Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 KwikPen (Page 3 of 5)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The limited available data with Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).

Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of 1 unit/kg/day (see Data).

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data

Human Data

Published data from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups.

Animal Data

Animal reproduction studies have not been performed with Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro (a component of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25). In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter.

In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days 7 through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.

8.2 Lactation

Risk Summary

There are no data on the presence of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin was present in human milk. However, there is insufficient information to determine the effects of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 on the breastfed infant and no available information on the effects of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for insulin, any potential adverse effects on the breastfed child from Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 in patients less than 18 years of age has not been established.

8.5 Geriatric Use

Clinical studies of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)].

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 has not been studied. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 dose adjustment and more frequent glucose monitoring [see Warnings and Precautions (5.3)].

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 has not been studied. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 dose adjustment and more frequent glucose monitoring [see Warnings and Precautions (5.3)].

10 OVERDOSAGE

Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular or subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately [see Warnings and Precautions (5.3, 5.6)].

11 DESCRIPTION

Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 is a mixture of 75% insulin lispro protamine, an intermediate-acting human insulin analog, and 25% insulin lispro, a rapid-acting human insulin analog. Insulin lispro is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. Insulin lispro differs from human insulin in that the amino acid proline at position B28 is replaced by lysine and the lysine in position B29 is replaced by proline. Chemically, it is Lys(B28), Pro(B29) human insulin analog and has the empirical formula C257 H383 N65 O77 S6 and a molecular weight of 5808, both identical to that of human insulin. Insulin lispro protamine suspension is a suspension of crystals produced from combining insulin lispro and protamine sulfate under appropriate conditions for crystal formation.

Insulin lispro has the following primary structure:

Primary Structure
(click image for full-size original)

Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 KwikPens contain a white and cloudy, sterile suspension of insulin lispro protamine suspension mixed with soluble insulin lispro for use as an injection.

Each milliliter of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 injection contains insulin lispro 100 units, 0.28 mg protamine sulfate, 16 mg glycerin, 3.78 mg dibasic sodium phosphate, 1.76 mg Metacresol, zinc oxide content adjusted to provide 0.025 mg zinc ion, 0.715 mg phenol, and Water for Injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.

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