APIDRA 100 units/mL injectable solution in vial

Introduction

Package Leaflet: Information for the User

Apidra100Units/ml solution for injection in a vial

Insulin glulisine

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What is Apidra and what is it used for

1. What you need to know before you use Apidra
2. How to use Apidra
3. Possible side effects
4. Storage of Apidra
5. Contents of the pack and other information

1. What is Apidra and what is it used for

Apidra is an antidiabetic agent used to reduce high blood sugar levels in patients with diabetes mellitus. It can be administered to adults, adolescents, and children from 6 years of age. Diabetes mellitus is a disease in which your body does not produce enough insulin to control blood sugar levels.

It is produced by biotechnology. It has a rapid onset of action between 10-20 minutes and a short duration of action, around 4 hours.

2. What you need to know before you use Apidra

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 sugar level is too low (hypoglycemia), follow the hypoglycemia guide (see the box at the end of this leaflet).

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting Apidra.

Follow carefully the instructions for dosing, monitoring (blood tests), diet, and physical activity (physical work and exercise) as indicated by your doctor.

Special patient groups

If you have liver or kidney problems, consult your doctor as you may need a lower dose.

There is no clinical information available on the use of Apidra in children under 6 years of age.

Skin changes at the injection site

The injection site should be rotated to avoid skin changes, such as lumps under the skin. Insulin may not work as well if injected into a swollen area (see How to use Apidra). Contact your doctor if you are currently injecting into a swollen area before starting to inject into a different area. Your doctor may advise you to check your blood sugar levels more closely and adjust your insulin or other antidiabetic medications.

Travel

Before traveling, consult your doctor. You may need to discuss:

• the availability of your insulin in the country you are traveling to,
• insulin, syringes, etc. supplies,
• proper storage of insulin during travel,
• meal and insulin administration schedules during travel,
• possible effects of crossing time zones,
• new health risks in the countries you will visit,
• what to do in emergency situations when you are ill or become sick.

Illness and injury

Your diabetes management may require special care in the following situations:

• If you are ill or have a major injury, your blood sugar level may increase (hyperglycemia).
• If you do not eat enough, your blood sugar level may drop too low (hypoglycemia).

In most cases, you will need a doctor. Make sure to consult a doctor immediately.

If you have type 1 diabetes (insulin-dependent diabetes mellitus), do not stop taking your insulin and follow a proper diet. Always inform the people in charge of your care or treatment that you need insulin.

Some patients with long-standing type 2 diabetes mellitus and previous heart disease or stroke who were treated with pioglitazone and insulin developed heart failure. Inform your doctor as soon as possible if you experience symptoms of heart failure such as unusual shortness of breath or rapid weight gain or localized swelling (edema).

Using Apidra with other medicines

Some medicines produce changes in blood sugar levels (an increase, a decrease, or both depending on the situation). In each case, it may be necessary to adjust your insulin dose to avoid blood sugar levels that are too low or too high. Be careful when starting to take another medicine and also when stopping it.

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. Ask your doctor before taking a medicine if it can affect your blood sugar level and what measures you should take, if any.

Among the medicines that may cause a decrease in your blood sugar level (hypoglycemia) are:

• all other medicines for treating diabetes,
• angiotensin-converting enzyme (ACE) inhibitors (used to treat certain heart diseases or high blood pressure),
• disopyramide (used to treat certain heart diseases),
• fluoxetine (used to treat depression),
• fibrates (used to reduce high lipid levels in the blood),
• monoamine oxidase inhibitors (MAOIs) (used to treat depression),
• pentoxifylline, propoxyphene, salicylates (such as aspirin, used to relieve pain and reduce fever),
• antibiotics of the sulfonamide group.

Among the medicines that may cause an increase in your blood sugar level (hyperglycemia) are:

• corticosteroids (such as "cortisone" used to treat inflammation),
• danazol (a medicine that acts on ovulation),
• diazoxide (used to treat high blood pressure),
• diuretics (used to treat high blood pressure and excess fluid retention),
• glucagon (a pancreatic hormone used to treat severe hypoglycemia),
• isoniazid (used to treat tuberculosis),
• estrogens and progestogens (such as the birth control pill, used for birth control),
• phenothiazine derivatives (used to treat psychiatric disorders),
• somatotropin (growth hormone),
• sympathomimetic medicines (such as epinephrine [adrenaline], salbutamol, terbutaline, used to treat asthma),
• thyroid hormones (used to treat thyroid gland disorders),
• protease inhibitors (used to treat HIV),
• atypical antipsychotic medicines (such as olanzapine and clozapine).

Your blood sugar level may rise or fall 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 parasitic infections) may cause hypoglycemia, which can sometimes be followed by hyperglycemia.

Beta-blockers, like other sympatholytic medicines (such as clonidine, guanethidine, and reserpine), may mask or completely suppress the early warning symptoms that could help you recognize hypoglycemia.

If you are unsure whether you are taking any of these medicines, ask your doctor or pharmacist.

Using Apidra with alcohol

Your blood sugar levels may rise or fall if you drink alcohol.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using 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 changed during pregnancy and after delivery. Careful control of your diabetes and prevention of hypoglycemia are important for the health of your baby.

There are limited or no data on the use of Apidra in pregnant women.

If you are breastfeeding, consult your doctor as you may need to adjust your insulin doses and diet.

Driving and using machines

Your ability to concentrate or react may be reduced if:

• you have hypoglycemia (low blood sugar levels),
• you have hyperglycemia (high blood sugar levels).

Be aware of this possible problem, considering all situations that may pose a risk to you or others (such as driving a vehicle or using machines).

You should ask your doctor for advice on your ability to drive if:

• you have frequent episodes of hypoglycemia,
• the early warning symptoms that could help you recognize hypoglycemia have decreased or disappeared.

Important information about some of the ingredients of Apidra

This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is essentially "sodium-free".

Apidra contains metacresol

Apidra contains metacresol, which may cause allergic reactions.

3. How to use Apidra

Dose

Follow exactly the instructions for administration of this medicine given by your doctor. If you are unsure, consult your doctor or pharmacist again.

Your doctor will determine the dose of Apidra you need based on your lifestyle and the results of your blood sugar (glucose) tests and previous insulin treatment.

Apidra is a short-acting insulin. Your doctor may advise you to use it in combination with an intermediate-acting, long-acting, or basal insulin, or with tablets used to treat high blood sugar levels.

If you switch from another insulin to insulin glulisine, your dose may need to be adjusted by your doctor.

Many factors can influence your blood sugar level. You should know these factors so that you can react correctly to changes in your blood sugar level and avoid it becoming too high or too low. See the box at the end of the leaflet for more information.

Method of administration

Apidra is injected under the skin (subcutaneously). It can also be administered intravenously by healthcare professionals under strict medical supervision.

Your doctor will show you which area of the skin to inject Apidra into. Apidra can be injected into the abdominal wall, thigh, or upper arm, or by continuous infusion into the abdominal wall. The effect will be slightly faster if the insulin is injected into your abdomen. As with other insulins, the injection and infusion sites within an injection area (abdomen, thigh, or upper arm) should be rotated from one injection to another.

Frequency of administration

Apidra should be administered shortly (0-15 minutes) before or shortly after meals.

Instructions for correct use

How to handle the vials

Apidra vials are used with insulin syringes with a graduated scale and with an insulin pump system.

Inspect the vial before use. It should only be used if the solution is clear, colorless, and has no visible particles.

Do not shake or mix before use.

Always use a new vial if you notice that your blood sugar control is worsening unexpectedly. 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.

Apidra should not be mixed with any other insulin preparation other than human insulin NPH.

If Apidra is mixed with human insulin NPH, Apidra should be drawn into the syringe first. The injection should be performed immediately after mixing.

Before using Apidra in a pump system, you should have received detailed instructions on how to use the pump system. You should also have been informed about what to do if you become ill or if your blood sugar levels become too high or too low, or if the pump system fails.

Use the pump system recommended by your doctor. Read and follow the instructions that come with your insulin infusion pump. Follow your doctor's instructions regarding basal infusion rate and insulin bolus administration at mealtime. Check your blood sugar level regularly to ensure you are getting the benefit of insulin infusion and that the pump is working properly.

Change the infusion set and reservoir at least every 48 hours using an aseptic technique. These instructions may differ from the instructions that come with your insulin infusion pump. When using Apidra in the pump system, it is important to always follow these specific instructions. Not following these specific instructions can lead to serious adverse reactions.

Apidra should never be mixed with diluents or any other insulin when used in a pump.

Problems with the pump or infusion set or incorrect use of the pump can result in you not getting enough insulin. This can cause your blood sugar level to rise rapidly and lead to diabetic ketoacidosis (buildup of acid in the blood because your body is breaking down fat instead of sugar).

If your blood sugar level starts to rise, contact your doctor, pharmacist, or nurse as soon as possible. They will inform you what to do.

You may need to use Apidra with syringes or pens. You should always have an alternative insulin delivery system available for subcutaneous injection in case the pump system fails.

If you use more Apidra than you should

• If you have injected too much Apidra, your blood sugar level may become very low (hypoglycemia). Check your blood sugar level frequently. In general, to prevent hypoglycemia, you should eat more and monitor your blood sugar level. For more information on treating hypoglycemia, see the box at the end of the leaflet.

If you forget to use Apidra

• If you have missed a dose of Apidra or if you have not injected enough insulin, your blood sugar level may rise significantly (hyperglycemia). Check your blood sugar level frequently. For more information on treating hyperglycemia, see the box at the end of the leaflet.
• Do not use a double dose to make up for forgotten doses.

If you stop using Apidra

This could lead to severe hyperglycemia (very high blood sugar levels) and ketoacidosis (buildup of acid in the blood because your body is breaking down fat instead of sugar). Do not stop your treatment with Apidra without consulting your doctor; they will tell you what to do.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

Mix-ups between insulins

You should always check the insulin label before each injection to avoid mix-ups between Apidra and other insulins.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Severe Adverse Effects

Hypoglycemia (low blood sugar levels) can be very severe.Hypoglycemia is a very frequently observed adverse effect (it can affect more than 1 in 10 patients).

Hypoglycemia (low blood sugar levels)means that you do not have enough sugar in your blood.If your blood sugar level drops too low, you may lose consciousness. Severe hypoglycemia can cause brain damage and can be life-threatening. If you experience symptoms of low blood sugar, act immediatelyto raise your blood sugar level. See the box at the end of this leaflet, where you will find more important information about hypoglycemia and its treatment.

If you experience the following symptoms, contact your doctor immediately:

Systemic allergic reactionsare adverse effects that are rarely observed (they can affect up to 1 in 100 patients).

Generalized allergy to insulin:related symptoms may include large-scale skin reactions (skin rash and itching all over the body), severe swelling of the skin or mucous membranes (angioedema), difficulty breathing, decreased blood pressure with rapid heartbeat and sweating. These can be symptoms of severe generalized allergy to insulin, including anaphylactic reaction that can be life-threatening.

Hyperglycemia (high blood sugar levels) means that there is too much sugar in the blood.

The frequency of hyperglycemia cannot be estimated. If your blood sugar level is too high, this indicates that you may need more insulin than you have injected.

Hyperglycemia can cause diabetic ketoacidosis (increase in acid in the blood due to the body breaking down fat instead of sugar).

These are severe adverse effects.

These conditions can occur when there are problems with the infusion pump or when the pump system is not used correctly.

This means that you may not always be able to get enough insulin to treat your diabetes.

If this happens, you should seek urgent medical help.

You should always have an alternative insulin administration system for subcutaneous injection(see section 3 "How to handle the infusion pump system" and "What to do if the pump system fails or when the pump is not used correctly". For more information on the signs and symptoms of hyperglycemia, see the box at the end of this leaflet.

Other Adverse Effects

• Changes in the skin at the injection site.

If insulin is injected too frequently in the same place, the fatty tissue can shrink (lipoatrophy) or become thicker (lipohypertrophy) (can affect up to 1 in 1,000 people). Lumps under the skin can also occur due to the accumulation of a protein called amyloid (cutaneous amyloidosis; the frequency of this is unknown). Insulin may not work very well if injected into a lumpy area. Change the injection site to help avoid these skin changes.

Frequent Adverse Effects(can affect up to 1 in 10 patients)

• Allergic reactions and skin reactions at the injection site

Reactions at the injection site (such as redness, intense pain, itching, hives, swelling, or inflammation) can be experienced. These reactions can also spread around the injection site. Most minor insulin reactions usually resolve on their own in a few days or weeks.

Adverse Effectswhose frequency cannot be estimated from the available data

• Ocular reactions

A significant change (improvement or worsening) in the control of your blood sugar level can temporarily worsen your vision. If you have proliferative retinopathy (an eye disease related to diabetes), severe hypoglycemic attacks can cause temporary loss of vision.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that is not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Apidra

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date stated on the packaging and on the label of the vial after CAD/EXP. The expiration date is the last day of the month indicated.

Unopened vials

Store in a refrigerator (between 2°C and 8°C).

Do not freeze.

Do not place Apidra near the freezer compartment or next to a cold accumulator.

Keep the vial in the outer packaging to protect it from light.

Opened vials

Once in use, the vial can be stored for a maximum of 4 weeks in the outer packaging below 25°C, protected from direct heat or direct light. Do not use the vial after this period.

It is recommended to note the date of the first use on the label.

Do not use this medicine if it is not colorless and transparent.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines that are no longer needed. This will help protect the environment.

6. Container Contents and Additional Information

Composition of Apidra

• The active substance is insulin glulisine. Each milliliter of solution contains 100 Units of insulin glulisine (equivalent to 3.49 mg). Each vial contains 10 ml of injectable solution, equivalent to 1000 Units.
• The other components are: metacresol (see section 2 "Apidra contains metacresol"), sodium chloride (see section 2 "Important information about some of the components of Apidra"), trometamol, polysorbate 20, concentrated hydrochloric acid, sodium hydroxide, water for injectable preparations.

Appearance of the Product and Container Contents

Apidra 100 Units/ml injectable solution in a vial is a clear, colorless, aqueous solution without visible particles.

Each vial contains 10 ml of solution (1000 Units). There are packs of 1, 2, 4, and 5 vials of 10 ml.

Only some pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Sanofi-Aventis Deutschland GmbH

D-65926 Frankfurt am Main

Germany

Manufacturer:

Sanofi-Aventis Deutschland GmbH

Industriepark Höchst, D-65926 Frankfurt

Germany

You can request more information about this medicinal product by contacting the local representative of the Marketing Authorization Holder:

Date of Last Revision of this Leaflet:

Other Source of Information

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

HYPERGLYCEMIA AND HYPOGLYCEMIA

Always carry some sugar with you (at least 20 grams).

Always carry information that indicates you are a person with diabetes.

HYPERGLYCEMIA (high blood sugar levels)

If you have very high blood sugar levels (hyperglycemia), you may not have injected enough insulin.

Why does hyperglycemia occur?

Some examples are:

• you did not inject your insulin or did not inject enough, or if its effect has decreased, for example, due to incorrect storage,
• you are doing less exercise than usual, are under stress (emotional distress, excitement), or are suffering from an injury, surgery, infection, or fever,
• you are taking or have taken certain medications (see section 2, "Use of Apidra with other medications").

Warning signs of hyperglycemia

Thirst, increased need to urinate, fatigue, dry skin, redness of the face, loss of appetite, low blood pressure, rapid heartbeat, and the presence of glucose and ketone bodies in the urine. Abdominal pain, deep and rapid breathing, drowsiness, or even loss of consciousness may be signs of a serious condition (ketoacidosis) due to lack of insulin.

What to do in case of hyperglycemia?

You should check your blood sugar level and your urine acetone level as soon as any of the above symptoms occur. Severe hyperglycemia or ketoacidosis should always be treated by a doctor, usually in a hospital.

HYPOGLYCEMIA (low blood sugar levels)

If your blood sugar level drops too low, you may lose consciousness. Severe hypoglycemia can cause a heart attack or brain damage and can be life-threatening. You should normally be able to recognize when your blood sugar level is dropping too low to take the necessary measures.

Why does hypoglycemia occur?

Some examples are:

• you inject too much insulin,
• you miss meals or delay them,
• you do not eat enough, or eat foods that contain less carbohydrates than usual (sugar and substances similar to sugar are called carbohydrates; however, artificial sweeteners are NOT carbohydrates),
• you lose carbohydrates due to vomiting or diarrhea,
• you drink alcohol, especially if you are not eating much,
• you are doing more exercise than usual or a different type of physical activity,
• you are recovering from an injury, surgery, or other types of stress,
• you are recovering from an illness or fever,
• you are taking or have stopped taking certain medications (see section 2, "Use of Apidra with other medications").

It is also more likely to occur if:

• you have just started insulin treatment or changed to another insulin preparation,
• your blood sugar levels are almost normal or are unstable,
• you change the injection site (for example, from the thigh to the upper arm),
• you have severe kidney or liver disease, or other conditions such as hypothyroidism.

Warning signs of hypoglycemia

• In your body

Examples of symptoms that indicate your blood sugar level is dropping too low or too quickly: sweating, moist and sticky skin, anxiety, rapid heartbeat, high blood pressure, palpitations, and irregular heartbeat. These symptoms often occur before symptoms of low blood sugar in the brain.

• In your brain

Examples of symptoms that indicate low blood sugar in the brain: headaches, intense hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, restlessness, aggressive behavior, concentration problems, altered reactions, depression, confusion, speech disorders (sometimes, complete loss of speech), visual disturbances, tremors, paralysis, tingling sensations (paresthesias), numbness and tingling sensations in the mouth area, dizziness, loss of self-control, inability to take care of oneself, convulsions, and loss of consciousness.

The first warning signs of hypoglycemia ("warning symptoms") may change, weaken, or be absent if:

• you are elderly,
• you have had diabetes for a long time,
• you have a certain type of nerve disease (autonomic diabetic neuropathy),
• you have recently had a hypoglycemic episode (for example, the day before) or if it develops gradually,
• you have almost normal or improved blood sugar levels,
• you are taking or have taken certain medications (see section 2, "Use of Apidra with other medications").

In this case, you may develop severe hypoglycemia (and even lose consciousness) before you realize the problem. Always be familiar with your warning symptoms. If necessary, more frequent blood sugar testing can help identify mild hypoglycemic episodes that might otherwise go unnoticed. If you are not sure you can recognize your warning symptoms, avoid situations (such as driving a car) that could put you or others at risk due to hypoglycemia.

What to do if you experience hypoglycemia?

1. Do not inject insulin. Immediately ingest 10 to 20 grams of sugar, such as glucose, sugar cubes, or a sugary drink. Note: Artificial sweeteners and sugar-free products do not help treat hypoglycemia.
2. Afterwards, eat something that has a prolonged effect on increasing your blood sugar level (such as bread or pasta). Your doctor or nurse should have discussed this with you.
3. If hypoglycemia recurs, take another 10 to 20 grams of sugar.
4. Consult a doctor immediately if you are unable to control hypoglycemia or if it recurs.

Tell your family, friends, and people close to you the following:

If you are unable to swallow or lose consciousness, you will need an injection of glucose or glucagon (a medication that increases blood sugar levels). These injections are justified even if you are not sure you have hypoglycemia.

It is recommended to check your blood sugar level immediately after ingesting glucose to confirm that you actually have hypoglycemia.

THE FOLLOWING INFORMATION IS INTENDED ONLY FOR HEALTHCARE PROFESSIONALS:

Apidra can be administered intravenously, and this should be done by healthcare professionals.

Instructions for Intravenous Administration

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

After dilution for intravenous use, the solution should be visually inspected for particles before administration. It should only be used if the solution is clear and colorless; it should not be used if it is cloudy or contains visible particles.

Apidra has been shown 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.