Admelog

Dosage Forms And Strengths

Insulin lispro injection 100 units per mL (U-100) is available as:

• 10 mL multiple-dose vials
• 3 mL single patient use SoloStar prefilled pens

ADMELOG: Insulin Lispro Injection 100 units per mL (U-100) is available as:

Dosage Unit	Package Size	NDC#
10 mL multiple-dose vials	Carton of 1	0024-5924-10
3 mL single patient use SoloStar prefilled pen	Carton of 5	0024-5925-05

Each prefilled SoloStar pen is for use by a single patient. ADMELOG SoloStar 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.

Storage And Handling

Do not use after the expiration date.

Not in-use (unopened) ADMELOG should be stored in a refrigerator (36°F-46°F [2°C-8°C]), but not in the freezer. Do not use ADMELOG if it has been frozen.

In-use (opened) ADMELOG vials and ADMELOG SoloStar pens should be stored at room temperature (below 86°F [30°C]) and must be used within 28 days or be discarded, even if they still contain ADMELOG. Protect from direct heat and light.

See table below:

ADMELOG	Not In-Use (Unopened) Room Temperature (Below 86°F [30°C])	Not In-Use (Unopened) Refrigerated (36°F-46°F [2°C-8°C])	In-Use (Opened) Room Temperature (Below 86°F [30°C])
10 mL multiple-dose vial	28 days	Until expiration date	28 days refrigerated/room

Use In An External Insulin Pump

Insulin in the reservoir should be discarded after 7 days. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion set insertion site should be selected at least every 3 days.

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.

Preparation And Handling

Diluted ADMELOG For Subcutaneous Injection

ADMELOG may be diluted with sterile 0.9% sodium chloride for subcutaneous injection. Diluting one part ADMELOG to one part 0.9% sodium chloride will yield a concentration one-half that of ADMELOG (equivalent to U-50).

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].

Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY. Revised: Dec 2017

The following adverse reactions are also discussed elsewhere:

• Hypoglycemia [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity and allergic reactions [see WARNINGS AND PRECAUTIONS]
• Hypokalemia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

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].

The data in Table 1 reflect the exposure of 252 patients with type 1 diabetes to ADMELOG with mean exposure duration of 49 weeks. The type 1 diabetes population had the following characteristics: Mean age was 43 years and mean duration of diabetes was 20 years. Fifty-nine percent were male, 80% were White, 6% were Black or African American and 7% were Hispanic. At baseline, the mean eGFR was 90 mL/min/1.73 m² and 49% of patients had eGFR ≥90 mL/min/1.73 m². The mean BMI was 26 kg/m². The mean HbA1c at baseline was 8.07%.

Two hundred fifty-three patients with type 2 diabetes were exposed to ADMELOG with mean exposure duration of 25 weeks. The type 2 diabetes population had the following characteristics: Mean age was 62 years and mean duration of diabetes was 17 years. Fifty-four percent were male, 90% were White, 6% were Black or African American and 17% were Hispanic. At baseline, the mean eGFR was 77 mL/min/1.73 m² and 27% of patients had eGFR ≥90 mL/min/1.73 m². The mean BMI was 32 kg/m². The mean HbA1c at baseline was 7.99%.

Common adverse reactions were defined as reactions occurring 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) occurring in ≥5% of ADMELOG-treated patients (n=253) were observed.

Table 1: Adverse Reactions Occurring in ≥5% of ADMELOG-Treated Patients with Type 1 Diabetes in a 52-Week Trial

	ADMELOG + Insulin Glargine (100 units/mL), % (n=252)
Nasopharyngitis	13.1%
Upper respiratory tract infection	6.0%

Severe Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including ADMELOG [see WARNINGS AND PRECAUTIONS]. 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].

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. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy [see DOSAGE AND ADMINISTRATION].

Weight Gain

Weight gain can occur with insulin therapy, including ADMELOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

Peripheral Edema

Insulin, 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)

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 children and adolescents with type 1 diabetes, adverse event reports related to infusion-site reactions for another insulin lispro product, 100 units/mL, occurred in 21% of patients. 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 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].

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with ADMELOG may develop anti-insulin antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, the incidence of antibodies to ADMELOG in the studies described below cannot be directly compared with the incidence of antibodies in other studies or to other products.

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).

Postmarketing Experience

The following additional adverse reactions have been identified during postapproval 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 postapproval use [see Patient Counseling Information].

Mechanism Of Action

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

Subcutaneous Administration

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 2.07 (0.78) 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

* Body Weight Standardized

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].

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 2. 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.

Table 2: Mean Blood Glucose Concentrations (mg/dL) During Intravenous Infusions of 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
* Results shown as mean ± SD

Pharmacokinetics

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 t½ of 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. Careful glucose monitoring and dose adjustments of insulin, including ADMELOG, may be necessary in patients with renal dysfunction.

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. Careful glucose monitoring and dose adjustments of insulin, including ADMELOG, may be necessary in patients with hepatic dysfunction.

Clinical Studies

Overview Of Clinical Studies

The safety and effectiveness of ADMELOG 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 were studied in 507 adult patients with type 1 diabetes and 505 adult patients with type 2 diabetes.

The safety and effectiveness of another insulin lispro product, 100 units/mL, were studied in 1,087 adult and pediatric patients with type 1 diabetes and in 722 adult patients with type 2 diabetes.

Type 1 Diabetes Mellitus - Subcutaneous Injection

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.-approved insulin lispro, 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 subjects was 43 years, and 59.6% were male. The population was 82.1% White, 4.7% Black or African American and 5.3% 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 m² and 48.7% of patients had GFR ≥90 mL/min/1.73 m². The mean BMI was approximately 26 kg/m². At baseline, 60.6%, 37.5% and 2.0% 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 3).

Table 3: Type 1 Diabetes Mellitus - Adults - Mean Change in HbA1c (ADMELOG plus Insulin Glargine, 100 units/mL, versus Comparator plus Insulin Glargine, 100 units/mL)

Treatment Duration Treatment in Combination with:	26 Weeks Insulin Glargine
	ADMELOG	Comparator
N*	253	254
HbA1c (%)
Baseline (mean)	8.08	7.99
Adjusted mean change from baseline*	-0.40	-0.46
Adjusted mean difference§	0.06
(95% CI)	(-0.086 to 0.201)
* ITT: Intent-to-treat; all randomized patients. ‡ Estimated using a multiple imputation method that models a “return to baseline” for patients having missing data who discontinued treatment. ANCOVA was used with treatment and stratification groups as fixed factors and baseline HbA1c as a covariate. § Treatment difference: ADMELOG -Comparator

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. 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 subjects was 31 years (range 12 to 70 years), and 47% were male. The population was 97% White.

Table 4: Type 1 Diabetes Mellitus - Adults and Pediatric Patients 12 Years of Age and Older - Mean Change in HbA1c% (another insulin lispro product, 100 units/mL, versus regular human insulin, 100 units/mL)

Treatment Duration Treatment in Combination with:	12 Months Human Insulin Extended Zinc
	Another Insulin Lispro Product	Regular Human Insulin
N	81	86
Baseline HbA1c (%)*	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)
* Values are Mean ± SD.

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 5).

Table 5: Type 1 Diabetes Mellitus - Pediatric Patients 9 Years of Age and Older - Mean Change in HbA1c (%) (another insulin lispro product, 100 units/mL, versus regular human insulin, 100 units/mL)

	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
* Values are Mean ± SD.

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.

Type 1 Diabetes Mellitus - Continuous Subcutaneous Infusion

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.

One study involved 39 patients, ages 19 to 58 years, treated for 24 weeks with another insulin lispro product, 100 units/mL, or regular human insulin 100 units/mL. After 12 weeks of treatment, the mean HbA1c values decreased from 7.8% to 7.2% in patients treated with another insulin lispro, and from 7.8% to 7.5% in the regular human insulin-treated patients.

Another study involved 60 patients (mean age 39, range 15 to 58 years) treated for 24 weeks with either another insulin lispro product, 100 units/mL, or buffered regular human insulin, 100 units/mL. After 12 weeks of treatment, the mean HbA1c values decreased from 7.7% to 7.4% in patients treated with insulin lispro, and remained unchanged from 7.7% in the buffered regular human insulin-treated patients.

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 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 6).

Table 6: Type 1 Diabetes Mellitus - Pediatric Patients 4 Years of Age and Older - Mean Change in HbA1c (%) (another insulin lispro product, 100 units/mL, versus insulin aspart, 100 units/mL) in Insulin Pump Study

Treatment duration	16 Weeks
	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)
* Values are Mean ± SD

Type 2 Diabetes Mellitus

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.-approved 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 subjects was 62.5 years, and 53.1% were male. The population was 88.3% White, 6.1% Black or African American and 17.8% 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 m² and 26.9% of patients had GFR >90 mL/min/1.73 m². The mean BMI was approximately 32.2 kg/m². At baseline, 51.4%, 48.2%, 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 7).

Table 7: Type 2 Diabetes Mellitus - Adults - Mean Change in HbA1c (%) (ADMELOG plus insulin glargine, 100 units/mL, versus comparator plus insulin glargine, 100 units/mL)

Treatment Duration Treatment in Combination with:	26 Weeks Insulin Glargine
	ADMELOG	Comparator
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)
* ITT: Intent-to-treat; all randomized patients. ‡ Estimated using a multiple imputation method that models a “return-to-baseline” for patients having missing data who discontinued treatment. ANCOVA was used with treatment and stratification groups as fixed factors and baseline HbA1c as a covariate. § Treatment difference: ADMELOG -Comparator

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. 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 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 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 8).

Table 8: Type 2 Diabetes Mellitus - Adults - Mean Change in HbA1c (%) (another insulin lispro product, 100 units/mL, versus regular human insulin, 100 units/mL)

Treatment Duration	Baseline	3 Months
		Another Insulin Lispro Product + Basal	Regular Human Insulin + Basal
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
* Values are Mean ± SD.

The following adverse reactions are also discussed elsewhere:

• Hypoglycemia [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity and allergic reactions [see WARNINGS AND PRECAUTIONS]
• Hypokalemia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

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].

The data in Table 1 reflect the exposure of 252 patients with type 1 diabetes to ADMELOG with mean exposure duration of 49 weeks. The type 1 diabetes population had the following characteristics: Mean age was 43 years and mean duration of diabetes was 20 years. Fifty-nine percent were male, 80% were White, 6% were Black or African American and 7% were Hispanic. At baseline, the mean eGFR was 90 mL/min/1.73 m² and 49% of patients had eGFR ≥90 mL/min/1.73 m². The mean BMI was 26 kg/m². The mean HbA1c at baseline was 8.07%.

Two hundred fifty-three patients with type 2 diabetes were exposed to ADMELOG with mean exposure duration of 25 weeks. The type 2 diabetes population had the following characteristics: Mean age was 62 years and mean duration of diabetes was 17 years. Fifty-four percent were male, 90% were White, 6% were Black or African American and 17% were Hispanic. At baseline, the mean eGFR was 77 mL/min/1.73 m² and 27% of patients had eGFR ≥90 mL/min/1.73 m². The mean BMI was 32 kg/m². The mean HbA1c at baseline was 7.99%.

Common adverse reactions were defined as reactions occurring 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) occurring in ≥5% of ADMELOG-treated patients (n=253) were observed.

Table 1: Adverse Reactions Occurring in ≥5% of ADMELOG-Treated Patients with Type 1 Diabetes in a 52-Week Trial

	ADMELOG + Insulin Glargine (100 units/mL), % (n=252)
Nasopharyngitis	13.1%
Upper respiratory tract infection	6.0%

Severe Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including ADMELOG [see WARNINGS AND PRECAUTIONS]. 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].

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. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy [see DOSAGE AND ADMINISTRATION].

Weight Gain

Weight gain can occur with insulin therapy, including ADMELOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

Peripheral Edema

Insulin, 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)

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 children and adolescents with type 1 diabetes, adverse event reports related to infusion-site reactions for another insulin lispro product, 100 units/mL, occurred in 21% of patients. 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 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].

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with ADMELOG may develop anti-insulin antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, the incidence of antibodies to ADMELOG in the studies described below cannot be directly compared with the incidence of antibodies in other studies or to other products.

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).

Postmarketing Experience

The following additional adverse reactions have been identified during postapproval 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 postapproval use [see Patient Counseling Information].

Read the entire FDA prescribing information for Admelog (Insulin Lispro Injection)

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