Rev. April 2004a
APIDRA™ (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:
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.
Mechanism of Action
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.
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
profile of insulin glulisine and regular human insulin in patients
with type 1 diabetes after a dose of 0.15 IU/kg.
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 to 140 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 profile of insulin glulisine and regular human insulin in patients with type 2 diabetes after a dose of 0.2 IU/kg.
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
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.
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).
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.
Type 1 Diabetes:
Table 1: Type 1 Diabetes Mellitus–Adult
Type 2 Diabetes:
Table 2: Type 2 Diabetes Mellitus–Adult
Pre- and Post-Meal Administration (Type 1 Diabetes):
Table 3: Type 1 Diabetes Mellitus–Adult
Continuous Subcutaneous Insulin Infusion (CSII)
(Type 1 Diabetes):
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, RECOMMENDED STORAGE.)
APIDRA is contraindicated during episodes of hypoglycemia and in patients hypersensitive to APIDRA or one of its excipients.
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 dose. Concomitant oral antidiabetic treatment may need to be
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.)
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.
Such situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to patients’ awareness of hypoglycemia.
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.
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 RECOMMENDED STORAGE.)
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
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 RECOMMENDED STORAGE.)
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.
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
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.
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.
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.)
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
Continuous Subcutaneous Insulin Infusion (CSII) (Type 1 Diabetes): The rates of catheter occlusions and infusion site reactions were similar for APIDRA and insulin aspart (see Table 5).
Table 5: Catheter Occlusions and
Infusion Site Reactions.
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.
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
When it is used in a pump, APIDRA should not be mixed with other insulins or with a diluent.
APIDRA 100 units per mL (U-100) is available in
the following package size:
Open (In-Use) Vial:
Rev. April 2004a
US Patent Number 6,221,633
©2004 Aventis Pharmaceuticals Inc.
† Lantus® is a registered trademark of Aventis
© 2004, Aventis Pharmaceuticals Inc.
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