APIDRA®(insulin glulisine [rDNA origin] injection)

apidra (insulin glulisineinjection, solution 
[sanofi-aventis U.S. LLC]

DESCRIPTION

APIDRA® (insulin glulisine [rDNA origin] injection) is a human insulin analog that is a rapid-acting, parenteral blood glucose lowering agent. Insulin glulisine is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. Chemically, it is 3B-lysine-29B-glutamic acid-human insulin, has the empirical formula C258H384N64O78S6 and a molecular weight of 5823. It has the following structural formula:

Image from Drug Label Content

APIDRA is a sterile, aqueous, clear, and colorless solution. Each milliliter of APIDRA (insulin glulisine [rDNA origin] injection) contains 100 IU (3.49 mg) insulin glulisine, 3.15 mg m-cresol, 6 mg tromethamine, 5 mg sodium chloride, 0.01 mg polysorbate 20, and water for injection. APIDRA has a pH of approximately 7.3. The pH is adjusted by addition of aqueous solutions of hydrochloric acid and/or sodium hydroxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

The primary activity of insulins and insulin analogs, including insulin glulisine, is regulation of glucose metabolism. Insulins lower blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis in the adipocyte, inhibit proteolysis, and enhance protein synthesis.

The glucose lowering activities of APIDRA and of regular human insulin are equipotent when administered by the intravenous route. After subcutaneous administration, the effect of APIDRA is more rapid in onset and of shorter duration compared to regular human insulin.

Pharmacokinetics

Absorption and Bioavailability

Pharmacokinetic profiles in healthy volunteers and patients with diabetes (type 1 or type 2) demonstrated that absorption of insulin glulisine was faster than regular human insulin.

In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15 IU/kg, the median time to maximum concentration (Tmax) was 55 minutes (range 34 to 91 minutes) and the peak concentration (Cmax) was 82 µIU/mL (range 42 to 134 µIU/mL) for insulin glulisine compared to a median Tmax of 82 minutes (range 52 to 308 minutes) and a Cmax of 46 µIU/mL (range 32 to 70 µIU/mL) for regular human insulin. The mean residence time of insulin glulisine was shorter(median: 98 minutes, range 55 to 149 minutes) than for regular human insulin (median: 161 minutes, range 133 to 193 minutes). (See Figure 1.)

Figure 1. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with type 1 diabetes after a dose of 0.15 IU/kg.

Image from Drug Label Content

In a euglycemic clamp study in patients with type 2 diabetes (n=24) with a body mass index (BMI) between 20 to 36 kg/m2 after subcutaneous administration of 0.2 IU/kg, the median time to maximum concentration (Tmax) was 89 minutes (range 74 to 103 minutes) and the median peak concentration (Cmax) was 81µIU/mL (range 75 to 112 µIU/mL) for insulin glulisine compared to a median Tmax of 94 minutes (range 55 to140 minutes) and a median Cmax of 39 µIU/mL (range 30 to 56 µIU/mL) for regular human insulin. The mean residence time of insulin glulisine was shorter (median: 154 minutes, range 122 to 174 minutes) than for regular human insulin (median: 280 minutes, range 227 to 294 minutes).

Figure 2. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with type 2 diabetes after a dose of 0.2 IU/kg.

Image from Drug Label Content

In a euglycemic clamp study in obese, non-diabetic subjects (n=18) with a body mass index (BMI) between 30 to 40 kg/m2 after subcutaneous administration of 0.3 IU/kg, the median time to maximum concentration (Tmax) was 76 minutes (range 51 to 118 minutes) and the median peak concentration (Cmax) was 199 µIU/mL (range 99 to 387 µIU/mL) for insulin glulisine compared to a median Tmax of 144 minutes (range 110 to 207 minutes) and a median Cmax of 79 µIU/mL (range 39 to 166 µIU/mL) for regular human insulin. The mean residence time of insulin glulisine was shorter (median: 141 minutes, range 105 to 210 minutes) than for regular human insulin (median: 226 minutes, range 188 to 293 minutes).

When APIDRA was injected subcutaneously into different areas of the body, the time-concentration profiles were similar. The absolute bioavailability of insulin glulisine after subcutaneous administration is about 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%).

Distribution and Elimination

The distribution and elimination of insulin glulisine and regular human insulin after intravenous administration are similar with volumes of distribution of 13 and 21 L and half-lives of 13 and 17 minutes, respectively. After subcutaneous administration, insulin glulisine is eliminated more rapidly than regular human insulin with an apparent half-life of 42 minutes compared to 86 minutes.

Pharmacodynamics

Studies in healthy volunteers and patients with diabetes demonstrated that APIDRA has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously.

In a study in patients with type 1 diabetes (n= 20), the glucose-lowering profiles of APIDRA and regular human insulin were assessed at various times in relation to a standard meal at a dose of 0.15 IU/kg. (See Figure 3.)

Figure 3. Serial mean blood glucose collected up to 6 hours following single dose of APIDRA and regular human insulin. APIDRA given 2 minutes (APIDRA - pre) before the start of a meal compared to regular human insulin given 30 minutes (Regular - 30 min) before start of the meal (Figure 3A) and compared to regular human insulin (Regular - pre) given 2 minutes before a meal (Figure 3B). APIDRA given 15 minutes (APIDRA - post) after start of a meal compared to regular human insulin (Regular - pre) given 2 minutes before a meal (Figure 3C). On the x-axis zero (0) is the start of a 15-minute meal.

Image from Drug Label ContentImage from Drug Label Content
Image from Drug Label ContentImage from Drug Label Content

The maximum blood glucose excursion (ΔGLUmax; baseline subtracted glucose concentration) for APIDRA injected 2 minutes before meal was 65 mg/dL compared to 64 mg/dL for regular human insulin injected 30 minutes before meal (see Figure 3A), and 84 mg/dL for regular human insulin injected 2 minutes before meal (see Figure 3B). The maximum blood glucose excursion for APIDRA injected 15 minutes after the start of a meal was 85 mg/dL compared to 84 mg/dL for regular human insulin injected 2 minutes before meal (see Figure 3C).

Special Populations

Pediatric Patients

The pharmacokinetic and pharmacodynamic properties of APIDRA and regular human insulin were assessed in a study conducted in pediatric patients with type 1 diabetes (children [7 to 11 years, n = 10] and adolescents [12 to 16 years, n = 10]). The relative differences in pharmacokinetics and pharmacodynamics between APIDRA and regular human insulin in pediatric patients with type 1 diabetes were similar to those in healthy adult subjects and adults with type 1 diabetes.

Gender

Information on the effect of gender on the pharmacokinetics of APIDRA is not available.

Race

A study was performed in 24 healthy Caucasians and Japanese to compare the pharmacokinetic and pharmacodynamic parameters after subcutaneous injection of insulin glulisine, insulin lispro, and regular human insulin. With subcutaneous injection of insulin glulisine, Japanese subjects had a greater initial exposure (33%) for the ratio of AUC(0-1h) to AUC(0-clamp end) than that in Caucasians (21%) though the total exposures were similar. Similar findings were observed with insulin lispro and regular human insulin for the racial difference.

Obesity

The more rapid onset of action and shorter duration of activity of APIDRA and insulin lispro compared to regular human insulin were maintained in an obese non-diabetic population (n= 18). (See Figure 4.)

Figure 4. Glucose infusion rates (GIR) in a euglycemic clamp study after subcutaneous injection of 0.3 IU/kg of APIDRA, insulin lispro or regular human insulin in an obese population.

Image from Drug Label Content

Renal Impairment

Studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. In a study performed in 24 non-diabetic subjects covering a wide range of renal function (ClCr >80 mL/min; 30-50 mL/min; <30 mL/min), the subjects with moderate and severe renal impairment showed increased exposure to insulin glulisine by 29% to 40% and reduced clearance of insulin glulisine by 20% to 25% compared to normal subjects. Careful glucose monitoring and dose adjustments of insulin, including APIDRA, may be necessary in patients with renal dysfunction. (See PRECAUTIONS, Renal Impairment.)

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of APIDRA has not been studied. 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 APIDRA, may be necessary in patients with hepatic dysfunction. (See PRECAUTIONS, Hepatic Impairment.)

Pregnancy

The effect of pregnancy on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied. (See PRECAUTIONS, Pregnancy.)

Smoking

The effect of smoking on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied.

CLINICAL STUDIES

The safety and efficacy of APIDRA was studied in adult patients with type 1 and type 2 diabetes (n =1833). The primary efficacy parameter was glycemic control, as measured by glycated hemoglobin (GHb), and expressed as hemoglobin A1c equivalents (HbA1c).

Type 1 Diabetes

A 26-week, randomized, open-label, active-control study was conducted in patients with type 1 diabetes to assess the safety and efficacy of APIDRA (n= 339) compared to insulin lispro (n= 333) when administered subcutaneously within 15 minutes before a meal. Lantus® (insulin glargine [rDNA origin] injection) was administered once daily in the evening as the basal insulin. There was a 4-week run-in period combining insulin lispro and Lantus followed by randomization. Most patients were Caucasian (97%). Fifty eight percent of the patients were male. The mean age was 38.5 years (range 18 to 74 years). Glycemic control (see Table 1) and the rates of hypoglycemia requiring intervention from a third party (see Adverse Reactions), were comparable for the two treatment regimens. The number of daily short-acting insulin injections and the total daily doses of APIDRA and insulin lispro were similar. (See Table 1.)

Table 1: Type 1 Diabetes Mellitus–Adult
Treatment duration
Treatment in combination with:
26 weeks
Lantus®
APIDRAInsulin Lispro
HbA1c (%)
  Number of patients

331

322
  Baseline mean7.607.58
  Adj. mean change from baseline-0.14-0.14
    APIDRA – Insulin Lispro0.00
    95% CI for treatment difference(-0.09; 0.10)
Basal insulin dose (IU/day)
  Endstudy mean24.1626.43
  Adj. mean change from baseline0.121.82
Short-acting insulin dose (IU/day)
  Endstudy mean29.0330.12
  Adj. mean change from baseline-1.07-0.81
   
Mean number of short-acting insulin injections per day3.363.42

Type 2 Diabetes

A 26-week, randomized, open-label, active-control study was conducted in insulin-treated patients with type 2 diabetes to assess the safety and efficacy of APIDRA (n= 435) given within 15 minutes before a meal compared to regular human insulin (n=441) administered 30 to 45 minutes prior to a meal. NPH human insulin was given twice a day as the basal insulin. All patients participated in a 4-week run-in period combining regular human insulin and NPH human insulin. Eighty-five percent of patients were Caucasian and 11% were Black. The mean age was 58.3 years (range 26 to 84 years). The average body mass index (BMI) was 34.55 kg/m2. At randomization, 58% of the patients were on an oral antidiabetic agent and were instructed to continue use of their oral antidiabetic agent at the same dose. The majority of patients (79%) mixed their short-acting insulin with NPH human insulin immediately prior to injection. The reductions from baseline in HbA1c were similar between treatment groups (see Table 2). The rates of hypoglycemia, requiring intervention from a third party, were comparable for the two treatment regimens (see Adverse Reactions). No differences between APIDRA and regular human insulin groups were seen in the number of daily short-acting insulin injections or basal or short-acting insulin doses. (See Table 2.)

Table 2: Type 2 Diabetes Mellitus–Adult
Treatment duration26 weeks
Treatment in combination with:NPH human insulin
APIDRARegular Human Insulin
HbA1c (%)
  Number of patients

404

403
  Baseline mean7.577.50
  Adj. mean change from baseline-0.46-0.30
    APIDRA – Regular Human Insulin-0.16
    95% CI for treatment difference(-0.26; -0.05)
Basal insulin dose (IU/day)
  Endstudy mean65.3463.05
  Adj. mean change from baseline5.736.03
Short-acting insulin dose (IU/day)
  Endstudy mean35.9936.16
  Adj. mean change from baseline3.695.00
   
Mean number of short-acting insulin injections per day2.272.24

Pre- and Post-Meal Administration (Type 1 Diabetes)

A 12-week, randomized, open-label, active-control study was conducted in patients with type 1 diabetes to assess the safety and efficacy of APIDRA administered at different times with respect to a meal. APIDRA was administered subcutaneously either within 15 minutes before a meal (n=286) or immediately after a meal (n=296) and regular human insulin (n= 278) was administered subcutaneously 30 to 45 minutes prior to a meal. Lantus® was administered once daily at bedtime as the basal insulin. There was a 4-week run-in period combining regular human insulin and Lantus followed by randomization. Most patients were Caucasian (94%). The mean age was 40.3 years (range 18 to 73 years). Glycemic control (see Table 3) and the rates of hypoglycemia requiring intervention from a third party (see Adverse Reactions) were comparable for the treatment regimens. No changes from baseline between the treatments were seen in the total daily number of short-acting insulin injections. (See Table 3.)

Table 3: Type 1 Diabetes Mellitus–Adult
Treatment duration
Treatment in combination with:
12 weeks
Lantus®
12 weeks
Lantus®
12 weeks
Lantus®
APIDRA
pre meal
APIDRA
post meal
Regular Human
Insulin
*
Adj. mean change from baseline treatment difference (98.33% CI for treatment difference): APIDRA pre meal vs. Regular Human Insulin - 0.13 (-0.26; 0.01); APIDRA post meal vs. Regular Human Insulin 0.02 (-0.11; 0.16); APIDRA post meal vs. pre meal 0.15 (0.02; 0.29).
HbA1c (%)
  Number of patients

268

276

257
  Baseline mean7.737.707.64
  Adj. mean change from baseline*-0.26-0.11-0.13
Basal insulin dose (IU/day)
  Endstudy mean29.4928.7728.46
  Adj. mean change from baseline0.990.240.65
Short-acting insulin dose (IU/day)
  Endstudy mean28.4428.0629.23
  Adj. mean change from baseline-0.88-0.471.75
    
Mean number of short-acting insulin injections per day3.153.133.03

Continuous Subcutaneous Insulin Infusion (CSII) (Type 1 Diabetes)

To evaluate the use of APIDRA for administration using an external pump, a 12-week randomized, active control study (APIDRA versus insulin aspart) was conducted in patients with type 1 diabetes (APIDRA n= 29, insulin aspart n=30). All patients were Caucasian. The mean age was 45.8 years (range 21 to 73 years). Glycemic control (mean HbA1c value at endpoint 6.98% with APIDRA and 7.18% with insulin aspart) and the rates of hypoglycemia requiring intervention from a third party were comparable for the two treatment regimens.

INDICATIONS AND USAGE

APIDRA is indicated for the treatment of adult patients with diabetes mellitus for the control of hyperglycemia.

APIDRA has a more rapid onset of action and a shorter duration of action than regular human insulin. APIDRA should normally be used in regimens that include a longer-acting insulin or basal insulin analog. (See WARNINGS and DOSAGE AND ADMINISTRATION.)

APIDRA may also be infused subcutaneously by external insulin infusion pumps. (See WARNINGS, PRECAUTIONS, Usage in Pumps, Information for Patients, Mixing of Insulins, DOSAGE AND ADMINISTRATION, HOW SUPPLIED, Storage.)

CONTRAINDICATIONS

APIDRA is contraindicated during episodes of hypoglycemia and in patients hypersensitive to APIDRA or one of its excipients.

WARNINGS

APIDRA differs from regular human insulin by its rapid onset of action and shorter duration of action. When used as a meal time insulin, the dose of APIDRA should be given within 15 minutes before a meal or within 20 minutes after starting a meal.

Because of the short duration of action of APIDRA, patients with diabetes also require a longer-acting insulin or insulin infusion pump therapy to maintain adequate glucose control.

Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analogs), or species (animal, human) may result in the need for a change in dose. Concomitant oral antidiabetic treatment may need to be adjusted.

Glucose monitoring is recommended for all patients with diabetes.

Hypoglycemia is the most common adverse effect of insulin therapy, including APIDRA. The timing of hypoglycemia may differ among various insulin formulations.

Insulin Pumps: When used in an external insulin pump for subcutaneous infusion, APIDRA should not be diluted or mixed with any other insulin. Physicians and patients should carefully evaluate information on pump use in the APIDRA prescribing information, Patient Information Leaflet, and the pump manufacturer's manual. APIDRA-specific information should be followed for in-use time, frequency of changing infusion sets, or other details specific to APIDRA usage, because APIDRA-specific information may differ from general pump manual instructions. Pump or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a short time. This is especially pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim therapy with subcutaneous injection may be required. (See PRECAUTIONS, Usage in Pumps, Information for Patients, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and HOW SUPPLIED, Storage.)

PRECAUTIONS

General

As with all insulin preparations, the time course of APIDRA action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity.

Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan.

Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances, or stress.

Hypoglycemia

As with all insulin preparations, hypoglycemic reactions may be associated with the administration of APIDRA. 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 long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control. (See PRECAUTIONS, Drug Interactions.)

Such situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to patient's awareness of hypoglycemia.

Renal Impairment

The requirements for APIDRA may be reduced in patients with renal impairment. (See CLINICAL PHARMACOLOGY, Special Populations.)

Hepatic Impairment

Studies have not been performed in patients with hepatic impairment. APIDRA requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism, similar to observations found with other insulins. (See CLINICAL PHARMACOLOGY, Special Populations.)

Allergy

Local Allergy

As with other insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. 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

Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reactions, may be life threatening.

In controlled clinical trials up to 12 months, potential systemic allergic reactions were reported in 79 of 1833 patients (4.3%) who received APIDRA and 58 of 1524 patients (3.8%) who received the comparator short-acting insulins. During these trials treatment with APIDRA was permanently discontinued in 1 of 1833 patients due to a potential systemic allergic reaction.

Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.

As with any insulin therapy, lipodystrophy may occur at the injection site and delay insulin absorption.

Antibody Production

In a study in patients with type 1 diabetes (n=333), the concentrations of insulin antibodies that react with both human insulin and insulin glulisine (cross-reactive insulin antibodies) remained near baseline during the first 6 months of the study in the patients treated with APIDRA. A decrease in antibody concentration was observed during the following 6 months of the study. In a study in patients with type 2 diabetes (n=411), a similar increase in cross-reactive insulin antibody concentration was observed in the patients treated with APIDRA and in the patients treated with human insulin during the first 9 months of the study. Thereafter the concentration of antibodies decreased in the APIDRA patients and remained stable in the human insulin patients. There was no correlation between cross-reactive insulin antibody concentration and changes in HbA1c, insulin doses, or incidences of hypoglycemia.

Usage in Pumps

APIDRA has been studied in the following pumps and infusion sets: Disetronic® H-Tron® plus V100 and D-Tron®with Disetronic catheters (Rapid, Rapid C, Rapid D, and Tender); MiniMed® Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate QR, and Quick-set).

Based on in vitro studies which have shown loss of m-cresol, and insulin degradation, APIDRA should not be used beyond 48 hours at 98.6°F (37°C) in infusion sets and reservoirs. APIDRA in clinical use should not be exposed to temperatures greater than 98.6°F (37°C). APIDRA should not be mixed with other insulins or with a diluent when used in the pump. (See WARNINGS, PRECAUTIONS, Information for Patients, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and HOW SUPPLIED, Storage.)

Information for Patients

For all patients

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and hypoglycemia and hyperglycemia management. Patients must be instructed on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, or skipped meals. Refer patients to the APIDRA Patient Information Leaflet for additional information.

Women with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy.

For patients using pumps

Patients using external pump infusion therapy should be trained appropriately. APIDRA has been studied in the following pumps and infusion sets: Disetronic H-Tron plus V100 and D-Tron with Disetronic catheters (Rapid, Rapid C, Rapid D, and Tender); MiniMed Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate QR, and Quick-set).

To minimize insulin degradation, infusion set occlusion, and loss of the preservative (m-cresol), the infusion sets (reservoir, tubing, and catheter) and the APIDRA in the reservoir should be replaced every 48 hours or less and a new infusion site should be selected. The temperature of the insulin may exceed ambient temperature when the pump housing, cover, tubing or sport case is exposed to sunlight or radiant heat. Insulin exposed to temperatures higher than 98.6°F (37°C) should be discarded. Infusion sites that are erythematous, pruritic, or thickened should be reported to the healthcare professional, and a new site selected because continued infusion may increase the skin reaction and/or alter the absorption of APIDRA.

Pump or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a short time. This is especially pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump malfunction may occur. If these problems cannot be promptly corrected, patients should resume therapy with subcutaneous insulin injection and contact their healthcare professional. (See WARNINGS, PRECAUTIONS, Usage in Pumps, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and HOW SUPPLIED, Storage.)

Drug Interactions

A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.

The following are examples of substances that may reduce the blood-glucose-lowering effect of insulin: corticosteroids, danazol, diazoxide, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors, and atypical antipsychotic medications (e.g., olanzepine and clozapine).

The following are examples of substances that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates, sulfonamide antibiotics.

Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent.

Mixing of Insulins

In a clinical study in healthy volunteers (n=32) the total insulin glulisine bioavailability was similar after subcutaneous injection of insulin glulisine and NPH insulin (premixed in the syringe) and following separate simultaneous subcutaneous injections. There was some attenuation (27%) of the maximum concentration (Cmax) after premixing, however the time to maximum concentration (Tmax) was not affected.

If APIDRA is mixed with NPH human insulin, APIDRA should be drawn into the syringe first. Injection should be made immediately after mixing.

No data are available on mixing APIDRA with insulin preparations other than NPH. (See CLINICAL STUDIES.) APIDRA should not be mixed with insulin preparations other than NPH.

Mixtures should not be administered intravenously.

The effects of mixing APIDRA with diluents or other insulins when used in external subcutaneous infusion pumps for insulin have not been studied. Therefore, APIDRA should not be mixed in these instances.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed. In Sprague Dawley rats, a 12-month repeat dose toxicity study was conducted with insulin glulisine at subcutaneous doses of 2.5, 5, 20 or 50 IU/kg twice daily (dose resulting in an exposure 1, 2, 8, and 20 times the average human dose, based on body surface area comparison).

There was a non-dose dependent higher incidence of mammary gland tumors in female rats administered insulin glulisine compared to untreated controls. The incidence of mammary tumors for insulin glulisine and regular human insulin was similar. The relevance of these findings to humans is not known.

Insulin glulisine was not mutagenic in the following tests: Ames test, in vitro mammalian chromosome aberration test in V79 Chinese hamster cells, and in vivo mammalian erythrocyte micronucleus test in rats.

In fertility studies in male and female rats at subcutaneous doses up to 10 IU/kg once daily (dose resulting in an exposure 2 times the average human dose, based on body surface area comparison), no clear adverse effects on male and female fertility, or general reproductive performance of animals were observed.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Reproduction and teratology studies have been performed with insulin glulisine in rats and rabbits using regular human insulin as a comparator.

The drug was given to female rats throughout pregnancy at subcutaneous doses up to 10 IU/kg once daily (dose resulting in an exposure 2 times the average human dose, based on body surface area comparison). Insulin glulisine did not have any remarkable toxic effects on the embryo-fetal development in rats.

The drug was given to female rabbits throughout pregnancy at subcutaneous doses up to 1.5 IU/kg/day (dose resulting in an exposure 0.5 times the average human dose, based on body surface area comparison). Adverse effects on embryo-fetal development were only seen at maternal toxic dose levels inducing hypoglycemia. Increased incidence of post-implantation losses and skeletal defects were observed at a dose level of 1.5 IU/kg once daily (dose resulting in an exposure 0.5 times the average human dose, based on body surface area comparison) that also caused mortality in dams. A slight increased incidence of post-implantation losses was seen at the next lower dose level of 0.5 IU/kg once daily (dose resulting in an exposure 0.2 times the average human dose, based on body surface area comparison) which was also associated with severe hypoglycemia but there were no defects at that dose. No effects were observed in rabbits at a dose of 0.25 IU/kg once daily (dose resulting in an exposure 0.1 times the average human dose, based on body surface area comparison). The effects of insulin glulisine did not differ from those observed with subcutaneous regular human insulin at the same doses and were attributed to secondary effects of maternal hypoglycemia.

There are no well-controlled clinical studies of the use of insulin glulisine in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. 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 such patients.

Nursing Mothers

It is unknown whether insulin glulisine is excreted in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when APIDRA is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in APIDRA dose, meal plan, or both.

Pediatric Use

Safety and effectiveness of APIDRA in pediatric patients have not been established.

Geriatric Use

In Phase III clinical trials (n=2408), APIDRA was administered to 147 patients ≥65 years of age and 27 patients ≥75 years of age. The majority of these were patients with type 2 diabetes. The change in HbA1c values and hypoglycemia frequencies did not differ by age, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS

Overall, clinical studies comparing APIDRA with short-acting insulins did not demonstrate a difference in frequency of adverse events.

Adverse events commonly associated with human insulin therapy include the following:

Body as a whole: allergic reactions. (See PRECAUTIONS.)

Skin and appendages: injection site reaction, lipodystrophy, pruritus, rash. (See PRECAUTIONS.)

Other: hypoglycemia. (See WARNINGS and PRECAUTIONS.)

The rates and incidence of severe symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party, were comparable for all treatment regimens (see Table 4).

Table 4: Severe Symptomatic Hypoglycemia
Type 1 Diabetes – Mellitus Adult 12 weeks in combination with Lantus®*Type 1 Diabetes Mellitus– Adult 26 weeks in combination with Lantus®Type 2 Diabetes Mellitus– Adult 26 weeks in combination with NPH human insulin
APIDRA Pre-mealAPIDRA Post-mealRegular Human InsulinAPIDRAHumalog®APIDRARegular Human Insulin
*
Entire treatment phase (3 months) has been included.
Last three months of treatment have been considered.
Severe symptomatic hypoglycemia
(events/month/patient)
0.050.050.130.020.020.000.00
Severe symptomatic hypoglycemia
Percent of patients (n/total N)
8.4%
(24/286)
8.4%
(25/296)
10.1%
(28/278)
4.8%
(16/335)
4.0%
(13/326)
1.4%
(6/416)
1.2%
(5/420)

Continuous Subcutaneous Insulin Infusion (CSII) (Type 1 Diabetes): The rates of catheter occlusions and infusion site reactions were similar for APIDRA and Novolog® (see Table 5).

Table 5: Catheter Occlusions and Infusion Site Reactions.
APIDRANovolog®
Catheter occlusions/month0.080.15
Infusion site reactions10.3% (3/29)13.3% (4/30)

OVERDOSAGE

Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both.

Mild/Moderate episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed.

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.

DOSAGE AND ADMINISTRATION

APIDRA is a recombinant insulin analog that has been shown to be equipotent to human insulin. One unit of APIDRA has the same glucose-lowering effect as one unit of regular human insulin. After subcutaneous administration, it has a more rapid onset and shorter duration of action.

APIDRA should be given within 15 minutes before a meal or within 20 minutes after starting a meal.

APIDRA is intended for subcutaneous administration and for use by external infusion pump.

The dosage of APIDRA should be individualized and determined based on the physician's advice in accordance with the needs of the patient. APIDRA should normally be used in regimens that include a longer-acting insulin or basal insulin analog.

APIDRA should be administered by subcutaneous injection in the abdominal wall, the thigh or the deltoid or by continuous subcutaneous infusion in the abdominal wall. As with all insulins, injection sites and infusion sites within an injection area (abdomen, thigh or deltoid) should be rotated from one injection to the next.

As for all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by injection site, exercise and other variables. Blood glucose monitoring is recommended for all patients with diabetes.

Preparation and Handling

Parenteral drug products should be inspected visually prior to administration whenever the solution and the container permit. APIDRA must only be used if the solution is clear and colorless with no particles visible.

When it is used in a pump, APIDRA should not be mixed with other insulins or with a diluent.

* Cartridge system: If OptiClik®, the Insulin Delivery Device for APIDRA, malfunctions, APIDRA may be drawn from the cartridge system into a U-100 syringe and injected.

HOW SUPPLIED

APIDRA 100 units per mL (U-100) is available in the following package size:

*
Cartridge systems are for use only in OptiClik® (Insulin Delivery Device)
10 mL vials(NDC 0088-2500-33)
3 mL cartridge system*, package of 5(NDC 0088-2500-52)

Storage

Unopened Vial/Cartridge System

Unopened APIDRA vials and cartridge systems should be stored in a refrigerator, 36°F–46°F (2°C–8°C). Protect from light. APIDRA should not be stored in the freezer and it should not be allowed to freeze. Discard if it has been frozen.

Open (In-Use) Vial

Opened vials, whether or not refrigerated, must be used within 28 days. They must be discarded if not used within 28 days. If refrigeration is not possible, the open vial in use can be kept unrefrigerated for up to 28 days away from direct heat and light, as long as the temperature is not greater than 77°F (25°C).

Open (In-Use) Cartridge System

The opened (in-use) cartridge system inserted in OptiClik® should NOT be refrigerated but should be kept below 77°F (25°C) away from direct heat and light. The opened (in-use) cartridge system must be discarded after 28 days. Do not store OptiClik®, with or without cartridge system, in a refrigerator at any time.

Not in-use
(unopened) Refrigerated
Not in-use (unopened) Below 77°F (25°C)In-use (opened)
Refrigerated or below 77°F
(25°C)
10 mL VialUntil expiration date28 days28 days,
3 mL Cartridge systemUntil expiration date28 days28 days
3 mL Cartridge system inserted in OptiClik®28 days
below 77°F (25°C) only (Do not refrigerate)

Infusion sets

Infusion sets (reservoirs, tubing, and catheters) and the APIDRA in the reservoir should be discarded after no more than 48 hours of use or after exposure to temperatures that exceed 98.6°F (37°C).

Rev. November 2005

Manufactured by:
Aventis Pharma Deutschland GmbH
D-65926 Frankfurt am Main
Frankfurt, Germany

Manufactured for:
Aventis Pharmaceuticals Inc.
Kansas City, MO 64137 USA
a member of the sanofi-aventis Group
Bridgewater, NJ 08807

www.aventis-us.com

©2005 Aventis Pharmaceuticals Inc.

OptiClik® and Lantus® are registered trademarks of Aventis Pharmaceuticals Inc.

The brands listed are the registered trademarks of their respective owners and are not trademarks of Aventis Pharmaceuticals Inc.

Patient Information
APIDRA®10 mL vial (1000 units per vial) 100 units per mL (U-100)
(insulin glulisine [recombinant DNA origin] injection)

Read this "Patient Information" that comes with APIDRA (uh-PEE-druh) before you start using it and each time you get a refill because there may be new information. This leaflet does not take the place of talking with your healthcare provider about your condition or treatment. If you have questions about APIDRA or about diabetes, talk with your healthcare provider.

What is the most important information I should know about APIDRA?

What is diabetes?

What is APIDRA?

Who should not take APIDRA?

Do not take APIDRA if you are allergic to insulin glulisine or any of the inactive ingredients in APIDRA. Check with your healthcare provider if you are not sure.

Before starting APIDRA, tell your healthcare provider about all your medical problems including if you:

How should I use APIDRA?

See "Instructions for Use"" including the sections "How do I draw the insulin into the syringe?" and "How should I infuse APIDRA with an external subcutaneous insulin infusion pump?" for additional information.

What kind of syringe should I use?

Mixing with APIDRA

Instructions for Use

How do I draw the insulin into the syringe?

Follow these steps:

1.
Wash your hands.
2.
Check the insulin to make sure it is clear and colorless. Do not use the insulin after the expiration date stamped on the label, if it is colored or cloudy or if you see particles in the solution.
3.
If you are using a new vial, remove the protective cap. Do not remove the stopper.

Image from Drug Label Content

4.
Wipe the top of the vial with an alcohol swab. You do not have to shake the vial of APIDRA before use.

Image from Drug Label Content

5.
Use a new needle and syringe every time you give an injection. Use disposable syringes and needles only once. Throw them away properly. Never share needles and syringes.
6.
Draw air into the syringe equal to your insulin dose. Put the needle through the rubber top of the vial and push the plunger to inject the air into the vial.

Image from Drug Label Content                                Image from Drug Label Content

7.
Leave the syringe in the vial and turn both upside down. Hold the syringe and vial firmly in one hand.
8.
Make sure the tip of the needle is in the insulin. With your free hand, pull the plunger to withdraw the correct dose into the syringe.

Image from Drug Label Content

9.
Before you take the needle out of the vial, check the syringe for air bubbles. If bubbles are in the syringe, hold the syringe straight up and tap the side of the syringe until the bubbles float to the top. Push the bubbles out with the plunger and draw insulin back in until you have the correct dose. If you are mixing APIDRA with NPH insulin, check with your healthcare professional on how to mix.

Image from Drug Label Content

10.
Remove the needle from the vial. Do not let the needle touch anything. You are now ready to inject.

For information on mixing insulins, see section "Mixing with Apidra".

How do I inject APIDRA?

Inject APIDRA under your skin. Take APIDRA as prescribed by your healthcare provider.

Follow these steps:

1.
Decide on an injection area - either upper arm, thigh or abdomen. Injection sites within an injection area must be different from one injection to the next.
2.
Use alcohol or soap and water to clean the injection site. The injection site should be dry before you inject.

Image from Drug Label Content

3.
Pinch the skin. Stick the needle in the way your healthcare provider showed you. Release the skin.
4.
Slowly push in the plunger of the syringe all the way, making sure you have injected all the insulin. Leave the needle in the skin for about 10 seconds.

Image from Drug Label Content

Pull the needle straight out and gently press on the spot where you injected yourself for several seconds. Do not rub the area.

5.
Follow your healthcare provider’s instructions for throwing away the needle and syringe. Do not recap the used needle. The used needle and syringe should be placed in sharps containers (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.

How should I infuse APIDRA with an external subcutaneous insulin infusion pump?

Do not mix APIDRA with any other insulin or liquid when used in a pump.

The infusion set, reservoir with insulin, and infusion site should be changed:

What can affect how much insulin I need?

Illness. Illness may change how much insulin you need. It is a good idea to think ahead and make a "sick day" plan with your healthcare provider in advance so you will be ready when this happens. Be sure to test your blood sugar more often and call your healthcare provider if you are sick.

Medicines. Many medicines can affect your insulin needs. Other medicines, including prescription and non-prescription medicines, vitamins and herbal supplements, can change the way insulin works. You may need a different dose of insulin when you are taking certain other medicines. Know all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. You may want to keep a list of the medicines you take. You can show this list to all your healthcare providers and pharmacists anytime you get a new medicine or refill. Your healthcare provider will tell you if your insulin dose needs to be changed.

Meals. The amount of food you eat can affect your insulin needs. If you eat less food, skip meals, or eat more food than usual, you may need a different dose of insulin. Talk to your healthcare provider if you change your diet so that you know how to adjust your APIDRA and other insulin doses.

Alcohol. Alcohol, including beer and wine, may affect the way APIDRA works and affect your blood sugar levels. Talk to your healthcare providerabout drinking alcohol.

Exercise or Activity level. Exercise or activity level may change the way your body uses insulin. Check with your healthcare provider before you start an exercise program because your dose may need to be changed.

Travel. If you travel across time zones, talk with your healthcare professional about how to time your injections. When you travel, wear your medical alert identification. Take extra insulin and supplies with you.

Pregnancy or nursing. The effects of APIDRA on an unborn child or on a nursing baby are unknown. Therefore, tell your healthcare provider if you are planning to have a baby, are pregnant, or nursing a baby. Good control of diabetes is especially important during pregnancy and nursing.

What are the possible side effects of APIDRA and other insulins?

Insulins, including APIDRA, can cause hypoglycemia (low blood sugar), hyperglycemia (high blood sugar), allergy, and skin reactions.

Hypoglycemia (low blood sugar):

Hypoglycemia is often called an "insulin reaction" or "low blood sugar". It may happen when you do not have enough sugar in your blood. Common causes of hypoglycemia are illness, emotional or physical stress, too much insulin, too little food or missed meals, and too much exercise or activity.

Early warning signs of hypoglycemia may be different, less noticeable or not noticeable at all in some people. That is why it is important to check your blood sugar as you have been advised by your healthcare provider.

Hypoglycemia can happen with:

Hypoglycemia can be mild to severe. Its onset may be rapid. Some patients have few or no warning symptoms, including:

Hypoglycemia may reduce your ability to drive a car or use mechanical equipment and you may risk injury to yourself or others.

Severe hypoglycemia can be dangerous and can cause temporary or permanent harm to your heart or brain. It may cause unconsciousness, seizures, or death.

Symptoms of hypoglycemia may include:

If you have hypoglycemia often or it is hard for you to know if you have the symptoms of hypoglycemia, talk to your healthcare provider.

Mild to moderate hypoglycemia is treated by eating or drinking carbohydrates such as fruit juice, raisins, sugar candies, milk, or glucose tablets. Talk to your healthcare provider about the amount of carbohydrates you should eat to treat mild to moderate hypoglycemia.

Severe hypoglycemia may require the help of another person or emergency medical people. A person with hypoglycemia who is unable to take foods or liquids with sugar by mouth, or is unconscious needs medical help fast and will need treatment with a glucagon injection or glucose given intravenously (IV). Without medical help right away, serious reactions or even death could happen.

Hyperglycemia (high blood sugar):

Hyperglycemia happens when you have too much sugar in your blood. Usually, it means there is not enough insulin to break down the food you eat into energy your body can use. Hyperglycemia can be caused by a fever, an infection, stress, eating more than you should, taking less insulin than prescribed, or it can mean your diabetes is getting worse.

Hyperglycemia can happen with:

For pump users, this can also be caused when the bolus dose of APIDRA infusion or the basal infusion is set too low or the pump is delivering too little insulin.

Testing your blood or urine often will let you know if you have hyperglycemia. If your tests are often high, tell your healthcare provider so your dose of insulin can be changed.

Hyperglycemia can be mild or severe. It can progress to diabetic ketoacidosis (DKA) or very high glucose levels (hyperosmolar coma) and result in unconsciousness and death.

Although diabetic ketoacidosis occurs most often in patients with type 1 diabetes, it can also happen in patients with type 2 diabetes who become very sick. Because some patients get few symptoms of hyperglycemia, it is important to check your blood/urine sugar and ketones regularly.

Symptoms of hyperglycemia include:

Symptoms of DKA also include:

Severe or continuing hyperglycemia or DKA needs evaluation and treatment right away by your healthcare provider.

Other possible side effects of APIDRA include:

Serious allergic reactions:

Some times severe, life-threatening allergic reactions can happen with insulin. If you think you are having a severe allergic reaction, get medical help right away. Signs of insulin allergy include:

Reactions at the injection site:

Injecting insulin can cause the following reactions on the skin at the injection site:

You can reduce the chance of getting an injection site reaction if you change (rotate) the injection site each time. An injection site reaction should clear up in a few days or a few weeks. If injection site reactions do not go away or keep happening call your healthcare provider.

Tell your healthcare provider if you have any side effects that bother you.

These are not all the side effects of APIDRA. Ask your healthcare provider or pharmacist for more information.

How should I store APIDRA?

Not in-use
(unopened)

Refrigerated
Not in-use
(unopened)

Below 77°F (25°C)
In-use
(opened)

(See Temperature Below)
10 mL VialUntil expiration date28 days28 days
Refrigerated or below 77°F (25°C)

General Information about APIDRA

ADDITIONAL INFORMATION

DIABETES FORECAST is a national magazine designed especially for patients with diabetes and their families and is available by subscription from the American Diabetes Association, National Service Center, 1701 N. Beauregard Street, Alexandria, Virginia 22311, 1-800-DIABETES (1-800-342-2383). You may also visit the ADA website at www.diabetes.org. Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research Foundation International (JDRF), 120 Wall Street, 19th Floor, New York, New York 10005, 1-800-JDF-CURE (1-800-533-2873). You may also visit the JDRF website at www.jdrf.org.

To get more information about diabetes, check with your healthcare professional or diabetes educator or visit www.DiabetesWatch.com.

Rev. November 2005
Aventis Pharmaceuticals Inc.
Kansas City, MO 64137 USA
a member of the sanofi-aventis Group
Bridgewater NJ 08807

©2005 Aventis Pharmaceuticals Inc.

The brands listed are the registered trademarks of their respective owners and are not trademarks of Aventis Pharmaceuticals Inc.

Patient Information
APIDRA® 3 mL cartridge system (300 units per cartridge system)
100 units per mL (U-100)
(insulin glulisine [recombinant DNA origin] injection)

Read this "Patient Information" that comes with APIDRA (uh-PEE-druh) before you start using it and each time you get a refill because there may be new information. This leaflet does not take the place of talking with your healthcare provider about your condition or treatment. If you have questions about APIDRA or about diabetes, talk with your healthcare provider.

What is the most important information I should know about APIDRA?

What is Diabetes?

What is APIDRA?

Who should NOT take APIDRA?

Do not take APIDRA if you are allergic to insulin glulisine or any of the inactive ingredients in APIDRA. Check with your healthcare provider if you are not sure.

Before starting APIDRA, tell your healthcare provider about all your medical conditions including if you:

How should I use APIDRA?

See the "Instructions for OptiClik® Use" section for additional information.

What kind of insulin Pen should I use with APIDRA cartridge system?

Instructions for OptiClik® Use

It is important to read, understand, and follow the step-by-step instructions in the "OptiClik® Instruction Leaflet" before using OptiClik® insulin Pen. Failure to follow the instructions may result in getting too much or too little insulin. If you have lost your leaflet or have a question, go to www.opticlik.com or call 1-800-633-1610.

OptiClik® insulin Pen is for use with BD Ultra-Fine needles.

The following general notes should be taken into consideration before injecting APIDRA:

If your blood glucose reading is high or low, tell your healthcare provider so the dose can be adjusted.

What can affect how much insulin I need?

Illness. Illness may change how much insulin you need. It is a good idea to think ahead and make a "sick day" plan with your healthcare provider in advance so you will be ready when this happens. Be sure to test your blood sugar more often and call your healthcare provider if you are sick.

Medicines. Many medicines can affect your insulin needs. Other medicines, including prescription and non-prescription medicines, vitamins and herbal supplements, can change the way insulin works. You may need a different dose of insulin when you are taking certain other medicines.Know all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. You may want to keep a list of the medicines you take. You can show this list to all your healthcare providers and pharmacists anytime you get a new medicine or refill. Your healthcare provider will tell you if your insulin dose needs to be changed.

Meals. The amount of food you eat can affect your insulin needs. If you eat less food, skip meals, or eat more food than usual, you may need a different dose of insulin. Talk to your healthcare provider if you change your diet so that you know how to adjust your APIDRA and other insulin doses.

Alcohol. Alcohol, including beer and wine, may affect the way APIDRA works and affect your blood sugar levels. Talk to your healthcare provider about drinking alcohol.

Exercise or Activity level. Exercise or activity level may change the way your body uses insulin. Check with your healthcare provider before you start an exercise program because your dose may need to be changed.

Travel. If you travel across time zones, talk with your healthcare provider about how to time your injections. When you travel, wear your medical alert identification. Take extra insulin and supplies with you.

Pregnancy or nursing. The effects of APIDRA on an unborn child or on a nursing baby are unknown. Therefore, tell your healthcare provider if you are planning to have a baby, are pregnant, or nursing a baby. Good control of diabetes is especially important during pregnancy and nursing.

What are the possible side effects of APIDRA and other insulins?

Insulins, including APIDRA, can cause hypoglycemia (low blood sugar), hyperglycemia (high blood sugar), allergy, and skin reactions.

Hypoglycemia (low blood sugar):

Hypoglycemia is often called an "insulin reaction" or "low blood sugar". It may happen when you do not have enough sugar in your blood. Common causes of hypoglycemia are illness, emotional or physical stress, too much insulin, too little food or missed meals, and too much exercise or activity.

Early warning signs of hypoglycemia may be different, less noticeable or not noticeable at all in some people. That is why it is important to check your blood sugar as you have been advised by your healthcare provider.

Hypoglycemia can happen with:

Hypoglycemia can be mild to severe. Its onset may be rapid. Some patients have few or no warning symptoms, including:

Hypoglycemia may reduce your ability to drive a car or use mechanical equipment and you may risk injury to yourself or others.

Severe hypoglycemia can be dangerous and can cause temporary or permanent harm to your heart or brain. It may cause unconsciousness, seizures, or death.

Symptoms of hypoglycemia may include:

If you have hypoglycemia often or it is hard for you to know if you have the symptoms of hypoglycemia, talk to your healthcare provider.

Mild to moderate hypoglycemia is treated by eating or drinking carbohydrates such as fruit juice, raisins, sugar candies, milk or glucose tablets. Talk to your healthcare provider about the amount of carbohydrates you should eat to treat mild to moderate hypoglycemia.

Severe hypoglycemia may require the help of another person or emergency medical people. A person with hypoglycemia who is unable to take foods or liquids with sugar by mouth, or is unconscious needs medical help fast and will need treatment with a glucagon injection or glucose given intravenously (IV). Without medical help right away, serious reactions or even death could happen.

Hyperglycemia (high blood glucose):

Hyperglycemia happens when you have too much sugar in your blood. Usually, it means there is not enough insulin to break down the food you eat into energy your body can use. Hyperglycemia can be caused by a fever, an infection, stress, eating more than you should, taking less insulin than prescribed, or it can mean your diabetes is getting worse.

Hyperglycemia can happen with:

Testing your blood or urine often will let you know if you have hyperglycemia. If your tests are often high, tell your healthcare provider so your dose of insulin can be changed.

Hyperglycemia can be mild or severe. It can progress to diabetic ketoacidosis (DKA) or very high glucose levels (hyperosmolar coma) and result in unconsciousness and death.

Although diabetic ketoacidosis occurs most often in patients with type 1 diabetes, it can also happen in patients with type 2 diabetes who become very sick. Because some patients get few symptoms of hyperglycemia, it is important to check your blood sugar regularly.

Symptoms of hyperglycemia include:

Symptoms of DKA also include:

Severe or continuing hyperglycemia or DKA needs evaluation and treatment right away by your healthcare provider.

Other possible side effects of APIDRA include:

Serious allergic reactions:

Some times severe, life-threatening allergic reactions can happen with insulin. If you think you are having a severe allergic reaction, get medical help right away. Signs of insulin allergy include:

Reactions at the injection site:

Injecting insulin can cause the following reactions on the skin at the injection site:

You can reduce the chance of getting an injection site reaction if you change (rotate) the injection site each time. An injection site reaction should clear up in a few days or a few weeks. If injection site reactions do not go away or keep happening, call your healthcare provider.

Tell your healthcare provider if you have any side effects that bother you.

These are not all the side effects of APIDRA. Ask your healthcare provider or pharmacist for more information.

How should I store APIDRA?

These storage conditions are summarized in the following table:

Not in-use
(unopened)

Refrigerated
Not in-use
(unopened)

Below 77°F (25°C)
In-use
(opened)

(See Temperature Below)
3 mL Cartridge systemUntil expiration date28 days28 days
Refrigerated or below 77°F (25°C)
3 mL Cartridge system inserted in OptiClik® insulin Pen28 days
below 77°F (25°C only (Do not refrigerate)

General Information about APIDRA

ADDITIONAL INFORMATION

DIABETES FORECAST is a national magazine designed especially for patients with diabetes and their families and is available by subscription from the American Diabetes Association, (ADA), P.O. Box 363, Mt. Morris, IL 61054-0363, 1-800-DIABETES (1-800-342-2383). You may also visit the ADA website at www.diabetes.org.

Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research Foundation International (JDRF), 120 Wall Street, 19th Floor, New York, New York 10005, 1-800-JDF-CURE (1-800-533-2873). You may also visit the JDRF website at www.jdf.org.

To get more information about diabetes, check with your healthcare professional or diabetes educator or visit www.DiabetesWatch.com.

Additional information about APIDRA or OptiClik® can be obtained by calling 1-800-633-1610 or by visiting www.apidra.com or www.opticlik.com.

Rev. November 2005
Aventis Pharmaceuticals Inc.
Kansas City, MO 64137 USA
a member of the sanofi-aventis Group
Bridgewater NJ 08807

©2005 Aventis Pharmaceuticals Inc.

OptiClik® is a registered trademark of Aventis Pharmaceuticals Inc.

OptiClik®

INSTRUCTION LEAFLET

OptiClik® is a reusable insulin delivery device (insulin Pen) for use with 3 mL Lantus® or Apidra® cartridge (U-100) systems.

OptiClik® allows you to dial the dose in one-unit step increments between one unit and a maximum of 80 units per injection.

OptiClik® is available in different colors. For patients that use two different types of insulin, Lantus or Apidra, it is recommended to use a different color pen for each insulin.

Read these instructions carefully before using your OptiClik®. Read both sides of the leaflet. If you are not able to follow all the instructions completely on your own, use OptiClik® only if you have help from a person who is able to follow the instructions.
Hold the pen as shown in this leaflet. The word “OptiClik” must be readable to the left of the digital dose display to ensure the correct reading of the dose.
If you do not follow these instructions completely, you may get too much or too little insulin.

Keep this leaflet for future reference for each time you use OptiClik®.

You will find further useful information on the back side of this leaflet in the chapters:

(A.)
  General Notes
(B.)
  Troubleshooting
(C.)
  Storage Instructions
(D.)
  Other Information

Talk with your healthcare provider before using OptiClik® about proper injection technique. Before using OptiClik®, your healthcare provider should provide training for the use of the pen, or direct you to the appropriate person to get training.

If you have visual problems, use OptiClik® only if you have help from a trained person with good vision.

Additional items needed for use with OptiClik®

If you have any questions about OptiClik® or about diabetes, ask your healthcare professional, go to www.opticlik.com or call Sanofi Aventis at 1-800-633-1610.

Image from Drug Label Content

General Warnings and Precautions

This pen is only for your use. Do not share it with anyone else.

Insulin

Check the label on your Cartridge System to make sure you have the correct insulin before injecting. Using the wrong insulin may result in unwanted changes in blood sugar that could be harmful to your health.

Needles

You must use a new sterile needle (intact protective seal) for each injection. This prevents a blocked needle and air bubbles. In order to avoid injuries, replace Outer Needle Cap before removing and disposing of used needles.

Safety test

Before each injection, carry out the Safety Test (Step Image from Drug Label Content ). If you do not follow the instructions completely, you may get too much or too little insulin. Injecting too much or too little insulin dose may lead to unwanted blood sugar changes (see the package leaflet for your insulin). Do not perform the safety test without the needle attached.

Damage to OptiClik®

OptiClik® may become damaged by rough handling, dropping, or turning of the Dosage Knob by force. Make sure that no dirt gets in contact with the mechanical parts. You should always make sure that:

a)
The Cartridge System is undamaged.
b)
The Start Button, Dosage Knob, and Digital Dose Display operate properly.

Do not use tools on OptiClik®. If you are not sure whether or not your OptiClik® is damaged, contact your healthcare professional or call 1-800-633-1610. If damaged, it is no longer safe to use. In an emergency, you can draw up the insulin from the Cartridge System using a U-100 insulin syringe.

OptiClik® should not be used near electrical and electronic equipment.

Step 1: Inserting the Cartridge System

Do not shake the Cartridge System before use. You should look at the solution in the Cartridge System before inserting it into OptiClik®. If the solution is cloudy, slightly colored, or has particles in it, do not use the Cartridge System.

Image from Drug Label Content

A Make sure the Dosage Knob is pushed in.

Image from Drug Label Content    Image from Drug Label Content

B Hold the Pen Body with the release button facing up. Insert the Cartridge System straight into the Pen Body. If you meet resistance, slightly raise and rotate the Cartridge System while inserting it. Make sure that it clicks in. Do not use force.

Image from Drug Label Content

C To make sure that the Cartridge System clicked in place properly, gently try pulling out the Cartridge System. The Cartridge System should not come out. Make sure you do not press the Cartridge Release button during or after this check.

OptiClik® is now ready for Step 2 (Attaching the needle), or it can be stored with the attached Pen Cap.

DO NOT STORE YOUR OPTICLIK® IN A REFRIGERATOR AFTER CARTRIDGE SYSTEM IS INSERTED IN OPTICLIK®

Step 2: Attaching the needle

Image from Drug Label Content

A Peel off the Protective Seal on the needle.

Image from Drug Label Content

Image from Drug Label Content

B Use an alcohol swab to wipe the rubber seal on the end of the Cartridge System. Attach a new needle straight to the Cartridge System and screw into place without removing the Outer and Inner Needle Caps.

Image from Drug Label Content

C Remove Outer Needle Cap from the needle.
Save Outer Needle Cap for use later on in discarding the needle.

Step 3: Safety Test

Before each injection, carry out the Safety Test or you may get too much or too little insulin. Make sure a needle is attached to OptiClik® before you do the Safety Test. Do not press the Cartridge Release Button during these steps.

Image from Drug Label Content

A Press the Start Button.

Image from Drug Label Content

B The Dosage Knob must come out. "00"appears in the Digital Dose Display.

Image from Drug Label Content

C Turn the Dosage Knob to the right (clockwise) until it clicks. "01" appears in the Digital Dose Display.

Image from Drug Label Content

D Remove and discard the Inner Needle Cap. Handle the exposed needle carefully.

Image from Drug Label Content

E Hold OptiClik® with the needle pointing up.

Press the Dosage Knob fully until it stays in.

Insulin must appear at the tip of the needle. If not, repeat the Safety Test. When replacing an empty cartridge system with a new one, it might require repeating this procedure several times. A Safety Test must be carried out before each injection.

Additional information about "Cartridge System" and "Removing air bubbles" is on the back side of this leaflet.

Step 4: Setting the dose

Image from Drug Label Content

A Press the Start Button

Image from Drug Label Content

B Turn the Dosage Knob slowly to the right (clockwise) until you reach your required dose. Make sure that the dosage knob is not in between two dose steps. You must feel and hear a click.

If you have selected a dose that is too high, simply turn the Dosage Knob back (to the left). If you have dialed past 80 units, see (B.) TROUBLESHOOTING , Dose-setting on the back of this leaflet.

Step 5: Injecting the dose

Image from Drug Label Content

A Check the label on your cartridge system to make sure you have the correct insulin before injecting. Clean the injection area with alcohol. Insert the needle as recommended by your healthcare professional (e.g., lightly pinch a fold of skin on your upper arm, stomach, or thigh. Insert the needle straight into the pinched skin).

Image from Drug Label Content

B Press the Dosage Knob slowly and completely. Slowly count to 10 while holding the Dosage Knob in before withdrawing the needle. The Dosage Knob must stay in. The Dosage Knob staying in after injection indicates the delivery of the full dose.

After injecting your dose, the Digital Dose Display will not go back to "0" but will show the delivered dose for 2 minutes. Do not re-inject your dose as this may result in an overdose.

Do not press the Cartridge Release Button or the Start Button while injecting.

Step 6: Removing the needle

Image from Drug Label Content

A Replace Outer Needle Cap carefully.

Image from Drug Label Content

B Remove the needle after the injection. For safe disposal of needles see (A.) GENERAL NOTES, Needles for OptiClik® on the back of this leaflet. Always replace Pen Cap on the Pen Body after use.

OptiClik® can be stored with the attached Cartridge System until your next injection. See (C.) STORAGE INSTRUCTIONS.

Step 7: Replacing an empty Cartridge System

Image from Drug Label Content

A Make sure the Dosage Knob is pushed in.

Image from Drug Label Content

B Press the Cartridge Release Button, and remove the entire Cartridge System. Dispose of the Cartridge System.

Start again at Step 1 (Inserting the Cartridge System).

Image from Drug Label Content

A. GENERAL NOTES

Cartridge System

The Cartridge System is sold separately. Before every injection, check the appearance of the solution in the Cartridge System and follow the instructions in the "Patient Information" leaflet for the insulin. It is important to follow the directions of this Instruction Leaflet closely to help avoid side effects (e.g., infections, improper dosing). Consult with your healthcare professional before using OptiClik®.

Before the use of an unopened, refrigerated Cartridge System, take it out of the refrigerator and leave it at room temperature for about 1 to 2 hours. Do not remove the Cartridge System from packaging until ready to use. This will prevent dust or dirt from getting into the mechanical parts of the Cartridge System. Use an alcohol swab to wipe the rubber seal on the end of the Cartridge System before inserting the needle. Do not open or manipulate the Cartridge System in any way.

Needles for OptiClik®

BD Ultra-Fine needles are available from BD Consumer Healthcare. Contact your healthcare professional for further information.

Needles may vary from country to country and may not be interchangeable. If you intend to travel abroad, make sure that you have sufficient needles and insulin with you.

Never store OptiClik® with a needle attached. Storing OptiClik® with the needle attached may allow insulin to leak from OptiClik® and air bubbles to form in the Cartridge System. Used needles should be placed in sharps containers (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.

Removing air bubbles

Air bubbles must be removed before each injection during the Safety Test (Step 3 for Safety Test). If air bubbles still remain, repeat the Safety Test, turning the Dosage Knob to the right until "02" appears on the display. Gently tap the Cartridge System until the air rises to the top of the Cartridge System tip. Then press the Dosage Knob until it stays in. If necessary, keep repeating the Safety Test until insulin appears at the tip of the needle.

Setting the dose and Display feature

To read the dose correctly, hold OptiClik® as shown in Step 4B, Setting the dose. The printed “OptiClik” must be readable left of the dose display. Do not hold the pen upside down when reading the dose display; otherwise you may misread the dose on the Digital Dose Display.
The Digital Dose Display shows the delivered dose for 2 minutes after every injection and then turns off to conserve battery power. With the Dosage Knob released the display also switches off after 2 minutes.

How long will OptiClik® last

The expected lifetime of OptiClik® is 3 years.

Image from Drug Label Content flashes when the Start Button is pressed:

OptiClik® is reaching the end of its expected lifetime (3 years). The Digital Dose Display will continue to operate for about 4 more weeks. Please obtain a new OptiClik®.

Image from Drug Label Content stays when the Start Button is pressed:

OptiClik® has reached the end of its lifetime. When you continue to turn the Dosage Knob, the display still shows Image from Drug Label Content. Please obtain a new OptiClik®.

B. TROUBLESHOOTING

Safety test

No insulin appears at the needle tip during Step 3 (Safety Test):

    Repeat Step 3 (Safety Test). If no insulin appears this time either, confirm that:

  1. The needle is firmly in position. Replace a blocked or defective needle with a new one.
  2. The Dosage Knob has been set correctly (always turn the Dosage Knob to the right/clockwise to preselect the dose).
    Turn the Dosage Knob one click to the right, equal to one unit.
  3. The Cartridge System has been inserted correctly. Check by trying to pull the Cartridge System gently out. If the Cartridge System comes out, reinsert it completely, see Step 1 (Inserting the Cartridge System). Repeat Step 3 (Safety Test).
  4. The Cartridge System is not empty. If it is empty, insert a new one. Repeat Step 3 (Safety Test).

You hear no clicking sound during dose-setting:

The Cartridge System may have been inserted incorrectly. Check by trying to pull the Cartridge System gently out. If the Cartridge System comes out, reinsert it completely, see Step 1 (Inserting the Cartridge System). Repeat Step 3 (Safety Test).

If you still hear no clicking sound, try a new Cartridge System and listen for clicking sound. If there is still no clicking sound, obtain a new OptiClik®.

Dose-setting

Insulin drips from the needle tip during dose-setting:

The maximum dose of OptiClik® is 80 units. If you continue to dial after reaching 80 units, insulin will drip from the needle and the display will continue to show "80". In such a case, DO NOT turn back to the required dose, instead dial back (to the left) to "00". Press the Dosage Knob to expel excess insulin and to reset OptiClik®. OptiClik® is now again ready for dose setting. If you need a dose greater than 80 units, you should give it as more than one injection

You feel resistance during dose-setting and the Dosage Knob will not turn further forward (to the right):

a)
You are turning to the left and trying to dial down below zero. Turn the Dosage Knob to the right to dial your dose.
b)
The Cartridge System is almost empty and no longer contains a sufficient amount of insulin for the dose you need. For example, if there are only 20 units left in the Cartridge System and you need 25 units, the dosage knob will stop at 20 units. You can choose to do one of the following:
1)
Do not force the Dosage Knob any further (to the right). Inject the partial dose (20 units in the example), and replace the empty Cartridge System with a new one. Perform the Safety Test as described in Step 3, then inject the remainder of the dose to equal your total prescribed dose. In the above example, the remaining dose is 5 units.
OR
2)
Dial back (to the left) to "00". Follow Step 7 (Replacing an empty Cartridge System), Step 1 (Inserting the Cartridge System), Step 2 (Attaching the needle), and Step 3 (Safety Test).
c)
You have dialed (to the right) past the maximum dose of 80 units and have no needle (or a clogged needle) mounted. Dial completely back (to the left) to "00", and perform Step 2 (Attaching the needle) and Step 3 (Safety Test). Do not force the Dosage Knob to turn further.

The Dosage Knob does not stop at "00":

When turned back completely, the Dosage Knob should stop at "00", however, sometimes it may stop at "02" or "01". Make sure that a needle is attached; then press the Dosage Knob down (insulin will appear at the tip of the needle). OptiClik® is now ready for dose setting.

The Dosage Knob no longer turns after a new Cartridge System has been inserted:

Check that the Cartridge System is firmly clicked in. Reseat the Cartridge System and try again. If it still does not work, try again with a new Cartridge System, see Step 1 (Inserting the Cartridge System). Otherwise, get a new OptiClik®.

The Dosage Knob does not come out after you pressed the Start Button:

Do not pull out the Dosage Knob. Check that the Cartridge System is firmly clicked in, see Step 1B-Inserting the Cartridge System.

Insulin injection

The Dosage Knob cannot be pressed down for the insulin injection or it does not stay down:

  1. In setting the dose, you have turned the Dosage Knob so that it is between two dose steps. Turn the Dosage Knob to the right or the left to the desired dose.
  2. The needle may be blocked or defective. Use a new needle.
  3. Avoid pushing the Start Button and Dosage Knob at the same time.

After withdrawing the needle from your skin, more than one drop of insulin drips from the needle:

It is possible that you may not have injected your full insulin dose. DO NOT try to make up for the shortfall in your insulin dose by giving a second injection (otherwise you will be at risk for low blood sugar).

Please check your blood sugar and consult with your healthcare professional.

You can avoid the problem next time by taking the following steps:

  1. Remove any air bubbles that may be present in the Cartridge System
    (see "GENERAL NOTES: Removing air bubbles").
  2. After delivering the insulin dose, slowly count to 10 before withdrawing the needle from your skin.

Cartridge System replacement

The Cartridge System and Pen Body do not click back together properly:

  1. Check that the Dosage Knob is pushed in.
  2. Check that you have put the Cartridge System correctly into the Pen Body. Take the Cartridge System out and insert it again (see under Step 7 for replacing an empty Cartridge System and Step 1 for inserting the Cartridge System). Repeat Step 2 for attaching the needle and Step 3 for Safety Test.

Digital Dose Display functions

Image from Drug Label Content is displayed:

The Dosage Knob has been forced into the negative range with excessive force. The Cartridge System might be damaged and needs to be replaced. Follow the instructions under Step 7 to replace the Cartridge System and dispose of the damaged Cartridge System. Repeat Step 1 for inserting the Cartridge System, Step 2 for attaching the needle, and Step 3 for Safety Test.

Image from Drug Label Content and Image from Drug Label Content flash alternately:

a)
The Dosage Knob has been forced into the negative range and was pushed in. The Cartridge System might be damaged and needs to be replaced. Repeat Step 7 for replacing an empty Cartridge System and dispose of the damaged Cartridge System. Repeat Step 1 for inserting the Cartridge System, Step 2 for attaching the needle, and Step 3 for Safety Test.
b)
The Dosage Knob has been turned too quickly. You can choose to do one of the following:
1)
Dispose of the unknown pre-set dose by pressing the Dosage Knob. Set your dose (Step 4) and inject your dose (Step 5). OR
2)
Turn the Dosage Knob slowly backward (to the left) until it stops, and then push the Dosage Knob in. Restart OptiClik® and dial your dose.

No numbers appear on the Digital Dose Display when the Start Button is pressed or when the Dosage Knob is released:

Press the Dosage Knob. Start with a Safety Test (Step 3).

If there are still no numbers on Digital Dose Display, you should obtain a new OptiClik®.

The Digital Dose Display goes blank during dose setting (e.g., if you are interrupted in the middle of your injection preparations):

The energy save function has automatically come into operation. Turn the Dosage Knob one click further (to the right). OptiClik® should now be ready to use again; check the Digital Dose Display and adjust for the right dose if needed.

Battery Information

Image from Drug Label Content flashes when the Start Button is pressed:

Your battery is running out. Please obtain a new OptiClik® as soon as possible.

Image from Drug Label Content is displayed when the Start Button is pressed:

Your battery has run out. Please obtain a new OptiClik®.

C. STORAGE INSTRUCTIONS

Always store OptiClik® Pen Body at room temperature below 86°F (30°C). Do not store OptiClik®, (with or without the Cartridge System inserted), in a refrigerator at any time. ®Protect OptiClik® from moisture and direct heat. When OptiClik® is not in use, push the Dosage Knob in to conserve the battery and to ensure OptiClik® functions throughout its expected lifetime.

To avoid dust or dirt from getting into OptiClik®, always replace the Pen Cap.

Once the Cartridge System is used with OptiClik®, the Cartridge System can be used for up to 28 days under normal carrying conditions (for Lantus®, below 86°F [30°C]; for Apidra®, below 77°F [25°C]). For specific insulin storage information, see "Patient Information" for Lantus® or Apidra® 3 mL Cartridge System.

Do not store OptiClik® with the needle attached to the Cartridge System.

D. OTHER INFORMATION

Care, cleaning, and maintenance instructions

Handle OptiClik® carefully. To keep it clean, use a clean damp cloth. Clean it once a week. Dirt can impede the operation. DO NOT use cleaning agents. Use an alcohol swab only for cleaning the Cartridge System's rubber seal.

Lifetime

OptiClik® has a lifetime of 3 years. See " (A.) GENERAL NOTES, How long will OptiClik® last" for details.

Manufacturedfor and distributed by:

sanofi-aventis U.S. LLC,
Bridgewater NJ 08807

OptiClik®, Lantus® and Apidra® are registered trademarks of sanofi-aventis U.S. LLC

For more information call toll free 1-800-633-1610 or visit www.opticlik.com


Date of revision:
December 2006

Image from Drug Label Content


Apidra (insulin glulisine)
PRODUCT INFO
Product Code0088-2500Dosage FormINJECTION, SOLUTION
Route Of AdministrationSUBCUTANEOUSDEA Schedule
INGREDIENTS
Name (Active Moiety)TypeStrength
insulin glulisine (insulin glulisine) Active100 UNITS  In 1 MILLILITER
m-cresolInactive3.15 MILLIGRAM  In 1 MILLILITER
tromethamineInactive6 MILLIGRAM  In 1 MILLILITER
sodium chlorideInactive5 MILLIGRAM  In 1 MILLILITER
polysorbate 20Inactive0.01 MILLIGRAM  In 1 MILLILITER
waterInactive 
IMPRINT INFORMATION
CharacteristicAppearanceCharacteristicAppearance
ColorScore
ShapeSymbol
Imprint CodeCoating
Size
PACKAGING
#NDCPackage DescriptionMultilevel Packaging
10088-2500-3310 MILLILITER In 1 VIAL, GLASSNone
20088-2500-525 CARTRIDGE In 1 PACKAGEcontains a CARTRIDGE
23 MILLILITER In 1 CARTRIDGEThis package is contained within the PACKAGE (0088-2500-52)

Revised: 03/2007sanofi-aventis U.S. LLC