APIDRA

(tm)

Insulin glulisine (rDNA origin) injection

Rx only DESCRIPTION

APIDRA(tm) (insulin glulisine [rDNA origin]) 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:

A-chain

S S

Ile

Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn

S S

S

S

3 29

Phe Val Lys Gln His LeuCys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly PhePhe Tyr Thr Pro Glu Thr

B-chain

APIDRA is a sterile, aqueous, clear, and colorless solution. Each milliliter of APIDRA (insulin glulisine 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.

Submission date: 4/15/04 1

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 uIU/mL (range 42 to 134 uIU/mL) for insulin glulisine compared to a median Tmax of 82 minutes (range 52 to 308 minutes) and a Cmax of 46 uIU/mL (range 32 to 70 uIU/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 profile of insulin glulisine and regular human insulin in patients with type 1 diabetes after a dose of 0.15 IU/kg.

INSULIN - uIU/mL

GLULISINE REGULAR

0 60 120 180 240 300 360

TIME - min

In a euglycaemic 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 81uIU/mL (range 75 to 112 uIU/mL) for insulin glulisine compared to a median Tmax of 94 minutes (range 55 to140 minutes) and a median Cmax of 39 uIU/mL ( range 30 to 56 uIU/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).

Submission date: 4/15/04 2

Figure 2.

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

INSULIN - uIU/mL

GLULISINE REGULAR

0 120 240 360 480 600

TIME - min

In a euglycaemic 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 uIU/mL (range 99 to 387 uIU/mL) for insulin glulisine compared to a median Tmax of 144 minutes (range 110 to 207 minutes) and a median Cmax of 79 uIU/mL (range 39 to 166 uIU/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, ranging between 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 L 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

Submission date: 4/15/04 3 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.

GLUCOSE - mg/dL

APIDRA - pre REGULAR - 30 min

GLUCOSE - mg/dL

APIDRA - pre REGULAR - pre

-1 0 1 2 3 4 5 6 7

TIME - hour

-1 0 1 2 3 4 5 6 7

TIME - hour

Figure 3A Figure 3B

GLUCOSE - mg/dL

APIDRA - post REGULAR - pre

-1 0 1 2 3 4 5 6 7

TIME - hour

Figure 3C

Start of a 15-minute meal

The maximum blood glucose excursion ([? ]GLUmax; 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.h/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.h/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.

Submission date: 4/15/04 4

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(0-1hr) 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.

GIR - mg/kg/min

APIDRA LISPRO REGULAR

0 600

TIME - min

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 >80mL/min; 30-50 mL/min; <30 mL/min), the subjects with moderate and severe renal impairment showed increased exposure of 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.)

Submission date: 4/15/04 5

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)+ 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:

HbA1c (%)

26 weeks Lantus(r)

APIDRA Insulin Lispro

Number of patients 331 322

Baseline mean 7.60 7.58

Adj. mean change from baseline -0.14 -0.14 APIDRA - Insulin Lispro 0.00

95% CI for treatment difference (-0.09; 0.10) Basal insulin dose (IU/day)

Endstudy mean 24.16 26.43

Adj. mean change from baseline 0.12 1.82

Short-acting insulin dose (IU/day)

Endstudy mean 29.03 30.12

Adj. mean change from baseline -1.07 -0.81 Mean number of short-acting insulin injections per day 3.36 3.42

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

Submission date: 4/15/04 6 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 duration 26 weeks

Mean number of short-acting insulin injections per day 2.27 2.24

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.)

Submission date: 4/15/04 7

Table 3: Type 1 Diabetes Mellitus-Adult

Treatment duration

Treatment in combination with:

HbA1c

12 weeks Lantus(r)

APIDRA

pre meal

12 weeks Lantus(r)

APIDRA

post meal

12 weeks Lantus(r)

Regular Human Insulin

Number of patients 268 276 257

Mean number of short-acting insulin injections per day 3.15 3.13 3.03

* 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).

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 (range 21-73 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.

CONTRAINDICATIONS

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

Submission date: 4/15/04 8

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 or immediately after 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 dosage. 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 RECOMMENDED 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.

Submission date: 4/15/04 9

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 patients' 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

Submission date: 4/15/04 10 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(r) H-Tron(r) plus V100 and D-Tron(r) with Disetronic catheters (Rapid(tm), Rapid C(tm), Rapid D(tm), and Tender(tm)); MiniMed(r) Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate QR(tm), and Quick-set(tm))++. Based on in vitro studies which have shown loss of m-cresol, and insulin degradation, APIDRA should not be used beyond 48 hours at 98.6degF (37degC) in infusion sets and reservoirs. APIDRA in clinical use should not be exposed to temperatures greater than 98.6degF (37degC). 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 RECOMMENDED 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. Insulin exposed to temperatures higher than 98.6F (37C) should be discarded.

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.

deg

deg

Infusion sites that are erythematous, pruritic,

Submission date: 4/15/04 11 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 RECOMMENDED 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.

Submission date: 4/15/04 12 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

Submission date: 4/15/04 13 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 A1C values and hypoglycemia frequencies did not differ by age, but greater sensitivity of some older individuals cannot be ruled out.

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.

Submission date: 4/15/04 15 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.

HOW SUPPLIED

APIDRA 100 units per mL (U-100) is available in the following package size: 10 mL vials NDC 0088-2500-33

Storage: Unopened Vial:

Unopened APIDRA vials should be stored in a refrigerator, 36degF-46degF (2degC-8degC). Protect from light. APIDRA should not be stored in the freezer and it should not be allowed to freeze. Discard vial if 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 77degF (25degC).

Submission date: 4/15/04 16

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 98.6degF (37degC). Rx only Rev. April 2004 Manufactured by: Aventis Pharma Deutschland GmbH D-65926 Frankfurt am Main Frankfurt, Germany Manufactured for: Aventis Pharmaceuticals Inc. Kansas City, MO 64137 USA US Patent Number 6,221,633 www.aventis-us.com (c)2004 Aventis Pharmaceuticals Inc.

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Lantus(r) is a trademark of Aventis Pharmaceuticals Inc.

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

Submission date: 4/15/04 17