulin requirements Careful glucose monitoring and dose adjustments of insulin or insulin analogues including APIDRA may be necessary see WARNINGS AND PRECAUTIONS Renal Hepatic Biliary Pancreatic impairment In Phase HI clinical trials n 2408 APIDRA was administered to 147 patients gt 65 years of age and 27 patients 275 years of age The majority of these were patients with Type 2 diabetes The change in glycated hemoglobin Alc values and hypoglycemia frequencies did not differ by age but greater sensitivity of some older individuals cannot be ruled out Other The presence of diseases such as Acromegaly Cushing s Syndrome Hyperthyroidism and Pheochromocytoma can complicate the control of Diabetes Mellitus Page 10 of 61 Pens to be used with APIDRA cartridge The APIDRA cartridge should only be used with the following pens e JuniorSTAR which delivers APIDRA in 0 5 unit dose increments e ClikSTAR which delivers APIDRA in 1 unit dose increments e AllStar Pro which delivers APIDRA in 1 unit dose increments This cartridge should not be used with any other reusable pen as the dosing accuracy has only been established with the listed pens Occupational Hazards The patient s ability to concentrate and react may be impaired as a result of hypoglycemia or hy
27. the MedEffect Canada Web site at www healthcanada gc ca medeffect NOTE Should you require information related to the management of side effects contact your health professional The Canada Vigilance Program does not provide medical advice MORE INFORMATION Your physician pharmacist and nurse are always your best source of information about your condition and treatment If you have additional questions or concerns be sure to ask them This document plus the full product monograph prepared for health professionals can be found at www sanofi ca or by contacting the sponsor sanofi aventis Canada Inc at 1 888 852 6887 It is also available in large print format Page 48 of 61 IMPORTANT PLEASE READ This leaflet was prepared by sanofi aventis Canada sanofi aventis Canada Inc Inc Laval Quebec H7V 0A3 Last revised October 19 2017 Page 49 of 61 PART III CONSUMER INFORMATION APIDRA CARTRIDGES insulin glulisine injection rDNA origin Cartridges are for use ONLY with ClikSTAR AllStar Pro and JuniorSTAR pens This leaflet is part III of a three part Product Monograph published when APIDRA was approved for sale in Canada and is designed specifically for Consumers This leaflet is a summary and will not tell you everything about APIDRA Contact your health professional if you have any questions about the drug ABOUT THIS MEDICATION What the medication is used for APIDRA
28. threatening see CONTRAINDICATIONS and ADVERSE REACTIONS Patients who have demonstrated an allergic reaction to other insulin products may demonstrate an allergic reaction to APIDRA Page 7 of 61 Antibody Production Insulin administration may cause insulin antibodies to form Insulin antibodies are frequently cross reactive Insulin administration may cause the insulin antibodies to form Insulin antibodies are frequently cross reactive In clinical studies cross reactive antibodies were observed in both insulin glulisine and comparator insulin lispro regular human insulin treatment groups with similar percents of increased and decreased titers There was no correlation between cross reactive insulin antibody concentration and changes in Alc insulin doses or incidence of hypoglycemia and the clinical significance of these antibodies is not clear In theory the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyperglycemia or hypoglycemia but has not been found on review of APIDRA clinical trials Intercurrent conditions Insulin requirements may be altered during illness emotional disturbances or stress Insulin pumps Patients using external pump infusion therapy should be trained appropriately Physicians and patients should carefully evaluate information on pump use in the APIDRA product monograph package insert and the pump manufacturer s manual see
29. to mating HR1799 Reference compound human insulin Findings Administration of both insulin glulisine and HR1799 caused clinical signs and mortality at the daily dose of 10 U kg body weight A slightly prolonged pre coital interval and slightly decreased epididymidal sperm counts were observed in the group treated with 10 U HR1799 kg body weight With regard to the present study the No Observable Adverse Effect Level is at the daily dose of 3 15 U insulin glulisine kg body weight and at the daily dose of 1 0 U HR1799 kg body weight Page 36 of 61 Table 14 Reproductive amp Developmental Toxicity Effects on Embryofetal Development Species Strain Dosage Duration No of Animals Group Findings Sprague Subcutaneous Insulin glulisine once Groups of 6 There was treatment related mortality and Dawley daily as a solution in mated females clinical signs due to hypoglycemia at all rats placebo solution at dose levels tested the dose levels of 0 Food consumption was slightly higher at 15 50 150 or 500 the dose level of 150 U kg U kg body weight No compound related findings were from day 6 17 of observed at necropsy pregnancy The animals found dead exhibited only empty implantation sites or conceptuses in the uterus Fetal weight and crown rump lengths were slightly decreased at 150 U kg No abnormalities were detected at caesarean section of the other animals Based on the results of this stud
30. toll free at 1 866 234 2345 e Complete a Canada Vigilance Reporting Form and Fax toll free to 1 866 678 6789 or Mail to Canada Vigilance Program Health Canada Postal Locator 1908C Ottawa ON K1A 0K9 Postage paid labels Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect Canada Web site at www healthcanada gc ca medeffect NOTE Should you require information related to the management of side effects contact your health professional The Canada Vigilance Program does not provide medical advice MORE INFORMATION Your physician pharmacist and nurse are always your best source of information about your condition and treatment If you have additional questions or concerns be sure to ask them This document plus the full product monograph prepared for health professionals can be found at www sanofi ca or by contacting the sponsor sanofi aventis Canada Inc at 1 888 852 6887 It is also available in large print format sanofi aventis Canada Inc Laval Quebec H7V 0A3 This leaflet was prepared by sanofi aventis Canada Inc Last revised October 19 2017 Page 55 of 61 PART II CONSUMER INFORMATION APIDRA SoloSTAR insulin glulisine injection rDNA origin This leaflet is part III of a three part Product Monograph published when APIDRA was approved for sale in Canada and is designed specifically for Consumers This leaflet is a
31. way you live your diet careful monitoring of your glucose levels exercise or planned physical activity and following your health professional s recommendations all work with your insulin to help you control your diabetes In some situations your need in insulin may change for example if you are stress or suffering from other illnesses e g infections Your diabetes may also be more difficult to control if you suffer from acromegaly too much growth hormone Cushing s syndrome too much cortisol hormone hyperthyroidism too much thyroid hormone or have a pheochromocytoma tumor of the adrenal glands If you also take other oral drugs to reduce your blood sugar their dose may need to be adjusted The use of thiazolidinediones such as rosiglitazone and pioglitazone alone or in combination with other antidiabetic agents including insulin has been associated with heart failure and swelling of the lower extremities Please contact your physician immediately if you develop symptoms of shortness of breath fatigue exercise intolerance or swelling of the lower extremities while you are on these agents Hypokalemia low potassium is a possible side effect You might be more at risk if you are on potassium lowering drugs or losing potassium e g diarrhea Always keep an extra supply of insulin as well as the appropriate injection supplies on hand Always wear medical alert identification and carry informatio
32. 1 2 and events 0 41 vs 0 23 when all subjects had been randomized following a 4 week of run in period with individualized dose adjustment of insulin lispro The incidence of severe symptomatic hypoglycemia and the incidence of severe nocturnal symptomatic hypoglycemia were comparable between the treatment groups Skin and appendages As with other insulin therapy lipodystrophy may occur at the injection site and delay insulin absorption Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions Weight gain Weight gain can occur with insulin therapy including APIDRA and has been attributed to the anabolic effects of insulin and the decrease in glucosuria Page 13 of 61 Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug Adverse drug reaction information from clinical trials is useful for identifying drug related adverse events and for approximating rates Table 3 Common 21 Adverse Drug Reactions in pooled adult Type 1 and 2 studies Adverse Event System Organ Class Preferred Term General Disorders and Administration Site Condition Injection site hypertrophy Metabolism and Nutrition Disorders Hypoglycemia NOS Hypoglycem
33. 20 26 55 Endstudy mean 28 44 28 86 Rapid acting insulin dose U day Baseline mean 24 26 24 34 Endstudy mean 25 48 26 97 Percentage of patients with an average number of 77 0 80 3 rapid acting insulin injections per day 2 3 Body Weight kg Baseline mean 51 5 50 8 Endstudy mean 53 6 53 0 Mean weight change from baseline 2 2 2 2 Page 31 of 61 Type 2 Diabetes A 26 week randomized open label active control study n 876 was conducted in insulin treated patients with Type 2 diabetes to assess the safety and efficacy of APIDRA given within 15 minutes before a meal compared to regular human insulin administered 30 to 45 minutes prior to a meal NPH human insulin was given twice a day as the basal insulin All patients participated in a 4 week run in period combining regular human insulin and NPH human insulin The average body mass index BMI of patients was 34 55 kg m At randomization 58 of the patients were on an oral antidiabetic agent and were instructed to continue use of their oral antidiabetic agent at the same dose The majority of patients 79 mixed their short acting insulin with NPH human insulin immediately prior to injection Changes from baseline to endpoint in Alc were 0 46 in the insulin glulisine group and 0 30 in the regular insulin group The difference in adjusted means between the 2 treatments was 0 16 95 C1 ranging from 0 26 to 0 05 with respective p value of 0 0029 At end of treatment
34. ATION usciti lezioni cairo nitriti 29 PHARMACEUTICAL INFORMATION sssessscssssssessonissesoossscececesssossensesaseecssssconsesneesonnsveses 29 CEINICAL TRIALS eniamasania aliena 30 TOXICOLOGY stecsticussensesssesebvsvsbassnesdcshwsnnsessncesesabysesiastuaebesevecesbacsesebesebscveessbeesbecssvensseaseees 34 REFERENCES sugar 40 PART III CONSUMER INFORMATION ccsssssssssssssssssscsssssssccssssnsscssessessssssssasssssessessees 41 PART III CONSUMER INFORMA TION 2ccscccssccsnsessscavccstcccoseacscsecesssecesecvacsecesesssssctecsouestecunces 50 PART III CONSUMER INFORMA TION wicissccicssascsssessscicasstcescunusseidesdtcsueesnssoddtssscatdecastsssssase 56 Page 2 of 61 PRODUCT MONOGRAPH APIDRA insulin glulisine injection rDNA origin Antidiabetic Agent Short acting Recombinant Human Insulin Analogue PART I HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form Clinically Relevant Nonmedicinal Ingredients Administration Strength Subcutaneous Solution for injection m cresol trometamol sodium chloride polysorbate 20 water for injection 100 U mL hydrochloric acid and sodium hydroxide for pH adjustment For a complete listing see Dosage Forms Composition and Packaging section DESCRIPTION APIDRA insulin glulisine injection rDNA origin is a recombinant human insulin analogue that is a rapid acting parenteral blood glucose lowering agent Insulin glulisine is produced by
35. INGES MUST NOT BE SHARED Preparing the Dose 1 To avoid medication errors check the vial label of the insulin before each injection 2 Inspect the insulin APIDRA must only be used if the solution is clear colorless with no solid particles visible and if it is of a water like consistency Do not use it if you notice anything unusual in the appearance of the solution Do not use the insulin after the expiry date on the label 3 Make sure the insulin is at room temperature to minimize local irritation at the injection site 4 Wash your hands It is not necessary to shake or rotate the vial before use Shaking the vial vigorously may cause frothing Froth may interfere with the correct measurement of the dose 6 If APIDRA is mixed with NPH human insulin APIDRA should be drawn into the syringe first Refer to the instructions for mixing below 7 Before withdrawing insulin from the vial for the first time remove the plastic protective cap but DO NOT remove the stopper Wipe the top of the vial with an alcohol swab A new Sterile syringe must be used a ee Page 44 of 61 10 Draw air into the syringe equal to your insulin dose Put the needle through the rubber top of the insulin vial and inject the air into the vial 11 Turn the vial and syringe upside down Hold the vial and syringe firmly in one hand 12 Make sure the tip of the needle is in the insulin and withdraw the correct dose of insulin into the
36. Insulin Pre meal Post meal Pre meal Number of subjects treated 286 296 278 A1c Endstudy mean 7 46 7 58 7 52 Adjusted mean change from baseline 0 26 0 11 0 13 Basal insulin dose U day Endstudy mean 29 49 28 77 28 46 Adjusted mean change from baseline 0 99 0 24 0 65 Short acting insulin dose Endstudy mean U day 28 44 28 06 29 23 Adjusted mean change from baseline 0 88 0 47 1 75 Severe hypoglycemia Number of subjects 24 286 8 4 25 296 8 4 28 278 10 1 Rate events month patient 0 05 0 05 0 13 Mean number of short acting insulin injections per day 3 15 3 13 3 03 Adjusted mean change from baseline treatment difference 98 33 Confidence Interval for treatment difference APIDRA pre meal vs Regular Human Insulin 0 13 0 26 0 01 APIDRA post meal vs Regular Human Insulin 0 02 0 11 0 16 APIDRA post meal vs pre meal 0 15 0 02 0 29 Events requiring assistance from third party for the entire treatment phase Page 33 of 61 Continuous Subcutaneous Insulin Infusion CSII Type 1 Diabetes To evaluate the use of APIDRA for administration using an external pump a 12 week randomized open label active control study APIDRA versus insulin aspart was conducted in Type 1 diabetes patients n 59 A low monthly rate of catheter occlusion in both treatment groups was observed APIDRA 0 08 occlusions month insulin aspart 0 15 occlusions month A similar incidence of infusion site reactions was see
37. PRODUCT MONOGRAPH APIDRA insulin glulisine injection rDNA origin Solution for injection 100 U mL ATC code A10AB Antidiabetic Agent Short acting Recombinant Human Insulin Analogue sanofi aventis Canada Inc Date of Revision 2905 Place Louis R Renaud October 19 2017 Laval Quebec H7V 0A3 Submission Control No 208393 s a version 14 0 dated October 17 2017 Page 1 of 61 Table of Contents PART I HEALTH PROFESSIONAL INFORMATION ccccssssssssssssssssssssssssssssssssssessessesees 3 SUMMARY PRODUCT INFORMATION scssissiassssscenssussteseasercerscsosssuesbansedssuenseneedsetasebionses 3 DESCRIPTION vactsssusostassnuassachesvishscoussbussnvsuwssapesnbussbiGeeassbdebuernnevcbsstngebssubetubbsstnesbeussnsvsbeainseses 3 INDICATIONS AND CLINICAL USE sein 4 CONTRAINDICATION siisssnatonscnssetssetasonsasstononstbsusooisusapoucnbnsvolseedsonssuscusosssnesbsenasnissisavbenous 4 WARNINGS AND PRECAUTIONS scsiessscasctssessuesantecadencssovsbiaseacsudsssevonssbascbicepeesesuessssduseses 4 ADVERSE REACTIONS siena pece renano rss 11 DRUGINTERACTIONS nea 16 DOSAGE AND ADMINISTRATION ccvcscsccssscssssssssssociosseonssessconssvosocioenascoostssseoveansesonasveses 18 OV ER DOSAGE quei 20 ACTION AND CLINICAL PHARMACOLOGY ccccsssssesssssssecesssscscosnsetssesosneseasscssvenssessesss 21 SPECIAL HANDLING INSTRUCTIONS vii 28 DOSAGE FORMS COMPOSITION AND PACKAGING scscssssssssessesssessssssesssessenes 28 PART II SCIENTIFIC INFORM
38. abetes to assess the safety and efficacy of APIDRA administered at different times with respect to a meal APIDRA was administered subcutaneously either within 15 minutes before a meal or immediately after completing a meal or 20 minutes after starting a meal and regular human insulin was administered subcutaneously 30 to 45 minutes prior to a meal The comparisons performed in this study were pre meal APIDRA compared to regular human insulin post meal APIDRA compared to regular human insulin and post meal APIDRA compared to pre meal APIDRA Insulin glargine was administered once daily at bedtime as the basal insulin in all groups Before start of the study there was a 4 week run in period with regular human insulin and insulin glargine followed by randomization Glycemic control and the rates of hypoglycemia requiring intervention from a third party were comparable for the treatment regimens Significant reductions from baseline in Alc were observed in all three treatment regimens No changes from baseline between the treatments were seen in the total daily number of insulin injections An increase in daily short acting insulin dose was seen with regular human insulin see Table 11 Table 11 Type 1 Diabetes Mellitus Adult Treatment duration 12 weeks 12 weeks 12 weeks Treatment in combination with following basal insulin LANTUS LANTUS LANTUS insulin glargine insulin glargine insulin glargine APIDRA APIDRA Regular Human
39. administration of the test compound first collection in all groups and were 10 6 46 7 and 159 ng ml in the low intermediate and high dose group respectively Page 37 of 61 Species Dosage Duration Strain Group Himalayan Subcutaneous Insulin glulisine once Groups of 6 rabbits daily as a solution in mated female placebo solution at the dose levels of 0 2 10 or 50 U kg body weight from day 6 18 of pregnancy Dose levels of 0 0 25 0 50 or 1 50 U kg body weight of insulin glulisine or HR1799 at the dose levels of 0 25 or 1 50 U kg body weight once daily as a solution in placebo from day 6 18 of pregnancy Himalayan Subcutaneous rabbits Groups of 20 26 mated female Himalayan Subcutaneous rabbits Insulin glulisine once Groups of 10 daily as a solution in mated females placebo solution at the dose levels of 0 25 0 5 or 1 5 U kg body weight from day 6 12 of pregnancy Findings Treatment related mortality and clinical signs due to hypoglycemia were seen at all dose levels tested Food consumption was slightly higher at the dose levels of 2 and 10 U kg The animals found dead exhibited only empty implantation sites or conceptuses in the uterus Foetal weight and crown rump lengths were not altered in the dose groups The number of intrauterine deaths was higher in the 2 and 10 U kg group Based on the r
40. an intermediate or long acting insulin APIDRA can also be used alone in insulin infusion pump therapy to maintain adequate glucose control e APIDRA can be mixed with NPH human insulin except when administered with pump e Insulin products shall not be used if it is not water clear and colourless or if it has formed a deposit of solid particles on the wall of the vial or cartridge Insulin injections play an important role in keeping your diabetes under control But the way you live your diet careful monitoring of your glucose levels exercise or planned physical activity and following your health professional s recommendations all work with your insulin to help you control your diabetes Page 50 of 61 In some situations your need in insulin may change for example if you are stress or suffering from other illnesses e g infections Your diabetes may also be more difficult to control if you suffer from acromegaly too much growth hormone Cushing s syndrome too much cortisol hormone hyperthyroidism too much thyroid hormone or have a pheochromocytoma tumor of the adrenal glands If you also take other oral drugs to reduce your blood sugar their dose may need to be adjusted The use of thiazolidinediones such as rosiglitazone and pioglitazone alone or in combination with other antidiabetic agents including insulin has been associated with heart failure and swelling of the lower extremities P
41. as a meal time insulin the dose of APIDRA should be given within 15 minutes before or within 20 minutes after starting a meal e APIDRA given by subcutaneous injection should generally be used in regimens with an intermediate or long acting insulin APIDRA can also be used alone in insulin infusion pump therapy to maintain adequate glucose control e APIDRA can be mixed with NPH human insulin except when administered with pump e Insulin products shall not be used if it is not water clear and colourless or if it has formed a deposit of solid particles on the wall of the vial or cartridge Insulin injections play an important role in keeping your diabetes under control But the way you live your diet careful monitoring of your glucose levels exercise or planned physical activity and following your health professional s recommendations all work with your insulin to help you control your diabetes Page 56 of 61 In some situations your need in insulin may change for example if you are stress or suffering from other illnesses e g infections Your diabetes may also be more difficult to control if you suffer from acromegaly too much growth hormone Cushing s syndrome too much cortisol hormone hyperthyroidism too much thyroid hormone or have a pheochromocytoma tumor of the adrenal glands If you also take other oral drugs to reduce your blood sugar their dose may need to be adjusted The use of thia
42. consistently show the presence of glucose your diabetes is not properly controlled and you must let your health professional know When it should not be used You should not take APIDRA if you are allergic to this drug or to any ingredient in the formulation or component of the container What the medicinal ingredient is The active ingredient in APIDRA is insulin glulisine rDNA origin What the nonmedicinal ingredients are The nonmedicinal ingredients are m cresol polysorbate 20 sodium chloride trometamol water and hydrochloric acid and sodium hydroxide for pH adjustment What dosage forms it comes in APIDRA is a solution for injection 100 U mL available in the following package size 3 mL SoloSTAR pre filled disposable pen package of 5 It is also available in 10 mL vials 3 mL Cartridges package of 5 for use only with ClikSTAR AllStar Pro and JuniorSTAR pens WARNINGS AND PRECAUTIONS Serious Warnings and Precautions e Hypoglycemia low blood sugar is the most common adverse effect of insulin including APIDRA e Blood glucose blood sugar monitoring is recommended for all patients with diabetes e Uncorrected hypoglycemic low blood sugar or hyperglycemic high blood sugar reactions can cause loss of consciousness coma or death e Any change of insulin should be made cautiously and only under medical supervision This may result in dosage adjustment e When used
43. crements CAREFULLY FOLLOW THE PACKAGE DIRECTIONS SUPPLIED FOR ClikSTAR AllStar Pro and JuniorSTAR TO e HELP AVOID CONTAMINATION AND POSSIBLE INFECTION e OBTAIN AN ACCURATE DOSE Do not reuse needles INJECTION PENS CARTRIDGES NEEDLES AND SYRINGES MUST Page 52 of 61 NOT BE SHARED To prevent the possible transmission of disease never share an injection pen or APIDRA cartridge between patients even if the needle on the injection pen is changed Preparing the APIDRA Cartridge for Insertion into the injection pen 1 To avoid medication errors check the cartridge label of the insulin before each insertion 2 Inspect the insulin cartridge APIDRA should be a clear and colorless solution with no visible particles Do not use it if you notice anything unusual in the appearance of the solution Do not use the insulin after the expiry date on the label 3 Make sure the insulin is at room temperature to minimize local irritation at the injection site Wash your hands 5 Carefully follow the injection pen directions for loading the cartridge into the injection pen Injecting Each Dose 1 Wash your hands 2 Inspect the insulin APIDRA should be a clear and colorless solution with no visible particles Do not use it if you notice anything unusual in the appearance of solution 3 Itis not necessary to shake or rotate the cartridge inserted into the injection pen before use 4 Remove the protective cap 5 Foll
44. ction technique You can reduce the chance of getting an injection site reaction if you change the injection site each time If you have local injection site reactions contact your health professional This is not a complete list of side effects For any unexpected effects while taking APIDRA contact your health professional HOW TO STORE IT Unopened Cartridge Unopened APIDRA cartridges should be stored in a refrigerator between 2 C 8 C Keep APIDRA away from direct heat and light APIDRA should not be stored in the freezer and should not be allowed to freeze If APIDRA freezes or overheats discard it Opened In Use Cartridge The opened cartridge in use must be kept unrefrigerated 15 25 C for up to 28 days away from direct heat and light as long as the temperature is not greater than 25 C If the cartridge overheats or if there is any remaining insulin after 28 days discard it The opened cartridge in use must never be removed from and reinserted into the injection pen Do not use a cartridge of APIDRA after the expiration date stamped on the label or if it is cloudy or if you see particles As with all medications and devices keep out of reach of children REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways e Report online at www healthcanada gc ca medeffect e Call
45. ctions In rare cases a patient may be allergic to an insulin product Severe insulin allergies may be life threatening If you think you are having an allergic reaction seek medical help immediately Signs of insulin allergy include e arash all over your body shortness of breath wheezing trouble breathing a fast pulse sweating low blood pressure Possible reactions on the skin at the injection site Injecting insulin can cause the following reactions on the skin at the injection site e a little depression in the skin lipoatrophy Page 47 of 61 e skin thickening lipohypertrophy e redness itching swelling or hemorrhage at injection site In some instances these reactions may be related to factors other than insulin such as irritants in the skin cleansing agent or poor injection technique You can reduce the chance of getting an injection site reaction if you change the injection site each time If you have local injection site reactions contact your health professional This is not a complete list of side effects For any unexpected effects while taking APIDRA contact your health professional HOW TO STORE IT Unopened Vial Unopened APIDRA vials should be stored in a refrigerator between 2 C 8 C Keep APIDRA away from direct heat and light APIDRA should not be stored in the freezer and should not be allowed to freeze If APIDRA freezes or overheats discard it Opened In Use Vial The
46. d A new sterile syringe must be used at each injection SIDE EFFECTS AND WHAT TO DO ABOUT THEM COMMON PROBLEMS OF DIABETES Hypoglycemia Insulin Reaction Hypoglycemia too little glucose in the blood is one of the most frequent adverse events experienced by insulin users It can be brought on by situations such as e intercurrent conditions illness stress or emotional disturbances e accidental injection of an increased insulin dose e malfunction and or misuse of medical devices too low food intake or skipped meals an increase in exercise a new insulin type or schedule some new medications including prescriptions over the counter medications herbs vitamins and street drugs Symptoms of mild to moderate hypoglycemia may occur suddenly and can include e abnormal behavior anxiety irritability restlessness trouble concentrating personality changes mood changes confusion or nervousness fatigue tingling in your hands feet lips or tongue tremor shaking unsteady gait walking dizziness light headedness or drowsiness headache blurred vision slurred speech palpitations rapid heartbeat cold sweat pale skin nightmares or trouble sleeping nausea hunger Mild to moderate hypoglycemia can be treated by consuming foods or drinks that contain sugar Patients should always carry a quick source of sugar such as Page 53 of 61 candy juice or glucose tablets prominently labelled
47. d Blackwell Science Ltd 1997 32 1 2 14 Pickup JC Williams G EDITOR Normal Metabolism The physiology of Fuel Homoeostasy In Pickup JC Williams G Textbook of Diabetes Oxford Blackwell Science Ltd 1997 11 1 11 37 Dreyer M 26 week multinational multicenter controlled open 1 1 randomized parallel clinical trial comparing HMR1964 with insulin lispro injected subcutaneously in subjects with type 1 diabetes mellitus also using insulin glargine and which will lead into a comparative 26 week safety extension study HMR1964A 3011 HMR1964A 3001 Final report Department of Diabetes and Metabolism Krankenhaus Bethanien Hamburg Germany 2003 Apr Report No B2002CLN0255 Ways K 26 week multinational multicenter controlled open 1 1 randomized parallel clinical trial comparing HMR1964 with regular insulin injected subcutaneously in subjects with type 2 diabetes mellitus also using NPH insulin and which will lead into a comparative 26 week safety extension study HMR1964A 3012 HMR1964A 3002 Final report Aventis Pharmaceuticals Inc 2003 Apr Report No B2002CLN0287 Ways K 12 week multinational multicenter controlled open 1 1 1 randomized parallel clinical trial to assess noninferiority between pre and postmeal administration of HMR1964 and premeal regular human insulin in subjects with type 1 diabetes mellitus receiving insulin glargine as the basal insulin therapy HMR1964A 3004 Final report Aventis Phar
48. d by addition of aqueous solutions of hydrochloric acid and sodium hydroxide APIDRA insulin glulisine injection DNA origin 100 units per mL is available in the following package sizes e 10 mL vials e 3 mL cartridges package of 5 for use with ClikSTAR AllStar Pro and JuniorSTAR e 3 mL APIDRA SoloSTAR pre filled disposable pen package of 5 Page 28 of 61 PART II SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Proper name insulin glulisine rDNA origin Chemical name 3 lysine 29 glutamic acid human insulin Molecular formula C35gHsg4N e407gS6 Molecular mass 5823 Structural formula A chain Phe Val Gin His LeuCys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly PhePhe Tyr Thr Pro Thr B chain Page 29 of 61 CLINICAL TRIALS The safety and efficacy of APIDRA insulin glulisine was studied in adult patients with Type 1 and Type 2 diabetes n 2408 and in children and adolescent patients 4 to 17 years with type 1 diabetes n 572 The primary efficacy parameter was glycemic control as measured by glycated hemoglobin Alc Type 1 Diabetes A 26 week randomized open label active control study n 672 was conducted in patients with Type 1 diabetes to assess the safety and efficacy of APIDRA compared to insulin lispro when administered subcutaneously within 15 minutes before a meal Insulin glargine LANTUS was administered once daily in the evening
49. d with glucagon injected in the muscle or subcutaneous tissue or glucose injected in the vein You should continue checking your blood sugar even if you feel better because hypoglycemia may recur In case of drug overdose contact a health professional hospital emergency department or regional Poison Control Centre immediately even if there are no symptoms INSTRUCTIONS FOR USE Your doctor has recommended the type of insulin that he she believes is best for you DO NOT USE ANY OTHER INSULIN EXCEPT ON THE ADVICE AND DIRECTION OF YOUR DOCTOR Mixing of Insulins APIDRA can be mixed with NPH human insulin except for pump see section below for use of continuous subcutaneous insulin infusion pump APIDRA should be drawn into the syringe first Injection should be made immediately after mixing Mixtures should not be administered intravenously Correct Syringe It is important to use a syringe that is marked for U 100 insulin preparations since APIDRA contains 100 units mL Using an incorrect syringe could lead to a mistake in dosing and cause medical problems for you such as a blood glucose level that is too low or too high Syringe Use CAREFULLY FOLLOW THE DIRECTIONS SUPPLIED BY YOUR HEALTH PROFESSIONAL ON HOW TO USE SYRINGES TO e HELP AVOID CONTAMINATION AND POSSIBLE INFECTION e OBTAIN AN ACCURATE DOSE Disposable syringes and needles should be used only once and then properly discarded NEEDLES AND SYR
50. diatric A 26 week phase III open label active controlled study n 572 evaluated the efficacy and safety of APIDRA in children and adolescents with type I diabetes mellitus in comparison with insulin lispro when administered subcutaneously within 15 minutes before a meal LANTUS insulin glargine was administered once daily in the evening or NPH twice daily in the morning and in the evening as basal insulin The study consisted of a 4 week run in phase during which patients received NPH or insulin glargine combined with insulin lispro followed by a 26 week treatment phase comparing insulin glulisine and insulin lispro given at least twice daily within15 minutes prior to a meal in combination with NPH insulin administered twice daily or insulin glargine administered once daily in the evening Most patients were Caucasian 91 Fifty percent of the patients were male The mean age was 12 5 years range 4 to 17 years Mean BMI was 20 6 kg m Glycemic control see Table 9 was comparable for the two treatment regimens Table 9 Type 1 Diabetes Mellitus Pediatric Treatment duration 26 weeks mITT Treatment in combination with NPH or LANTUS insulin glargine APIDRA Insulin lispro A1c Number of patients 271 291 Baseline mean 8 20 8 17 Endstudy mean 8 31 8 37 Adjusted mean change from baseline 0 10 0 16 APIDRA Insulin lispro 0 06 95 CI for treatment difference 0 24 0 12 Basal insulin dose U day Baseline mean 27
51. ed in the presence of drugs with hypoglycemic activity such as oral antidiabetic agents salicylates for example aspirin sulfa antibiotics blood pressure medications including ACE inhibitors and certain psychiatric medications including MAO inhibitors or antidepressants and anti anxiety medications Substances including beta blockers used for conditions including blood pressure heart arrhythmias palpitations and headache and alcohol may enhance or weaken the blood glucose lowering effect of insulins and signs of hypoglycemia may be reduced or absent Exercise If your exercise routine changes discuss with your health professional the possible need to adjust your insulin regimen Exercise may lower your body s need for insulin during and for some time after the activity As for all insulins the rate of absorption and consequently the onset and duration of action may be affected by exercise and other variables Travel Consult your health professional concerning possible adjustments in your insulin schedule if you will be traveling across time zones You may want to take along extra insulin and supplies whenever you travel Missed dose If you have missed a dose of APIDRA or if you have not injected enough insulin your blood sugar level may become too high hyperglycemia Check your blood sugar frequently For information on the treatment of hyperglycemia see Side Effects and What To Do About Them below Do no
52. esults of this study the dose of 1 5 U insulin glulisine kg body weight per day is considered to be a suitable high dose for the main study Administration of both insulin glulisine and HR1799 caused clinical signs and mortality at the daily dose of 1 5 U kg body weight The incidence of dams with total litter loss and the incidence of resorptions were increased Morphological examination of the fetuses revealed an increased incidence of fetuses showing anomalies in the region of vertebral column and ribs Clinical signs were also observed in one animal from the group dosed with 0 5 U insulin glulisine kg body weight The incidence of resorptions was slightly increased in this group No compound related effects were observed by morphological examination of the fetuses With regard to the present study the No Observable Adverse Effect Level is at the daily dose of 0 25 U insulin glulisine kg body weight and at the daily dose of 0 25 U HR1799 kg body weight for maternal and developmental effects The animal of the 1 5 U kg group found dead exhibited only 5 corpora lutea The insulin glulisine pharmacokinetic parameters following the 7th administration are found below At 0 25 U kg tmax 0 25 Cmax 7 8ng ml At 0 5 U kg tmax 0 25 Cmax 15 3ng ml At 1 5 U kg tmax 10 50 h Cmax 80 2ng ml HR1799 Reference compound human insulin Page 38 of 61 Table 15 Reproductive amp Developmental Toxicity Effects on Pre
53. etoacidosis usually come on over a period of hours or days With ketoacidosis urine tests show large amounts of glucose and acetone Symptoms of diabetic ketoacidosis include First symptoms e drowsiness flushed face thirst loss of appetite fruity smelling breath rapid deep breathing abdominal stomach area pain Severe symptoms e heavy breathing e rapid pulse Prolonged hyperglycemia or diabetic ketoacidosis can lead to nausea vomiting dehydration loss of consciousness death Severe or continuing hyperglycemia or DKA requires prompt evaluation and treatment by your health professional Page 54 of 61 Allergic reactions In rare cases a patient may be allergic to an insulin product Severe insulin allergies may be life threatening If you think you are having an allergic reaction seek medical help immediately Signs of insulin allergy include e arash all over your body shortness of breath wheezing trouble breathing a fast pulse sweating low blood pressure Possible reactions on the skin at the injection site Injecting insulin can cause the following reactions on the skin at the injection site e a little depression in the skin lipoatrophy e skin thickening lipohypertrophy e redness itching swelling or hemorrhage at injection site In some instances these reactions may be related to factors other than insulin such as irritants in the skin cleansing agent or poor inje
54. f you are planning to have a baby are pregnant or are nursing a baby consult your health professional Good control of diabetes is especially important for you and your unborn baby Pregnancy may make managing your diabetes more difficult Medication Always discuss any medications you are taking prescription or over the counter with your health professional To prevent drug interactions volunteer the names of everything you are taking even before they ask if there have been any changes Insulin requirements may be increased in the presence of drugs with hyperglycemic activity such as contraceptives for example birth control pills injections and patches and hormone replacement therapies corticosteroids thyroid replacement therapy and sympathomimetic agents such as decongestants and diet pills Insulin requirements may be reduced in the presence of drugs with hypoglycemic activity such as oral antidiabetic agents salicylates for example aspirin sulfa antibiotics blood pressure medications including ACE inhibitors and certain psychiatric medications including MAO inhibitors or antidepressants and anti anxiety medications Substances including beta blockers used for conditions including blood pressure heart arrhythmias palpitations and headache and alcohol may enhance or weaken the blood glucose lowering effect of insulins and signs of hypoglycemia may be reduced or absent Exercise If your exercise routi
55. ic seizure Hypoglycemic unawareness Nervous System Disorders Hypoglycemic coma Not otherwise specified Insulin Glulisine Lispro Regular Aspart All studies n 333 Insulin n 30 n 1833 of subjects n 1161 of of subjects of subjects subjects Table 4 summarizes the adverse reactions occurring with frequency higher than 1 in a clinical study in children and adolescents with type 1 diabetes treated with insulin glulisine n 277 or insulin lispro Page 14 of 61 Table 4 Common 21 Adverse Drug Reactions in children and adolescents with Type 1 diabetes Adverse Event PEAL ees mig System Organ Class Preferred Term of subjects of subjects General Disorders and Administration Site Condition Injection site hypertrophy 3 1 1 1 0 3 Metabolism and Nutrition Disorders Hypoglycemia NOS 6 2 2 7 2 4 Hypoglycemic seizure 17 6 1 14 4 7 Nervous System Disorders Hypoglycemic coma 1 0 4 3 1 0 Not otherwise specified During clinical studies there were no clinically noteworthy differences between insulin glulisine and comparator short acting insulins in the overall incidences of adverse events The adverse events observed were those known in this pharmacological class and consequently common to insulins Less Common Clinical Trial Adverse Drug Reactions lt 1 Gastrointestinal disorders nausea General disorders administration site conditions fatigue inject
56. in glulisine is eliminated more rapidly than regular human insulin with an apparent half life of 42 minutes compared to 86 minutes Special Populations and Conditions Pediatrics The pharmacokinetic and pharmacodynamic properties of insulin glulisine and regular human insulin were assessed in a study conducted in pediatric patients with Type 1 diabetes children 7 11 years n 10 and adolescents 12 16 years n 10 The relative differences in pharmacokinetics and pharmacodynamics between insulin glulisine and regular human insulin in pediatric patients with Type 1 diabetes were similar to those in healthy adult subjects and adults with Type 1 diabetes Gender Information on the effect of gender on the pharmacokinetics of insulin glulisine is not available However in Phase III clinical trials in adults n 2408 subgroup analyses based on Page 25 of 61 gender did not show differences in safety and efficacy between insulin glulisine and other short acting insulin formulations Hepatic Insufficiency The effect of hepatic impairment on the pharmacokinetics of insulin glulisine has not been studied However some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure see WARNINGS AND PRECAUTIONS Race Information on the effect of race on the pharmacokinetics of insulin glulisine is not available Renal Insufficiency Studies with human insulin have shown increased ci
57. ined in subjects with renal impairment Studies have not been performed in patients with hepatic impairment As with all insulins APIDRA requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism similar to observations found with other insulins see ACTION AND CLINICAL PHARMACOLOGY Special Populations and Conditions Careful glucose monitoring and dose adjustments of insulin or insulin analogues including APIDRA may be necessary in patients with hepatic or renal dysfunction Transferring Patients from Other Insulins Any change of insulin should be made cautiously and only under medical supervision Changes in insulin strength timing of administration manufacturer type e g regular NPH or insulin analogs species animal human or method of manufacture recombinant DNA versus animal source insulin may result in the need for a change in dosage Concomitant oral antidiabetic treatment may need to be adjusted Special Populations Pregnant Women There are no well controlled clinical studies of the use of APIDRA in pregnant women Animal reproduction studies have not revealed any differences between APIDRA and human insulin regarding pregnancy embryonal foetal development parturition or postnatal development see Part II TOXICOLOGY Reproduction toxicity It is essential for patients with pre existing or gestational diabetes to maintain good metabolic control before conception and du
58. into the vial Adjust APIDRA to the correct dose Remove the needle from the APIDRA vial 8 Gently rotate the NPH human insulin vial to mix the insulin 9 Put the needle with the APIDRA into the NPH human insulin vial and turn upside down as before 10 Pull back the plunger until you have the total number of units required APIDRA NPH human insulin units Do not go past the total dose 11 Make sure you do not push any APIDRA into the NPH human insulin vial If you pull up too much of the NPH human insulin into the syringe throw it out and start again Do not put the insulin back into the vial 12 Remove the needle from the vial Do not let the needle touch anything prior to injection 13 APIDRA should be injected immediately after mixing It is important to be consistent in your method Never use APIDRA if it has become cloudy Injection There is no relevant difference in absorption of APIDRA between abdominal thigh buttock or upper arm subcutaneous injection areas However injection sites within an injection area abdomen thigh buttock or upper arm must be rotated from one injection to the next Cleanse the skin with alcohol where the injection is to be made Pinch and hold the skin and insert the needle as instructed by your health professional Slowly push the plunger of the syringe in completely Slowly count to 10 before removing the needle from the injection site and gently apply pressure for several second
59. ion site reaction NOS peripheral oedema asthenia increased fat tissue injection site stinging Infections and infestations cellulitis Injury poisoning and procedural complications overdose NOS Metabolism and nutrition disorders hyperglycemia NOS Nervous system disorders paraesthesia Skin and subcutaneous tissue disorders acquired lipodystrophy Not otherwise specified Page 15 of 61 Post Market Adverse Drug Reactions Other Medication errors have been reported in which other insulins particularly long acting insulins have been accidentally administered instead of insulin glulisine DRUG INTERACTIONS Overview Drug Drug Interactions The following are examples of potential drug drug interactions that may occur with APIDRA treatment Table 5 Established or Potential Drug Drug Interactions Effect Clinicalcomment_ Oral antidiabetic agents Theoretical May enhance May require close monitoring of blood ACE inhibitors the blood glucose level and dose adjustment Disopyramide glucose reduction of APIDRA Fibrates lowering effect Fluoxetine and increase MAO inhibitors susceptibility to Pentoxifylline hypoglycemia Propoxyphene Salicylates Sulfonamide antibiotics Page 16 of 61 Corticosteroids Danazol Diazoxide Diuretics Glucagon Isoniazid Estrogens and progestogens e g in oral contraceptives Phenothiazine derivatives Somatropin Sympathomimetic agents e g epinephrine salb
60. iousness before a patient has symptoms Page 59 of 61 Some people may not recognize when their blood sugar drops low Without recognition of early warning symptoms you may not be able to take steps to avoid more serious hypoglycemia Be alert for all of the various types of symptoms that may indicate hypoglycemia Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose frequently especially prior to activities such as driving a car or use mechanical equipment If the blood glucose is below your normal fasting glucose you should consider eating or drinking sugar containing foods to treat your hypoglycemia If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the symptoms you should consult your health professional to discuss possible changes in therapy meal plans and or exercise programs to help you avoid hypoglycemia Hyperglycemia Hyperglycemia too much glucose in the blood may develop if your body has too little insulin Hyperglycemia can be brought about by e intercurrent conditions illness stress or emotional disturbances e not taking your insulin or taking less than recommended by your health professional e malfunction and or misuse of medical devices e eating significantly more than your meal plan suggests e anew insulin type or schedule e some new medications including prescriptions over the counter medications herb
61. lease contact your physician immediately if you develop symptoms of shortness of breath fatigue exercise intolerance or swelling of the lower extremities while you are on these agents Hypokalemia low potassium is a possible side effect You might be more at risk if you are on potassium lowering drugs or losing potassium e g diarrhea Always keep an extra supply of insulin as well as the appropriate injection supplies on hand Always wear medical alert identification and carry information about your diabetes so that appropriate treatment can be given if complications occur away from home Accidental mix ups between insulin glulisine and other insulins particularly long acting insulins have been reported To avoid medication errors between insulin glulisine and other insulins patients should be instructed to always check the insulin label before each injection Your needles and syringes are only for you and must not be shared to avoid disease transmission BEFORE you use APIDRA talk to your health professional if e you are planning to have a baby are pregnant or are nursing a baby e you drink alcohol e you are ill you exercise more than usual or if you want to change your usual diet you are traveling you drive or use tools or machine you have trouble with your kidneys or liver you are taking any other medication Your ability to concentrate or react may be reduced if you have hypoglycemia low blood
62. maceuticals Inc 2003 Apr Report No B2002CLN0288 Hanaire Broutin H 12 week multinational multicenter controlled open 1 1 randomized parallel clinical trial comparing the safety of HMR1964 and insulin aspart used in continuous subcutaneous insulin infusion CSII in subjects with type 1 diabetes mellitus HMR1964A 3006 Final report Service de Diab tologie H pital de Rangueil France 2003 Apr Report No B2002CLN0357 Page 40 of 61 PART III CONSUMER INFORMATION APIDRA VIALS insulin glulisine injection rDNA origin This leaflet is part III of a three part Product Monograph published when APIDRA was approved for sale in Canada and is designed specifically for Consumers This leaflet is a summary and will not tell you everything about APIDRA Contact your health professional if you have any questions about the drug ABOUT THIS MEDICATION What the medication is used for APIDRA insulin glulisine injection DNA origin is an antidiabetic agent short acting recombinant human insulin analogue used to reduce high blood sugar in adults and children 6 years or older with diabetes mellitus What it does Insulin is a hormone produced by the pancreas a large gland that lies near the stomach This hormone is necessary for the body s correct use of food especially sugar Diabetes occurs when the pancreas does not make enough insulin to meet your body s needs or when your body cannot use properly the
63. n about your diabetes so that appropriate treatment can be given if complications occur away from home Accidental mix ups between insulin glulisine and other insulins particularly long acting insulins have been reported To avoid medication errors between insulin glulisine and other insulins patients should be instructed to always check the insulin label before each injection Your needles and syringes are only for you and must not be shared to avoid disease transmission BEFORE you use APIDRA talk to your health professional if e you are planning to have a baby are pregnant or are nursing a baby e you drink alcohol e you are ill you exercise more than usual or if you want to change your usual diet you are traveling you drive or use tools or machine you have trouble with your kidneys or liver you are taking any other medication Your ability to concentrate or react may be reduced if you have hypoglycemia low blood sugar or hyperglycemia high blood sugar Please keep these possible problems in mind in all situations where you might put yourself or others at risk for example driving a car or operating machinery You should contact your doctor about the advisability of driving if you have e frequent episodes of hypoglycemia e reduced or absent warning signs of hypoglycemia Page 42 of 61 INTERACTIONS WITH THIS MEDICATION Other medicines including non prescription medicines and dietary sup
64. n with APIDRA n 3 29 10 3 and insulin aspart n 4 30 13 3 APIDRA has been studied in the following pumps and infusion sets Disetronic H Tron plus V100 and D Tron with Disetronic catheters Rapid Rapid C and DIM and Tender and with MiniMed Models 506 507 507c and 508 with MiniMed catheters Sof set Ultimate QR and Quick set TOXICOLOGY Single and Repeated Dose Toxicity Single and repeated dose toxicity studies were conducted in mice rats and dogs in order to predict the safety profile for the therapeutic use of insulin glulisine in humans all studies used normoglycemic animals After a single injection of insulin glulisine the approximate LDs9 was gt 1000 U kg in rats and mice and 40 U kg in dogs After repeated once daily subcutaneous injection of insulin glulisine the No Observable Adverse Effect Level NOAEL in rats were 50 U kg after 1 month and 5 U kg after 6 months The NOAEL in dogs were 1 U kg in both the 1 month and 6 month studies The toxicological profile of insulin glulisine was limited to the effects resulting from excessive hypoglycemia attributed to the exaggerated pharmacodynamic action of the compound after high doses in normoglycemic animals Repeated dose toxicity studies in rats and dogs did not reveal any unexpected findings different from human regular insulin Insulin glulisine related effects in toxicity studies were dose dependent reversible and restricted to toxic
65. ne changes discuss with your health professional the possible need to adjust your insulin regimen Exercise may lower your body s need for insulin during and for some time after the activity As for all insulins the rate of absorption and consequently the onset and duration of action may be affected by exercise and other variables Travel Consult your health professional concerning possible adjustments in your insulin schedule if you will be traveling across time zones You may want to take along extra insulin and supplies whenever you travel Missed dose If you have missed a dose of APIDRA or if you have not injected enough insulin your blood sugar level may become too high hyperglycemia Check Page 43 of 61 your blood sugar frequently For information on the treatment of hyperglycemia see Side Effects and What To Do About Them below Do not take a double dose to make up for a forgotten dose Overdose If you have injected too much APIDRA your blood sugar level may become too low hypoglycemia Check your blood sugar frequently In general to prevent hypoglycemia you must eat more food and monitor your blood sugar For information on the treatment of hypoglycemia see Side Effects and What To Do About Them below Hypoglycemia may occur as a result of an excess of insulin relative to food intake energy expenditure or both In severe cases coma seizure and brain disorders may be seen and treate
66. ness especially with nausea and vomiting diarrhea and or fever may change how much insulin you need Even if you are not eating you will still require insulin You and your health professional should establish a sick day plan for you to use in case of illness When you are sick test your blood urine frequently and call your health professional as instructed Pregnancy If you are planning to have a baby are pregnant or are nursing a baby consult your health professional Good control of diabetes is especially important for you and Page 51 of 61 your unborn baby Pregnancy may make managing your diabetes more difficult Medication Always discuss any medications you are taking prescription or over the counter with your health professional To prevent drug interactions volunteer the names of everything you are taking even before they ask if there have been any changes Insulin requirements may be increased in the presence of drugs with hyperglycemic activity such as contraceptives for example birth control pills injections and patches and hormone replacement therapies corticosteroids thyroid replacement therapy and sympathomimetic agents such as decongestants and diet pills Insulin requirements may be reduced in the presence of drugs with hypoglycemic activity such as oral antidiabetic agents salicylates for example aspirin sulfa antibiotics blood pressure medications including ACE inhibitors and certain
67. nformation when the use of these drugs in combination with any insulin including APIDRA is contemplated Page 5 of 61 To avoid transmission of disease cartridge or a prefilled syringe pen shall not be used by more than one person Accidental mix ups between insulin glulisine and other insulins particularly long acting insulins have been reported To avoid medication errors between insulin glulisine and other insulins patients should be instructed to always check the insulin label before each injection see ADVERSE REACTIONS Endocrine and Metabolism Hypoglycemia As with all insulin preparations hypoglycemic reactions may be associated with the administration of APIDRA Hypoglycemia is the most common adverse effect of insulin therapy including APIDRA see ADVERSE REACTIONS Hypoglycemia may occur if the insulin dose is too high in relation to the insulin requirement see OVERDOSAGE Use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia e g the pediatric population and patients who fast or have erratic food intake Early warning symptoms of hypoglycemia may be different be less pronounced or absent under certain conditions as for example if glycemic control is markedly improved if hypoglycemia is developing gradually in elderly patients in patients with a long history of diabetes in patients with diabetic nerve disease in patients using some medications such as be
68. ng less than recommended by your health professional e malfunction and or misuse of medical devices e eating significantly more than your meal plan suggests e anew insulin type or schedule e some new medications including prescriptions over the counter medications herbs vitamins and street drugs Symptoms of hyperglycemia include e confusion or drowsiness increased thirst decreased appetite nausea or vomiting rapid heart rate increased urination and dehydration too little fluid in your body blurred vision e flushed dry skin e acetone odour of breath Hyperglycemia can be mild or severe It can progress to high glucose levels diabetic ketoacidosis DKA and result in unconsciousness and death Diabetic ketoacidosis DKA The first symptoms of diabetic ketoacidosis usually come on over a period of hours or days With ketoacidosis urine tests show large amounts of glucose and acetone Symptoms of diabetic ketoacidosis include First symptoms e drowsiness flushed face thirst loss of appetite fruity smelling breath rapid deep breathing abdominal stomach area pain Severe symptoms e heavy breathing e rapid pulse Prolonged hyperglycemia or diabetic ketoacidosis can lead to e nausea e vomiting e dehydration e loss of consciousness e death Severe or continuing hyperglycemia or DKA requires prompt evaluation and treatment by your health professional Allergic rea
69. nsulin glulisine compared to a median Tmax of 82 minutes range 52 to 308 minutes and a Cmax of 46 uIU mL range 32 to 70uIU mL for regular human insulin The mean residence time of insulin glulisine was shorter median 98 minutes range 55 to 149 minutes than for regular human insulin median 161 minutes range 133 to 193 minutes see Figure 2 Page 24 of 61 Figure 2 Pharmacokinetic profile of insulin glulisine and regular human insulin in patients with Type 1 diabetes after a dose of 0 15 U kg 80 5 APIDRA REGULAR 60 5 40 20 5 INSULIN CONC pU mL TIME hour When APIDRA was injected subcutaneously into different areas of the body the time concentration profiles were similar with a slightly faster absorption when administered in the abdomen compared to the deltoid or thigh see DOSAGE AND ADMINISTRATION The absolute bioavailability of insulin glulisine after subcutaneous administration is about 70 regardless of injection area abdomen 73 deltoid 71 thigh 68 The Tmax for the abdomen was 44 min range 27 69 min 58 min for the deltoid range 30 85 min and 66 min for the thigh range 35 108 min Distribution and Elimination The distribution and elimination of insulin glulisine and regular human insulin after intravenous administration are similar with volumes of distribution of 13 L and 21 L and half lives of 13 and 17 minutes respectively After subcutaneous administration insul
70. od pressure rapid pulse or sweating Severe cases of generalized allergy including anaphylactic reactions may be life threatening Localized reactions and generalized myalgias have been reported with the use of m cresol as an injectable excipient Hypoglycemia Hypoglycemia a frequent adverse reaction to insulin therapy may occur if the insulin dose is too high in relation to the insulin requirement As with all insulins prolonged or severe hypoglycemic attacks especially if recurrent may lead to neurological damage loss of consciousness coma or death The risk of all categories of symptomatic hypoglycemia did not differ between APIDRA and short acting insulin comparators in subjects with type 1 or type 2 diabetes see WARNINGS AND PRECAUTIONS Table 1 Number of subjects with at least one episode of symptomatic hypoglycemia in studies in adults with Type 1 and Type 2 diabetes Type 1 diabetes Type 2 diabetes Glulisine Comparator Glulisine Comparator n N n N n N n N Subcutaneous 783 921 85 0 516 611 84 5 562 883 63 6 578 883 65 5 injection Continuous subcutaneous 26 29 89 7 24 30 80 0 5 3 infusion n number of subjects with at least 1 episode of hypoglycemia N total number of evaluable ITT subjects a insulin lispro regular human insulin regular human insulin insulin aspart Page 12 of 61 Table 2 Number percentage of pediatric subjects with Type 1 diabe
71. of 61 Drug Food Interactions Interactions with food have not been established Drug Herb Interactions Interactions with herbal products have not been established Drug Laboratory Interactions Interactions with laboratory tests have not been established DOSAGE AND ADMINISTRATION Dosing Considerations The dosage of APIDRA should be individualized and determined based on the physician s advice in accordance with the needs of the patient APIDRA insulin glulisine injection rDNA origin is a recombinant human insulin analogue that has been shown to be equipotent to human insulin One unit of APIDRA has the same glucose lowering effect as one unit of regular human insulin After subcutaneous administration it has a more rapid onset and a shorter duration of action see ACTION AND CLINICAL PHARMACOLOGY APIDRA should be given by injection within 15 minutes before or within 20 minutes after starting a meal APIDRA should normally be used in regimens that include a longer acting insulin or basal insulin analogue see ACTION AND CLINICAL PHARMACOLOGY APIDRA is intended for subcutaneous administration by injection and for use as a continuous subcutaneous insulin infusion CSII in pump systems suitable for insulin infusion APIDRA should be administered by subcutaneous injection in the abdominal wall the thigh the buttock or the deltoid or by continuous subcutaneous infusion CSII in the abdominal wall As with all insulins injecti
72. of shorter duration compared to regular human insulin This has been demonstrated in studies in healthy volunteers and patients with diabetes In a study in patients with Type 1 diabetes n 20 the glucose lowering profiles of APIDRA and regular human insulin were assessed at various times in relation to a standard meal at a dose of 0 15 U kg see Figure 1 Page 21 of 61 Figure 1 Glucose lowering effect over 6 hours APIDRA given 2 minutes glulisine pre before the start of a meal compared to regular human insulin given 30 minutes Regular 30 min before start of the meal Figure 1A and compared to regular human insulin Regular pre given 2 minutes before a meal Figure 1B APIDRA given 15 minutes glulisine post after start of a meal compared to regular human insulin Regular pre given 2 minutes before a meal Figure 1C On the x axis zero 0 is the start of a 15 minute meal Figure 1A APIDRA before BLOOD GLUCOSE mg dL REGULAR 30 min a 1 2 3 4 5 TIME hour Legend T Injection time Regular Human Insulin T Injection time Apidra wi AA a BLOOD GLUCOSE mg dL Figure 1B APIDRA before REGULAR before 2 3 4 5 TIME hour 6 BLOOD GLUCOSE mg dL Figure 1C APIDRA after REGULAR before TIME hour Page 22 of 61 Pharmacokinetics APIDRA exhibits dose proportionality in insulin exposure and less than dose proportional
73. on sites and infusion sites within an injection area abdomen thigh buttock or deltoid should be rotated from one injection to the next As for all insulins the rate of absorption and consequently the onset and duration of action may be affected by injection site exercise and other variables Blood glucose monitoring is recommended for all patients with diabetes Page 18 of 61 Administration Preparation and Handling APIDRA must only be used if the solution is clear colourless with no solid particles visible and if it is of a water like consistency To minimize local irritation at the injection site it is recommended to allow the insulin to reach room temperature before injection The instructions for using the APIDRA in a pump or with an injection pen must be followed carefully Patient must be instructed to not re use needles INJECTION PENS CARTRIDGES NEEDLES AND SYRINGES MUST NOT BE SHARED To prevent the possible transmission of disease never share an injection pen or cartridge between patients even if the needle on the injection pen is changed An empty vial cartridge or SoloSTAR must never be reused and must be properly discarded Vials Before withdrawing insulin from the vial for the first time remove the plastic protective cap Do not shake the vial vigorously as this may cause frothing Froth may interfere with the correct measurement of the dose Mixing of Insulins APIDRA can be mixed with NPH h
74. ou drive or use tools or machine you have trouble with your kidneys or liver you are taking any other medication Your ability to concentrate or react may be reduced if you have hypoglycemia low blood sugar or hyperglycemia high blood sugar Please keep these possible problems in mind in all situations where you might put yourself or others at risk for example driving a car or operating machinery You should contact your doctor about the advisability of driving if you have e frequent episodes of hypoglycemia e reduced or absent warning signs of hypoglycemia INTERACTIONS WITH THIS MEDICATION Other medicines including non prescription medicines and dietary supplements such as vitamins can change the way insulin works Your dose of insulin or other medications may need to be changed in consultation with your healthcare professional Please see Proper use of medication section below for potential medication interactions with insulin PROPER USE OF THIS MEDICATION Dosage The dosage of APIDRA should be individualized and determined based on your health professional s advice in accordance with your needs APIDRA should be given by subcutaneous injection within 15 minutes before a meal or within 20 minutes after starting a meal Many factors may affect your usual APIDRA dose which may include changes in your diet activity or work schedule Follow your health professional s instructions carefully Con
75. ow the injection pen directions for attaching and changing the needle 6 Check the cartridge inserted into the injection pen for air bubbles If bubbles are present remove them as instructed in the injection pen directions 7 Follow the injection pen directions for performing the Safety Test or Priming 8 Set the injection pen to the correct APIDRA dose as instructed in the injection pen directions 9 There is no relevant difference in absorption of APIDRA between abdominal thigh buttock or upper arm subcutaneous injection areas However injection sites within an injection area abdomen thigh buttock or upper arm must be rotated from one injection to the next 10 Cleanse the skin with alcohol where the injection is to be made 11 Pinch and hold the skin and insert the needle attached to the injection pen as instructed by your health professional 12 To inject APIDRA follow the directions for the injection pen 13 Slowly count to 10 before removing the needle from the injection site and gently apply pressure for several seconds DO NOT RUB THE AREA 14 Remove the needle from the injection pen immediately after each injection as instructed in the directions for the injection pen Dispose of the needle appropriately Do not reuse the needle 15 An empty cartridge must never be reused and must be properly discarded If the pen malfunctions APIDRA may be drawn from the cartridge into an insulin syringe and injecte
76. perglycemia or for example as a result of visual impairment This may constitute a risk in situations where these abilities are of special importance e g driving a car or operating machinery Patients should be advised to take precautions to avoid hypoglycemia whilst driving This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycemia or have frequent episodes of hypoglycemia It should be considered whether it is advisable to drive or operate machinery in these circumstances ADVERSE REACTIONS Adverse Drug Reaction Overview Overall clinical studies comparing APIDRA with short acting insulins did not demonstrate a difference in frequency of adverse events The adverse events observed were those known in this pharmacological class and consequently common to insulins Body as a whole Local Allergy As with other insulin therapy local allergy in patient may occur as redness itching swelling or hemorrhage These minor reactions usually resolve in a few days to a few weeks In some instances these reactions may be related to factors other than insulin such as irritants in a skin cleansing agent or poor injection technique Page 11 of 61 Systemic Allergy Less common but potentially more serious is generalized allergy to insulin including insulin glulisine which may cause rash including pruritus over the whole body shortness of breath wheezing reduction in blo
77. plements such as vitamins can change the way insulin works Your dose of insulin or other medications may need to be changed in consultation with your healthcare professional Please see Proper use of medication section below for potential medication interactions with insulin PROPER USE OF THIS MEDICATION Dosage The dosage of APIDRA should be individualized and determined based on your health professional s advice in accordance with your needs APIDRA should be given by subcutaneous injection within 15 minutes before a meal or within 20 minutes after starting a meal It can also be used in an external insulin pump for continuous subcutaneous insulin infusion CSI Many factors may affect your usual APIDRA dose which may include changes in your diet activity or work schedule Follow your health professional s instructions carefully Consult your health professional if you notice your insulin requirements changing markedly Other factors that may affect your dose of insulin or your need to do additional blood urine testing are Illness Illness especially with nausea and vomiting diarrhea and or fever may change how much insulin you need Even if you are not eating you will still require insulin You and your health professional should establish a sick day plan for you to use in case of illness When you are sick test your blood urine frequently and call your health professional as instructed Pregnancy I
78. rculating levels of insulin in patients with renal failure In a study performed in 24 non diabetic subjects covering a wide range of renal function CrCl gt 80mL min 30 50mL min lt 30mL min the pharmacokinetic properties of insulin glulisine were generally maintained see WARNINGS AND PRECAUTIONS Pregnancy The effect of pregnancy on the pharmacokinetics and pharmacodynamics of insulin glulisine has not been studied Lactation It is unknown whether APIDRA is excreted in human milk Obesity The more rapid onset of action and shorter duration of activity of insulin glulisine and insulin lispro compared to regular human insulin were maintained in an obese non diabetic population The rapid onset of action was better maintained with insulin glulisine than with insulin lispro see Figure 3 Figure 3 Glucose infusion rates GIR after subcutaneous injection of 0 3 U kg of APIDRA glulisine insulin lispro or regular human insulin in an obese population APIDRA 54 LISPRO REGULAR GIR mg kg min TIME hour Page 26 of 61 STORAGE AND STABILITY Vials Unopened Vial Unopened APIDRA vials should be stored in a refrigerator between 2 C 8 C Keep APIDRA away from direct heat and light APIDRA should not be stored in the freezer and should not be allowed to freeze If APIDRA freezes or overheats discard it Opened In Use Vial The opened vial can be kept refrigerated or unrefrigerated 15 25
79. re markedly improved in elderly patients in patients with diabetic nerve disease in patients with a long history of diabetes or in patients receiving concurrent treatment with certain other drugs Such situations may result in severe hypoglycemia and possibly loss of consciousness before a patient has symptoms Some people may not recognize when their blood sugar drops low Without recognition of early warning symptoms you may not be able to take steps to avoid more serious hypoglycemia Be alert for all of the various types of symptoms that may indicate hypoglycemia Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose frequently especially prior to activities such as driving a car or use mechanical equipment If the blood glucose is below your normal fasting glucose you should Page 46 of 61 consider eating or drinking sugar containing foods to treat your hypoglycemia If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the symptoms you should consult your health professional to discuss possible changes in therapy meal plans and or exercise programs to help you avoid hypoglycemia Hyperglycemia Hyperglycemia too much glucose in the blood may develop if your body has too little insulin Hyperglycemia can be brought about by e intercurrent conditions illness stress or emotional disturbances e not taking your insulin or taki
80. recombinant DNA technology utilizing a non pathogenic laboratory strain of Escherichia coli K12 Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid see PHARMACEUTICAL INFORMATION In some studies regular human insulin refers to short acting insulin marketed internationally Page 3 of 61 INDICATIONS AND CLINICAL USE APIDRA insulin glulisine injection rDNA origin is a recombinant human insulin analogue indicated for the treatment of adult patients with diabetes mellitus where treatment with insulin is required the treatment of pediatric patients with type 1 diabetes mellitus who require a short acting insulin There is insufficient clinical data on the use of APIDRA in children below the age of 6 years see WARNINGS AND PRECAUTIONS Special Populations Pediatrics APIDRA has a more rapid onset of action and a shorter duration of action than regular human insulin APIDRA should normally be used in regimens that include a longer acting insulin or basal insulin analogue to maintain adequate glucose control see DOSAGE AND ADMINISTRATION APIDRA can be used with oral hypoglycemic agents CONTRAINDICATIONS e Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container For a complete listing see DOSAGE FORMS COMPOSITION AND PACKAGING
81. ring pregnancy Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters Immediately after delivery insulin requirements decline rapidly Careful monitoring of glucose control is essential Patients with diabetes must inform their doctor if they are pregnant or are contemplating pregnancy Nursing Women It is unknown whether APIDRA is excreted in human milk Many drugs including human insulin are excreted in human milk There are no adequate and well controlled studies in nursing women For this reason caution should be exercised when APIDRA is administered to a nursing Page 9 of 61 woman Lactating women may require adjustments in insulin dose and diet see Part II TOXICOLOGY Reproduction toxicity Pediatrics The safety and effectiveness of APIDRA have been investigated in pediatric patients age 4 to 17 years with Type 1 diabetes 9 1 6 lt 6 years 32 5 6 between 6 and 8 years 149 26 between 8 and 12 years and 382 67 above 12 years old APIDRA has not been studied in pediatric patients younger than 4 years of age There is insufficient clinical data on the use of APIDRA in children below the age of 6 years As in adults the dosage of APIDRA must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose Geriatrics 65 years of age Hypoglycemia may be difficult to recognize in the elderly
82. s DO NOT RUB THE AREA Preparation and handling for continuous subcutaneous insulin infusion pump CSID The instructions for using the APIDRA in a pump must be followed carefully APIDRA may be used for CSII in pump systems suitable for insulin infusion When used with an insulin infusion pump APIDRA should not be mixed with any other insulin or diluted with any other solution Patients using CSII should be comprehensively instructed on the use of the system pump The Page 45 of 61 infusion set and reservoir must be changed at least every 48 hours using sterile technique It is important that patients follow these instructions even if they differ from the general pump manual instructions Patients administering APIDRA by CSII must have an alternative insulin delivery system available in case of pump system failure SIDE EFFECTS AND WHAT TO DO ABOUT THEM COMMON PROBLEMS OF DIABETES Hypoglycemia Insulin Reaction Hypoglycemia too little glucose in the blood is one of the most frequent adverse events experienced by insulin users It can be brought on by situations such as e intercurrent conditions illness stress or emotional disturbances e accidental injection of an increased insulin dose e malfunction and or misuse of medical devices too low food intake or skipped meals an increase in exercise a new insulin type or schedule some new medications including prescriptions over the counter medica
83. s vitamins and street drugs Symptoms of hyperglycemia include e confusion or drowsiness increased thirst decreased appetite nausea or vomiting rapid heart rate increased urination and dehydration too little fluid in your body blurred vision e flushed dry skin e acetone odour of breath Hyperglycemia can be mild or severe It can progress to high glucose levels diabetic ketoacidosis DKA and result in unconsciousness and death Diabetic ketoacidosis DKA The first symptoms of diabetic ketoacidosis usually come on over a period of hours or days With ketoacidosis urine tests show large amounts of glucose and acetone Symptoms of diabetic ketoacidosis include First symptoms e drowsiness flushed face thirst loss of appetite fruity smelling breath rapid deep breathing abdominal stomach area pain Severe symptoms e heavy breathing e rapid pulse Prolonged hyperglycemia or diabetic ketoacidosis can lead to e nausea e vomiting e dehydration e loss of consciousness e death Severe or continuing hyperglycemia or DKA requires prompt evaluation and treatment by your health professional Allergic reactions In rare cases a patient may be allergic to an insulin product Severe insulin allergies may be life threatening If you think you are having an allergic reaction seek medical help immediately Signs of insulin allergy include e arash all over your body shortness of breath
84. sionals can be found at www sanofi ca or by contacting the sponsor sanofi aventis Canada Inc at 1 888 852 6887 It is also available in large print format sanofi aventis Canada Inc Laval Quebec H7V 0A3 This leaflet was prepared by sanofi aventis Canada Inc Last revised October 19 2017 Page 61 of 61
85. skin with alcohol where the injection is to be made 13 Pinch and hold the skin and insert the needle attached to the SoloSTAR as instructed by your health professional 14 To inject APIDRA follow the directions for the SoloSTAR 15 Slowly count to 10 before removing the needle from the injection site and gently apply pressure for several seconds DO NOT RUB THE AREA 16 Remove the needle from the SoloSTAR immediately after each injection as instructed in the directions for the SoloSTAR Dispose of the needle appropriately Do not reuse the needle SIDE EFFECTS AND WHAT TO DO ABOUT THEM COMMON PROBLEMS OF DIABETES Hypoglycemia Insulin Reaction Hypoglycemia too little glucose in the blood is one of the most frequent adverse events experienced by insulin users It can be brought on by situations such as e intercurrent conditions illness stress or emotional disturbances e accidental injection of an increased insulin dose e malfunction and or misuse of medical devices e too low food intake or skipped meals e an increase in exercise e anew insulin type or schedule e some new medications including prescriptions over the counter medications herbs vitamins and street drugs Symptoms of mild to moderate hypoglycemia may occur suddenly and can include e abnormal behavior anxiety irritability restlessness trouble concentrating personality changes mood changes confusion or nervousness fatigue
86. sugar or hyperglycemia high blood sugar Please keep these possible problems in mind in all situations where you might put yourself or others at risk for example driving a car or operating machinery You should contact your doctor about the advisability of driving if you have e frequent episodes of hypoglycemia e reduced or absent warning signs of hypoglycemia INTERACTIONS WITH THIS MEDICATION Other medicines including non prescription medicines and dietary supplements such as vitamins can change the way insulin works Your dose of insulin or other medications may need to be changed in consultation with your healthcare professional Please see Proper use of medication section below for potential medication interactions with insulin PROPER USE OF THIS MEDICATION Dosage The dosage of APIDRA should be individualized and determined based on your health professional s advice in accordance with your needs APIDRA should be given by subcutaneous injection within 15 minutes before a meal or within 20 minutes after starting a meal Many factors may affect your usual APIDRA dose which may include changes in your diet activity or work schedule Follow your health professional s instructions carefully Consult your health professional if you notice your insulin requirements changing markedly Other factors that may affect your dose of insulin or your need to do additional blood urine testing are Illness Ill
87. sult your health professional if you notice your insulin requirements changing markedly Other factors that may affect your dose of insulin or your need to do additional blood urine testing are Illness Illness especially with nausea and vomiting diarrhea and or fever may change how much insulin you need Even if you are not eating you will still require insulin You and your health professional should establish a sick day plan for you to use in case of illness When you are sick test your blood urine frequently and call your health professional as instructed Page 57 of 61 Pregnancy If you are planning to have a baby are pregnant or are nursing a baby consult your health professional Good control of diabetes is especially important for you and your unborn baby Pregnancy may make managing your diabetes more difficult Medication Always discuss any medications you are taking prescription or over the counter with your health professional To prevent drug interactions volunteer the names of everything you are taking even before they ask if there have been any changes Insulin requirements may be increased in the presence of drugs with hyperglycemic activity such as contraceptives for example birth control pills injections and patches and hormone replacement therapies corticosteroids thyroid replacement therapy and sympathomimetic agents such as decongestants and diet pills Insulin requirements may be reduc
88. summary and will not tell you everything about APIDRA Contact your health professional if you have any questions about the drug ABOUT THIS MEDICATION What the medication is used for APIDRA insulin glulisine injection DNA origin is an antidiabetic agent short acting recombinant human insulin analogue used to reduce high blood sugar in adults and children 6 years or older with diabetes mellitus What it does Insulin is a hormone produced by the pancreas a large gland that lies near the stomach This hormone is necessary for the body s correct use of food especially sugar Diabetes occurs when the pancreas does not make enough insulin to meet your body s needs or when your body cannot use properly the insulin you normally produce When your body does not make enough insulin you need an external source of insulin That is why you must take insulin injections APIDRA is similar to the insulin made by your body APIDRA has a rapid onset of action and a short duration of about 4 hours APIDRA should normally be used with a longer acting insulin to maintain adequate blood sugar APIDRA can also be used with oral drugs to reduce blood sugar You have been instructed to test your blood and or your urine regularly for glucose sugar it is especially important to test even more often when changing insulins or dosing schedule If your blood tests consistently show above or below normal glucose levels or your urine tests
89. t take a double dose to make up for a forgotten dose Overdose If you have injected too much APIDRA your blood sugar level may become too low hypoglycemia Check your blood sugar frequently In general to prevent hypoglycemia you must eat more food and monitor your blood sugar For information on the treatment of hypoglycemia see Side Effects and What To Do About Them below Hypoglycemia may occur as a result of an excess of insulin relative to food intake energy expenditure or both In severe cases coma seizure and brain disorders may be seen and treated with glucagon injected in the muscle or subcutaneous tissue or glucose injected in the vein You should continue checking your blood sugar even if you feel better because hypoglycemia may recur In case of drug overdose contact a health professional hospital emergency department or regional Poison Control Centre immediately even if there are no symptoms INSTRUCTIONS FOR USE Your doctor has recommended the type of insulin that he she believes is best for you DO NOT USE ANY OTHER INSULIN EXCEPT ON THE ADVICE AND DIRECTION OF YOUR DOCTOR CAREFULLY FOLLOW THE PACKAGE DIRECTIONS SUPPLIED WITH THE SOLOSTAR TO e HELP AVOID CONTAMINATION AND POSSIBLE INFECTION e OBTAIN AN ACCURATE DOSE Do not reuse needles INJECTION PENS CARTRIDGES NEEDLES AND SYRINGES MUST NOT BE SHARED To prevent the possible transmission of disease this injection
90. ta blockers or intensified diabetes control see DRUG INTERACTIONS Such situations may result in severe hypoglycemia and possibly loss of consciousness prior to patients awareness of hypoglycemia Severe hypoglycemia may require the assistance of another person Patients who are unable to take sugar orally or who are unconscious may require an intramuscular subcutaneous injection of glucagon or should be treated with intravenous administration of glucose by medical personnel Without immediate medical help serious reactions or even death could occur The time of occurrence of hypoglycemia depends on the action profile of the insulins used and may therefore change when treatment regimen is changed As with all insulins prolonged or severe hypoglycemic attacks especially if recurrent may lead to neurological damage loss of consciousness coma or death see ADVERSE REACTIONS Hypoglycemic reactions following treatment with insulin products such as APIDRA are mostly mild and easily managed Changes in insulin therapy or changes in life style i e diet omission of a meal exercise physical activity may require a change in dosage to avoid hypoglycemia Glucose monitoring is recommended for all patients with diabetes Page 6 of 61 Diabetic patients should be instructed to carry a few lumps of sugar candies or biscuits to prevent the progression of a hypoglycemic reaction should one occur see PART III CONSUMER INFORMATION
91. tes with all symptomatic hypoglycemia Glulisine Lispro Number Number n N of n N of episodes episodes Screening 198 277 71 5 1269 213 295 72 2 1144 run in phase Month 1 195 277 70 4 1212 184 295 62 4 973 Month 2 125 274 45 6 781 125 295 42 4 756 Month 3 158 270 58 5 864 168 292 57 5 870 MOD 199 268 74 3 2686 199 291 68 4 2747 treatment end Entire treatment 230 277 83 0 5543 238 295 80 7 5346 phase n number of subjects reporting at least one episode of symptomatic hypoglycemia N number of randomized and treated subjects evaluable In pediatric subjects with type 1 diabetes the overall incidence of symptomatic hypoglycaemia was comparable between the treatment groups 83 for insulin glulisine vs 81 for insulin lispro However there was a significant difference between treatment groups during the first month of treatment in the frequency 70 4 in the insulin glulisine group 62 4 in the insulin lispro group p 0 0330 and in the monthly rate 4 77 vs 3 59 respectively p 0 0094 of symptomatic hypoglycemia For nocturnal symptomatic hypoglycemia a difference was noted between the two treatment groups in the frequency and monthly rate per subject with a higher frequency 39 7 vs 30 5 and more events 0 25 vs 0 19 reported in the insulin glulisine group The difference was especially notable in the first month of treatment frequency 19 9 vs 1
92. tions herbs vitamins and street drugs Symptoms of mild to moderate hypoglycemia may occur suddenly and can include e abnormal behavior anxiety irritability restlessness trouble concentrating personality changes mood changes confusion or nervousness fatigue tingling in your hands feet lips or tongue tremor shaking unsteady gait walking dizziness light headedness or drowsiness headache blurred vision slurred speech palpitations rapid heartbeat cold sweat pale skin nightmares or trouble sleeping nausea hunger Mild to moderate hypoglycemia can be treated by consuming foods or drinks that contain sugar Patients should always carry a quick source of sugar such as candy juice or glucose tablets prominently labelled for rescuers Contact your health professional about appropriate proportions of carbohydrates Signs of severe hypoglycemia can include e disorientation e convulsions e loss of consciousness e seizures Severe hypoglycemia may require the assistance of another person Patients who are unable to take sugar orally or who are unconscious may require an injection of glucagon or should be treated with intravenous administration of glucose by medical personnel Without immediate medical help serious reactions or even death could occur The early warning symptoms of hypoglycemia may be changed be less pronounced or be absent as for example in patients whose sugar levels a
93. tive insulin delivery system available in case of pump system failure see WARNINGS AND PRECAUTIONS Insulin pumps OVERDOSAGE Hypoglycemia may occur as a result of an excess of insulin relative to food intake energy exposure or both Mild moderate episodes of hypoglycemia can usually be treated with oral carbohydrates Adjustments in dosage of the medicinal product meal patterns or physical activity may be needed Severe episodes with coma seizure or neurologic impairment may be treated with intramuscular subcutaneous glucagon or concentrated intravenous glucose Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery For management of a suspected drug overdose contact your regional Poison Control Centre Page 20 of 61 ACTION AND CLINICAL PHARMACOLOGY Pharmacodynamics The primary activity of insulins and insulin analogues including insulin glulisine is regulation of glucose metabolism Insulins lower blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle and fat and by inhibiting hepatic glucose production Insulins inhibit lipolysis in the adipocyte inhibit proteolysis and enhance protein synthesis The glucose lowering activities of APIDRA and of regular human insulin are equipotent when administered by the intravenous route After subcutaneous administration the effect of APIDRA is more rapid in onset and
94. ts per group Insulin glulisine Human regular insulin Controls 2x2 5 2x 5 0 2x20 2x50 2x 5 0 2x20 2x50 U k U k U k U k IU k IU k IU k Total Tumor 0 6 3 6 3 3 6 4 Bearers Benign and Malignant Significant increase in the one sided Fisher Exact Test p lt 0 05 No dose dependency for insulin glulisine treated groups in regard of tumor incidence indicated by Peto Trend Test p lt 0 01 Mutagenesis Insulin glulisine was not mutagenic in the following tests Ames test in vitro mammalian chromosome aberration test in V79 cells and in vivo mammalian chromosome aberration test erythrocyte micronucleus test Impairment of Fertility In fertility studies in male and female rats at subcutaneous doses up to 10 U kg once daily dose resulting in an exposure equivalent to approximately 50 times the human Cmax at the average human dose no adverse effects on male and female fertility or general reproductive performance of animals were observed Page 35 of 61 Reproduction toxicity Table 13 Reproductive amp Developmental Toxicity Fertility amp Early Embryonic Development to Implantation Species Strain Sprague Subcutaneous Dawley rats Dosage Duration No of Animals Group Dose levels of 0 1 23 male and 3 15 or 10 U kg females body weight of insulin glulisine or HR1799 at the dose levels of 1 or 10 U kg body weight Once daily as a solution in placebo prior
95. uman insulin except when administered with pump see DOSAGE AND ADMINISTRATION Continuous Subcutaneous Insulin Infusion pump If APIDRA is mixed with NPH human insulin APIDRA should be drawn into the syringe first Injection should be made immediately after mixing No data are available on mixing APIDRA with insulin preparations other than NPH human insulin Mixtures should not be administered intravenously Cartridges or SoloSTAR APIDRA cartridges or APIDRA SoloSTAR are not designed to allow any other insulin to be mixed in the cartridge If the injection pen malfunctions the solution may be drawn from the cartridge into a syringe suitable for an insulin with U 100 and injected Page 19 of 61 Continuous Subcutaneous Insulin Infusion pump APIDRA may be used for Continuous Subcutaneous Insulin Infusion CSI in pump systems suitable for insulin infusion Patients using CSII must be comprehensively instructed on the use of the system pump The infusion set and reservoir used with APIDRA must be changed at least every 48 hours using aseptic technique It is important that patients follow these instructions even if they differ from the general pump manual instructions Failure to follow these instructions may lead to serious adverse events When used with an insulin infusion pump APIDRA should not be mixed with any other insulin or diluted with any other solution Patients administering APIDRA by CSII must have an alterna
96. utamol terbutaline Protease inhibitors Atypical antipsychotic medications e g olanzapine and clozapine Somatostatin analogs Thyroid hormones Theoretical Theoretical Alcohol Beta blockers Clonidine Lithium salts Theoretical Theoretical Pentamidine Theoretical Sympatholytic medicinal products such as beta blockers clonidine guanethidine and reserpine Other Effect Clinical comment May reduce the blood glucose lowering effect May enhance or decrease the insulin requirements May either potentiate or weaken the blood glucose lowering effect of insulin May cause hypoglycemia which may sometimes be followed by hyperglycemia The signs of hypoglycemia may be reduced or absent May require close monitoring of blood glucose level and dose adjustment increase or decrease of APIDRA May require close monitoring of blood glucose level and dose adjustment increase or decrease of APIDRA May require close monitoring of blood glucose level and dose adjustment increase or decrease of APIDRA May require close monitoring of blood glucose level and dose adjustment increase or decrease of APIDRA May require close monitoring of blood glucose level and dosage adjustment increase or decrease of APIDRA To avoid the risk of developing new or worsening heart failure the use of TZDs in combination therapy with insulin is not indicated see WARNINGS AND PRECAUTIONS Page 17
97. y the dose of 10 U insulin glulisine kg body weight per day is considered to be a suitable high dose for the main study Sprague Subcutaneous Dose levels of 0 1 Groups of 20 25 Administration of both insulin glulisine and Dawley 3 15 or 10 U kg mated female HR1799 caused clinical signs and mortality rats body weight of at the daily dose of 10 U kg body weight insulin glulisine or Slightly increased incidences of minor rib HR1799 at the dose anomalies were seen at this maternally levels of 1 or 10 U toxic dose level in the fetuses from the kg body weight HR1799 group once daily as a Neither maternal nor embryo fetal toxicity solution in placebo were observed after administration of from day 6 17 of insulin glulisine at the daily dose of 3 15 pregnancy U kg body weight and after administration of HR1799 at the daily dose of 1 U kg body weight Sprague Subcutaneous Insulin glulisine once Groups of 10 Treatment related mortality due to Dawley daily as a solution in mated females hypoglycemia was seen in the 10 0 U Kg rats placebo solution at the dose levels of 1 0 3 15 or 10 0 U kg body weight from day 6 12 of pregnancy group No abnormalities were observed by caesarean section Rats displayed a systemic exposure to substantial concentrations of insulin glulisine over 1h and an overproportional increase of Cmax with escalating dose Highest plasma concentration of insulin glulisine were detected 15 minutes after
98. ys discard it Opened APIDRA SoloSTAR should not be stored in the freezer and should not be allowed to freeze If APIDRA SoloSTAR freezes discard it Do not use an APIDRA SoloSTAR after the expiration date stamped on the label or if it is cloudy or if you see particles As with all medications and devices keep out of reach of children REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways e Report online at www healthcanada gc ca medeffect e Call toll free at 1 866 234 2345 e Complete a Canada Vigilance Reporting Form and Fax toll free to 1 866 678 6789 or Mail to Canada Vigilance Program Health Canada Postal Locator 1908C Ottawa ON K1A 0K9 Postage paid labels Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect Canada Web site at www healthcanada gc ca medeffect NOTE Should you require information related to the management of side effects contact your health professional The Canada Vigilance Program does not provide medical advice MORE INFORMATION Your physician pharmacist and nurse are always your best source of information about your condition and treatment If you have additional questions or concerns be sure to ask them This document plus the full product monograph prepared for health profes
99. zolidinediones such as rosiglitazone and pioglitazone alone or in combination with other antidiabetic agents including insulin has been associated with heart failure and swelling of the lower extremities Please contact your physician immediately if you develop symptoms of shortness of breath fatigue exercise intolerance or swelling of the lower extremities while you are on these agents Hypokalemia low potassium is a possible side effect You might be more at risk if you are on potassium lowering drugs or losing potassium e g diarrhea Always keep an extra supply of insulin as well as the appropriate injection supplies on hand Always wear medical alert identification and carry information about your diabetes so that appropriate treatment can be given if complications occur away from home Accidental mix ups between insulin glulisine and other insulins particularly long acting insulins have been reported To avoid medication errors between insulin glulisine and other insulins patients should be instructed to always check the insulin label before each injection Your needles and syringes are only for you and must not be shared to avoid disease transmission BEFORE you use APIDRA talk to your health professional if e you are planning to have a baby are pregnant or are nursing a baby e you drink alcohol e youareill you exercise more than usual or if you want to change your usual diet you are traveling y

Apidra (insulin glulisine)

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