sanofi-aventis

Apidra 100 Units/ml solution for injection in a vial

Each ml contains 100 Units insulin glulisine (equivalent to 3.49 mg).

Each vial contains 10 ml of solution for injection, equivalent to 1000 Units.

Insulin glulisine is produced by recombinant DNA technology in Escherichia coli.

For a full list of excipients, see section 6.1.

Solution for injection in a vial.

Clear, colourless, aqueous solution.

Treatment of adults, adolescents and children, 6 years or older with diabetes mellitus, where treatment with insulin is required.

The potency of this preparation is stated in units. These units are exclusive to Apidra and are not the same as IU or the units used to express the potency of other insulin analogues (see section 5.1).

Apidra should be used in regimens that include an intermediate or long acting insulin or basal insulin analogue and can be used with oral hypoglycaemic agents.

The dose of Apidra should be individually adjusted.

Special populations

Renal impairment

The pharmacokinetic properties of insulin glulisine are generally maintained in patients with renal impairment. However, insulin requirements may be reduced in the presence of renal impairment (see section 5.2).

Hepatic impairment

The pharmacokinetic properties of insulin glulisine have not been investigated in patients with decreased liver function. In patients with hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism.

Elderly

Limited pharmacokinetic data are available in elderly patients with diabetes mellitus. Deterioration of renal function may lead to a decrease in insulin requirements.

Paediatric population

There is insufficient clinical information on the use of Apidra in children younger than the age of 6 years.

Administration

Intravenous use

Apidra can be administered intravenously. This should be carried out by health care professionals.

Apidra must not be mixed with glucose or Ringer's solution or with any other insulin.

Subcutaneous use

Apidra should be given by subcutaneous injection shortly (015 min) before or soon after meals or by continuous subcutaneous pump infusion.

Apidra should be administered subcutaneously in the abdominal wall, thigh or deltoid or by continuous infusion in the abdominal wall. Injection sites and infusion sites within an injection area (abdomen, thigh or deltoid) should be rotated from one injection to the next. The rate of absorption, and consequently the onset and duration of action, may be affected by the injection site, exercise and other variables. Subcutaneous injection in the abdominal wall ensures a slightly faster absorption than other injection sites (see section 5.2).

Care should be taken to ensure that a blood vessel has not been entered. After injection, the site of injection should not be massaged. Patients must be educated to use proper injection techniques.

When used with a subcutaneous insulin infusion pump, Apidra must not be mixed with diluents or any other insulin.

Mixing with insulins

When administered as a subcutaneous injection, Apidra must not be mixed with other medicinal products except NPH human insulin.

For further details on handling, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients.

Hypoglycaemia.

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular, neutral protamine Hagedorn [NPH], lente, long-acting, etc.), origin (animal, human, human insulin analogue) and/or method of manufacture may result in the need for a change in dose. Concomitant oral antidiabetic treatment may need to be adjusted.

The use of inadequate doses or discontinuation of treatment, especially in insulindependent diabetic, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.

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

Conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, intensified insulin therapy, diabetic nerve disease, medicinal products such as beta blockers or after transfer from animalsource insulin to human insulin.

Adjustment of dose may be also necessary if patients undertake increased physical activity or change their usual meal plan. Exercise taken immediately after a meal may increase the risk of hypoglycaemia.

When compared with soluble human insulin, if hypoglycaemia occurs after an injection with rapid acting analogues, it may occur earlier.

Uncorrected hypoglycaemic or hyperglycaemic reactions can cause loss of consciousness, coma, or death.

Insulin requirements may be altered during illness or emotional disturbances.

Medication errors have been reported in which other insulins, particularly long-acting insulins, have been accidentally administered instead of insulin glulisine. Insulin label must always be checked before each injection to avoid medication errors between insulin glulisine and other insulins.

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially 'sodiumfree'.

Apidra contains metacresol, which may cause allergic reactions.

Combination of Apidra with pioglitazone

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind if treatment with the combination of pioglitazone and Apidra is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema.

Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Studies on pharmacokinetic interactions have not been performed. Based on empirical knowledge from similar medicinal products, clinically relevant pharmacokinetic interactions are unlikely to occur.

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

Substances that may enhance the bloodglucoselowering activity and increase susceptibility to hypoglycaemia include oral antidiabetic agents, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors (MAOIs), pentoxifylline, propoxyphene, salicylates and sulfonamide antibiotics.

Substances that may reduce the bloodglucoselowering activity include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, phenothiazine derivatives, somatropin, sympathomimetic agents (e.g. epinephrine [adrenaline], salbutamol, terbutaline), thyroid hormones, estrogens, progestins (e.g. in oral contraceptives), protease inhibitors and atypical antipsychotic medicinal products (e.g. olanzapine and clozapine).

Betablockers, clonidine, lithium salts or alcohol may either potentiate or weaken the bloodglucoselowering activity of insulin. Pentamidine may cause hypoglycaemia, which may sometimes be followed by hyperglycaemia.

In addition, under the influence of sympatholytic medicinal products such as betablockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation may be reduced or absent.

Pregnancy

There are no adequate data on the use of insulin glulisine in pregnant women.

Animal reproduction studies have not revealed any differences between insulin glulisine and human insulin regarding pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Caution should be exercised when prescribing to pregnant women. Careful monitoring of glucose control is essential.

It is essential for patients with preexisting or gestational diabetes to maintain good metabolic control throughout 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.

Lactation

It is unknown whether insulin glulisine is excreted in human milk, but in general insulin does not pass into breast milk and is not absorbed after oral administration.

Breastfeeding mothers may require adjustments in insulin dose and diet.

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia 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 machines).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

Hypoglycaemia, the most frequent undesirable effect of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement.

The following related adverse reactions from clinical studies were listed below by system organ class and in order of decreasing incidence (very common: 1/10; common: 1/100 to <1/10; uncommon: 1/1,000 to <1/100; rare: 1/10,000 to <1/1,000; very rare: <1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Metabolism and nutrition disorders

Symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation. Hypoglycaemia can become severe and may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.

Skin and subcutaneous tissue disorders

Local hypersensitivity reactions (redness, swelling and itching at the injection site) may occur during treatment with insulin. These reactions are usually transitory and normally they disappear during continued treatment.

Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area.

General disorders and administration site conditions

Systemic hypersensitivity reactions may include urticaria, chest tightness, dyspnea, allergic dermatitis and pruritus. Severe cases of generalized allergy, including anaphylactic reaction, may be lifethreatening.

Hypoglycaemia may occur as a result of an excess of insulin activity relative to food intake and energy expenditure.

There are no specific data available concerning overdoses with insulin glulisine. However, hypoglycaemia may develop over sequential stages:

Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient constantly carries some sugar lumps, sweets, biscuits or sugary fruit juice.

Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated by glucagon (0.5 mg to 1 mg) given intramuscularly or subcutaneously by a person who has received appropriate instruction, or by glucose given intravenously by a healthcare professional. Glucose must also be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes.

Upon regaining consciousness, administration of oral carbohydrate is recommended for the patient in order to prevent relapse.

After an injection of glucagon, the patient should be monitored in a hospital in order to find the reason for this severe hypoglycaemia and prevent other similar episodes.

Pharmacotherapeutic group: Insulins and analogues for injection, fastacting. ATC code: A10AB06

Insulin glulisine is a recombinant human insulin analogue that is equipotent to regular human insulin. Insulin glulisine has a more rapid onset of action and a shorter duration of action than regular human insulin.

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, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.

Studies in healthy volunteers and patients with diabetes demonstrated that insulin glulisine is more rapid in onset of action and of shorter duration of action than regular human insulin when given subcutaneously. When insulin glulisine is injected subcutaneously, the glucose lowering activity will begin within 10 – 20 minutes. After intravenous administration, a faster onset and shorter duration of action, as well as a greater peak response were observed as compared with subcutaneous administration. The glucoselowering activities of insulin glulisine and regular human insulin are equipotent when administered by intravenous route. One unit of insulin glulisine has the same glucose lowering activity as one unit of regular human insulin.

Dose proportionality

In a study with 18 male subjects with diabetes mellitus type 1 aged 21 to 50 years, insulin glulisine displayed doseproportional glucose lowering effect in the therapeutic relevant dose range 0.075 to 0.15 Units/kg, and less than proportional increase in glucose lowering effect with 0.3 Units/kg or higher, like human insulin.

Insulin glulisine takes effect about twice as fast as regular human insulin and completes the glucose lowering effect about 2 hours earlier than regular human insulin.

A phase I study in patients with type 1 diabetes mellitus assessed the glucose lowering profiles of insulin glulisine and regular human insulin administered subcutaneously at a dose of 0.15 Units/kg, at different times in relation to a 15minute standard meal. Data indicated that insulin glulisine administered 2 minutes before the meal gives similar postprandial glycemic control compared to regular human insulin given 30 minutes before the meal. When given 2 minutes prior to meal, insulin glulisine provided better postprandial control than regular human insulin given 2 minutes before the meal. Insulin glulisine administered 15 minutes after starting the meal gives similar glycemic control as regular human insulin given 2 minutes before the meal (see figure 1).

Figure 1: Average glucoselowering effect over 6 hours in 20 patients with type 1 diabetes mellitus. Insulin glulisine given 2 minutes (GLULISINE pre) before the start of a meal compared to regular human insulin given 30 minutes (REGULAR 30 min) before the start of the meal (figure 1A) and compared to regular human insulin given 2 minutes (REGULAR pre) before a meal (figure 1B). Insulin glulisine given 15 minutes (GLULISINE post) after start of a meal compared to regular human insulin given 2 minutes (REGULAR pre) before start of the meal (figure 1C). On the xaxis, zero (arrow) is the start of a 15minute meal.

Obesity

A phase I study carried out with insulin glulisine, lispro and regular human insulin in an obese population has demonstrated that insulin glulisine maintains its rapidacting properties. In this study, the time to 20 % of total AUC and the AUC (02h) representing the early glucose lowering activity were respectively of 114 minutes and 427 mg/kg for insulin glulisine, 121 minutes and 354 mg/kg for lispro, 150 minutes and 197 mg/kg for regular human insulin (see figure 2).

Figure 2: Glucose infusion rates (GIR) after subcutaneous injection of 0.3 Units/kg of insulin glulisine (GLULISINE) or insulin lispro (LISPRO) or regular human insulin (REGULAR) in an obese population.

Another phase I study with insulin glulisine and insulin lispro in a nondiabetic population in 80 subjects with a wide range of body mass indices (1846 kg/m²) has demonstrated that rapid action is generally maintained across a wide range of body mass indices (BMI), while total glucose lowering effect decreases with increasing obesity.

The average total GIR AUC between 0–1 hour was 102±75 mg/kg and 158±100 mg/kg with 0.2 and 0.4 Units/kg insulin glulisine, respectively, and was 83.1±72.8 mg/kg and 112.3±70.8 mg/kg with 0.2 and 0.4 Units/kg insulin lispro respectively.

A phase I study in 18 obese patients with type 2 diabetes mellitus (BMI between 35 and 40 kg/m²) with insulin glulisine and insulin lispro [90% CI:0.81, 0.95 (p=<0.01)] has shown that insulin glulisine effectively controls diurnal postprandial blood glucose excursions.

Clinical studies

Type 1 diabetes mellitus-Adults

In a 26week phase III clinical study comparing insulin glulisine with insulin lispro both injected subcutaneously shortly (0-15 minutes) before a meal in patients with type 1 diabetes mellitus using insulin glargine as basal insulin, insulin glulisine was comparable to insulin lispro for glycemic control as reflected by changes in glycated haemoglobin (expressed as HbA_1c equivalent) from baseline to endpoint. Comparable selfmonitored blood glucose values were observed. No increase in the basal insulin dose was needed with insulin glulisine, in contrast to insulin lispro.

A 12week phase III clinical study performed in patients with type 1 diabetes mellitus receiving insulin glargine as basal therapy indicate that the immediate postmeal administration of insulin glulisine provides efficacy that was comparable to immediate premeal insulin glulisine (015 minutes) or regular insulin (3045 minutes).

In the per protocol population there was a significantly larger observed reduction in GHb in the premeal glulisine group compared with the regular insulin group.

Type 1 diabetes mellitus -Paediatric

A 26week phase III clinical study compared insulin glulisine with insulin lispro both injected subcutaneously shortly (015 minutes) before a meal in children (45 years: n=9; 67 years: n=32 and 811 years: n=149) and adolescents (1217 years: n=382) with type 1 diabetes mellitus using insulin glargine or NPH as basal insulin. Insulin glulisine was comparable to insulin lispro for glycaemic control as reflected by changes in glycated haemoglobin (GHb expressed as HbA_1c equivalent) from baseline to endpoint and by self-monitored blood glucose values.

There is insufficient clinical information on the use of Apidra in children younger than the age of 6 years.

Type 2 diabetes mellitus-Adults

A 26week phase III clinical study followed by a 26week extension safety study was conducted to compare insulin glulisine (015 minutes before a meal) with regular human insulin (3045 minutes before a meal) injected subcutaneously in patients with type 2 diabetes mellitus also using NPH insulin as basal insulin. The average body mass index (BMI) of patients was 34.55 kg/m². Insulin glulisine was shown to be comparable to regular human insulin with regard to glycated haemoglobin (expressed as HbA_1c equivalent) changes from baseline to the 6month endpoint (-0.46% for insulin glulisine and -0.30% for regular human insulin, p=0.0029) and from baseline to the 12month endpoint (-0.23% for insulin glulisine and -0.13% for regular human insulin, difference not significant). In this study, the majority of patients (79%) mixed their short acting insulin with NPH insulin immediately prior to injection and 58% of subjects used oral hypoglycemic agents at randomization and were instructed to continue to use them at the same dose.

Race and gender

In controlled clinical trials in adults, insulin glulisine did not show differences in safety and efficacy in subgroup analyses based on race and gender.

In insulin glulisine the replacement of the human insulin amino acid asparagine in position B3 by lysine and the lysine in position B29 by glutamic acid favors more rapid absorption.

In a study with 18 male subjects with diabetes mellitus type 1 aged 21 to 50 years, insulin glulisine displays doseproportionality for early, maximum and total exposure in the dose range 0.075 to 0.4 Units/kg^.

Absorption and bioavailability

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

In a study in patients with type 1 diabetes mellitus after subcutaneous administration of 0.15 Units/kg, for insulin glulisine the T_max was 55 minutes and C_max was 82 ± 1.3 µUnits/ml compared to a T_max of 82 minutes and a C_max of 46 ± 1.3 µUnits/ml for regular human insulin. The mean residence time of insulin glulisine was shorter (98 min) than for regular human insulin (161 min) (see figure 3).

Figure 3: Pharmacokinetic profile of insulin glulisine and regular human insulin in type 1 diabetes mellitus patients after a dose of 0.15 Units/kg.

In a study in patients with type 2 diabetes mellitus after subcutaneous administration of 0.2 Units/kg insulin glulisine, the C_max was 91 µUnits/ml with the interquartile range from 78 to 104 µUnits/ml.

When insulin glulisine was injected subcutaneously into abdomen, deltoid and thigh, the concentrationtime profiles were similar with a slightly faster absorption when administered in the abdomen compared to the thigh. Absorption from deltoid sites was inbetween (see section 4.2). The absolute bioavailability (70%) of insulin glulisine was similar between injection sites and of low intrasubject variability (11%CV). Intravenous bolus administration of insulin glulisine resulted in a higher systemic exposure when compared to subcutaneous injection, with a C_max approximately 40fold higher.

Obesity

Another phase I study with insulin glulisine and insulin lispro in a nondiabetic population in 80 subjects with a wide range of body mass indices (1846 kg/m²) has demonstrated that rapid absorption and total exposure is generally maintained across a wide range of body mass indices.

The time to 10% of total INS exposure was reached earlier by approximately 5–6 min with insulin glulisine.

Distribution and elimination

The distribution and elimination of insulin glulisine and regular human insulin after intravenous administration is similar with volumes of distribution of 13 l and 22 l and halflives of 13 and 18 minutes, respectively.

After subcutaneous administration, insulin glulisine is eliminated more rapidly than regular human insulin with an apparent halflife of 42 minutes compared to 86 minutes. In an across study analysis of insulin glulisine in either healthy subjects or subjects with type 1 or type 2 diabetes mellitus the apparent halflife ranged from 37 to 75 minutes (interquartile range).

Insulin glulisine shows low plasma protein binding, similar to human insulin.

Special populations

Renal impairment

In a clinical study performed in nondiabetic subjects covering a wide range of renal function (CrCl> 80 ml/min, 3050 ml/min, < 30 ml/min), the rapidacting properties of insulin glulisine were generally maintained. However, insulin requirements may be reduced in the presence of renal impairment.

Hepatic impairment

The pharmacokinetic properties have not been investigated in patients with impaired liver function.

Elderly

Very limited pharmacokinetic data are available for elderly patients with diabetes mellitus.

Children and adolescents

The pharmacokinetic and pharmacodynamic properties of insulin glulisine were investigated in children (711 years) and adolescents (1216 years) with type 1 diabetes mellitus. Insulin glulisine was rapidly absorbed in both age groups, with similar T_max and C_max as in adults (see section 4.2). Administered immediately before a test meal, insulin glulisine provided better postprandial control than regular human insulin, as in adults (see section 5.1). The glucose excursion (AUC _0-6h) was 641 mg.h.dl^-1 for insulin glulisine and 801 mg.h.dl^-1 for regular human insulin.

Nonclinical data did not reveal toxicity findings others than those linked to the blood glucose lowering pharmacodynamic activity (hypoglycemia), different from regular human insulin or of clinical relevance for humans.

Metacresol

Sodium chloride

Trometamol

Polysorbate 20

Hydrochloric acid, concentrated

Sodium hydroxide

Water for injections

Subcutaneous use

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except NPH human insulin.

When used with an insulin infusion pump, Apidra must not be mixed with other medicinal products.

Intravenous use

Apidra was found to be incompatible with Glucose 5 % solution and Ringer's solution and, therefore, must not be used with these solution fluids. The use of other solutions has not been studied.

2 years.

Shelf life after first use of the vial

The product may be stored for a maximum of 4 weeks below 25°C away from direct heat or direct light. Keep the vial in the outer carton in order to protect from light.

It is recommended that the date of the first use from the vial be noted on the label.

Shelf life for intravenous use

Insulin glulisine for intravenous use at a concentration of 1 Unit/ml is stable between 15 C and 25 ºC for 48 hours (see section 6.6).

Unopened vials

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Do not put Apidra next to the freezer compartment or a freezer pack.

Keep the vial in the outer carton in order to protect from light.

Opened vials

For storage conditions, see section 6.3.

10 ml solution in a vial (type I colourless glass) with a stopper (flanged aluminium overseal, elastomeric chlorobutyl rubber) and a polypropylene tearoff cap. Packs of 1, 2, 4 and 5 vials are available.

Not all pack sizes may be marketed.

Subcutaneous use

Apidra vials are for use with insulin syringes with the corresponding unit scale and for use with an insulin pump system (see section 4.2).

Inspect the vial before use. It must only be used if the solution is clear, colourless, with no solid particles visible. Since Apidra is a solution, it does not require resuspension before use.

Insulin label must always be checked before each injection to avoid medication errors between insulin glulisine and other insulins (see section 4.4).

Mixing with insulins

When mixed with NPH human insulin, Apidra should be drawn into the syringe first. Injection should be given immediately after mixing as no data are available regarding the mixtures made up a significant time before injection.

Continuous subcutaneous infusion pump

Apidra may be used for Continuous Subcutaneous Insulin Infusion (CSII) in pump systems suitable for insulin infusion with the appropriate catheters and reservoirs.

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

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

Intravenous use

Apidra should be used at a concentration of 1 Unit/ml insulin glulisine in infusion systems with sodium chloride 9 mg/ml (0.9%) solution for infusion with or without 40 mmol/l potassium chloride using coextruded polyolefin/polyamide plastic infusion bags with a dedicated infusion line. Insulin glulisine for intravenous use at a concentration of 1 Unit/ml is stable at room temperature for 48 hours.

After dilution for intravenous use, the solution should be inspected visually for particulate matter prior to administration. It must only be used if the solution is clear and colourless, not when cloudy or with visible particles.

Apidra was found to be incompatible with Glucose 5% solution and Ringer's solution and, therefore, must not be used with these solution fluids. The use of other solutions has not been studied.

Sanofi-Aventis Deutschland GmbH

D-65926 Frankfurt am Main

Germany.

EU/1/04/285/001-004

Date of first authorisation: 27 September 2004

Date of latest renewal: 20 August 2009

January 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu/