Apidra

Apidra

insulin glulisine

Manufacturer:

Sanofi-Aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Insulin glulisine.
Description
Each mL contains insulin glulisine 100 units (equivalent to 3.49 mg).
Insulin glulisine is produced by recombinant DNA technology in Escherichia coli.
Action
Pharmacotherapeutic Group: Fast-acting insulin and analogues. ATC Code: A10AB06.
Pharmacology: Pharmacodynamics: 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 SC. When insulin glulisine is injected SC, the glucose-lowering activity will begin within 10-20 min. The glucose-lowering activities of insulin glulisine and regular human insulin are equipotent when administered by IV route. One unit of insulin glulisine has the same glucose-lowering activity as 1 unit of regular human insulin.
Dose Proportionality: Insulin glulisine displayed dose-proportional glucose-lowering effect in the therapeutic relevant dose range 0.075-0.15 unit/kg, and less than proportional increase in glucose-lowering effect with ≥0.3 unit/kg, like human insulin.
Insulin glulisine takes effect about twice as fast as regular human insulin and completes the glucose-lowering effect about 2 hrs 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 SC at a dose of 0.15 unit/kg, at different times in relation to a 15-min standard meal. Data indicated that insulin glulisine administered 2 min before the meal gives similar postprandial glycemic control compared to regular human insulin given 30 min before the meal. When given 2 min prior to meal, insulin glulisine provided better postprandial control than regular human insulin given 2 min before the meal. Insulin glulisine administered 15 min after starting the meal gives similar glycemic control as regular human insulin given 2 min before the 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 rapid-acting properties. In this study, the time to 20% of total AUC and the AUC (0-2 hrs) representing the early glucose-lowering activity were respectively of 114 min and 427 mg/kg for insulin glulisine, 121 min and 354 mg/kg for lispro, 150 min and 197 mg/kg for regular human insulin.
Another phase I study with insulin glulisine and insulin lispro in a nondiabetic population with a wide range of body mass indices (18-46 kg/m2) has demonstrated that rapid action generally maintained across a wide range of body mass indices, while total glucose-lowering effect decreases with increasing obesity.
Insulin glulisine consistently displayed greater early glucose-lowering effect. The average total AUC between 0-1 hr was 102±75 mg/kg and 158±100 mg/kg with 0.2 and 0.4 unit/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 unit/kg insulin lispro, respectively.
A phase I study in obese patients with type 2 diabetes mellitus [ body mass index (BMI) between 35 and 40 kg/m2] with insulin glulisine and insulin lispro has shown that overall insulin glulisine more effectively controls postprandial blood glucose excursions. In total, the maximum glucose excursions were less by 12% with insulin glulisine.
Clinical Studies: Type 1 Diabetes Mellitus: Adults: In a 26-week, phase III clinical study comparing insulin glulisine with insulin lispro both injected SC shortly (0-15 min) 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 (GHb) (expressed as HbA1c equivalent) from baseline to endpoint. Comparable self-monitored blood glucose values were observed. No increase in the 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 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 (0-15 min) or regular insulin (30-45 min).
In the per protocol population, there was a significantly larger observed reduction in GHb in the premeal glulisine group compared with regular insulin group.
Pediatric: In a 26-week, phase III clinical study comparing insulin glulisine with insulin lispro both injected SC shortly (0-15 min) before a meal in children and adolescents with type 1 diabetes mellitus using insulin glargine or neutral protamine hagedorn (NPH) as basal insulin, insulin glulisine was comparable to insulin lispro for glycemic control as reflected by changes in GHb (GHb expressed as HbA1c equivalent) from baseline to endpoint. Comparable self-monitored blood glucose values were observed . To achieve similar glycemic control, subjects in the insulin glulisine group required significantly less increase in both the basal and rapid-acting insulin doses as compared to subjects treated with insulin lispro.
Type 2 Diabetes Mellitus: Adults: A 26-week, phase III clinical study followed by a 26-week extension safety study was conducted to compare insulin glulisine (0-15 min before a meal) with regular human insulin (30-45 min before a meal) injected SC in patients with type 2 diabetes mellitus also using NPH insulin as basal insulin. The average BMI of patients was 34.55 kg/m2. Insulin glulisine was shown to be comparable to regular human insulin with regard to GHb (expressed as HbA1c equivalent) changes from baseline to the 6-month endpoint (-0.46% for insulin glulisine and -0.3% 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 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.
Pharmacokinetics: In insulin glulisine, 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.
Insulin glulisine displays dose proportionality for early, maximum and total exposure in the dose range 0.075-0.4 unit/kg. Absorption and Bioavailability: Pharmacokinetic profiles in healthy volunteers and diabetic patients (type 1 or 2) demonstrated that absorption of insulin glulisine was about twice as fast with peak concentration approximately twice as high as compared to regular human insulin.
In a study in patients with type 1 diabetes mellitus after SC administration of 0.15 unit/kg, for insulin glulisine the Tmax was 55 min and Cmax was 82±1.3 microunit/mL compared to a Tmax of 82 min and a Cmax of 46±1.3 microunit/mL for regular human insulin. The mean residence time of insulin glulisine was shorter (98 min) than for regular human insulin (161 min).
In a study in patients with type 2 diabetes mellitus after SC administration of 0.2 unit/kg insulin glulisine, the Cmax was 91 microunit/mL with the interquartile range from 78-104 microunit/mL. When insulin glulisine was injected SC into abdomen, deltoid and thigh, the concentration-time profiles were similar with a slightly faster absorption when administered in the abdomen compared to the thigh. Absorption from deltoid sites was in-between (see Dosage & Administration). The absolute bioavailability (70%) of insulin glulisine was similar between injection sites and low intrasubject variability (11% CV).
Obesity: Another phase I study with insulin glulisine and insulin lispro in a nondiabetic population with a wide range of body mass indices (18-46 kg/m2) has demonstrated that rapid absorption and total exposure is generally maintained across a wide range of body mass indices.
Insulin glulisine consistently displayed faster early exposure. 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 IV administration is similar with volumes of distribution of 13 and 22 L and half-lives of 13 and 18 min, respectively. After SC administration, insulin glulisine is eliminated more rapidly than regular human insulin with an apparent half-life of 42 min compared to 86 min. In an across study analysis of insulin glulisine in either healthy subjects or subjects with type 1 or type 2 diabetes mellitus, the apparent half-life ranged from 37-75 min (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 [creatinine clearance (CrCl) >80 mL/min, 30-50 mL/min, <30 mL/min], the rapid-acting 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 (7-11 years) and adolescents (12-16 years) with type I diabetes mellitus. Insulin glulisine was rapidly absorbed in both age groups, with similar Tmax and Cmax as in adults (see Dosage & Administration).
Administered immediately before a test meal, insulin glulisine provided better postprandial control than regular human insulin, as in adults (see Pharmacodynamics). The glucose excursion (AUC0-6 hrs) was 641 and 801 mg/hr/dL for insulin glulisine and for regular human insulin, respectively.
Toxicology: Preclinical Safety Data: Preclinical data did not reveal toxicity findings other than those linked to the blood glucose-lowering pharmacodynamic activity (hypoglycemia), different from regular human insulin or of clinical relevance for humans.
Indications/Uses
Treatment of adults, adolescents and children ≥4 years with diabetes mellitus, where treatment with insulin is required.
Dosage/Direction for Use
Apidra should be given shortly (0-15 min) before or soon after meals.
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 dosage 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 Pharmacokinetics under Actions).
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.
Children and Adolescents: Efficacy and safety of Apidra have been demonstrated in children and adolescents ≥4 years.
Administration: Apidra should be given by SC injection or by continuous SC pump infusion.
Apidra should be administered SC in the abdominal wall, thigh or deltoid or by continuous infusion in the abdominal wall. Injection and infusion sites within an injection area (abdomen, thigh or deltoid) should be rotated from 1 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. SC injection in the abdominal wall ensures a slightly faster absorption than other injection sites (see Pharmacokinetics under Actions).
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.
Mixing with Insulins: Apidra must not be mixed with any preparations other than human insulin.
For further details on handling, see Instructions for Use and Handling under Cautions For Usage.
Overdosage
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 overdose 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 sugar lumps, sweets, biscuits or sugary fruit juice.
Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated by glucagon (0.5-1 mg) given IM or SC by a person who has received appropriate instruction or by glucose given IV by a medical professional. Glucose must also be given IV, if the patient does not respond to glucagon within 10-15 min. 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.
Contraindications
Hypersensitivity to insulin glulisine or to any of the excipients of Apidra.
Hypoglycaemia.
Special Precautions
Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, etc), species (animal) and/or method of manufacturing may result in a change in dosage. Concomitant oral antidiabetic treatment may need to be adjusted.
The use of inadequate dosages or discontinuation of treatment, especially in insulin-dependent diabetic, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.
Hypoglycaemia: 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 eg, β-blockers or after transfer from animal source insulin to human insulin.
Adjustment of dosage may also be 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.
Effects on the Ability to Drive or Operate Machinery: The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or eg, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (eg, driving a car or operating machinery).
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.
Use in 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 Pharmacology: Toxicology under Actions).
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 1st trimester and generally increase during the 2nd and 3rd trimesters. Immediately after delivery, insulin requirements decline rapidly.
Use in Lactation: In general insulin does not pass into breastmilk and is not absorbed after oral administration, but it is unknown whether insulin glulisine is excreted in human milk.
Breastfeeding mothers may require adjustments in insulin dose and diet.
Use In Pregnancy & Lactation
Use in 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 Pharmacology: Toxicology under Actions).
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 1st trimester and generally increase during the 2nd and 3rd trimesters. Immediately after delivery, insulin requirements decline rapidly.
Use in Lactation: In general insulin does not pass into breastmilk and is not absorbed after oral administration, but it is unknown whether insulin glulisine is excreted in human milk.
Breastfeeding mothers may require adjustments in insulin dose and diet.
Adverse Reactions
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 investigations were listed as follows by system organ class and in order of decreasing incidence [very common: >1/10; common: >1/100 to <1/10; uncommon: >1/1000 to <1/100; rare: >1/10,000 to <1/1000; very rare: <1/10,000); not known (cannot be estimated from the available data)].
Metabolism and Nutrition Disorders: Very Common: Hypoglycaemia.
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: Common: Injection site reactions and local hypersensitivity reactions.
Local hypersensitivity reactions (redness, swelling and itching at the injection site) may occur during treatment with insulin. These reactions are usually transitory and normally disappear during continued treatment.
Rare: Lipodystrophy.
Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area.
General Disorders: Uncommon: Systemic hypersensitivity reactions.
Systemic hypersensitivity reactions may include urticaria, chest tightness, dyspnea, allergic dermatitis and pruritus. Severe cases of generalized allergy, including anaphylactic reaction may be life-threatening.
Drug Interactions
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 blood glucose-lowering 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 blood glucose-lowering activity include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, phenothiazine derivatives, somatropin, sympathomimetic agents [eg, epinephrine (adrenaline), salbutamol, terbutaline], thyroid hormones, estrogens, progestins (eg, in oral contraceptives), protease inhibitors and atypical antipsychotic medicinal products (eg, olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood glucose-lowering activity of insulin. Pentamidine may cause hypoglycaemia, which may sometimes be followed by hyperglycaemia.
In addition, under the influence of sympatholytic medicinal products eg, β-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation may be reduced or absent.
Incompatibilities: In the absence of compatibility studies, Apidra must not be mixed with any preparations other than NPH human insulin.
Caution For Usage
Instructions for Use and Handling: Before first use, the pen must be stored at room temperature for 1-2 hrs. Inspect the cartridge before use. It must only be used if the solution is clear, colourless, with no solid particles visible and if it is of water-like consistency. Since Apidra is a solution, it does not require resuspension before use.
Empty pens must never be used and must be properly discarded. To prevent any kind of contamination, the use of the pre-filled pen should remain strictly for a single patient use.
SoloStar is a disposable pen for the injection of insulin. Doses can be set from 1-80 units in steps of 1 unit.
Important Information for Use: Always attach a new needle before each use. Only use needles that are compatible for use with SoloStar. Always perform the safety test before each injection. The pen is for single patient use. Do not share it with anyone else. If the injection is given by another person, special caution must be taken by this person to avoid accidental needle injury and transmission of infection. Never use SoloStar if it is damaged or if not sure that it is working properly. Always have a spare SoloStar in case it gets lost or damaged.
Storage Instructions: If the SoloStar is in cool storage, take it out 1-2 hrs before injection to allow it to warm up to room temperature. Cold insulin is more painful to inject. Maintenance: Protect SoloStar pen from dust and dirt. Clean the outside of SoloStar pen by wiping it with a damp cloth. Do not soak, wash or lubricate the pen as this may damage it. SoloStar pen is designed to work accurately and safely. It should be handled with care. Avoid situations where SoloStar might be damaged. If concerned that the SoloStar pen may be damaged, use a new one.
Step 1: Check the Insulin: Check the label on the SoloStar pen to make sure that it is the correct insulin. The Apidra SoloStar is blue. It has a dark blue injection button with a raised ring on the top. Take off the pen cap. Check the appearance of the insulin. Apidra is a clear insulin. Do not use if the insulin is cloudy, coloured or has particles.
Step 2: Attach the Needle: Always use a new sterile needle for each injection. This helps prevent contamination and potential needle blocks. Remove the protective seal from a new needle. Line up the needle with the pen and keep it straight while attaching it (screw or push on, depending on the needle type). If the needle is not kept straight while attaching it, it can damage the rubber seal and cause leakage, or break the needle.
Step 3: Perform a Safety Test: Always perform the safety test before each injection. This ensures an accurate dose by: Ensuring that pen and needle work properly and removing air bubbles.
Select a dose of 2 units by turning the dosage selector. Take off the outer needle cap and keep it to remove the used needle after injection. Take off the inner needle cap and discard it. Hold the pen with the needle pointing upwards. Tap the insulin reservoir so that any air bubbles rise up towards the needle. Press the injection button all the way in. Check if insulin comes out of the needle tip.
Safety test may have to be performed several times before insulin is seen. If no insulin comes out, check for air bubbles and repeat safety test two more times to remove them. If still no insulin comes out, the needle may be blocked. Change the needle and try again. If no insulin comes out after changing the needle, SoloStar pen may be damaged. Do not use this SoloStar.
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 is needed. If a dose >80 units is needed, give it as ≥2 injections.
Check that the dose window shows "0" following the safety test. Select the required dose. If a turn is made past the dose, turn back down.
Do not push the injection button while turning, as insulin will come out. The dosage selector cannot be turned past the number of units left in the pen. Do not force the dosage selector to turn. In this case, either inject what is remaining in the pen and complete the dose with a new SoloStar or use a new SoloStar for a full dose.
Step 5: Inject the Dose: Use the injection method as instructed by the healthcare professional. Insert the needle into the skin. Deliver the dose by pressing the injection button in all the way. The number in the dose window will return to "0" as it is injected. Keep the injection button pressed all the way in. Slowly count to 10 before withdrawing the needle from the skin. This ensures that the full dose will be delivered.
Step 6: Remove and Discard the Needle: Always remove the needle after each injection and store SoloStar without a needle attached. This helps prevent: Contamination and/or infection; entry of air into the insulin reservoir and leakage of insulin which can cause inaccurate dosing.
Put the needle cap back on the needle, and use it to unscrew the needle from the pen. To reduce the risk of accidental needle injury, never replace the inner needle cap. If the injection is given by another person, special caution must be taken by this person when removing and disposing the needle. Follow recommended safety measures for removal and disposal of needles (eg, a one handed capping technique) in order to reduce the risk of accidental needle injury and transmission of infectious diseases. Dispose of the needle safely, as instructed by the healthcare professional. Always put the pen cap back on the pen, then store the pen until the next injection.
Storage
Not-In-Use Pens: Store in a refrigerator (2-8°C). Do not freeze. Do not put Apidra next to the freezer compartment or a freezer pack.
In-Use Pens: Store for a maximum of 4 weeks not above 25°C away from direct heat or light. Keep the pre-filled pen in the outer carton in order to protect from light.
It is recommended that the date of the first use be noted on the label. Pens in use must not be stored in the refrigerator. The pen cap must be back on the pen after each injection in order to protect from light.
Shelf Life: 2 years.
ATC Classification
A10AB06 - insulin glulisine ; Belongs to the class of fast-acting insulins and analogues. Used in the treatment of diabetes.
Presentation/Packing
SoloStar pre-filled pen 100 units/mL (clear, colourless, aqueous soln) x 3 mL x 5's.
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