APIDRA(tm) (insulin glulisine [rDNA origin]) is a recombinant human insulin analogue 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 (See PHARMACEUTICAL INFORMATION).

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

APIDRATM 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(tm) should be given within 15 minutes before or within 20 minutes after starting a meal.

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

Hypoglycemia may occur if the insulin dose is too high in relation to the insulin requirement (see Hypoglycemia section below). The use of too low insulin dosages or discontinuation of treatment, especially in Type 1 diabetes, may lead to hyperglycemia and diabetic ketoacidosis. Uncorrected hypoglycemic or hyperglycemic reactions can cause loss of consciousness, coma, or death.

Any change of insulin should be made cautiously and only under medical supervision. As with other insulins, additional caution should be exercised in patients with a long history of diabetes on insulin who might be prone to develop hypoglycemia and in patients with a previous history of cardiac ischemic disorders who might be prone to develop cardiac adverse events. Changes in insulin strength, manufacturer, type (e.g. regular, NPH, or insulin analogues), or species (animal,

human), or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage. Concomitant oral antidiabetic treatment may need to be adjusted.

As with all insulin preparations, the time course of APIDRATM 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.

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

As with all insulin preparations, hypoglycemic reactions may be associated with the administration of APIDRA(tm). Early warning symptoms of hypoglycemia may be different, be less pronounced or absent, under certain conditions, as for example if glycemic control is markedly improved, if hypoglycemia is developing gradually, in elderly patients, in patients with a long history of diabetes, in patients with diabetic nerve disease, in patients using some medications such as beta-blockers, or intensified diabetes control (See DRUG INTERACTIONS). Such situations may result in severe hypoglycemia (and possibly, loss of consciousness) prior to patients' awareness of hypoglycemia.

Severe hypoglycemia may require the assistance of another person. Patients who are unable to take sugar orally or who are unconscious may require an intramuscular/subcutaneous injection of glucagon or should be treated with intravenous administration of glucose by medical personnel. Without immediate medical help, serious reactions or even death could occur.

Hypoglycemia is the most common adverse effect of insulin therapy, including APIDRATM. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations.

The time of occurrence of hypoglycemia depends on the action profile of the insulins used and may, therefore, change when treatment regimen is changed.

Insulin requirements may be altered during illness, emotional disturbances or stress.

When used in an external insulin pump for subcutaneous infusion, APIDRATM should not be mixed with any other insulin or diluted with any other solution. Patients using external pump infusion therapy should be trained appropriately. Physicians and patients should carefully evaluate information on pump use in the APIDRATM product monograph, package insert, and the pump manufacturer's manual.

APIDRATM specific information should be followed for period of use, frequency of changing infusion sets, or other details specific to APIDRATM usage, because APIDRATM specific information may differ from general or other insulin's 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 analogues that are more rapidly absorbed 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 DOSAGE AND ADMINISTRATION, Continuous Subcutaneous Insulin Infusion Pump, CONSUMER INFORMATION, Vials, Continuous Subcutaneous Insulin Infusion Pump, STORAGE AND STABILITY).

The pharmacokinetic properties of APIDRATM were generally maintained in subjects with renal impairment. However, as with all insulins, the requirements for APIDRATM may be reduced in patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY).

Pregnant Women:

There are no well-controlled clinical studies of the use of APIDRATM in pregnant women. Animal reproduction studies have not revealed any differences between APIDRATM and human insulin regarding pregnancy, embryonal/foetal development, parturition or postnatal development.

It is essential for patients with pre-existing or gestational diabetes to maintain good metabolic control before conception and during pregnancy. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly.

Patients with diabetes must inform their doctor if they are pregnant or are contemplating pregnancy.

Nursing Women:

It is unknown whether APIDRATM is excreted in human milk. Many drugs including human insulin, are excreted in human milk. For this reason, caution should be exercised when APIDRATM is administered to a nursing woman. Lactating women may require adjustments in insulin dose and diet.

Pediatrics:

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

Geriatrics (>= 65 years of age):

Hypoglycemia may be difficult to recognize in the elderly. In Phase III clinical trials (n=2408), APIDRATM 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 glycated hemoglobin (A1c) values and hypoglycemia frequencies did not differ by age, but greater sensitivity of some older individuals cannot be ruled out.

The patient's ability to concentrate and react may be impaired as a result of hypoglycemia or hyperglycemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycemia or have frequent episodes of hypoglycemia. It should be considered whether it is advisable to drive or operate machinery in these circumstances.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Overall, clinical studies comparing APIDRA(tm) 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:

Local Allergy

As with other insulin therapy, local allergy in patient may occur as redness, swelling, or itching at the site of insulin 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.

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

Hypoglycemia:

Hypoglycemia, a frequent adverse reaction to insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement.

As with all insulins, prolonged or severe hypoglycemic attacks, especially if recurrent, may lead to neurological damage, loss of consciousness, coma or death.

The risk of all categories of symptomatic hypoglycemia did not differ between APIDRA(tm) and short-acting insulin comparators in subjects with type 1 or type 2 diabetes (See WARNINGS AND PRECAUTIONS).

Table 1 - Number of subjects with at least one episode of symptomatic hypoglycemia in studies in type 1 and type 2 diabetes

	Type 1 diabetes					Type 2 diabetes
	Glulisine n/N %		Comparat a n/N %		Glulisine n/N %		Comparat b n/N %
Subcutaneous injection	783/921	85.0	516/611	84.5	562/883	63.6	578/883	65.5
Continuous c subcutaneous	26/29	89.7	24/30	80.0	-	-	-	-
infusion	26/29	89.7	24/30	80.0	-	-	-	-
n = number of subjects with at least 1 episode of hypoglycemia; N = total number of evaluable ITT subjects. a b c

Skin and appendages:

As with other insulin therapy, lipodystrophy may occur at the injection site and delay insulin absorption. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 2 - Common (>=1%) Adverse Drug Reactions in pooled Type 1 and 2 studies

Adverse Event System Organ Class/ Preferred Term	Insulin Glulisine (All studies) n=1833 (% of subjects)	Lispro n= 333 (% of subjects)	Regular Insulin n=1161 (% of subjects)	Aspart n= 30 (% of subjects)
General Disorders and Administration Site Condition Injection site hypertrophy	9 (0.5)	7 (2.1)	- (-)	- (-)
Metabolism and Nutrition	83 (4.5)	22 (6.6)	33 (2.8)	2 (6.7)
Disorders
Hypoglycemia NOS *
Hypoglycemic seizure	16 (0.9)	7 (2.1)	9 (0.8)	- (-)
Hypoglycemic unawareness	1 (0.1)	4 (1.2)	- (-)	2 (6.7)
Nervous System Disorders Hypoglycemic coma	49 (2.7)	13 (3.9)	19 (1.6)	- (-)

*Not otherwise specified

During clinical studies, there were no clinically noteworthy differences between insulin glulisine and comparator short-acting insulins in the overall incidences of adverse events. The adverse events observed were those known in this pharmacological class and consequently common to insulins.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Gastrointestinal disorders

: nausea

General disorders administration site conditions: fatigue, injection site reaction NOS *, peripheral oedema, asthenia, increased fat tissue, injection site stinging

Infections and infestations: cellulitis

Injury, poisoning and procedural (complications): overdose NOS * Metabolism and nutrition disorders: hyperglycemia NOS * Nervous system disorders: paraesthesia

Skin and subcutaneous tissue disorders: acquired lipodystrophy

*Not otherwise specified

DRUG INTERACTIONS

The following are examples of potential drug-drug interactions that may occur with APIDRA(tm) treatment:

Table 3- Established or Potential Drug-Drug Interactions

DOSAGE AND ADMINISTRATION

The dosage of APIDRATM should be individualized and determined based on the physician's advice in accordance with the needs of the patient.

APIDRATM (insulin glulisine [rDNA origin]) is a recombinant human insulin analogue that has been shown to be equipotent to human insulin. One unit of APIDRATM has the same glucose- lowering effect as one unit of regular human insulin. After subcutaneous administration it has a more rapid onset and a shorter duration of action (See ACTION AND CLINICAL PHARMACOLOGY).

APIDRATM should be given by injection within 15 minutes before or within 20 minutes after starting a meal. APIDRATM should normally be used in regimens that include a longer-acting insulin or basal insulin analogue.

APIDRA(tm) is intended for subcutaneous administration by injection and for use as a continuous subcutaneous insulin infusion (CSII) in pump systems suitable for insulin infusion.

APIDRA(tm) should be administered by subcutaneous injection in the abdominal wall, the thigh or the deltoid or by continuous subcutaneous infusion (CSII) 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:

APIDRATM must only be used if the solution is clear, colourless, with no solid particles visible, and if it is of a water-like consistency. To minimize local irritation at the injection site, it is recommended to allow the insulin to reach room temperature before injection.

The instructions for using the APIDRATM in a pump or with an injection pen must be followed carefully.

An empty vial, cartridge, OptiSet(tm) or SoloStar(tm) must never be reused and must be properly discarded.

Before withdrawing insulin from the vial for the first time, remove the plastic protective cap.

Do not shake the vial vigorously as this may cause frothing. Froth may interfere with the correct measurement of the dose.

Mixing of Insulins

APIDRATM can be mixed with NPH human insulin (except when administered with pump (see DOSAGE AND ADMINISTRATION, Continuous Subcutaneous Insulin Infusion pump)).

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

No data are available on mixing APIDRA(tm) with insulin preparations other than NPH human insulin.

APIDRATM cartridges, APIDRATM OptiSet(tm) or APIDRATM SoloStarTM are not designed to allow any other insulin to be mixed in the cartridge.

If the injection pen malfunctions, the solution may be drawn from the cartridge into a syringe (suitable for an insulin with U-100) and injected.

APIDRATM may be used for Continuous Subcutaneous Insulin Infusion (CSII) in pump systems suitable for insulin infusion.

When used with an insulin infusion pump, APIDRATM should not be mixed with any other insulin or diluted with any other solution.

Patients using CSII should be comprehensively instructed on the use of the system pump. The infusion set and reservoir should be changed every 48 hours using aseptic technique.

Patients administering APIDRATM by CSII must have an alternative insulin delivery system available in case of pump system failure.

OVERDOSAGE

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

Mild/moderate episodes of hypoglycemia can usually be treated with oral carbohydrates. Adjustments in dosage of the medicinal product, meal patterns, or physical activity 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.

ACTION AND CLINICAL PHARMACOLOGY

The primary activity of insulins and insulin analogues, 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 APIDRATM and of regular human insulin are equipotent when administered by the intravenous route.

After subcutaneous administration the effect of APIDRATM is more rapid in onset and of shorter duration compared to regular human insulin. This has been demonstrated in studies in healthy volunteers and patients with diabetes.

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

Figure 1: Glucose-lowering effect over 6 hours.

APIDRATM given 2 minutes (glulisine-pre) before the start of a meal compared to regular human insulin given 30 minutes (Regular - 30 min) before start of the meal

(Figure 1A) and compared to regular human insulin (Regular - pre) given 2 minutes before a meal (Figure 1B). APIDRATM given 15 minutes (glulisine-post) after start of a meal compared to regular human insulin (Regular - pre) given 2 minutes before a meal (Figure 1C). On the x-axis zero (0) is the start of a 15-minute meal.

APIDRATM exhibits dose-proportionality in insulin exposure and less than dose-proportional increases in effect, as common to short and rapid acting insulins.

Table 4. Pharmacokinetic and Pharmacodynamic Results in Type 1 Diabetes Mellitus subjects treated with s.c insulin glulisine

Values in bold font represent the geometric means, all others are based on the mean & standard deviation, unless denoted with ( *) to indicate the median, minimum & maximum range.

The table below compares pharmacokinetic and pharmacodynamic parameters for APIDRATM (s.c.) from a study in patients with Type I diabetes (n=18) with historical data

for Huminsulin(r) Normal 100 (s.c.) from a study in healthy adult subjects (n = 24; see Table 5).

Table 5. Pharmacokinetic and Pharmacodynamic Results for s.c ApidraTM and Huminsulin(r) Normal 100

Values represent mean and standard deviation, unless denoted with ( *) to indicate the median, minimum & maximum range. Historical data and different radioimmunoassay from Apidra study Type 1 Diabetes patients Healthy adult subjects.

Absorption and bioavailibility: Pharmacokinetic profiles in healthy volunteers and diabetes patients (Type 1 or 2) demonstrated that absorption of insulin glulisine was up to twice as fast with a peak concentration approximately up to twice as high compared to regular human insulin.

In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15 U/kg, the median time to maximum concentration (Tmax) was 55 minutes (range 34 to 91 minutes) and the peak concentration (Cmax) was 82 uU/mL (range 42 to 134 uU/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 IU/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 2).

Figure 2: Pharmacokinetic profile of insulin glulisine and regular human insulin in patients with Type 1 diabetes after a dose of 0.15 U/kg.

When APIDRATM was injected subcutaneously into different areas of the body, the time- concentration profiles were similar with a slightly faster absorption when administered in the abdomen compared to the deltoid or thigh (See DOSAGE AND ADMINISTRATION.) The absolute bioavailability of insulin glulisine after subcutaneous administration is about 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%). The Tmax for the abdomen was 44 min (range 27-69 min); 58 min for the deltoid (range 30-85 min), and 66 min for the thigh (range 35-108 min).

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.

Pediatrics: The pharmacokinetic and pharmacodynamic properties of insulin glulisine and regular human insulin were assessed in a study conducted in pediatric patients with Type 1 diabetes (children [7 - 11 years, n = 10] and adolescents [12 - 16 years, n = 10]). The relative differences in pharmacokinetics and pharmacodynamics between insulin glulisine 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 insulin glulisine is not available. However, in Phase III clinical trials in adults (n=2408), subgroup analyses based on gender did not show differences in safety and efficacy between insulin glulisine and other short- acting insulin formulations.

Hepatic Insufficiency: The effect of hepatic impairment on the pharmacokinetics of insulin glulisine has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure (See WARNINGS AND PRECAUTIONS).

Race: Information on the effect of race on the pharmacokinetics of insulin glulisine is not available.

Renal Insufficiency: 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 (CrCl>80mL/min; 30-50mL/min; <30mL/min), the pharmacokinetic properties of insulin glulisine were generally maintained (see WARNINGS AND PRECAUTIONS).

Pregnancy: The effect of pregnancy on the pharmacokinetics and pharmacodynamics of insulin glulisine has not been studied.

Obesity: The more rapid onset of action and shorter duration of activity of insulin glulisine and insulin lispro compared to regular human insulin were maintained in an obese non-diabetic population. The rapid onset of action was better maintained with insulin glulisine than with insulin lispro (see Figure 3).

Figure 3: Glucose infusion rates (GIR) after subcutaneous injection of 0.3 U/kg of APIDRATM (glulisine), insulin lispro or regular human insulin in an obese population.

STORAGE AND STABILITY

Unopened Vial:

Unopened APIDRATM vials should be stored in a refrigerator, between 2degC - 8degC. Keep APIDRATM away from direct heat and light. APIDRATM should not be stored in the freezer and it should not be allowed to freeze. Discard if frozen.

Opened (In Use) Vial:

Opened APIDRATM vials, whether or not refrigerated, must be discarded if not used within 28 days even if they contain insulin. The opened vial can also be kept unrefrigerated (15 - 25degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 25degC.

Opened APIDRATM vials should not be stored in the freezer and should not be allowed to freeze. If a vial freezes or overheats, discard it.

Unopened Cartridge:

Unopened APIDRATM cartridges should be stored in a refrigerator, between 2degC - 8degC. Keep APIDRATM away from direct heat and light. APIDRATM should not be stored in the freezer and it should not be allowed to freeze. Discard if frozen.

Opened (In Use) Cartridge:

The opened cartridge in use must be kept unrefrigerated (15 - 25degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 25degC. If the cartridge

overheats or if there is any remaining insulin after 28 days, discard it. The opened cartridge in use must never be removed from and reinserted into the injection pen.

Unopened OptiSet(tm):

Unopened APIDRATM OptiSetTM should be stored in a refrigerator, between 2degC - 8degC. Keep APIDRATM away from direct heat and light. APIDRATM should not be stored in the freezer and it should not be allowed to freeze. Discard if frozen.

Opened (In Use) OptiSet(tm):

Opened APIDRATM OptiSet(tm) in use must be kept unrefrigerated (15 - 25degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 25degC. If the APIDRATM OptiSet(tm) overheats or if there is any remaining insulin after 28 days, discard it.

Opened APIDRATM OptiSetTM should not be stored in the freezer and should not be allowed to freeze. If APIDRATM OptiSet(tm) freezes discard it.

Unopened SoloStar(tm):

Unopened APIDRATM SoloStar(tm) should be stored in a refrigerator, between 2degC - 8degC. Keep APIDRATM away from direct heat and light. APIDRATM should not be stored in the freezer and it should not be allowed to freeze. Discard if frozen.

Opened SoloStar(tm):

Opened APIDRATM SoloStar(tm) in use must be kept unrefrigerated (15-25degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 25degC. If the APIDRATM SoloStar(tm) overheats or if there is any remaining insulin after 28 days, discard it.

Opened APIDRATM SoloStar(tm) should not be stored in the freezer and should not be allowed to freeze. If APIDRATM SoloStar(tm) freezes discard it.

Infusion sets:

Infusion sets (reservoirs, tubing, and catheters) and the APIDRATM in the reservoir should be discarded after no more than 2 days of use or after exposure to temperatures that exceed 37degC.

SPECIAL HANDLING INSTRUCTIONS

See also PART III: CONSUMER INFORMATION, and refer patients to the APIDRATM Information for the Patient circular for APIDRATM VIAL, APIDRATM CARTRIDGE,

APIDRATM OPTISETTM, and APIDRATM SOLOSTAR(tm) for additional information. Refer patients to the User Manual for OptiPen(r) Pro or injection pens suitable for APIDRATM cartridges AS RECOMMENDED IN THE INFORMATION PROVIDED BY THE INJECTON PEN

MANUFACTURER, User Manual for the APIDRATM OptiSet(tm) and User Manual for the APIDRATM SoloStar(tm) for additional information on use of the pens.

DOSAGE FORMS, COMPOSITION AND PACKAGING

The vials, cartridges, OptiSetTM, and SoloStar(tm) contain a sterile solution of insulin glulisine for use as an injection. APIDRATM [Insulin Glulisine (rDNA origin)] consists of insulin glulisine dissolved in a clear aqueous solution.

Each milliliter of APIDRATM contains insulin glulisine 100 units. It also contains excipients: m- cresol, trometamol, sodium chloride, polysorbate 20, and water for injection. APIDRATM has a pH of approximately 7.3 and is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide.

APIDRATM [insulin glulisine (rDNA origin)] 100 units per mL is available in the following package sizes:

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Subcutaneous	Solution for injection 100 U/mL	m-cresol , trometamol, sodium chloride, polysorbate 20, water for injection, hydrochloric acid and sodium hydroxide (for pH adjustment) For a complete listing see Dosage Forms, Composition and Packaging section.

Proper name	Ref	Effect	Clinical comment
Oral antidiabetic agents ACE inhibitors Disopyramide Fibrates Fluoxetine MAO inhibitors Pentoxifylline Propoxyphene Salicylates Sulfonamide antibiotics	T	May enhance the blood-glucose- lowering effect and increase susceptibility to hypoglycemia	May require close monitoring of blood glucose level and dose adjustment (reduction) of APIDRA(tm)
Corticosteroids Danazol Diazoxide Diuretics Glucagon Isoniazid Estrogens and progestogens (e.g. in oral contraceptives) Phenothiazine derivatives Somatropin Sympathomimetic agents (e.g. epinephrine, salbutamol, terbutaline) Protease inhibitors Atypical antipsychotic medications (e.g. olanzapine and clozapine)	T	May reduce the blood-glucose- lowering effect. May enhance or decrease the insulin requirements	May require close monitoring of blood glucose level and dose adjustment (increase or decrease) of APIDRA(tm)
Thyroid hormones	T	May enhance or decrease the insulin requirements	May require close monitoring of blood glucose level and dose adjustment (increase or decrease) of APIDRA(tm)
Proper name	Ref	Effect	Clinical comment
Alcohol Beta-blockers Clonidine Lithium salts	T	May either potentiate or weaken the blood-glucose- lowering effect of insulin	May require close monitoring of blood glucose level and dose adjustment (increase or decrease) of APIDRA(tm)
Pentamidine	T	May cause hypoglycemia, which may sometimes be followed by hyperglycemia	May require close monitoring of blood glucose level and dose adjustment (increase or decrease) of APIDRA(tm)
Sympatholytic medicinal products such as beta- blockers, clonidine, guanethidine and reserpine	T	The signs of hypoglycemia may be reduced or absent	May require close monitoring of blood glucose level and dosage adjustment (increase or decrease) of APIDRA(tm)

Pharmacokinetic Parameters
Dose	0.075 U/kg	0.15 U/kg	0.3 U/kg
AU C 0-2h	3792	6676	12992
(uU.min.mL -1 )	3855 +- 677	6832 +- 1461	13237 +- 2599
AU C 0-end	5341	11196	24891
(uU.min.mL -1 )	5372 +- 589	11284 +- 1456	25076 +- 3209
C max	42	72	140
(uU.mL -1 )	43 +- 9	73 +- 16	142 +- 25
MRT (min)	115	121	134
MRT (min)	122 +- 50	125 +- 34	136 +- 28
Tmax	47	57	72
Min ( *)	34 - 99	44 - 93	50 - 112
T 10%- AUC	26	31	39
Min ( *)	18 - 53	24 - 52	28 - 64
T 90%- AUC	149	205	242
Min ( *)	116 - 260	141 - 295	169 - 345
T 1/2 (min)	64 +- 33	55 +- 17	56 +- 17
Volume of Distribution (mL/kg)	1075 +- 362	986 +- 274	930 +- 216
Glucose Infusion Rate - Pharmacodynamic Parameters
GIR-AUC (0-2h) (mg/kg)	314 +- 156	491 +- 167	536 +- 153
GIR-AUC (0-end) (mg/kg)	499 +- 233	1090 +- 271	1476 +- 300

	APIDRA TM (N=18) 2	Huminsulin (r) Normal 100 1 (N=24) 3
Dose	0.3 U/kg	0.3 IU/kg
Pharmacokinetic Parameters
AU C 0-end (uU.min.mL-1)	25076 +- 3209	17417 +- 2348
Cmax (uU.mL-1)	142 +- 25	56 +- 16
MRT (min)	136 +- 28	229 +- 41
Tmax	72	120
Min ( *)	50 - 112	60 - 240
T 10%- AUC	39	58
Min ( *)	28 - 64	45 - 81
T 90%- AUC	242	448
Min ( *)	169 - 345	321-590
T 1/2 (min)	56 +- 17	64 +- 28 4
Volume of Distribution (mL/kg)	930 +- 216	2375 +- 963
Glucose Infusion Rate - Pharmacodynamic Parameter
GIR-AUC (0-end) (mg/kg)	1476 +- 300	3032 +- 743

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3

DESCRIPTION 3

INDICATIONS AND CLINICAL USE 4

CONTRAINDICATIONS 4

WARNINGS AND PRECAUTIONS 4

ADVERSE REACTIONS 8

DRUG INTERACTIONS 11

DOSAGE AND ADMINISTRATION 12

OVERDOSAGE 14

ACTION AND CLINICAL PHARMACOLOGY 15

STORAGE AND STABILITY. 20

SPECIAL HANDLING INSTRUCTIONS 21

DOSAGE FORMS, COMPOSITION AND PACKAGING 22

PART II: SCIENTIFIC INFORMATION 23

PHARMACEUTICAL INFORMATION 23

CLINICAL TRIALS 24

TOXICOLOGY 27

REFERENCES 34

PART III: CONSUMER INFORMATION. 35

PART III: CONSUMER INFORMATION. 42

PART III: CONSUMER INFORMATION. 49

PART III: CONSUMER INFORMATION. 54

PRODUCT MONOGRAPH APIDRATM

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

DESCRIPTION

INDICATIONS AND CLINICAL USE