Humalog is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.
Humalog Dosage and Administration
Dosage Considerations
When given subcutaneously, Humalog has a more rapid onset of action and a shorter duration of action than regular human insulin.
The dosage of Humalog must be individualized. Blood glucose monitoring is essential in all patients receiving insulin therapy.
The total daily insulin requirement may vary and is usually between 0.5 to 1 unit/kg/day. Insulin requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or coadministered drugs.
Subcutaneous Administration
Humalog should be given within 15 minutes before a meal or immediately after a meal.
Humalog given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin.
Humalog administered by subcutaneous injection should be given in the abdominal wall, thigh, upper arm, or buttocks. Injection sites should be rotated within the same region (abdomen, thigh, upper arm, or buttocks) from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].
Continuous Subcutaneous Infusion (Insulin Pump)
Humalog may be administered by continuous subcutaneous infusion by an external insulin pump. Do not use diluted or mixed insulins in external insulin pumps. Infusion sites should be rotated within the same region to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)]. Change the Humalog in the reservoir at least every 7 days, change the infusion sets and the infusion set insertion site at least every 3 days.
The initial programming of the external insulin infusion pump should be based on the total daily insulin dose of the previous regimen. Although there is significant variability among patients, approximately 50% of the total dose is usually given as meal-related boluses of Humalog and the remainder is given as a basal infusion. Humalog is recommended for use in pump systems suitable for insulin infusion such as MiniMed, Disetronic, and other equivalent pumps [see For Patients Using Continuous Subcutaneous Insulin Pumps (17.2)].
Dosage Forms and Strengths
Humalog 100 units per mL (U-100) is available as:
- 10 mL vials
- 3 mL vials
- 3 mL prefilled pens
- 3 mL Humalog KwikPen (prefilled)
- 3 mL cartridges
Contraindications
Humalog is contraindicated:
- during episodes of hypoglycemia
- in patients who are hypersensitive to Humalog or to any of its excipients.
Warnings and Precautions
Dose Adjustment and Monitoring
Glucose monitoring is essential for patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in insulin dose. Concomitant oral antidiabetic treatment may need to be adjusted.
As with all insulin preparations, the time course of action for Humalog may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the site of injection, local blood supply, or local temperature. Patients who change their level of physical activity or meal plan may require adjustment of insulin dosages.
Hypoglycemia
Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. The risk of hypoglycemia increases with tighter glycemic control. Patients must be educated to recognize and manage hypoglycemia. Hypoglycemia can happen suddenly and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening or cause death.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions (7)].
As with all insulins, 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). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.
Rapid changes in serum glucose levels may induce symptoms similar to hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers [see Drug Interactions (7)], or intensified diabetes control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient's awareness of hypoglycemia.
Hypersensitivity and Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Humalog [see Adverse Reactions (6.1)].
Hypokalemia
All insulin products, including Humalog, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).
Renal or Hepatic Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment [see Clinical Pharmacology (12.3)].
Mixing of Insulins
Humalog for subcutaneous injection should not be mixed with insulin preparations other than NPH insulin. If Humalog is mixed with NPH insulin, Humalog should be drawn into the syringe first. Injection should occur immediately after mixing.
Do not mix Humalog with other insulins for use in an external subcutaneous infusion pump.
Subcutaneous Insulin Infusion Pumps
When used in an external insulin pump for subcutaneous infusion, Humalog should not be diluted or mixed with any other insulin. Change the Humalog in the reservoir at least every 7 days, change the infusion sets and the infusion set insertion site at least every 3 days. Humalog should not be exposed to temperatures greater than 98.6°F (37°C).
Malfunction of the insulin pump or infusion set or insulin degradation can rapidly lead to hyperglycemia and ketosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with Humalog may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure [see Dosage and Administration (2.3), How Supplied/Storage and Handling (16), and Patient Counseling Information (17.2)].
Drug Interactions
Some medications may alter insulin requirements and the risk for hypoglycemia or hyperglycemia [see Drug Interactions (7)].
Adverse Reactions
The following adverse reactions are discussed elsewhere:
- Hypoglycemia [see Warnings and Precautions (5.2)].
- Hypokalemia [see Warnings and Precautions (5.4)].
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared with those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The frequencies of Treatment-Emergent Adverse Events during Humalog clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
| Events, n (%) | Lispro (n=81) | Regular human insulin (n=86) | Total (n=167) |
|---|---|---|---|
| Flu syndrome | 28 (34.6) | 28 (32.6) | 56 (33.5) |
| Pharyngitis | 27 (33.3) | 29 (33.7) | 56 (33.5) |
| Rhinitis | 20 (24.7) | 25 (29.1) | 45 (26.9) |
| Headache | 24 (29.6) | 19 (22.1) | 43 (25.7) |
| Pain | 16 (19.8) | 14 (16.3) | 30 (18.0) |
| Cough increased | 14 (17.3) | 15 (17.4) | 29 (17.4) |
| Infection | 11 (13.6) | 18 (20.9) | 29 (17.4) |
| Nausea | 5 (6.2) | 13 (15.1) | 18 (10.8) |
| Accidental injury | 7 (8.6) | 10 (11.6) | 17 (10.2) |
| Surgical procedure | 5 (6.2) | 12 (14.0) | 17 (10.2) |
| Fever | 5 (6.2) | 10 (11.6) | 15 (9.0) |
| Abdominal pain | 6 (7.4) | 7 (8.1) | 13 (7.8) |
| Asthenia | 6 (7.4) | 7 (8.1) | 13 (7.8) |
| Bronchitis | 6 (7.4) | 6 (7.0) | 12 (7.2) |
| Diarrhea | 7 (8.6) | 5 (5.8) | 12 (7.2) |
| Dysmenorrhea | 5 (6.2) | 6 (7.0) | 11 (6.6) |
| Myalgia | 6 (7.4) | 5 (5.8) | 11 (6.6) |
| Urinary tract infection | 5 (6.2) | 4 (4.7) | 9 (5.4) |
| Events, n (%) | Lispro (n=714) | Regular human insulin (n=709) | Total (n=1423) |
|---|---|---|---|
| Headache | 63 (11.6) | 66 (9.3) | 149 (10.5) |
| Pain | 77 (10.8) | 71 (10.0) | 148 (10.4) |
| Infection | 72 (10.1) | 54 (7.6) | 126 (8.9) |
| Pharyngitis | 47 (6.6) | 58 (8.2) | 105 (7.4) |
| Rhinitis | 58 (8.1) | 47 (6.6) | 105 (7.4) |
| Flu syndrome | 44 (6.2) | 58 (8.2) | 102 (7.2) |
| Surgical procedure | 53 (7.4) | 48 (6.8) | 101 (7.1) |
Insulin initiation and intensification of glucose control
Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.
Lipodystrophy
Long-term use of insulin, including Humalog, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.2, 2.3)].
Weight gain
Weight gain can occur with insulin therapy, including Humalog, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.
Peripheral Edema
Insulin, including Humalog, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)
In a 12-week, randomized, crossover study in adult patients with type 1 diabetes (n=39), the rates of catheter occlusions and infusion site reactions were similar for Humalog and regular human insulin treated patients (see Table 3).
| Humalog (n=38) | Regular human insulin (n=39) | |
| Catheter occlusions/month | 0.09 | 0.10 |
| Infusion site reactions | 2.6% (1/38) | 2.6% (1/39) |
In a randomized, 16-week, open-label, parallel design study of children and adolescents with type 1 diabetes, adverse event reports related to infusion-site reactions were similar for insulin lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site adverse events were infusion site erythema and infusion site reaction.
Allergic Reactions
Local Allergy — As with any insulin therapy, patients taking Humalog may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of Humalog. 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.
Systemic Allergy — Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including Humalog. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving Humalog (n=2944).
Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in Humalog [see Contraindications (4)].
Antibody Production
In large clinical trials with patients with type 1 (n=509) and type 2 (n=262) diabetes mellitus, anti-insulin antibody (insulin lispro-specific antibodies, insulin-specific antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both regular human insulin and Humalog (including patients previously treated with human insulin and naive patients). As expected, the largest increase in the antibody levels occurred in patients new to insulin therapy. The antibody levels peaked by 12 months and declined over the remaining years of the study These antibodies do not appear to cause deterioration in glycemic control or necessitate an increase in insulin dose. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding for any of the antibody types.
Postmarketing Experience
The following additional adverse reactions have been identified during post-approval use of Humalog. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Medication errors in which other insulins have been accidentally substituted for Humalog have been identified during postapproval use [see Patient Counseling Information (17)].
Drug Interactions
A number of drugs affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.
Following are some of the examples:
- Drugs That May Increase the Blood-Glucose-Lowering Effect of Humalog and Susceptibility to Hypoglycemia: Oral antidiabetic agents, salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, pramlintide, disopyramide, fibrates, propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g., octreotide).
- Drugs That May Reduce the Blood-Glucose-Lowering Effect of Humalog: corticosteroids, isoniazid, niacin, estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid hormones.
- Drugs That May Increase or Reduce the Blood-Glucose-Lowering Effect of Humalog: beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
- Drugs That May Reduce the Signs of Hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. In patients with diabetes or gestational diabetes insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. Therefore, female patients should be advised to tell their physicians if they intend to become, or if they become pregnant while taking Humalog.
Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome.
In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/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 0.24 times the human subcutaneous dose of 1 unit/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.
Nursing Mothers
It is unknown whether insulin lispro is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Humalog is administered to a nursing woman. Use of Humalog is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.
Pediatric Use
Humalog is approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump. Humalog has not been studied in pediatric patients younger than 3 years of age. Humalog has not been studied in pediatric patients with type 2 diabetes [see Clinical Studies (14)].
As in adults, the dosage of Humalog must be individualized in pediatric patients based on metabolic needs and results of frequent monitoring of blood glucose.
Geriatric Use
Of the total number of subjects (n=2834) in eight clinical studies of Humalog, twelve percent (n=338) were 65 years of age or over. The majority of these had type 2 diabetes. HbA1c values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed.
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/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.
Humalog Description
Humalog® (insulin lispro injection, USP [rDNA origin]) is a rapid-acting human insulin analog used to lower blood glucose. 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 C257H383N65O77S6 and a molecular weight of 5808, both identical to that of human insulin.
Humalog has the following primary structure:
Humalog is a sterile, aqueous, clear, and colorless solution. Each milliliter of Humalog contains insulin lispro 100 units, 16 mg glycerin, 1.88 mg dibasic sodium phosphate, 3.15 mg Metacresol, zinc oxide content adjusted to provide 0.0197 mg zinc ion, trace amounts of phenol, and Water for Injection. Insulin lispro has a pH of 7.0 to 7.8. The pH is adjusted by addition of aqueous solutions of hydrochloric acid 10% and/or sodium hydroxide 10%.
Humalog - Clinical Pharmacology
Mechanism of Action
Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.
Pharmacodynamics
Humalog has been shown to be equipotent to human insulin on a molar basis. One unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that Humalog has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously.
The time course of action of insulin and insulin analogs, such as Humalog, may vary considerably in different individuals or within the same individual. The parameters of Humalog activity (time of onset, peak time, and duration) as designated in Figure 1 should be considered only as general guidelines. The rate of insulin absorption, and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.1)].
Figure 1: Blood Glucose Levels After Subcutaneous Injection of Regular Human Insulin or Humalog (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetes.a
a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.
Pharmacokinetics
Absorption and Bioavailability — Studies in healthy volunteers and patients with diabetes demonstrated that Humalog is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of Humalog ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes (see Figure 2).
Figure 2: Serum Humalog and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or Humalog (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetes.a
a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.
Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 unit/kg at abdominal, deltoid, or femoral subcutaneous sites. After Humalog was administered in the abdomen, serum drug levels were higher and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of Humalog is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive.
Distribution — After subcutaneous administration, the volume of distribution for Humalog is identical to that of regular human insulin, with a range of 0.26 to 0.36 L/kg. When administered intravenously, the volume of distribution of Humalog (range of 0.26 to 0.36 L/kg) was similar to that of regular human insulin (range of 0.32 to 0.67 L/kg).
Metabolism — Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of Humalog is identical to that of regular human insulin.
Elimination — After subcutaneous administration of Humalog, the t1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, Humalog and regular human insulin demonstrated similar dose-dependent elimination, with a t1/2 of 0.44 hours (26 min) and 0.34 hours (20 min), respectively (0.1 unit/kg dose) and 0.86 hours (52 min) and 1.1 hours (66 min), respectively (0.2 unit/kg dose).
Specific Populations
Age — The effect of age on the pharmacokinetics of Humalog has not been studied. However, in large clinical trials, sub-group analysis based on age did not indicate any difference in postprandial glucose parameters between Humalog and regular human insulin.
Gender — The effect of gender on the pharmacokinetics of Humalog has not been studied. However, in large clinical trials, sub-group analysis based on gender did not indicate any difference in postprandial glucose parameters between Humalog and regular human insulin.
Renal Impairment — Type 2 diabetic patients with varying degree of renal impairment showed no difference in pharmacokinetics of regular insulin and Humalog. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary in patients with renal dysfunction [see Warnings and Precautions (5.5)].
Hepatic Impairment — Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetic of Humalog as compared to patients with no hepatic dysfunction. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary in patients with hepatic dysfunction.
Race – The effects of race on the pharmacokinetics and pharmacodynamics of Humalog have not been studied.
Obesity – The effect of obesity on the pharmacokinetics and pharmacodynamics of Humalog has not been studied.
Pregnancy – The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Humalog has not been studied [see Use in Specific Populations (8.1)].
Smoking – The effect of smoking on the pharmacokinetics and pharmacodynamics of Humalog has not been studied.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose.
Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays.
Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area) for 6 months were mated with untreated female rats. In a combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.16, 0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.
Animal Toxicology and /or Pharmacology
In standard biological assays in fasted rabbits, 0.2 unit/kg of insulin lispro injected subcutaneously had the same glucose-lowering effect and had a more rapid onset of action as 0.2 unit/kg of regular human insulin.
Clinical Studies
The safety and efficacy of Humalog were studied in children, adolescent, and adult patients with type 1 diabetes (n=789) and adult patients with type 2 diabetes (n=722).
Type 1 Diabetes — Adults and Adolescents
A 12-month, randomized, parallel, open-label, active-controlled study was conducted in patients with type 1 diabetes to assess the safety and efficacy of Humalog (n=81) compared with Humulin® R [REGULAR insulin human injection, USP (rDNA origin)] (n=86). Humalog was administered by subcutaneous injection immediately prior to meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® U [ULTRALENTE® human insulin (rDNA origin) extended zinc suspension] was administered once or twice daily as the basal insulin. There was a 2- to 4-week run-in period with Humulin R and Humulin U before randomization. Most patients were Caucasian (97%). Forty-seven percent of the patients were male. The mean age was 31 years (range 12 to 70 years). Glycemic control, the total daily doses of Humalog and Humulin R, and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar in the two treatment groups. There were no episodes of diabetic ketoacidosis in either treatment group.
a Values are Mean ± SD | ||
b Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat. | ||
| Treatment Duration Treatment in Combination with: | 12 months Humulin U | |
| Humalog | Humulin R | |
| N | 81 | 86 |
| Baseline HbA1c (%)a | 8.2 ± 1.4 | 8.3 ± 1.7 |
| Change from baseline HbA1c (%)a | -0.1 ± 0.9 | 0.1 ± 1.1 |
| Treatment Difference in HbA1c Mean (95% confidence interval) | 0.4 (0.0, 0.8) | |
| Baseline short-acting insulin dose (units/kg/day) | 0.3 ± 0.1 | 0.3 ± 0.1 |
| End-of-Study short-acting insulin dose (units/kg/day) | 0.3 ± 0.1 | 0.3 ± 0.1 |
| Change from baseline short-acting insulin dose (units/kg/day) | -0.0 ± 0.1 | 0.0 ±0.1 |
| Baseline Body weight (kg) | 72 ± 12.7 | 71 ± 11.3 |
| Weight change from baseline (kg) | 1.4 ± 3.6 | 1.0 ± 2.6 |
| Patients with severe hypoglycemia (n, %)b | 14 (17%) | 18 (21%) |
Type 2 Diabetes – Adults
A 6-month randomized, crossover, open-label, active-controlled study was conducted in insulin-treated patients with type 2 diabetes (n=722) to assess the safety and efficacy of Humalog for 3 months followed by Humulin R for 3 months or the reverse sequence. Humalog was administered by subcutaneous injection immediately before meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® N [NPH human insulin (rDNA origin) isophane suspension] or Humulin U was administered once or twice daily as the basal insulin. All patients participated in a 2- to 4-week run-in period with Humulin R and Humulin N or Humulin U. Most of the patients were Caucasian (88%), and the numbers of men and women in each group were approximately equal. The mean age was 58.6 years (range 23.8 to 85 years). The average body mass index (BMI) was 28.2 kg/m2. During the study, the majority of patients used Humulin N (84%) compared with Humulin U (16%) as their basal insulin. The reductions from baseline in HbA1c and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar between the two treatments from the combined groups (see Table 5).
a Values are Mean ± SD | |||
b Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat. | |||
| End point | |||
| Baseline | Humalog + Basal | Humulin R + Basal | |
| HbA1c (%)a | 8.9 ± 1.7 | 8.2 ± 1.3 | 8.2 ± 1.4 |
| Change from baseline HbA1c (%)a | — | -0.7 ± 1.4 | -0.7 ± 1.3 |
| Short-acting insulin dose (units/kg/day)a | 0.3 ±0.2 | 0.3 ± 0.2 | 0.3 ±0.2 |
| Change from baseline short-acting insulin dose (units/kg/day)a | — | 0.0 ± 0.1 | 0.0 ± 0.1 |
| Body weight (kg)a | 80 ± 15 | 81 ± 15 | 81 ±15 |
| Weight change from baseline | — | 0.8 ± 2.7 | 0.9 ± 2.6 |
| Patients with severe hypoglycemia (n, %)b | — | 15 (2%) | 16 (2%) |
Type 1 Diabetes – Pediatric and Adolescents
An 8-month, crossover study of adolescents with type 1 diabetes (n=463), aged 9 to 19 years, compared two subcutaneous multiple-dose treatment regimens: Humalog or Humulin R, both administered with Humulin N (NPH human insulin) as the basal insulin. Humalog achieved glycemic control comparable to Humulin R, as measured by HbA1c (see Table 6), and both treatment groups had a comparable incidence of hypoglycemia. In a 9-month, crossover study of prepubescent children (n=60) with type 1 diabetes, aged 3 to 11 years, Humalog administered immediately before meals, Humalog administered immediately after meals and Humulin R administered 30 minutes before meals resulted in similar glycemic control, as measured by HbA1c, and incidence of hypoglycemia, regardless of treatment group.
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