APIDRA 100 units/mL injectable solution in cartridge

2. What you need to know before you start using Apidra

Do not use Apidra

• If you are allergic to insulin glulisine or any of the other components 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

Apidra in cartridges is only intended for injection under the skin with a reusable pen (see also section 3). Consult your doctor if you need to inject insulin by another method.

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

Follow carefully the instructions for dosing, monitoring (blood tests), diet, and physical activity (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 not enough clinical information on the use of Apidra in children under 6 years of age.

Changes in the skin at the injection site.

The injection site should be rotated to avoid changes in the skin, such as lumps under the skin. Insulin may not work as well if injected into a lumpy area (see How to use Apidra). Contact your doctor if you are currently injecting into a lumpy 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 the dose of your other antidiabetic medications.

Travel

Before traveling, consult your doctor. You may need to consult about

• the availability of your insulin in the country you are traveling to,
• insulin, needles, etc. supplies,
• the correct storage of insulin during travel,
• meal and insulin administration schedules during travel,
• the possible effects of moving to areas with time differences,
• the possible new health risks in the countries you will visit,
• what to do in emergency situations when you feel unwell or become ill.

Illnesses and injuries

The management of your diabetes 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 sufficient carbohydrate 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 (increase, 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 can 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),
• sulfonamide antibiotics.

Among the medicines that can 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 or 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),
• somatropin (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 clozapine and olanzapine).

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) can cause hypoglycemia, which can sometimes be followed by hyperglycemia.

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

If you are not sure if 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 have a baby 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 dose 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, which is essentially "sodium-free".

Apidra contains metacresol

Apidra contains metacresol, which may cause allergic reactions.

3. How to use Apidra

Dose

Follow exactly the administration instructions of this medicine indicated by your doctor. In case of doubt, 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, 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 be aware of 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).

Your doctor will advise you on which area of the skin to inject Apidra. 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 cartridges

Apidra in cartridges is only intended for injection under the skin with a reusable pen. Consult your doctor if you need to inject insulin by another method.

To ensure you get the exact dose, Apidra cartridges should only be used with the following pens:

• JuniorSTAR which delivers doses in 0.5 unit steps
• ClikSTAR, Tactipen, Autopen 24, AllStar, or AllStar PRO which deliver doses in 1 unit steps.

In your country, only some of these pens may be marketed.

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

The manufacturer's instructions for using the pen should be followed carefully to load the cartridge, attach the needle, and administer the insulin injection.

Before inserting the cartridge into the reusable pen, the cartridge should be stored at room temperature for 1 to 2 hours.

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

It should not be shaken or mixed before use.

After inserting a new cartridge:

You should check that your insulin pen is working properly before injecting the first dose (see the instructions for use of your pen).

Special precautions before injection

Air bubbles should be removed from the cartridge before injection (see the instructions for use of the pen). Empty cartridges should not be refilled.

To prevent any contamination, the reusable pen should only be used by you.

Problems with the insulin pen?

Please consult the manufacturer's instructions for the pen.

If your insulin pen is damaged or not working properly (due to mechanical problems), it should be discarded and a new insulin pen used.

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 (increased acid in the blood because the body breaks down fat instead of sugar). Do not stop using Apidra without consulting your doctor; he 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

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 infrequently observed adverse effects (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, drop in blood pressure with rapid heartbeat and sweating.

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. This can be severe if your blood sugar level becomes very high.

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) (it 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 reactions to insulin are usually resolved within 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 cause a temporary worsening of 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 help provide 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 carton and on the label of the cartridge after CAD/EXP. The expiration date is the last day of the month indicated.

Unopened cartridges

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 cartridge in the outer packaging to protect it from light.

Cartridges in use

Cartridges in use (in the insulin pen) can be stored for a maximum of 4 weeks below 25°C, protected from direct heat or direct light, and should not be stored in a refrigerator. Do not use this medicine after this period.

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

Medicines should not be disposed of through 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. Package Contents and Additional Information

Apidra Composition

• The active ingredient is insulin glulisine. Each milliliter of solution contains 100 Units of insulin glulisine (equivalent to 3.49 mg). Each cartridge contains 3 ml of injectable solution, equivalent to 300 Units.

• The other ingredients are: metacresol (see section 2 "Apidra contains metacresol"), sodium chloride (see section 2 "Important information about some of the ingredients of Apidra"), trometamol, polysorbate 20, concentrated hydrochloric acid, sodium hydroxide, water for injectable preparations.

Product Appearance and Package Contents

Apidra 100 Units/ml injectable solution in a cartridge is a clear, colorless, particle-free aqueous solution.

Each cartridge contains 3 ml of solution (300 U). There are packs of 1, 3, 4, 5, 6, 8, 9, and 10 cartridges of 3 ml. Not all 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 medicine by contacting the local representative of the Marketing Authorization Holder.

Date of the Last Revision of this Leaflet:

Other Source of Information

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

HYPERGLYCEMIA AND HYPOGLYCEMIA

Always carry something sweet with you (at least 20 grams).

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

HYPERGLYCEMIA (high blood sugar levels)

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

Why does hyperglycemia occur?

Some examples are:

• you have not injected your insulin or have not injected enough, or if its effect has decreased, for example, due to incorrect storage,
• you are doing less exercise than usual, you are stressed (emotional distress, excitement), or you 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 symptoms 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. Stomach pain, deep and rapid breathing, drowsiness, or even loss of consciousness can be signs of a severe condition (ketoacidosis) due to lack of insulin.

What to do in case of hyperglycemia?

You must analyze your blood sugar level and your urine acetone level as soon as any of the above symptoms occur. Severe hyperglycemia or ketoacidosis must 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 usually 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 you eat foods that contain less carbohydrates than usual (sugar and similar substances are called carbohydrates; however, artificial sweeteners are NOT carbohydrates),
• you lose carbohydrates through 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 that hypoglycemia will 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 skin site where you inject insulin (e.g., from the thigh to the upper arm),
• you have severe kidney or liver disease, or other diseases such as hypothyroidism.

Warning symptoms of hypoglycemia

• In your body

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

• In your brain

Examples of symptoms that indicate there is a low level of sugar in the brain: headaches, intense hunger, nausea, vomiting, fatigue, drowsiness, sleep disorders, 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 symptoms of hypoglycemia ("warning symptoms") may change, weaken, or be absent if:

• you are an elderly person,
• 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 (e.g., the day before) or if it develops gradually,
• you have almost normal or at least very 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 analysis can help identify mild hypoglycemic episodes that would 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 in danger due to hypoglycemia.

What to do if hypoglycemia occurs?

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 long-acting effect on raising 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 analyze your blood sugar level immediately after ingesting glucose to confirm that you actually have hypoglycemia.