APIDRA 100U / ml injection solution into the bottle medication leaflet

Apidra 100 Units/ml solution for injection in a vial

Apidra 100 Units/ml solution for injection in a cartridge

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen

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

Apidra 100 Units/ml solution for injection in a vial

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

Apidra 100 Units/ml solution for injection in a cartridge

Each cartridge contains 3 ml of solution for injection, equivalent to 300 Units.

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen

Each pen contains 3 ml of solution for injection, equivalent to 300 Units.

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

For the full list of excipients, see section 6.1.

Apidra 100 Units/ml solution for injection in a vial

Solution for injection in a vial.

Apidra 100 Units/ml solution for injection in a cartridge

Solution for injection in a cartridge.

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen

Solution for injection in a pre-filled pen.

Clear, colourless, aqueous solution.

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

The potency of this preparation is stated in units. These units are exclusive to Apidra and are not thesame 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 insulinanalogue and can be used with oral hypoglycaemic agents.

The dose of Apidra should be individually adjusted.

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

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

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

There is insufficient clinical information on the use of Apidra in children younger than the age of6 years.

Apidra 100 Units/ml solution for injection in a vial

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

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

Continuous subcutaneous insulin infusion

Apidra may be used for Continuous Subcutaneous Insulin Infusion (CSII) in pump systems suitablefor insulin infusion with the appropriate catheters and reservoirs. Patients using CSII should becomprehensively instructed on the use of the pump system.

The infusion set and reservoir used with Apidra must be changed at least every 48 hours using aseptictechnique. These instructions may differ from general pump manual instructions. It is important thatpatients follow the Apidra specific instructions when using Apidra. Failure to follow Apidra specificinstructions may lead to serious adverse events.

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

Patients administering Apidra by CSII must have an alternative insulin delivery system available incase of pump system failure (see section 4.4 and 4.8).

Apidra 100 Units/ml solution for injection in a vial

For further details on handling, see section 6.6.

Apidra 100 Units/ml solution for injection in a cartridge

Apidra 100 Units/ml in cartridges is only suitable for subcutaneous injections from a reusable pen. Ifadministration by syringe, intravenous injection or infusion pump is necessary, a vial should be used(see section 4.4). For further details on handling, see section 6.6.

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen

Apidra SoloStar 100 Units/ml in pre-filled pen is only suitable for subcutaneous injections. Ifadministration by syringe, intravenous injection or infusion pump is necessary, a vial should be used(see section 4.4).

Subcutaneous use

Apidra should be given by subcutaneous injection shortly (0-15 min) before or soon after meals or bycontinuous subcutaneous pump infusion.

Apidra should be administered subcutaneously in the abdominal wall, thigh or deltoid or bycontinuous 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 in order to reduce the riskof lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

The rate of absorption, and consequently the onset and duration of action, may be affected by theinjection site, exercise and other variables. Subcutaneous injection in the abdominal wall ensures aslightly 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 ofinjection should not be massaged. Patients must be educated to use proper injection techniques.

Mixing with insulins

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

For further details on handling, see section 6.6.

Before using SoloStar, the Instructions for use included in the Package leaflet must be read carefully(see section 6.6).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

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

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulinabsorption and worsened glycaemic control following insulin injections at sites with these reactions. Asudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia.

Blood glucose monitoring is recommended after the change in the injection site, and dose adjustmentof antidiabetic medications may be considered.

The use of inadequate doses or discontinuation of treatment, especially in insulin-dependent 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 lesspronounced include long duration of diabetes, intensified insulin therapy, diabetic nerve disease,medicinal products such as beta blockers or after transfer from animal-source insulin to human insulin.

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

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

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

Insulin requirements may be altered during illness or emotional disturbances.

Apidra 100 Units/ml solution for injection in a cartridge

Pens to be used with Apidra 100 units/ml solution for injection in a cartridge

Apidra 100 units/ml in cartridges is only suitable for subcutaneous injections from a reusable pen. Ifadministration by syringe, intravenous injection or infusion pump is necessary, a vial should be used.

The Apidra cartridges should only be used with the following pens:

− JuniorSTAR which delivers Apidra in 0.5 unit dose increments− ClikSTAR, Tactipen, Autopen 24, AllStar and AllStar PRO which all deliver Apidra in 1 unit doseincrements.

These cartridges should not be used with any other reusable pen as the dosing accuracy has only beenestablished with the listed pens (see section 4.2 and 6.6).

Not all of these pens may be marketed in your country.

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

Apidra 100 Units/ml solution for injection in a vial

Continuous subcutaneous insulin infusion

Malfunction of the insulin pump or infusion set or handling errors can rapidly lead to hyperglycaemia,ketosis and diabetic ketoacidosis. Prompt identification and correction of the cause of hyperglycaemiaor ketosis or diabetic ketoacidosis is necessary.

Cases of diabetic ketoacidosis have been reported when Apidra has been given in continuoussubcutaneous insulin infusion in pump systems. Most of the cases were related to handling errors orpump system failure.

Interim subcutaneous injections with Apidra may be required. Patients using continuous subcutaneousinsulin infusion pump therapy must be trained to administer insulin by injection and have alternativeinsulin delivery system available in case of pump system failure (see section 4.2 and 4.8).

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially‘sodium-free’.

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 inmind if treatment with the combination of pioglitazone and Apidra is considered. If the combination isused, 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.

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen

Handling of the SoloStar pre-filled pen

Apidra SoloStar 100 units/ml in pre-filled pen is only suitable for subcutaneous injections. Ifadministration by syringe, intravenous injection or infusion pump is necessary, a vial should be used.

Before using SoloStar, the Instructions for use included in the Package leaflet must be read carefully.

SoloStar has to be used as recommended in these Instructions for use (see section 6.6).

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

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

Substances that may enhance the blood-glucose-lowering activity and increase susceptibility tohypoglycaemia include oral antidiabetic medicinal products, angiotensin converting enzyme (ACE)inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors (MAOIs), pentoxifylline,propoxyphene, salicylates and sulphonamide antibiotics.

Substances that may reduce the blood-glucose-lowering activity include corticosteroids, danazol,diazoxide, diuretics, glucagon, isoniazid, phenothiazine derivatives, somatropin, sympathomimeticmedicinal products (e.g. epinephrine [adrenaline], salbutamol, terbutaline), thyroid hormones,oestrogens, progestins (e.g. in oral contraceptives), protease inhibitors and atypical antipsychoticmedicinal products (e.g. olanzapine and clozapine).

Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken theblood-glucose-lowering activity of insulin. Pentamidine may cause hypoglycaemia, which maysometimes be followed by hyperglycaemia.

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

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of insulinglulisine in pregnant women.

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

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

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

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

Breast-feeding mothers may require adjustments in insulin dose and diet.

Animal reproduction studies with insulin glulisine have not revealed any adverse effects on fertility.

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia orhyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk insituations 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 isparticularly important in those who have reduced or absent awareness of the warning symptoms ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.

Hypoglycaemia, the most frequent adverse reaction of insulin therapy, may occur if the insulin dose istoo high in relation to the insulin requirement.

The following related adverse reactions from clinical studies were listed below by system organ classand 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 beestimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA Very common Common Uncommon Rare Not known

Organ systemclasses

Metabolism Hypoglycaemia Hyperglycaemiaand nutrition (potentiallydisorders leading to

Diabeticketoacidosis(1))

Skin and Injection site Lipodystrophy Cutaneoussubcutaneous reactions amyloidosistissue Localdisorders hypersensitivityreactions

General Systemicdisorders and hypersensitivityadministration reactionssite conditions(1) Apidra 100 Units/ml solution for injection in a vial: Most of the cases were related to handling errorsor pump system failure when Apidra was used with CSII.

* 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 inconcentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

Hypoglycaemia can become severe and may lead to unconsciousness and/or convulsions and mayresult in temporary or permanent impairment of brain function or even death.

Apidra 100 Units/ml solution for injection in a vial

Cases of hyperglycaemia have been reported with Apidra when used with CSII (see section 4.4) thathas led to Diabetic Ketoacidosis (DKA); most of the cases were related to handling errors or pumpsystem failure. The patient should always follow the Apidra specific instructions and always haveaccess to alternative insulin delivery system in case of pump system failure.

* Skin and subcutaneous tissue disorders

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

Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulinabsorption. Continuous rotation of the injection site within the given injection area may help to reduceor prevent these reactions (see section 4.4).

* General disorders and administration site conditions

Systemic hypersensitivity reactions may include urticaria, chest tightness, dyspnoea, allergicdermatitis and pruritus. Severe cases of generalized allergy, including anaphylactic reaction, may belife-threatening.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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 istherefore recommended that the diabetic patient constantly carries some sugar lumps, sweets, biscuitsor sugary fruit juice.

Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated byglucagon (0.5 mg to 1 mg) given intramuscularly or subcutaneously by a person who has receivedappropriate instruction, or by glucose given intravenously by a healthcare professional. Glucose mustalso 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 inorder to prevent relapse.

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

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, fast-acting.

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 humaninsulin.

The primary activity of insulins and insulin analogues, including insulin glulisine, is regulation ofglucose metabolism. Insulins lower blood glucose levels by stimulating peripheral glucose uptake,especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibitslipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.

Studies in healthy volunteers and patients with diabetes demonstrated that insulin glulisine is morerapid in onset of action and of shorter duration of action than regular human insulin when givensubcutaneously. When insulin glulisine is injected subcutaneously, the glucose lowering activity willbegin within 10-20 minutes. After intravenous administration, a faster onset and shorter duration ofaction, as well as a greater peak response were observed as compared with subcutaneousadministration. The glucose-lowering activities of insulin glulisine and regular human insulin areequipotent when administered by intravenous route.

One unit of insulin glulisine has the same glucose-lowering activity as one unit of regular humaninsulin.

Dose proportionality

In a study with 18 male subjects with diabetes mellitus type 1 aged 21 to 50 years, insulin glulisinedisplayed dose-proportional glucose lowering effect in the therapeutic relevant dose range 0.075 to0.15 Units/kg, and less than proportional increase in glucose lowering effect with 0.3 Units/kg orhigher, like human insulin.

Insulin glulisine takes effect about twice as fast as regular human insulin and completes the glucoselowering 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 ofinsulin glulisine and regular human insulin administered subcutaneously at a dose of 0.15 Units/kg, atdifferent times in relation to a 15-minute standard meal. Data indicated that insulin glulisineadministered 2 minutes before the meal gives similar postprandial glycaemic control compared toregular human insulin given 30 minutes before the meal. When given 2 minutes prior to meal, insulinglulisine provided better postprandial control than regular human insulin given 2 minutes before themeal. Insulin glulisine administered 15 minutes after starting the meal gives similar glycaemic controlas regular human insulin given 2 minutes before the meal (see figure 1).

220 220200 200180 180160 160140 140120 120100 100 10080 GLULISINE - pre80 GLULISINE - pre 80 GLULISINE - post

REGULAR - 30 min REGULAR - pre REGULAR - pre

- 1 0 1 2 3 4 5 6 7 60

- 1 0 1 2 3 4 5 6 7 -1 0 1 2 3 4 5 6 7

TIME - hour

TIME - hour TIME - hour

Figure 1A Figure 1B Figure 1C

Figure 1: Average glucose-lowering 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 regularhuman insulin given 30 minutes (REGULAR 30 min) before the start of the meal (figure 1A) andcompared 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 humaninsulin given 2 minutes (REGULAR pre) before start of the meal (figure 1C). On the x-axis, zero(arrow) is the start of a 15-minute meal.

Obesity

A phase I study carried out with insulin glulisine, lispro and regular human insulin in an obesepopulation has demonstrated that insulin glulisine maintains its rapid-acting properties. In this study,the time to 20% of total AUC and the AUC (0-2h) representing the early glucose lowering activitywere respectively of 114 minutes and 427 mg/kg for insulin glulisine, 121 minutes and 354 mg/kg forlispro, 150 minutes and 197 mg/kg for regular human insulin (see figure 2).

GLULISINE

LISPRO8 REGULAR0 2 4 6 8 10

TIME - hour

GLUCOSE - mg/dL

GIR - mg/kg/min

GLUCOSE - mg/dL

GLUCOSE - mg/dL

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 obesepopulation.

Another phase I study with insulin glulisine and insulin lispro in a non-diabetic population in80 subjects with a wide range of body mass indices (18-46 kg/m²) has demonstrated that rapid actionis generally maintained across a wide range of body mass indices (BMI), while total glucose loweringeffect 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 and0.4 Units/kg insulin glulisine, respectively, and was 83.1 ± 72.8 mg/kg and 112.3 ± 70.8 mg/kg with0.2 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 insulinglulisine effectively controls diurnal postprandial blood glucose excursions.

Type 1 diabetes mellitus-Adults

In a 26-week phase III clinical study comparing insulin glulisine with insulin lispro both injectedsubcutaneously shortly (0-15 minutes) before a meal in patients with type 1 diabetes mellitus usinginsulin glargine as basal insulin, insulin glulisine was comparable to insulin lispro for glycaemiccontrol as reflected by changes in glycated haemoglobin (expressed as HbA1c equivalent) frombaseline to endpoint. Comparable self-monitored blood glucose values were observed. No increase inthe basal insulin dose was needed with insulin glulisine, in contrast to insulin lispro.

A 12-week phase III clinical study performed in patients with type 1 diabetes mellitus receivinginsulin glargine as basal therapy indicate that the immediate post-meal administration of insulinglulisine provides efficacy that was comparable to immediate pre-meal insulin glulisine (0-15 minutes)or regular insulin (30-45 minutes).

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

Type 1 diabetes mellitus-Paediatric

A 26-week phase III clinical study compared insulin glulisine with insulin lispro both injectedsubcutaneously shortly (0-15 minutes) before a meal in children (4-5 years: n=9; 6-7 years: n=32 and8-11 years: n=149) and adolescents (12-17 years: n=382) with type 1 diabetes mellitus using insulinglargine or NPH as basal insulin. Insulin glulisine was comparable to insulin lispro for glycaemiccontrol as reflected by changes in glycated haemoglobin (GHb expressed as HbA1c equivalent) frombaseline 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 of6 years.

Type 2 diabetes mellitus-Adults

A 26-week phase III clinical study followed by a 26-week extension safety study was conducted tocompare insulin glulisine (0-15 minutes before a meal) with regular human insulin (30-45 minutesbefore a meal) injected subcutaneously in patients with type 2 diabetes mellitus also using NPHinsulin as basal insulin. The average body mass index (BMI) of patients was 34.55 kg/m2. Insulinglulisine was shown to be comparable to regular human insulin with regard to glycated haemoglobin(expressed as HbA1c equivalent) changes from baseline to the 6-month endpoint (-0.46% for insulinglulisine and -0.30% for regular human insulin, p=0.0029) and from baseline to the 12-month endpoint(-0.23% for insulin glulisine and -0.13% for regular human insulin, difference not significant). In thisstudy, the majority of patients (79%) mixed their short acting insulin with NPH insulin immediatelyprior to injection and 58% of subjects used oral hypoglycaemic agents at randomization and wereinstructed to continue to use them at the same dose.

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

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

In a study with 18 male subjects with diabetes mellitus type 1, aged 21 to 50 years, insulin glulisinedisplays dose-proportionality for early, maximum and total exposure in the dose range0.075 to 0.4 Units/kg.

Absorption and bioavailability

Pharmacokinetic profiles in healthy volunteers and diabetes patients (type 1 or 2) demonstrated thatabsorption of insulin glulisine was about twice as fast with a peak concentration approximately twiceas 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 Tmax was 55 minutes and Cmax was 82 ± 1.3 µUnits/ml compared to a Tmax of82 minutes and a Cmax of 46 ± 1.3 µUnits/ml for regular human insulin. The mean residence time ofinsulin 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 diabetesmellitus 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/kginsulin glulisine, the Cmax 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, theconcentration-time profiles were similar with a slightly faster absorption when administered in theabdomen compared to the thigh. Absorption from deltoid sites was in-between (see section 4.2). Theabsolute bioavailability (70%) of insulin glulisine was similar between injection sites and of lowintra-subject variability (11% CV). Intravenous bolus administration of insulin glulisine resulted in ahigher systemic exposure when compared to subcutaneous injection, with a Cmax approximately40-fold higher.

Obesity

Another phase I study with insulin glulisine and insulin lispro in a non-diabetic population in80 subjects with a wide range of body mass indices (18-46 kg/m²) has demonstrated that rapidabsorption 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 insulinglulisine.

Distribution and elimination

The distribution and elimination of insulin glulisine and regular human insulin after intravenousadministration is similar with volumes of distribution of 13 l and 22 l and half-lives of 13 and18 minutes, respectively.

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

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

In a clinical study performed in non-diabetic subjects covering a wide range of renal function(CrCl >80 ml/min, 30-50 ml/min, <30 ml/min), the rapid-acting properties of insulin glulisine weregenerally maintained. However, insulin requirements may be reduced in the presence of renalimpairment.

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

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 inchildren (7-11 years) and adolescents (12-16 years) with type 1 diabetes mellitus. Insulin glulisine wasrapidly absorbed in both age groups, with similar Tmax and Cmax as in adults (see section 4.2).

Administered immediately before a test meal, insulin glulisine provided better postprandial controlthan regular human insulin, as in adults (see section 5.1). The glucose excursion (AUC 0-6h) was641 mg.h.dl-1 for insulin glulisine and 801 mg.h.dl-1 for regular human insulin.

Non-clinical data did not reveal toxicity findings others than those linked to the blood glucoselowering pharmacodynamic activity (hypoglycaemia), different from regular human insulin or ofclinical relevance for humans.

Metacresol

Sodium chloride

Trometamol

Polysorbate 20

Hydrochloric acid, concentrated

Sodium hydroxide

Water for injections

Apidra 100 Units/ml solution for injection in a vial

Subcutaneous use

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

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

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.

Apidra 100 Units/ml solution for injection in a vial

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 directlight. 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°C

for 48 hours (see section 6.6).

Apidra 100 Units/ml solution for injection in a cartridge

Shelf life after first use of the cartridge

The product may be stored for a maximum of 4 weeks below 25°C away from direct heat or directlight.

The pen containing a cartridge must not be stored in the refrigerator.

The pen cap must be put back on the pen after each injection in order to protect from light.

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen

Shelf life after first use of the pen

The product may be stored for a maximum of 4 weeks below 25°C away from direct heat or direct light.

Pens in use must not be stored in the refrigerator. The pen cap must be put back on the pen after eachinjection in order to protect from light.

Apidra 100 Units/ml solution for injection in a vial

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 after first opening of the medicinal product, see section 6.3.

Apidra 100 Units/ml solution for injection in a cartridge

Unopened cartridges

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 cartridge in the outer carton in order to protect from light.

In-use cartridges

For storage conditions after first opening of the medicinal product, see section 6.3.

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen

Not in-use pens

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 pre-filled pen in the outer carton in order to protect from light.

In-use pens

For storage conditions after first opening of the medicinal product, see section 6.3.

Apidra 100 Units/ml solution for injection in a vial10 ml solution in a vial (type I colourless glass) with a stopper (flanged aluminium overseal,elastomeric chlorobutyl rubber) and a polypropylene tear-off cap. Packs of 1, 2, 4 and 5 vials areavailable.

Not all pack sizes may be marketed.

Apidra 100 Units/ml solution for injection in a cartridge3 ml solution in a cartridge (type I colourless glass) with a plunger (elastomeric bromobutyl rubber)and a flanged cap (aluminium) with a stopper (elastomeric bromobutyl rubber). Packs of 1, 3, 4, 5, 6,8, 9 and 10 cartridges are available.

Not all pack sizes may be marketed.

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen3 ml solution in a cartridge (colourless glass) with a plunger (elastomeric bromobutyl rubber) and aflanged cap (aluminium) with a stopper (elastomeric bromobutyl rubber). The cartridge is sealed in adisposable pre-filled pen. Packs of 1, 3, 4, 5, 6, 8, 9 and 10 pens are available.

Not all pack sizes may be marketed.

Apidra 100 Units/ml solution for injection in a vial

Subcutaneous use

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

Inspect the vial before use. It must only be used if the solution is clear, colourless, with no solidparticles 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 insulinglulisine 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 shouldbe given immediately after mixing as no data are available regarding the mixtures made up asignificant time before injection.

Continuous subcutaneous infusion pump

Refer to section 4.2 and 4.4 for advice.

Apidra should be used at a concentration of 1 Unit/ml insulin glulisine in infusion systems withsodium chloride 9 mg/ml (0.9%) solution for infusion with or without 40 mmol/l potassium chlorideusing coextruded polyolefin/polyamide plastic infusion bags with a dedicated infusion line. Insulinglulisine 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 priorto administration. It must only be used if the solution is clear and colourless, not when cloudy or withvisible 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.

Apidra 100 Units/ml solution for injection in a cartridge

Apidra 100 units/ml in a cartridge is only suitable for subcutaneous injections from a reusable pen. Ifadministration by syringe, intravenous injection or infusion pump is necessary, a vial should be used.

The Apidra cartridges are to be used only in conjunction with the pens: ClikSTAR, Autopen 24,

Tactipen, AllStar, AllStar PRO or JuniorSTAR (see section 4.2 and 4.4). Not all of these pens may bemarketed in your country.

The pen should be used as recommended in the information provided by the device manufacturer.

The manufacturer’s instructions for using the pen must be followed carefully for loading the cartridge,attaching the needle, and administering the insulin injection. Inspect the cartridge before use. It mustonly be used if the solution is clear, colourless, with no solid particles visible. Before insertion of thecartridge into the reusable pen, the cartridge must be stored at room temperature for 1 to 2 hours. Airbubbles must be removed from the cartridge before injection (see instruction for using pen). Emptycartridges must not be refilled.

If the insulin pen is damaged or not working properly (due to mechanical defects) it has to bediscarded, and a new insulin pen has to be used.

To prevent any kind of contamination, the re-usable pen should be used by a single patient only.

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

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen

Apidra SoloStar 100 units/ml in a pre-filled pen is only suitable for subcutaneous injections. Ifadministration by syringe, intravenous injection or infusion pump is necessary, a vial should be used.

Before first use, the pen must be stored at room temperature for 1 to 2 hours.

Inspect the cartridge before use. It must only be used if the solution is clear, colourless, with no solidparticles visible, and if it is of water-like consistency. Since Apidra is a solution, it does not requireresuspension before use.

Empty pens must never be reused and must be properly discarded.

To prevent any kind of contamination, the use of the pre-filled pen should remain strictly for a singlepatient use.

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

Handling of the pen

The patient should be advised to read the instructions for use included in the package leafletcarefully before using SoloStar.

Pen cap Pen needle (not included) Pen body

Protective seal Insulin reservoir Dosewindow

Outer Innerneedle needle Dosage Injectioncap cap Needle Rubber seal selector button

Schematic diagram of the pen

Important information for use of SoloStar:

* Before each use, a new needle must always be carefully attached and a safety test must beperformed. A dose should not be selected and/or the injection button should not be pressedwithout a needle attached. Only use needles that are compatible for use with SoloStar.

* Special caution must be taken to avoid accidental needle injury and transmission of infection.

* SoloStar must never be used if it is damaged or if the patient is not sure if it is workingproperly.

* The patient must always have a spare SoloStar available in case the SoloStar is lost ordamaged.

Storage instructions

Please check section 6.4 of this SPC for instructions on how to store SoloStar.

If SoloStar is in cool storage, it should be taken out 1 to 2 hours before you inject to allow it to warmup. Cold insulin is more painful to inject.

The used SoloStar must be discarded as required by your local authorities.

Maintenance

SoloStar has to be protected from dust and dirt.

The outside of the SoloStar can be cleaned by wiping it with a damp cloth.

The pen must not be soaked, washed or lubricated as this may damage it.

SoloStar is designed to work accurately and safely. It should be handled with care. The patient shouldavoid situations where SoloStar may be damaged. If the patient is concerned that the SoloStar may bedamaged, he must use a new one.

Step 1 Check the insulin

The label on the pen should be checked to make sure it contains the correct insulin. The Apidra

SoloStar is blue. It has a dark blue injection button with a raised ring on the top. After removing thepen cap, the appearance of insulin should also be checked: the insulin solution must be clear,colourless, with no solid particles visible, and must have a water-like consistency.

Step 2 Attach the needle

Only needles that are compatible for use with SoloStar should be used.

A new sterile needle will be always used for each injection. After removing the cap, the needle shouldbe carefully attached straight onto the pen.

Step 3 Perform a safety test

Prior to each injection a safety test has to be performed to ensure that pen and needle work properlyand to remove air bubbles.

A dose of 2 units has to be selected.

The outer and inner needle caps should be removed.

While holding the pen with the needle pointing upwards, the insulin reservoir should be tapped gentlywith the finger so that any air bubbles rise up towards the needle.

Then the injection button should be pressed in completely.

If insulin has been expelled through the needle tip, then the pen and the needle are working properly.

If no insulin appears at the needle tip, step 3 should be repeated until insulin appears at the needle tip.

Step 4 Select the dose

The dose can be set in steps of 1 unit, from a minimum of 1 unit to a maximum of 80 units. If a dosegreater than 80 units is required, it should be given as two or more injections.

The dose window must show “0” following the safety test. The dose can then be selected.

Step 5 Inject the dose

The patient should be informed on the injection technique by his health care professional.

The needle should be inserted into the skin.

The injection button should be pressed in completely. Then the injection button should be held down10 seconds before withdrawing the needle. This ensures that the full dose of insulin has been injected.

Step 6 Remove and discard the needle

The needle should always be removed after each injection and discarded. This helps preventcontamination and/or infection, entry of air into the insulin reservoir and leakage of insulin. Needlesmust not be reused.

Special caution must be taken when removing and disposing the needle. Recommended safetymeasures for removal and disposal of needles must be followed (e.g. a one handed capping technique)in order to reduce the risk of accidental needle injury and transmission of infectious diseases.

The pen cap should be replaced on the pen.

Sanofi-Aventis Deutschland GmbH

D-65926 Frankfurt am Main

Germany.

Apidra 100 Units/ml solution for injection in a vial

EU/1/04/285/001-004

Apidra 100 Units/ml solution for injection in a cartridge

EU/1/04/285/005-012

Apidra SoloStar 100 Units/ml solution for injection in a pre-filled pen

EU/1/04/285/029-036

Date of first authorisation: 27 September 2004

Date of latest renewal: 20 August 2009

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