Apidra (insulin glulisine) - Sanofi Canada

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Species/ Strain Himalayan rabbits Himalayan rabbits Himalayan rabbits Route Dosage/Duration Subcutaneous Insulin glulisine once daily as a solution in placebo solution at the dose levels of 0, 2, 10 or 50 U/kg body weight from day 6 - 18 of pregnancy Subcutaneous 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 Subcutaneous Insulin glulisine once daily as a solution in placebo solution at the dose levels of 0.25, 0.5 or 1.5 U/kg body weight from day 6 - 12 of pregnancy HR1799 = Reference compound (human insulin) No. of Animals/ Group Groups of 6 mated female Groups of 20-26 mated female Groups of 10 mated females 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 results 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 compoundrelated 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 h Cmax: 7.8ng/ml At 0.5 U/kg tmax : 0.25 h Cmax: 15.3ng/ml At 1.5 U/kg tmax : 0.50 h Cmax: 80.2ng/ml Page 36 of 61
Table 15: Reproductive & Developmental Toxicity: Effects on Pre- & Post-Natal Development Including Maternal Function Species/ Strain Sprague Dawley rats Route Dosage/Duration No. of Animals/ Group Subcutaneous Dose levels 0, 1, 3.15 or 8 U/kg body weight of insulin glulisine or HR1799 at the dose levels of 1 or 8 U/kg body weight, once daily as a solution in placebo from day 6 of gestation until day 21 post partum. HR1799 = Reference compound (human insulin) Groups of 23 mated females Findings • Administration of both insulin glulisine and HR1799 caused clinical signs and mortality in the F0-animals at the daily dose of 8 U/kg body weight when administered during embryo- and fetogenesis and during lactation in Sprague-Dawley rats. There were no specific effects on birth parameters or lactation of the F0-animals and on postnatal development, fertility or pregnancy of the F1-animals. • 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 37 of 61
Page 1 and 2: PRODUCT MONOGRAPH APIDRA ® insulin
Page 3 and 4: PRODUCT MONOGRAPH APIDRA ® insulin
Page 5 and 6: PHARMACOLOGY). APIDRA given by subc
Page 7 and 8: Hyperglycemia: The use of too low i
Page 9 and 10: and reduced insulin metabolism, sim
Page 11 and 12: Occupational Hazards The patient’
Page 13 and 14: Table 2 - Number (percentage) of pe
Page 15 and 16: Table 4 - Common (≥1%) Adverse Dr
Page 17 and 18: Table 5- Established or Potential D
Page 19 and 20: APIDRA should be administered by su
Page 21 and 22: ACTION AND CLINICAL PHARMACOLOGY Ph
Page 23 and 24: Table 7. Pharmacokinetic and Pharma
Page 25 and 26: gender did not show differences in
Page 27 and 28: Opened APIDRA SoloSTAR should not b
Page 29 and 30: glargine followed by randomization.
Page 31 and 32: treatment regimens. No differences
Page 33 and 34: TOXICOLOGY Single and Repeated Dose
Page 35: Table 14: Reproductive & Developmen
Page 39 and 40: PART III: CONSUMER INFORMATION APID
Page 41 and 42: INTERACTIONS WITH THIS MEDICATION O
Page 43 and 44: 12. Make sure the tip of the needle
Page 45 and 46: Hyperglycemia Hyperglycemia (too mu
Page 47 and 48: MORE INFORMATION Your physician, ph
Page 49 and 50: APIDRA should be given within 15 mi
Page 51 and 52: Do not take a double dose to make u
Page 53 and 54: history of diabetes, or in patients
Page 55 and 56: MORE INFORMATION Your physician, ph
Page 57 and 58: efore or within 20 minutes after st
Page 59 and 60: Preparing the Dose 1. To avoid medi
Page 61: • redness, itching, swelling, or

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