Active ingredients: Insulin (Insulin glulisine)
Apidra 100 Units / ml solution for injection in a vial
Apidra package inserts are available for pack sizes:- 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
Indications Why is Apidra used? What is it for?
Apidra is an antidiabetic used to reduce high blood sugar (blood sugar) levels in adult, adolescent and children aged 6 years and over with diabetes mellitus. Diabetes mellitus is a disease in which the body does not produce enough insulin to control blood sugar.
Apidra is produced using a biotechnological process. It has a rapid onset of action within 10-20 minutes and a short duration of action of approximately 4 hours.
Contraindications When Apidra should not be used
Do not use Apidra
- If you are allergic to insulin glulisine or any of the other ingredients of this medicine (listed in section 6).
- If your blood glucose is too low (hypoglycaemia), follow the guidelines for hypoglycaemia (see box at the end of this leaflet).
Precautions for use What you need to know before taking Apidra
Talk to your doctor, pharmacist or nurse before using Apidra.
Carefully follow the instructions regarding dose, monitoring (blood tests), diet and physical activity (work and exercise) discussed with your doctor.
Special patient groups
If you have liver or kidney problems, consult your doctor as you may need a lower dose.
There is insufficient clinical information on the use of Apidra in children under 6 years of age.
Trips
Before starting a trip, consult your doctor. You may need to discuss the following:
- availability of insulin in the country of destination,
- sufficient supplies of insulin, syringes, etc.,
- correct storage of insulin during travel,
- interval between meals and insulin administration during travel,
- possible effects of changing the time zone,
- possible risks of contracting new diseases in the countries visited,
- what to do in emergency situations if you feel unwell or get sick.
Diseases and injuries
In the following situations, diabetes control may require more attention:
- If you are ill or have severe injuries there is a risk of your blood sugar level rising (hyperglycaemia).
- If you don't eat enough, there is a risk that your blood sugar level will drop (hypoglycemia).
In most cases, medical attention is required. Contact your doctor quickly. Also, if you have type 1 diabetes (insulin-dependent diabetes mellitus) do not stop taking insulin or carbohydrates. E " It is also necessary to keep the people close to you informed of your need for insulin.
Some patients with long-standing type 2 diabetes mellitus and heart disease or a previous stroke treated with pioglitazone and insulin have developed heart failure. Tell your doctor as soon as possible if you have signs of heart failure such as unusually shortness of breath or rapid weight gain or localized swelling (edema).
Interactions Which drugs or foods may change the effect of Apidra
Other medicines and Apidra
Some medicines can cause changes in blood sugar values (decrease or increase or both depending on the situation). In any case, an optimization of the insulin dose is necessary to avoid too low or too high blood sugar levels. Be careful when starting or stopping the use of another drug.
Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines. Before taking a medicine ask your doctor if, and in what way, it can affect your blood sugar and if you need to take countermeasures.
Medicines that can cause low blood sugar levels (hypoglycemia) include:
- all other medicines used to treat diabetes,
- angiotensin converting enzyme (ACE) inhibitors (used to treat certain heart conditions or high blood pressure),
- disopyramide (used to treat some heart conditions),
- fluoxetine (used to treat depression),
- fibrates (used to lower high blood fat levels),
- monoamine oxidase (MAO) inhibitors (used to treat depression),
- pentoxifylline, propoxyphene, salicylates (such as aspirin, used to relieve pain and lower fever)
- sulfonamide antibiotics.
Medicines that can cause blood sugar levels to rise (hyperglycemia) include:
- corticosteroids (such as "cortisone" used to treat inflammation),
- danazol (a drug that acts on ovulation),
- diazoxide (used to treat high blood pressure),
- diuretics (used to treat high blood pressure or excessive fluid retention),
- glucagon (pancreatic hormone used to treat severe hypoglycaemia),
- isoniazid (used to treat tuberculosis),
- estrogen and progesterone (as in the birth control pill used for birth control),
- phenothiazine derivatives (used to treat psychiatric disorders),
- somatotropin (growth hormone),
- sympathomimetic agents (such as epinephrine [adrenaline], salbutamol, terbutaline used to treat asthma),
- thyroid hormones (used to treat thyroid disorders),
- protease inhibitors (used to treat HIV).
- atypical antipsychotic medicines (such as olanzapine and clozapine).
Your blood sugar levels may go down or up if you take:
- beta-blockers (used to treat high blood pressure),
- clonidine (used to treat high blood pressure),
- lithium salts (used to treat psychiatric disorders).
Pentamidine (used to treat some infections caused by parasites) can cause hypoglycemia, sometimes followed by hyperglycemia.
Beta-blockers, like all other sympatholytics (such as clonidine, guanethidine and reserpine), can reduce or completely cancel the warning signs that help you recognize hypoglycemia.
If you are not sure if you are taking any of these medicines ask your doctor or pharmacist.
Apidra with alcohol
Your blood sugar levels can go down or up if you drink alcohol.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Tell your doctor if you are planning to become pregnant, or if you are already pregnant. Your insulin dose may need to be adjusted during pregnancy and after delivery. It is important to control diabetes carefully and prevent hypoglycemia for the health of the child.
There are no or limited data on the use of Apidra in pregnant women.
If you are breast-feeding, consult your doctor as changes in your insulin dose and diet may be required.
Driving and using machines
Its ability to concentrate or react can be reduced in case of
- hypoglycemia (low blood sugar levels)
- hyperglycemia (high blood sugar levels)
Be aware of the possibility of this occurring in all situations where you could pose a risk both to yourself and to others (such as driving a car or operating machinery). Talk to your doctor for advice on whether you drive if:
- have frequent hypoglycaemic episodes,
- the typical signs that help you identify a "hypoglycaemia are reduced or absent. Important information about some of the ingredients of Apidra
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially sodium-free.
Apidra contains metacresol
Apidra contains metacresol which can cause allergic reactions.
HYPERGLYCEMIA AND HYPOGLYCEMIA
Always carry some sugar with you (at least 20 grams).
Bring information with you to indicate that you are a person with diabetes.
HYPERGLYCEMIA (high blood sugar levels)
If your blood sugar levels are too high (hyperglycemia), you may not have injected enough insulin. Why does hyperglycemia occur?
Examples include:
- has not injected insulin or has given insufficient insulin or when the insulin becomes less effective (for example, because it is not stored correctly),
- are exercising less than usual, or are particularly stressed (emotionally or physically), or in cases of injury, surgery, infection or fever,
- you are taking or have taken certain other medicines (see section 2, "Apidra and other medicines").
Hyperglycemia Warning Symptoms
Thirst, increased urge to urinate, weakness, dry skin, redness of the face, loss of appetite, low blood pressure, rapid heartbeat, and presence of glucose or ketone bodies in the urine. Abdominal pain, deep and rapid breathing, drowsiness or even loss of knowledge may indicate a serious condition (ketoacidosis) resulting from insulin deficiency.
What should you do in case of hyperglycaemia?
Check your blood sugar and urine for ketone bodies as soon as possible if any of the above symptoms occur. Severe hyperglycaemia or ketoacidosis should always be treated by your doctor, usually in a hospital setting.
Hypoglycaemia (low blood sugar levels)
If your blood sugar levels drop too low, you can lose consciousness. Severe hypoglycemic episodes can cause heart attack or brain damage and can be life-threatening. You usually need to be able to recognize when your blood sugar levels are getting too low so that you can take adequate precautions.
Why does hypoglycemia occur?
Examples include:
- injected too much insulin,
- missed or delayed meals,
- is not eating enough, or the food consumed contains less carbohydrates than is normally consumed (carbohydrates are sugar and sugar-like substances; however, artificial sweeteners are NOT carbohydrates),
- lost carbohydrates due to vomiting or diarrhea,
- drinks alcoholic beverages, particularly if you are eating little,
- are doing more exercise than usual, or a different type of physical activity,
- is recovering from injury, surgery or stress,
- recovering from an illness or fever,
- you are taking or have taken certain other medicines (see section 2, "Apidra and other medicines").
Hypoglycemia can also occur more easily if:
- you are at the start of your insulin treatment or have switched to a different type of insulin,
- blood sugar levels are nearly normal or show changes,
- the area of the skin where he injects the insulin has changed (for example from the thigh to the upper arm),
- suffer from severe kidney or liver disease, or from other diseases such as hypothyroidism.
Warning symptoms of hypoglycemia
- In the body Examples of symptoms that indicate that blood sugar levels are falling too much or too fast: sweating, clammy skin, anxiety, rapid heartbeat, high blood pressure, palpitations, and irregular heartbeat. These symptoms can often develop earlier than those that indicate a reduction in brain sugar levels.
- In the brain Examples of symptoms that indicate decreased brain sugar levels: headache, insatiable hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, restlessness, aggression, difficulty concentrating, decreased ability to react, depressed mood, confusion , slurred speech (sometimes aphasia), visual disturbances, tremor, paralysis, sensory disturbances (paraesthesia), tingling and numb sensations in the mouth, dizziness, loss of self-control, inability to provide for oneself, seizures and loss of of knowledge.
The first symptoms characteristic of a hypoglycemic state ("warning symptoms") may vary, be less evident or even completely absent if:
- is elderly,
- have had diabetes for a long time,
- suffer from a certain type of neurological disease (diabetic autonomic neuropathy),
- after a recent hypoglycemic episode (for example the day before) or if the hypoglycaemia appears slowly,
- blood glucose levels are nearly normal or at least significantly improved,
- you are taking or have taken certain other medicines (see section 2, "Apidra and other medicines").
In these cases, severe hypoglycemia (even with loss of consciousness) can develop without recognizing it in time. Therefore you learn about its warning symptoms. If necessary, more frequent blood glucose checks can help identify mild hypoglycemic episodes that might otherwise go unnoticed. If you are unable to recognize the warning symptoms of hypoglycemia, avoid all situations (such as driving a car) that can be risky for you and others due to hypoglycemia.
What should you do in case of hypoglycaemia?
- Do not inject insulin. Immediately take 10-20 g of sugar, such as glucose, sugar cubes or a sugar-sweetened drink. Warning: Artificial sweeteners and foods containing sweeteners (such as diet drinks) do not help treat hypoglycemia.
- At this point, you consume food that can cause a release of blood sugar over a long period of time (e.g. bread or pasta). Your doctor or nurse should discuss these measures with you in advance.
- If another hypoglycemia occurs, take 10-20g of sugar again.
- Talk to your doctor as soon as you notice that your hypoglycaemia cannot be controlled or if it occurs again.
Tell your relatives, friends and close colleagues that:
if you are unable to swallow or if you lose consciousness, an injection of glucose or glucagon (a medicine that raises blood sugar levels) is needed. These injections are justified even if you are not sure if this has occurred. a hypoglycemic event.
You should check your blood sugar immediately after taking sugar to confirm that a hypoglycaemic episode is in progress.
Dosage and method of use How to use Apidra: Dosage
Dose
Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Based on your lifestyle, the results of your blood sugar (blood sugar) tests and your previous use of insulin, your doctor will work out how much Apidra you need.
Apidra is a "short-acting insulin. Your doctor may recommend combining it with a" long-acting or intermediate-acting insulin, a "basal insulin, or tablets used to treat high blood sugar levels.
If you switch from "other insulin to" insulin glulisine, your doctor may need to adjust your insulin dose.
Many factors can affect your blood sugar levels. You should be aware of these factors so that you can act appropriately in the event of changes in blood sugar levels and thus prevent them from becoming too high or too low. For more information, see the box at the end of this sheet.
Method of administration
Apidra is injected under the skin (subcutaneously). It can also be administered intravenously by qualified healthcare personnel under careful medical supervision.
Your doctor will indicate the most suitable area to inject Apidra. Apidra can be injected into the abdominal wall, thigh or forearm or as a continuous infusion into the abdominal wall. The effect of insulin will be slightly faster when injected into the abdominal wall. As with all insulins, injection sites and of infusion should be rotated from one injection to another within a chosen area (abdomen, thigh or forearm).
Frequency of administration
Apidra should be administered shortly before or immediately after meals (0-15 minutes).
Instructions for correct use
How to use the vials
Apidra vials are for use with insulin syringes with the corresponding graduated scale and with an insulin pump infusion system.
Check the vial before use. Only use it if the solution is clear, colorless and with no visible particles inside. Do not shake or mix before use.
Always use a new vial if you notice that your blood sugar control has unexpectedly deteriorated. This is because the insulin may have lost some of its effectiveness. If you think you may have a problem with Apidra, have it checked by your doctor or pharmacist.
If you need to mix two types of insulin
Apidra must not be mixed with any preparation other than NPH human insulin.
If Apidra is mixed with NPH human insulin, Apidra should be drawn into the syringe first. The injection should be made immediately after mixing.
How to handle a pump infusion system
Before using Apidra in the pump system you should have received detailed instructions on how to use the pump system. In addition, you should have information on what to do in case of illness, too high or too low sugar levels or pump malfunction.
Use the pump system recommended by your doctor. Read and follow the instructions that are provided with the insulin infusion pump. Follow your doctor's instructions on the basal infusion rate and the amount of bolus insulin to take with meals. You measure your blood glucose regularly to make sure you are getting the benefits of the insulin infusion and to make sure the insulin pump is working properly.
Replace the infusion set and reservoir at least every 48 hours using aseptic technique. These instructions may differ from those provided with the insulin infusion pump. When using Apidra in your pump system, it is important to always follow these specific instructions. Not following these specific instructions can lead to serious adverse events.
Apidra must never be mixed with diluents or any other insulin when used in a pump.
What to do in case of malfunction or misuse of the infusion pump system
Problems with the pump or infusion set or incorrect use of the pump can result in insufficient insulin delivery. This can quickly lead to hyperglycemia and diabetic ketoacidosis (buildup of acid in the blood because the body is using fat instead of sugar).If your blood sugar starts to rise, see your doctor, pharmacist or nurse as soon as possible. They will tell you what to do. You may need to use Apidra with syringes or pens. You must always have an alternative insulin delivery system available for subcutaneous injection in the event of a pump system malfunction.
Overdose What to do if you have taken too much Apidra
If you use more Apidra than you should
If you have injected too much Apidra, your blood sugar levels may become too low (hypoglycaemia). Check your blood sugar frequently. In general, to prevent hypoglycemia, you need to eat more substantial meals and control your blood sugar. For information on treating hypoglycemia, see the box at the end of this leaflet.
If you forget to use Apidra
If you have missed a dose of Apidra or have not injected enough insulin, your blood sugar levels may become too high (hyperglycaemia). Check your blood sugar frequently. For information on treating hyperglycaemia, see the box at the end of this leaflet. Do not take a double dose to make up for a forgotten dose.
If you stop taking Apidra
This can lead to severe hyperglycemia (very high blood sugar levels) and ketoacidosis (buildup of acid in the blood because the body is breaking down fat instead of sugar). Do not stop Apidra without consulting a doctor, who will tell you what needs to be done.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Exchanges of insulins
You must always check the insulin label before each injection to avoid mix-ups between Apidra and other insulins.
Side Effects What are the side effects of Apidra
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects
Hypoglycaemia (low blood sugar levels) can be very serious. Hypoglycaemia is a very commonly reported adverse event (may affect more than 1 in 10 patients). Hypoglycemia (low sugar levels) means that there is not enough sugar in the blood. If your blood sugar levels drop too low, you may lose consciousness. Severe hypoglycemic episodes can cause brain damage and can be life-threatening. If you have symptoms of low blood sugar, take immediate action to raise your blood sugar levels. See the box at the end of this leaflet for additional important information about hypoglycaemia and how it should be treated.
If you have the following symptoms, contact your doctor immediately:
Systemic allergic reactions are uncommonly reported adverse events (may affect up to 1 in 100 patients)
Generalized insulin allergy: associated symptoms may include extensive skin reactions (rash and itching all over the body), severe edema of the skin or mucous membranes (angioedema), wheezing, low blood pressure with rapid heartbeats and sweating. They could be symptoms of severe cases of a generalized allergic reaction to insulins, including an anaphylactic reaction, which could be life-threatening.
Hyperglycemia means that there is too much sugar in the blood. The frequency of hyperglycaemia cannot be estimated. Too high a blood glucose may indicate that you may need more insulin than is being given. Hyperglycemia can cause diabetic ketoacidosis (buildup of acid in the blood because the body is using fat instead of sugar). These are serious side effects. These conditions can occur when there is a problem with the infusion pump or when it is used in a non-essential way. correct pump system.This means that you may not always be getting enough insulin to treat diabetes.
If this happens, seek urgent medical help. Always have an alternative insulin delivery system available for subcutaneous injection (see section 3 under "How to handle a pump infusion system" and "What to do in the event of a malfunction or misuse of the infusion pump system") . For more information on the signs and symptoms of hyperglycaemia refer to the box at the end of this leaflet.
Other side effects
Common reported side effects (may affect up to 1 in 10 patients)
- Skin and allergic reactions at the injection site You may experience reactions at the injection site (such as redness, unusually severe pain during injection, itching, wheals (blisters), swelling or inflammation). These disturbances can extend around the injection site. Most minor insulin reactions resolve within a few days or weeks.
Rare reported side effects (may affect up to 1 in 1,000 patients)
- Skin changes at the injection site (lipodystrophy) If insulin is injected too often into the same area of the skin, the subcutaneous fatty tissue beneath this area may shrink or thicken. Insulin that is injected into a site in such conditions may not be adequately effective. Varying the location of each injection can help prevent this type of skin change.
Undesirable effects whose frequency cannot be estimated from the available data:
- Eye reactions A marked change (improvement or worsening) in blood sugar levels can temporarily disturb vision. If you have proliferative retinopathy (an eye disease associated with diabetes), severe hypoglycaemic episodes can cause temporary loss of vision.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and vial label after EXP / Exp. The expiry date refers to the last day of that month.
Unopened vials
Store in a refrigerator (2 ° -8 ° C). Do not freeze. Do not place Apidra in direct contact with the freezer compartment or with refrigerated bags. Keep the vial in the outer carton to protect the medicine from light.
Open vials
Once used, the vial can be stored for up to 4 weeks in the original packaging below 25 ° C away from direct heat or direct light. Do not use the vial after this period. It is recommended to note the date of first use on the vial label.
Do not use this medicine if the solution does not appear clear and colorless.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Apidra contains
- The active substance is insulin glulisine. Each ml of the solution contains 100 Units of insulin glulisine (equivalent to 3.49 mg). Each vial contains 10 ml of solution for injection, equivalent to 1000 Units.
- The other ingredients are: metacresol (see section 2 "Apidra contains"), sodium chloride (see section 2 "Important information about some of the components of Apidra"), trometamol, polysorbate 20, concentrated hydrochloric acid, sodium hydroxide, water for preparations injectable.
What Apidra looks like and contents of the pack
Apidra 100 Units / ml solution for injection in a vial is a clear, colorless aqueous solution with no visible particles.
Each vial contains 10 ml of solution (1000 Units). Packs of 1, 2, 4 and 5 vials are available. Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
APIDRA SOLUTION FOR INJECTION IN A VIAL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 100 Units of insulin glulisine (equivalent to 3.49 mg).
Each vial contains 10 ml of solution for injection equivalent to 1,000 Units.
Insulin glulisine is produced by recombinant DNA technology in Escherichia coli.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection in a vial.
Aqueous, clear, colorless solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of adult, adolescent and child patients from 6 years of age with diabetes mellitus, where insulin treatment is required.
04.2 Posology and method of administration
Dosage
The potency of this preparation is expressed in units. These units refer to Apidra only and do not correspond to the IU or the units used to express the potency of other insulin analogues (see section 5.1).
Apidra should be used in therapeutic regimens that include an intermediate-acting or slow-acting insulin or a basal insulin analog and can be used concomitantly with oral hypoglycaemics.
The dose of Apidra must be established specifically for each patient.
Special populations
Kidney failure
The pharmacokinetic properties of insulin glulisine are usually maintained in patients with impaired renal function. However, insulin requirements may be reduced in the presence of renal impairment (see section 5.2).
Hepatic insufficiency
The pharmacokinetic properties of insulin glulisine have not been studied in patients with impaired hepatic function. In patients with impaired hepatic function, the need for insulin may be decreased due to impaired gluconeogenesis and reduced insulin metabolism.
Senior citizens
There are limited pharmacokinetic data in elderly patients with diabetes mellitus. Deterioration of kidney function can lead to a reduction in insulin requirements.
Pediatric population
There is insufficient clinical information on the use of Apidra in children under 6 years of age.
Method of administration
Intravenous use
Apidra can be administered intravenously. This must be done by qualified healthcare personnel.
Apidra must not be mixed with glucose solution or Ringer's solution or with other insulins.
Subcutaneous use
Apidra should be administered by subcutaneous injection shortly before or immediately after meals (0 - 15 minutes) or with a continuous subcutaneous infusion pump.
Apidra should be administered subcutaneously into the abdominal wall, thigh or deltoid muscle or by continuous infusion into the abdominal wall. The injection and infusion sites must be rotated between each injection within a "suitable" area for injection (abdomen, thigh or deltoid muscle). The rate of absorption and thus the onset of effect and duration of action may be affected by the injection site, exercise and other variables.
Subcutaneous injection into the abdominal wall ensures slightly faster absorption than other injection sites (see section 5.2).
Caution is needed to ensure that a vessel has not been penetrated. After the injection, the injection site should not be massaged. Patients should be instructed in the correct injection technique.
When used with an insulin infusion pump, Apidra must not be mixed with diluents or any other insulin.
Mixing with other insulins
Apidra, when administered by subcutaneous injection must not be mixed with other medicinal products except human NPH insulin.
For more information on handling, see section 6.6.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypoglycemia.
04.4 Special warnings and appropriate precautions for use
Switching the patient to another type or brand of insulin should be done under careful medical supervision. Changes in strength, brand (manufacturer), type (normal, neutral protamine Hagedorn [NPH], slow, long-lasting, etc.), origin (animal, human, human insulin analogue) and / or method of manufacture may determine the need for dose modification Concomitant oral antidiabetic treatment may require dose adjustments.
The use of inadequate doses or discontinuation of treatment, especially in insulin-dependent diabetic patients, can cause hyperglycemia and diabetic ketoacidosis, potentially fatal conditions.
Hypoglycemia
The onset time of hypoglycemia depends on the action profile of the insulins used and could, therefore, change when the therapeutic regimen is changed.
Conditions that could make the early warning signs of hypoglycemia different or less obvious include: long-lasting diabetes, intensified insulin therapy, diabetic neuropathy, medicinal products such as beta-blockers, or switching from animal to human insulin.
Dose adjustments may also be needed if patients increase the intensity of their physical activity or make changes to their usual dietary regimen. Exercise immediately after meals may increase the risk of hypoglycaemia.
If an episode of hypoglycaemia occurs after the injection of fast-acting insulin analogues, this may occur earlier than with soluble human insulin.
Uncorrected hypoglycemic or hyperglycemic reactions can result in unconsciousness, coma, or death.
Insulin requirements can be altered during illness or in the presence of emotional disturbances.
Medication administration errors
Medication errors have been reported in which other insulins, particularly long-acting insulins, have been accidentally administered in place of insulin glulisine. The insulin label should always be checked before each injection to avoid medication errors between insulin glulisine and other insulins.
Excipients
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially sodium-free.
Apidra contains metacresol which can cause allergic reactions.
Combination of Apidra with pioglitazone
Cases of heart failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for developing heart failure. This should be considered if treatment with the combination of pioglitazone and Apidra is set. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and edema.
Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.
04.5 Interactions with other medicinal products and other forms of interaction
Pharmacokinetic interaction studies have not yet been conducted. Based on the empirical knowledge of similar medicinal products, it is unlikely that there are drug interactions of clinical relevance.
Certain substances affect glucose metabolism and may require insulin glulisine dose adjustment and particularly careful monitoring.
Substances capable of potentiating hypoglycemic activity and increasing susceptibility to hypoglycemia include: oral antidiabetic agents, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline, propoxyphene, salicylates and sulfonamide antibiotics.
Substances that may reduce hypoglycemic activity include: corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, phenothiazine derivatives, somatropin, sympathomimetics (eg epinephrine [adrenaline], salbutamol, terbutaline), thyroid hormones, estrogens example in oral contraceptives), protease inhibitors and atypical antipsychotics (e.g. olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts or alcohols can potentiate or weaken the hypoglycemic activity of insulin. Pentamidine can cause hypoglycemia, which can sometimes be followed by hyperglycemia.
Furthermore, under the influence of sympatholytics such as beta-blockers, clonidine, guanethidine and reserpine, signs of adrenergic counter-regulation may be reduced or absent.
04.6 Pregnancy and lactation
Pregnancy
There are no or limited data (outcomes from less than 300 pregnancies) from the use of insulin glulisine in pregnant women.
Animal reproduction studies revealed no difference between insulin glulisine and human insulin in terms of pregnancy, embryo-fetal development, parturition or postnatal development (see section 5.3).
Caution should be exercised when prescribing the drug to pregnant women. Accurate blood glucose monitoring is essential.
It is essential that patients with pre-existing or gestational diabetes maintain good metabolic control during pregnancy. Insulin requirements may decrease during the first trimester of pregnancy and generally increase during the second and third trimesters.
Immediately after giving birth, the need for insulin is rapidly reduced.
Feeding time
It is not known whether insulin glulisine is excreted in human milk, but insulin does not usually pass into breast milk and is not absorbed after oral administration.
Breastfeeding may require adjustments in insulin dosage and diet.
Fertility
Animal reproduction studies with insulin glulisine showed no adverse effects on fertility.
04.7 Effects on ability to drive and use machines
The patient's ability to concentrate and react may be impaired following hypoglycemia or hyperglycemia or, for example, as a result of a "visual impairment. This could constitute a risk in situations where the aforementioned skills are of particular importance (for example driving and using machines).
Patients should be informed about the need to take appropriate precautions to avoid the onset of hypoglycaemia while driving vehicles. This is of particular relevance in cases where awareness of hypoglycemic symptoms is reduced or absent or there are frequent episodes. Hypoglycemia. It is important to consider whether or not it is appropriate to drive in these circumstances.
04.8 Undesirable effects
Summary of the safety profile
Hypoglycaemia, which is the most frequent adverse reaction with insulin therapy, can occur if the insulin dose is too high in relation to the insulin requirement.
Table of adverse reactions
The following drug related adverse reactions from clinical studies were listed by system organ class in order of decreasing incidence (very common: ≥1 / 10; common: ≥1 / 100,
Within each frequency class, adverse reactions are reported in order of decreasing severity.
Description of selected adverse reactions
Metabolism and nutrition disorders
Symptoms of hypoglycemia usually come on suddenly. They may include cold sweats, pale cold skin, fatigue, nervousness or tremors, anxiety, unusual tiredness or weakness, confusion, difficulty concentrating, sleepiness, excessive hunger, visual changes, headache, nausea and palpitations. Hypoglycemia can become very severe and lead to loss of consciousness and / or seizures and can 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 insulin therapy. These reactions are usually transient and usually disappear with continued therapy.
Lipodystrophy can occur at the injection site as a result of not changing injection points within one area.
General disorders and administration site conditions
Systemic hypersensitivity reactions may include hives, chest tightness, dyspnoea, allergic dermatitis and pruritus. Severe cases of generalized allergy, including anaphylactic reactions, can be life threatening.
04.9 Overdose
Symptoms
Hypoglycaemia may occur due to excess insulin activity related to food intake and energy consumption.
There are no specific data regarding overdose with insulin glulisine. However, hypoglycemia can occur in sequential stages.
Treatment
Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugar-rich products. Therefore, it is recommended that the diabetic patient always carry sugar lumps, sweets, biscuits or sugary fruit juices with them.
Severe hypoglycaemic episodes, in which the patient loses consciousness, can be treated with intramuscular or subcutaneous glucagon (0.5 mg to 1 mg) administered by an appropriately trained person, or with intravenous glucose administered by a qualified health care practitioner. If the patient does not respond to glucagon within 10-15 minutes, intravenous glucose should also be administered.
Once the state of consciousness has regained, the administration of oral carbohydrates is recommended to prevent relapses.
After the glucagon injection, the patient should be monitored in hospital to determine the reason for the severe hypoglycemic attack and to prevent other similar episodes.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: drugs used in diabetes, insulins and analogues for injection, fast acting. ATC code: A10AB06
Mechanism of action
Insulin glulisine is a recombinant analogue of human insulin equipotent to regular human insulin. Insulin glulisine has a faster 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 the regulation of glucose metabolism. Insulins reduce blood glucose by stimulating peripheral glucose uptake, especially from skeletal muscles and adipose tissue. and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in adipocytes, inhibits proteolysis and increases protein synthesis.
Studies in healthy volunteers and diabetic patients have shown that insulin glulisine exhibits a faster onset of action and a shorter duration of action than regular human insulin after subcutaneous administration. When insulin glulisine is injected under the skin, hypoglycemic activity will begin within 10-20 minutes. After intravenous administration, a more rapid onset of action and a shorter duration of action, as well as a greater peak response, were observed compared to subcutaneous administration. The hypoglycemic activities of insulin glulisine and regular human insulin are equipotent when administered intravenously.
An insulin glulisine unit exhibits the same hypoglycemic activity as a regular human insulin unit.
Proportionality of the dose
In a study of 18 male subjects with type 1 diabetes mellitus aged between 21 and 50 years, insulin glulisine showed a dose-proportional hypoglycemic effect in the therapeutic dose range of 0.075 to 0.15. Units / kg and a less than proportional increase in blood glucose lowering effect with doses of 0.3 Units / kg or higher, as for human insulin.
Insulin glulisine works approximately twice as rapidly as regular human insulin and completes the blood glucose lowering effect 2 hours earlier than regular human insulin.
A Phase I study in patients with type I diabetes mellitus examined the hypoglycemic profiles of insulin glulisine and regular human insulin administered subcutaneously at doses of 0.15 Units / kg, at different times in relation to a standard 15-minute meal.
The data indicated that insulin glulisine administered 2 minutes before a meal achieves the same post-meal glycemic control as regular human insulin administered 30 minutes before a meal. When given 2 minutes before a meal, insulin glulisine provided better post-meal control than regular human insulin given 2 minutes before a meal. Insulin glulisine taken 15 minutes after the start of a meal provides glycemic control similar to that of regular human insulin given 2 minutes before a meal.
Mean hypoglycemic effect over a period of 6 hours in 20 patients with type 1 diabetes mellitus. Insulin glulisine administered 2 minutes (GLULISIN-before) before the start of the meal compared with regular human insulin administered 30 minutes (REGULAR-30 min) before the start of the meal and compared to regular human insulin given 2 minutes (REGULAR-before) before the meal. Insulin glulisine administered 15 minutes (GLULISINE-after) after the start of the meal compared with regular human insulin administered 2 minutes (REGULAR-before) before the start of the meal. On the x-axis, zero (arrow) corresponds to the "start of a 15 minute meal.
Obesity
A Phase I study conducted with insulin glulisine, lispro and regular human insulin in an obese population demonstrated that insulin glulisine retains its fast-acting properties. In this study the time up to 20% of the total AUC and AUC (0-2h) representing early hypoglycemic activity were 114 minutes and 427 mg / kg for insulin glulisine, 121 minutes and 354 mg / kg for insulin lispro, 150 minutes and 197 mg / kg, respectively. kg for regular human insulin. Glucose infusion rate (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 population of 80 non-diabetic subjects with a wide range of body mass indices (18-46 kg / m2) showed that rapid action is generally maintained through a wide range of body mass indexes (BMI), while the total hypoglycemic effect decreases with increasing obesity.
The mean total range for GIR AUC, between 0-1 hour, was 102 ± 75 mg / kg and 158 ± 100 mg / kg, respectively, following administration of 0.2 and 0.4 Units / kg of insulin glulisine. and respectively 83.1 ± 72.8 mg / kg and 112.3 ± 70.8 mg / kg after administration of 0.2 and 0.4 Units / kg of insulin lispro.
A Phase I study in 18 obese patients with type 2 diabetes mellitus (BMI between 35 and 40 kg / m2) treated with insulin glulisine and insulin lispro [90% CI: 0.81, 0.95 (p =
Clinical efficacy and safety
Type 1 diabetes mellitus - Adults
In a 26-week Phase III clinical study comparing insulin glulisine with insulin lispro, both injected subcutaneously shortly before a meal (0-15 minutes) in patients with type 1 diabetes mellitus using insulin glargine as basal insulin, insulin glulisine was comparable to insulin lispro in glycemic control as shown by changes in glycated hemoglobin levels (expressed as HbA1c equivalent) from baseline to end-point. Comparable blood glucose values obtained by self-monitoring were observed. No increase in basal insulin dose was required with insulin glulisine compared with insulin lispro.
A 12-week Phase III clinical study in patients with type I diabetes mellitus treated with insulin glargine as basal therapy indicates that administration of insulin glulisine immediately after a meal provides "comparable efficacy to pre-meal". meal of insulin glulisine (0-15 minutes) or regular insulin (30-45 minutes).
In the per-protocol population, a significantly higher reduction in glycated hemoglobin was observed in the pre-meal glulisine group than in the regular insulin group.
Type 1 diabetes mellitus - Pediatric patients
A 26-week Phase III clinical study compared insulin glulisine with insulin lispro, both injected subcutaneously shortly before a meal (0-15 minutes) in children (4-5 years: n = 9 ; 6-7 years: n = 32 and 8-11 years: n = 149) and in adolescents (12-17 years: n = 382) with type 1 diabetes mellitus using insulin glargine or NPH insulin as basal insulin.
Insulin glulisine was comparable to insulin lispro in glycemic control as shown by changes in glycated hemoglobin levels (GHb expressed as HbA1c equivalent) from baseline to endpoint, and self-monitoring blood glucose values.
There is insufficient clinical information on the use of Apidra in children under 6 years of age.
Type 2 Diabetes Mellitus - Adults
A 26-week Phase III study followed by an extended 26-week safety study was conducted to compare insulin glulisine (0-15 minutes before a meal) with regular human insulin (30-45 minutes before) injected subcutaneous in patients with type 2 diabetes mellitus using NPH insulin as basal insulin. The mean body mass index (BMI) of the patients was 34.55 kg / m2. Insulin glulisine was comparable to regular human insulin with regard to changes from baseline to 6-month end-point in glycated hemoglobin (expressed as HbA1c equivalent) (-0.46% for insulin glulisine and -0 , 30% for human regular insulin, p = 0.0029) and from baseline to end-point at 12 months (-0.23% for insulin glulisine and -0.13% for regular human insulin , difference not significant). In this study, the majority of patients (79%) mixed short-acting insulin with NPH insulin immediately prior to injection and 58% of subjects used oral hypoglycemic agents at randomization and were were instructed to continue taking it at the same dosage.
Race and gender
In controlled clinical trials in adults, insulin glulisine showed no differences in safety and efficacy in subgroup analyzes based on race or gender.
05.2 "Pharmacokinetic properties
In insulin glulisine, the replacement of the amino acid asparagine of human insulin in position B3 with lysine and of lysine in position B29 with glutamic acid promotes faster absorption.
In a study of 18 male subjects with type 1 diabetes mellitus aged 21 to 50 years, insulin glulisine showed dose-related proportionality during initial, maximum and total exposure over the dose range of 0.075 and 0.4 Units / kg.
Absorption and bioavailability
Pharmacokinetic profiles in healthy volunteers and diabetic patients (type 1 or 2) demonstrated that insulin glulisine absorption was approximately twice as rapid with a peak concentration approximately twice as high as with 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 the Cmax was 82 ± 1.3 mcUnits / ml compared to a Tmax of 82 minutes and a Cmax of 46 ± 1.3 mcUnits / ml for regular human insulin. The mean residence time for insulin glulisine was shorter (98 min) than that for regular human insulin (161 min).
Pharmacokinetic profile of insulin glulisine and regular human insulin in patients with type 1 diabetes mellitus 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 Cmax was 91 μmUnits / ml with the interquartile range 78 to 104 μUnits / ml.
When insulin glulisine was injected subcutaneously into the abdomen, deltoid muscle and thigh, the time-concentration profiles were similar with slightly faster absorption in the abdomen than in the thigh. deltoid sites showed intermediate values (see section 4.2).The absolute bioavailability (70%) of insulin glulisine was similar at different administration sites and of low intra-individual variability (11% CV). Intravenous bolus administration of insulin glulisine resulted in greater systemic exposure than " subcutaneous injection, with a Cmax approximately 40 times higher.
Obesity
Another Phase I study with insulin glulisine and insulin lispro conducted in a population of 80 non-diabetic subjects with a wide range of body mass indices (18-46 kg / m2) showed that rapid absorption and total exposure they are generally maintained across a "wide range of body mass indices."
Time to 10% of total INS exposure was achieved early, within approximately 5-6 min, following administration of insulin glulisine.
Distribution and disposal
The distribution and elimination of insulin glulisine and regular human insulin after intravenous administration are similar with distribution volumes of 13 liters and 22 liters and the corresponding half-lives are 13 and 18 minutes, respectively.
After subcutaneous administration, insulin glulisine is cleared more rapidly than regular human insulin with an apparent half-life of 42 minutes compared to 86 minutes. In a review of multiple studies of insulin glulisine in healthy subjects or in subjects with diabetes mellitus. type 1 or 2, the apparent half-life was between 37 and 75 minutes (interquartile range).
Insulin glulisine demonstrated low plasma protein binding similar to that seen with human insulin.
Special populations
Kidney failure
In a clinical study conducted in non-diabetic subjects covering a wide range of renal function (CrCl> 80 mL / min, 30-50 mL / min,
Hepatic insufficiency
Pharmacokinetic properties have not been studied in patients with impaired hepatic function.
Senior citizens
There are very limited pharmacokinetic data available in elderly patients with diabetes mellitus.
Children and adolescents
The pharmacokinetic and pharmacodynamic properties of insulin glulisine were evaluated in children (7-11 years) and adolescents (12-16 years) with type 1 diabetes mellitus. Insulin glulisine was rapidly absorbed in both age groups. "age with Tmax and Cmax similar to those seen in adults (see section 4.2). When given immediately before a meal, insulin glulisine provided better postprandial control than regular human insulin, as in adults (see section 5.1). The glycemic range (AUC 0-6h) was 641 mg.h.dl-1 for insulin glulisine and 801mg.h.dl-1 for regular human insulin.
05.3 Preclinical safety data
Non-clinical data revealed no data of particular toxicity other than those related to the pharmacodynamic activity of lowering blood glucose (hypoglycemia), other than those of regular human insulin or of clinical relevance for humans.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Metacresol
Sodium chloride
Trometamol
Polysorbate 20
Hydrochloric acid, concentrated
Sodium hydroxide
Water for injections
06.2 Incompatibility
Subcutaneous use
In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products except human NPH insulin.
When used with an infusion pump, Apidra must not be mixed with other medicinal products.
Intravenous use
Apidra was found to be incompatible with 5% glucose solution and Ringer's solution and therefore should not be used with these solutions. The use of other solutions has not been studied.
06.3 Period of validity
2 years.
Shelf life after first use of the vial
The product can be stored for up to 4 weeks below 25 ° C away from direct heat or direct light. Keep the vial in the outer carton to protect the medicine from light.
It is recommended to write the date on which the contents of the vial are used for the first time on the label.
Validity 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).
06.4 Special precautions for storage
Unopened vials
Store in a refrigerator (2 ° C - 8 ° C).
Do not freeze.
Do not place Apidra in direct contact with the freezer compartment or with refrigerated bags.
Keep the vial in the outer carton to protect the medicine from light.
Open vials
For storage conditions after first opening of the medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
10 ml of solution in a vial (type I colorless glass), with a stopper (flanged aluminum cap, chlorobutyl elastomeric rubber) and a flip-off polypropylene cap. Packs of 1, 2, 4, and 5 vials are available.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Subcutaneous use
Apidra vials are to be used with insulin syringes with the corresponding unit scale or with a pump infusion system (see section 4.2).
Check the vial before use. The solution should only be used if it is clear, colorless, with no visible particles. As Apidra is a solution, no resuspension is required prior to use.
The insulin label should always be checked before each injection to avoid medication errors between insulin glulisine and other insulins (see section 4.4).
Mixing with other insulins
When mixed with NPH human insulin, Apidra should be drawn into the syringe first. The injection should be given immediately after mixing as there is no data on mixing long before injection.
Continuous subcutaneous infusion pump
Apidra can be used for continuous subcutaneous insulin infusion (CSII) into pumped systems suitable for infusing insulin with appropriate catheters and reservoirs.
Patients using CSII should be fully instructed in the use of the pump system. The infusion set and reservoir should be replaced every 48 hours using aseptic techniques.
Patients taking Apidra via CSII should have an "alternative insulin available in case of pump malfunction."
Intravenous use
Apidra is to 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 polyolefin / polyamide coextruded 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 visually inspected for the presence of suspended particles prior to administration. It should only be used if the solution is clear and colorless, it should not be used if it is cloudy or with visible particles.
Apidra was found to be incompatible with 5% glucose solution and Ringer's solution and therefore should not be used with these solutions. The use of other solutions has not been studied.
07.0 MARKETING AUTHORIZATION HOLDER
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany.
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/04/285 / 001-004
036684013
036684025
036684037
036684049
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 27 September 2004
Date of most recent renewal: August 20, 2009
