ADMELOG is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.
Subcutaneous Injection
Continuous Subcutaneous Infusion (Insulin Pump)
Intravenous Administration
Injection: 100 units/mL (U-100) is a clear and colorless solution available as:
Risk Summary
Published studies with another insulin lispro product 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 another insulin lispro product in animal reproduction studies during organogenesis. Fetal growth retardation was observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1.0 unit/kg/day. No adverse effects on embryo-fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.24 times the human subcutaneous dose of 1.0 unit/kg/day [see Data] .
The estimated background risk of major birth defects is 6%–10% in women with pregestational 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, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Human data
Published data from retrospective studies and meta-analyses do not report an association with another insulin lispro product 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
In a combined fertility and embryo-fetal development study with another insulin lispro product, 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 observed 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 with another insulin lispro product, 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.
Risk Summary
Available data from published literature suggest that exogenous human insulin products, including insulin lispro, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including insulin lispro, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ADMELOG and any potential adverse effects on the breastfed child from ADMELOG or from the underlying maternal condition.
The safety and effectiveness of ADMELOG to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of ADMELOG for this indication is supported by evidence from an adequate and well-controlled study with another insulin lispro product, 100 units/ml, in 60 pediatric patients 3 years of age and older with type 1 diabetes mellitus and studies in adult patients with diabetes mellitus [see Clinical Studies (14)] .
Of the total number of patients (n=2,834) in eight clinical studies of another insulin lispro product, 100 units/mL, 12% (n=338) were 65 years of age or over. The majority of these patients had type 2 diabetes. HbA1c values and hypoglycemia rates did not differ by age.
Of the total number of patients (n=1,011) in clinical studies of ADMELOG or another insulin lispro product, 100 units/mL, 26.5% (n=268) were 65 years of age or over. The majority of these patients 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 ADMELOG action have not been performed.
Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent ADMELOG dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology (12.3)] .
Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent ADMELOG dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology (12.3)] .
ADMELOG is contraindicated:
ADMELOG SoloStar prefilled pen must never be shared between patients, even if the needle is changed. Patients using ADMELOG vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)] .
Make any changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.
Hypoglycemia is the most common adverse reaction associated with insulins, including ADMELOG.
Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).
Hypoglycemia can happen suddenly, and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)] , or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of ADMELOG may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)] . Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7)] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)] .
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
Accidental mix-ups between insulin products have been reported. To avoid medication errors between ADMELOG and other insulins, instruct patients to always check the insulin label before each injection.
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including ADMELOG. If hypersensitivity reactions occur, discontinue ADMELOG; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6.1)] . ADMELOG is contraindicated in patients who have had hypersensitivity reactions to insulin lispro or any of the excipients in ADMELOG [see Contraindications (4)] .
All insulins, including ADMELOG, 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. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including ADMELOG, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with ADMELOG 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 How Supplied/Storage and Handling (16.2)and Patient Counseling Information (17)] .
The following adverse reactions are discussed elsewhere:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions with Subcutaneous Injections of ADMELOG
Two clinical trials with ADMELOG were conducted: one in patients with type 1 diabetes and one in patients with type 2 diabetes [see Clinical Studies (14)] .
Common adverse reactions were defined as reactions that occurred in ≥5% of the population studied.
Common adverse reactions (other than hypoglycemia) during a clinical trial in patients with type 1 diabetes mellitus are listed in Table 1. In a 26-week clinical trial in patients with type 2 diabetes mellitus, no adverse reactions (other than hypoglycemia) occurred in ≥5% of ADMELOG-treated patients (n=253) were observed.
| ADMELOG + Insulin Glargine (100 units/mL), % (n=252) | |
|---|---|
| Nasopharyngitis | 13% |
| Upper respiratory tract infection | 6% |
Severe Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including ADMELOG [see Warnings and Precautions (5.3)] . The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for ADMELOG with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.
In the ADMELOG trials, severe hypoglycemia was defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. The incidence of severe hypoglycemia in patients receiving ADMELOG with type 1 diabetes mellitus and type 2 diabetes mellitus was 13.5% at 52 weeks and 2.4% at 26 weeks, respectively [see Clinical Studies (14)] .
Adverse Reactions Associated with 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 ADMELOG, 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 [see Dosage and Administration (2.2)] .
Weight Gain
Weight gain can occur with insulins, including ADMELOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.
Peripheral Edema
Insulins, including ADMELOG, 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) of ADMELOG
In a randomized, open-label crossover study in adult patients with type 1 diabetes treated over two 4-week periods, the incidence of infusion set occlusions (defined as failure to correct hyperglycemia [plasma glucose ≥300 mg/dL] by insulin bolus via insulin pump) in ADMELOG-treated patients (n=25) was evaluated. Infusion set occlusions were reported by 24% of patients.
In a randomized, 16-week, open-label, parallel design study of pediatric patients with type 1 diabetes, adverse reactions related to infusion site-related reactions for another insulin lispro product, 100 units/mL, occurred in 21% of patients. The most frequently reported infusion site-related reactions were infusion site erythema and infusion site reaction.
Allergic Reactions
Local Allergy
As with any insulin therapy, patients taking ADMELOG 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 ADMELOG. 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 ADMELOG. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in ADMELOG [see Contraindications (4)] .
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to ADMELOG in the studies described below with the incidence of antibodies in other studies or to other insulin products may be misleading.
In a 52-week study of ADMELOG in type 1 diabetes patients, 49.4% were positive at baseline and 22.6% had treatment-emergent ADA (i.e., either new ADA, or increase in titer of at least 4-fold).
In a 26-week study of ADMELOG in type 2 diabetes patients, 26.4% were positive at baseline and 18.8% had treatment-emergent ADA (i.e., either new ADA, or increase in titer of at least 4-fold).
The following additional adverse reactions have been identified during post approval use of another insulin lispro product, 100 units/mL. 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 another insulin lispro product, 100 units/mL, have been identified during post approval use.
Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.
Table 2 presents clinically significant drug interactions with ADMELOG.
| Drugs That May Increase the Risk of Hypoglycemia | |
| Drugs: | Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. |
| Intervention: | Dose adjustment and increased frequency of glucose monitoring may be required when ADMELOG is concomitantly administered with these drugs. |
| Drugs That May Decrease the Blood Glucose Lowering Effect of ADMELOG | |
| Drugs: | Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. |
| Intervention: | Dose adjustment and increased frequency of glucose monitoring may be required when ADMELOG is concomitantly administered with these drugs. |
| Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of ADMELOG | |
| Drugs: | Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. |
| Intervention: | Dose adjustment and increased frequency of glucose monitoring may be required when ADMELOG is concomitantly administered with these drugs. |
| Drugs That May Blunt Signs and Symptoms of Hypoglycemia | |
| Drugs: | Beta-blockers, clonidine, guanethidine and reserpine. |
| Intervention: | Increased frequency of glucose monitoring may be required when ADMELOG is concomitantly administered with these drugs. |
Insulin lispro is a rapid-acting human insulin analog 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. Insulin lispro has a molecular weight of 5808 Da, identical to that of human insulin.
ADMELOG (insulin lispro) injection is a sterile, aqueous, clear, and colorless solution for subcutaneous or intravenous use. Each mL of ADMELOG contains 100 units of insulin lispro, and the inactive ingredients: dibasic sodium phosphate (1.88 mg), glycerin (16 mg), metacresol (3.15 mg), zinc oxide (content adjusted to provide 0.0197 mg zinc ion), and Water for Injection, USP. Insulin lispro has a pH of 7.0 to 7.8. The pH is adjusted by addition of aqueous solutions of hydrochloric acid and/or sodium hydroxide. ADMELOG is latex free.
Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro products. 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 of ADMELOG After Subcutaneous Injection
The pharmacodynamic profile of a single 0.3 unit/kg dose of ADMELOG administered subcutaneously was evaluated in a euglycemic clamp study enrolling 30 patients with type 1 diabetes. In this study, the mean (SD) time to maximum effect of ADMELOG (measured by the peak rate of glucose infusion) was approximately 2.1 (0.8) hours. The mean (SD) area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) and mean (SD) maximum glucose infusion rate were 1953.5 (547.3) mg/kg and 9.97 (2.37) mg/min/kg, respectively (see Figure 1).
|
Figure 1: Mean Smoothed Glucose Infusion Rate *after Subcutaneous Injection of ADMELOG (0.3 unit/kg) in Patients with Type 1 Diabetes |
|
The time course of action of insulin and insulin analogs, including insulin lispro products, may vary considerably in different individuals or within the same individual. 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 (5.2)] .
Pharmacodynamics of AMELOG after Intravenous Administration
The glucose lowering effect of intravenous administration of another insulin lispro product, 100 units/mL, was tested in 21 patients with type 1 diabetes. For the study, the patients' usual doses of insulin were held, and blood glucose concentrations were allowed to reach a stable range of 200 to 260 mg/dL during a one to three-hour run-in phase. The run-in phase was followed by a 6-hour assessment phase. During the assessment phase, patients received intravenous infusion of another insulin lispro product, 100 units/mL, at an initial infusion rate of 0.5 units/hour. The infusion rate could be adjusted at regular timed intervals to achieve and maintain blood glucose concentrations between 100 to 160 mg/dL.
The mean blood glucose levels during the assessment phase for patients on another insulin lispro product, 100 units/mL, therapy are summarized below in Table 3. All patients achieved the targeted glucose range at some point during the 6-hour assessment phase. At the endpoint, blood glucose was within the target range (100 to 160 mg/dL) for 17 of 20 patients treated with another insulin lispro product, 100 units/mL. The average time (±SE) required to attain near normoglycemia was 129 ± 14 minutes for another insulin lispro product, 100 units/mL.
| Time from Start of Infusion (minutes) | Mean Blood Glucose (mg/dL) Intravenous * |
|---|---|
| |
| 0 | 224 ± 16 |
| 30 | 205 ± 21 |
| 60 | 195 ± 20 |
| 120 | 165 ± 26 |
| 180 | 140 ± 26 |
| 240 | 123 ± 20 |
| 300 | 120 ± 27 |
| 360 | 122 ± 25 |
Absorption
The pharmacokinetic profile of a single 0.3 unit/kg dose of ADMELOG administered subcutaneously was evaluated in a study enrolling 30 patients with type 1 diabetes. In this study, the mean observed area under the plasma insulin lispro concentration-time curve from time zero to infinity and peak plasma insulin lispro concentration were 12800 pg∙hr/mL and 5070 pg/mL, respectively. The median time to maximum plasma insulin lispro concentration was 0.83 hours after injection (see Figure 2).
Figure 2: Mean Plasma Concentrations of ADMELOG after a Single Subcutaneous Administration of ADMELOG (0.3 unit/kg) in Patients with Type 1 Diabetes
The absolute bioavailability of another insulin lispro product, 100 units/mL, after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive.
Distribution
When administered intravenously as bolus injections of 0.1 and 0.2 unit/kg dose in two separate groups of healthy subjects, the mean volume of distribution of another insulin lispro product, 100 units/mL, appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively).
Elimination
Metabolism
Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of another insulin lispro product, 100 units/mL, is identical to that of regular human insulin.
Excretion
When administered intravenously, another insulin lispro product, 100 units/mL demonstrated dose-dependent clearance, with a mean clearance of 21.0 mL/min/kg (0.1 unit/kg dose), and 9.6 mL/min/kg (0.2 unit/kg dose). Another insulin lispro product, 100 units/mL, demonstrated a mean t 1/2of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses.
Specific Populations
The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of ADMELOG have not been studied.
Patients with Renal Impairment
Type 2 diabetic patients with varying degrees of renal impairment showed no difference in pharmacokinetics of another insulin lispro product, 100 units/mL. 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 [see Use in Specific Populations (8.6)] .
Patients with Hepatic Impairment
Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of another insulin lispro product, 100 units/mL, 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 [see Use in Specific Populations (8.7)] .
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.
The safety and effectiveness of ADMELOG to improve glycemic control in adult and pediatric patients with diabetes mellitus have been established based on adequate and well-controlled studies of ADMELOG in adult patients with type 1 and type 2 diabetes mellitus, and based on adequate and well-controlled studies of another insulin lispro product, 100 units/mL, in adult and pediatric patients 3 years of age and older with type 1 diabetes mellitus and adult patients with type 2 diabetes mellitus.
The safety and effectiveness of:
ADMELOG: Study in Adult Patients
A 26-week open-label, active-controlled study (NCT02273180) evaluated the glucose lowering effect of ADMELOG plus insulin glargine, 100 units/mL, compared to that of Comparator (another insulin lispro product, 100 units/mL, or a non–U.S.-licensed insulin lispro product, 100 units/mL), plus insulin glargine, 100 units/mL. A total of 507 patients with type 1 diabetes mellitus treated with insulin glargine 100 units/mL and rapid-acting mealtime insulin analogs participated in the study. Patients were randomized to ADMELOG (n=253) or Comparator (n=254). ADMELOG or Comparator was administered by subcutaneous injection immediately prior to meals.
The mean age of these patients was 43 years old, and 60% were male. The population was 82% White, 5% Black or African American and 5% were Hispanic. The population had type 1 diabetes mellitus for a mean duration of 19 years. The mean eGFR was 90.6 mL/min/1.73 m 2and 48.7% of patients had GFR ≥90 mL/min/1.73 m 2. The mean BMI was approximately 26 kg/m 2. At baseline, 61%, 38% and 2% of the patients were using other insulin lispro products, 100 units/mL, insulin aspart, 100 units/mL, or both, respectively.
At week 26, treatment with ADMELOG provided a mean reduction in HbA1c that was non-inferior to that achieved with the Comparator (see Table 4).
| ADMELOG + Insulin Glargine | Comparator + Insulin Glargine | |
|---|---|---|
| ||
| N * | 253 | 254 |
| HbA1c (%) | ||
| Baseline (mean) | 8.08 | 7.99 |
| Adjusted mean change from baseline † | -0.40 | -0.46 |
| Adjusted mean difference ‡ (95% CI) | 0.06 (-0.086 to 0.201) | |
Another Insulin Lispro Product, 100 units/mL: Study in Adult and Pediatric Patients 12 Years of Age and Older
A 12-month, randomized, parallel, open-label, active-controlled study was conducted in 167 patients with type 1 diabetes to assess the safety and efficacy of another insulin lispro product, 100 units/mL (n=81), compared with regular human insulin, 100 units/mL (n=86). This other insulin lispro product was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered 30 to 45 minutes before meals. Human insulin extended zinc suspension was administered once or twice daily as the basal insulin in both treatment groups. There was a 2 to 4-week run-in period with regular human insulin and human insulin extended zinc suspension before randomization.
The mean age of these patients was 31 years (range 12 to 70 years), and 47% were male. The population was 97% White.
| Another Insulin Lispro Product + Human Insulin Extended Zinc | Regular Human Insulin + Human Insulin Extended Zinc | |
|---|---|---|
| ||
| N | 81 | 86 |
| Baseline HbA1c (%) * | 8.2 ± 1.4 | 8.3 ± 1.7 |
| Change from baseline HbA1c (%) * | -0.1 ± 0.9 | 0.1 ± 1.1 |
| Treatment difference in HbA1c mean (95% confidence interval) | 0.4 (0.0; 0.8) | |
Another Insulin Lispro Product, 100 units/mL: Studies in Pediatric Patients 3 Years of Age and Older
An 8-month, crossover study of pediatric patients with type 1 diabetes (n=463), aged 9 to 19 years, compared two subcutaneous multiple-dose treatment regimens: another insulin lispro product, 100 units/mL, or regular human insulin, 100 units/mL, both administered with NPH human insulin isophane suspension as the basal insulin. Insulin lispro achieved glycemic control comparable to regular human insulin, as measured by HbA1c (see Table 6).
| Baseline | Another Insulin Lispro Product + NPH | Regular Human Insulin + NPH | |
|---|---|---|---|
| |||
| HbA1c (%) * | 8.6 ± 1.5 | 8.7 ± 1.5 | 8.7 ± 1.6 |
| Change from baseline HbA1c (%) * | - | 0.1 ± 1.1 | 0.1 ± 1.3 |
In a 9-month, crossover study of pediatric patients with type 1 diabetes mellitus (n=60), aged 3 to 11 years, compared three subcutaneous injection regimens: another insulin lispro product, 100 units/mL, administered immediately before meals, this same insulin lispro product, 100 units/mL, administered immediately after meals and regular human insulin, 100 units/mL administered 30 minutes before meals resulted in similar glycemic control, as measured by HbA1c, regardless of treatment group.
Another Insulin Lispro Product, 100 units/mL: Studies in Adult and Pediatric Patients 15 Years of Age and Older
To evaluate the administration of another insulin lispro product, 100 units/mL, as a subcutaneous infusion via external insulin pumps, two open-label, crossover studies were performed in patients with type 1 diabetes mellitus.
Another Insulin Lispro Product, 100 units/mL: Study in Pediatric Patients 4 Years of Age and Older
A randomized, 16-week, open-label, parallel design, study of pediatric patients with type 1 diabetes mellitus (n=298), aged 4 to 18 years, compared two subcutaneous continuous infusion regimens administered via an external insulin pump: insulin aspart, 100 units/mL (n=198), or another insulin lispro product, 100 units/mL (n=100). These two treatments resulted in comparable changes from baseline in HbA1c after 16 weeks of treatment (see Table 7).
| Another Insulin Lispro Product | Insulin Aspart | |
|---|---|---|
| ||
| N | 100 | 198 |
| Baseline HbA1c (%) * | 8.2 ± 0.8 | 8.0 ± 0.9 |
| Change from Baseline HbA1c (%) | -0.1 ± 0.7 | -0.1 ± 0.8 |
| Treatment Difference in HbA1c, Mean (95% confidence interval) | 0.1 (-0.3, 0.1) | |
ADMELOG: Study in Adult Patients
A 26-week open-label, active-controlled study (NCT02294474) evaluated the glucose lowering effect of ADMELOG plus insulin glargine, 100 units/mL, compared to that of Comparator (another insulin lispro product, 100 units/mL, or a non–U.S.-licensed insulin lispro, 100 units/mL) plus insulin glargine, 100 units/mL. A total of 505 patients with type 2 diabetes mellitus treated with insulin glargine, 100 units/mL, and rapid-acting mealtime insulin analogs participated in the study. Patients were randomized to ADMELOG, 100 units/mL (n=253) or Comparator (n=252). ADMELOG or Comparator, was administered by subcutaneous injection immediately prior to meals.
The mean age of these patients was 63 years, and 53% were male. The population was 88% White, 6% Black or African American and 18% were Hispanic. The population had type 2 diabetes mellitus for a mean duration of 17 years. The mean eGFR was 77.9 mL/min/1.73 m 2and 26.9% of patients had GFR >90 mL/min/1.73 m 2. The mean BMI was approximately 32.2 kg/m 2. At baseline, 51%, 48%, and 0.4% of the patients were using other insulin lispro products, 100 units/mL, insulin aspart, 100 units/mL, or both, respectively.
At week 26, treatment with ADMELOG provided a mean reduction in HbA1c that was non-inferior to that achieved with the Comparator (see Table 8).
| ADMELOG + Insulin Glargine | Comparator + Insulin Glargine | |
|---|---|---|
| ||
| N * | 253 | 252 |
| HbA1c (%) | ||
| Baseline (mean) | 8.00 | 8.03 |
| Adjusted mean change from baseline † | -0.86 | -0.80 |
| Adjusted mean difference ‡ (95% CI) | -0.06 (-0.209 to 0.091) | |
Another Insulin Lispro Product, 100 units/mL: Study in Adult Patients
A 6-month randomized, crossover, open-label, active-controlled study was conducted in 722 patients with type 2 diabetes mellitus treated with insulin to assess the safety and efficacy of another insulin lispro product, 100 units/mL, for 3 months followed by regular human insulin, 100 units/mL, for 3 months or the reverse sequence. This other insulin lispro product was administered by subcutaneous injection immediately before meals and regular human insulin was administered 30 to 45 minutes before meals. NPH human insulin isophane suspension or human insulin extended zinc suspension was administered once or twice daily as the basal insulin in both treatment groups. All patients participated in a 2 to 4-week run-in period with regular human insulin and NPH human insulin isophane suspension or human insulin extended zinc suspension.
Most of the patients were White (88%), and the numbers of males and females in each group were approximately equal. The mean age was 59 years (range 24 to 85 years). The average body mass index (BMI) was 28.2 kg/m 2. During the study, the majority of patients used NPH human insulin isophane suspension (84%) compared with human insulin extended zinc suspension (16%) as their basal insulin. The reductions from baseline in HbA1c were similar between the two treatments from the combined groups (see Table 9).
| Baseline | Another Insulin Lispro Product + Basal Insulin | Regular Human Insulin + Basal Insulin | |
|---|---|---|---|
| |||
| HbA1c (%) * | 8.9 ± 1.7 | 8.2 ± 1.3 | 8.2 ± 1.4 |
| Change from baseline HbA1c (%) * | - | -0.7 ± 1.4 | -0.7 ± 1.3 |
ADMELOG (insulin lispro) injection 100 units/mL (U-100) is available as a clear and colorless solution in:
NDC: 70518-4275-00
PACKAGING: 5 in 1 CARTON, 3 mL Syringe type 2
Use in an External Insulin Pump
Change the ADMELOG in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 98.6°F (37°C).
Diluted ADMELOG for Subcutaneous Injection
Diluted ADMELOG may remain in patient use for up to 24 hours when stored in a refrigerator (36°F–46°F [2°C–8°C]) or for up to 4 hours when stored at room temperature (86°F [30°C]). Do not dilute ADMELOG used in an external insulin pump.
Admixture for Intravenous Administration
Infusion bags prepared with ADMELOG are stable when stored in a refrigerator (36°F–46°F [2°C–8°C]) for 24 hours or may be used at room temperature for up to 4 hours [see Dosage and Administration (2.2)].
Repackaged and Distributed By:
Remedy Repack, Inc.
625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762
ADMELOG ®SoloStar ®[ad-mah-log]
(insulin lispro)
injection, for subcutaneous use
3 mL single-patient-use prefilled pen (100 units/mL, U-100)
Read this first
Do not share your ADMELOG SoloStar pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.
People who are blind or have vision problems should not use ADMELOG SoloStar prefilled pen without help from a person trained to use ADMELOG SoloStar prefilled pen.
ADMELOG SoloStar is a disposable prefilled pen used to inject ADMELOG. Each ADMELOG SoloStar has 300 units of insulin which can be used for multiple injections. You can select doses from 1 to 80 units in steps of 1 unit. The pen plunger moves with each dose. The plunger will only move to the end of the cartridge when 300 units of insulin have been given.
Important information
Learn to inject
Need help?
If you have any questions about your pen or about diabetes, ask your healthcare provider, or go to www.Admelog.com or call sanofi-aventis at 1-800-633-1610.
Extra items you will need:
Places to inject
Get to know your pen
Step 1: Check your pen
Take a new pen out of the refrigerator at least 1hour before you inject. Cold insulin is more painful to inject.
1A Check the name and expiration date on the label of your pen.
1B Pull off the pen cap.
1C Check that the insulin is clear.
1D Wipe the rubber seal with an alcohol swab.
If you have other injector pens:
Step 2: Attach a new needle
2A Take a new needle and peel off the protective seal.
2B Keep the needle straight and screw it onto the pen until fixed. Do not over-tighten.
2C Pull off the outer needle cap. Keep this for later.
2D Pull off the inner needle cap and throw away.
Handling needles:
Step 3: Do a safety test
Always do a safety test before each injection to:
3A Select 2 units by turning the dose selector until the dose pointer is at the 2 mark.
3B Press the injection button all the way in.
If no insulin appears:
If you see air bubbles:
Step 4: Select the dose
Do notselect a dose or press the injection button without a needle attached. This may damage your pen.
4A Make sure a needle is attached and the dose is set to "0."
4B Turn the dose selector until the dose pointer lines up with your dose.
How to read the dose window
Even numbers are shown in line with dose pointer.
| |
| 20 units selected |
Odd numbers are shown as a line between even numbers.
| |
| 21 units selected |
Units of insulin in your pen:
Step 5: Inject your dose
If you find it hard to press the injection button in, do notforce it as this may break your pen. See the section below for help.
5A Choose a place to inject as shown in the picture above.
5B Push the needle into your skin as shown by your healthcare provider.
5C Place your thumb on the injection button. Then press all the way in and hold.
5D Keep the injection button held in and when you see "0" in the dose window, slowly count to 10.
5E After holding and slowly counting to 10, release the injection button. Then remove the needle from your skin.
If you find it hard to press the button in:
Step 6: Remove the needle
6A Grip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap. Then push firmly on.
6B Grip and squeeze the widest part of the outer needle cap. Turn your pen several times with your other hand to remove the needle.
6C Throw away the used needle in a puncture-resistant container(see " Throwing your pen away" at the end of this Instructions for Use).
6D Put your pen cap back on.
How to store your pen
Before first use
After first use
How to care for your pen
Handle your pen with care
Protect your pen from dust and dirt
Throwing your pen and used needle pen away
Other brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Revised: August 2023
Repackaged and Distributed By:
Remedy Repack, Inc.
625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762
Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro products. 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.
