Package Insert: Information for the User

NovoMix 50 FlexPen 100100 units/mL injectable suspension in a pre-filled pen

50% soluble insulin aspart and 50% insulin aspart crystallized with protamine

Read this package insert carefully before starting to use this medication, as it contains important information for you.

• Keep this package insert, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• This medication has been prescribed only for you, and you should not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this package insert. See section 4.

NovoMix 50 is a modern insulin (insulin analogue) with rapid and intermediate action, in a 50/50 ratio. Modern insulins are improved versions of human insulin.

NovoMix 50 is used to reduce high levels of sugar in the blood in patients with diabetes mellitus (diabetes). Diabetes is a disease in which the body does not produce enough insulin to control the level of sugar in the blood. NovoMix 50 can be used with metformin.

NovoMix 50 will start to reduce your blood sugar level 10 – 20 minutes after injection, reaches its maximum effect between 1 and 4 hours after injection and its effect lasts until 14–24 hours.

No use NovoMix 50

• If you are allergic to insulin aspart or any of the other components of this medication (see section 6, Contents of the pack and additional information).
• If you suspect that you are starting to experience hypoglycemia (low blood sugar level), see a) Summary of frequent and very serious adverse reactions in section 4.
• In insulin infusion pumps.
• If your FlexPen has fallen, been damaged or broken.
• If it has not been stored properly or if it has been frozen, see section 5, Storage of NovoMix 50.
• If the insulin does not have a uniformly white, turbid and watery appearance when resuspended.
• If after resuspension it has lumps or there are white solid particles stuck to the bottom or sides of the cartridge.

If this happens, do not use NovoMix 50. Consult your doctor, nurse or pharmacist.

Before using NovoMix 50

• Check the label to ensure that it is the correct type of insulin.
• Always use a new needle for each injection to avoid contamination.
• Do not share needles or your NovoMix 50 FlexPen.
• NovoMix 50 FlexPen is only indicated for subcutaneous injection. Consult your doctor if you need to inject insulin by another method.

Consult your doctor if you need to inject insulin by another method.

Warnings and precautions

Some conditions and activities may affect your insulin needs. Consult your doctor:

• If you have kidney or liver problems, or adrenal, pituitary or thyroid gland problems.
• If you engage in more physical exercise than usual or if you plan to change your usual diet, as this may affect your blood sugar level.
• If you are ill, continue using your insulin and consult your doctor.
• If you are traveling abroad, traveling to different time zones may affect your insulin requirements and the timing of administration.

Changes in skin at the injection site

Rotate the injection site to help prevent changes in the fatty tissue, such as thickening of the skin, shrinking of the skin or lumps under the skin. Insulin may not work well if injected in an area that is thickened, shrunk or lumpy (see section 3, How to use, NovoMix 50). Inform your doctor if you notice any changes in the injection site. Inform your doctor if you are currently injecting in these affected areas, before starting to inject in a different area. Your doctor may advise you to check your blood sugar levels more closely, and adjust your insulin or other diabetes medications.

Other medications and NovoMix 50

Inform your doctor, nurse or pharmacist if you are using, have used recently or may need to use any other medication. Some medications affect your blood sugar level and this may require adjustment of your insulin dose.The following are the main medications that may affect your insulin treatment.

Your blood sugar level may decrease (hypoglycemia) if you take:

•Other diabetes medications

•Monamine oxidase inhibitors (MAOIs) (used to treat depression)

•Beta-blockers (used to treat high blood pressure)

•Angiotensin-converting enzyme inhibitors (ACE inhibitors) (used to treat certain heart conditions or high blood pressure)

•Salicylates (used to relieve pain and reduce fever)

•Anabolic steroids (such as testosterone)

•Sulfonamides (used to treat infections)

Your blood sugar level may increase (hyperglycemia) if you take:

• Oral contraceptives (birth control pills)
• Thiazides (used to treat high blood pressure or excessive fluid retention)
• Glucocorticoids (such as "cortisone" used to treat inflammation)
• Thyroid hormones (used to treat thyroid gland disorders)
• Adrenergic agonists (such as epinephrine, salbutamol or terbutaline used to treat asthma)
• Growth hormone (medication to stimulate growth and bone development that has a pronounced effect on metabolic processes)
• Danazol (medication that acts on ovulation)

Octreotide and lanreotide (used to treat acromegaly, a rare hormonal disorder that usually occurs in middle-aged adults, caused by the pituitary gland producing excessive growth hormone) may increase or decrease your blood sugar levels.

Beta-blockers (used to treat high blood pressure) may weaken or completely suppress the early warning signs that may help you recognize when you have low blood sugar.

Pioglitazone (tablets used to treat type 2 diabetes)

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

If you have taken any of the medications mentioned above, inform your doctor, nurse or pharmacist.

Alcoholic beverages and use of NovoMix 50

• If you drink alcohol, your insulin needs may change as your blood sugar level may be increased or decreased. It is recommended to monitor your blood sugar levels carefully.

Pregnancy and breastfeeding

• If you are pregnant, think you may be pregnant or plan to become pregnant, consult your doctor or pharmacist before using this medication. Clinical experience with insulin aspart during pregnancy is limited. You may need to adjust your insulin dose while pregnant and after delivery. It is essential for the health of your baby to have a careful control of your diabetes, especially the prevention of hypoglycemia.
• There are no restrictions on the treatment with NovoMix 50 during breastfeeding.

Consult your doctor, pharmacist or nurse before using any medication while pregnant or breastfeeding.

Driving and operating machinery

• Please ask your doctor if you can drive or operate machinery:
• If you experience frequent hypoglycemia.
• If you find it difficult to recognize hypoglycemia.

If your blood sugar levels are low or high, they may affect your concentration and reaction time and, therefore, also your ability to drive or operate machinery. You may put your life or the lives of others at risk.

Important information about some components of NovoMix 50

NovoMix 50 contains less than 1 mmol (23 mg) of sodium per dose, so NovoMix 50 is essentially "sodium-free".

Posology and when to administer insulin

Always use the insulin and adjust the dose exactly as recommended by your doctor. If in doubt, consult your doctor, pharmacist, or nurse again.

NovoMix 50 is usually administered immediately before a meal. Take some food within 10 minutes after the injection to avoid a drop in blood sugar. If necessary, NovoMix 50 can be administered shortly after a meal. For more information, see below How and where to inject.

When NovoMix 50 is used in combination with metformin, the dose should be adjusted.

Do not change insulin unless your doctor tells you to. If your doctor changes you to another type or brand of insulin, you may need to adjust your dose.

Use in children and adolescents

No clinical trials have been conducted with NovoMix 50 in children and adolescents under 18 years old.

Use in special patient groups

If you have kidney or liver dysfunction (renal or hepatic insufficiency), or if you are over 65 years old, you should monitor your blood sugar more frequently and consult with your doctor about changes in your insulin dose.

How and where to inject

NovoMix 50 is injected under the skin (subcutaneous administration). Never inject insulin directly into a vein (intravenous administration) or muscle (intramuscular administration). NovoMix 50 FlexPen is only indicated for subcutaneous injection. Consult your doctor if you need to inject insulin by another method.

In each injection, change the injection site within the specific area of skin you usually use. This may reduce the risk of developing lumps or depressions in the skin (see section 4, Possible adverse effects). The best areas for injection are: the front of the waist (abdomen), the gluteal region, the front of the thigh, or the upper arm. Insulin will act more quickly if injected in the abdominal area. You should always regularly measure your blood sugar level.

How to use NovoMix 50 FlexPen

NovoMix 50 FlexPen is a disposable pre-filled pen with a color code that contains a mixture of rapid-acting and intermediate-acting insulin aspart in a 50/50 ratio.

Read the usage instructions included in this prospectus carefully. You must use the pen as described in the usage instructions.

Always make sure you use the correct pen before injecting insulin.

If you use more insulin than you should

If you use too much insulin, your blood sugar level may become very low (hypoglycemia). See a) Summary of severe and very frequent adverse effects in section 4.

If you forget to use your insulin

If you forget to use your insulin, your blood sugar level may become very high (hyperglycemia). See c) Effects of diabetes in section 4.

If you interrupt your insulin treatment

Do not stop taking your insulin without consulting your doctor, he will tell you what to do. This could produce very high blood sugar levels (severe hyperglycemia) and ketoacidosis. See c) Effects of diabetes in section 4.

If you have any other questions about the use of this medication, ask your doctor, pharmacist, or nurse.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

a)Summary of serious and very frequent side effects

Low blood sugar (hypoglycemia)is a very frequent side effect. It can affect more than 1 in 10 people.

Symptoms of low blood sugar may appear if::

•Too much insulin is injected.

•Not enough food is eaten or a meal is skipped.

•More exercise than usual is done.

•Alcohol is consumed (see Alcoholic beverages and use of NovoMix 50 in section 2).

Symptoms of low blood sugar::

Sweating, cold and pale skin, headache, palpitations, nausea, excessive hunger, temporary changes in vision, drowsiness, fatigue and weakness, nervousness or tremors, feeling anxious, feeling confused, difficulty concentrating.

A severe hypoglycemia can cause loss of consciousness. If a severe and prolonged hypoglycemia is not treated, it can cause a transient or permanent brain injury and even death. You can regain consciousness more quickly with an injection of glucagon administered by someone who knows how to do it. If glucagon is administered to you, you should take glucose or a high-sugar food as soon as you regain consciousness. If you do not respond to glucagon treatment, you should be treated in a hospital.

What to do if your blood sugar level is low::

• If your blood sugar level is low, take glucose tablets or a high-sugar food (e.g. sweets, biscuits, fruit juice). Measure your blood sugar level if possible and rest. Always carry glucose tablets or high-sugar foods with you, just in case.
• When the symptoms of hypoglycemia have disappeared or when your blood sugar level has stabilized, continue your insulin treatment as usual.
• If you have had a blood sugar level so low that you have fainted, if you have needed a glucagon injection, or if you have had many episodes of low blood sugar, talk to your doctor. Your doctor may need to adjust the dose or frequency of insulin administration, your diet or the exercise you do.

Inform others that you are diabetic and what the consequences may be, including the risk of fainting (loss of consciousness), due to a drop in your blood sugar level. Let them know that if you faint, they should lay you down and seek immediate medical attention. Do not give you any food or drink as you may choke.

Severe allergic reactionsto NovoMix 50 or to any of its components (systemic allergic reaction) is a very rare but potentially life-threatening side effect. It can affect up to 1 in 10,000 people.

Consult your doctor immediately:

• If allergy symptoms spread to other parts of your body.
• If you suddenly feel unwell: you sweat, start to feel nauseous (vomiting), have difficulty breathing, palpitations or feel dizzy.
• If you notice any of these symptoms, consult your doctor immediately.

Changes in skin at the injection site: If insulin is injected in the same place, the fatty tissue may shrink (lipoatrophy) or become thicker (lipohypertrophy) (it can affect up to 1 in 100 people). Bumps under the skin can also occur due to the accumulation of a protein called amyloid (cutaneous amyloidosis; it is not known how often this occurs). Insulin may not work well if injected in a thickened, shrunk or swollen area. Change the injection site to help prevent these skin changes.

b)Other side effects list

Frequent side effects

They can affect up to 1 in 100 people.

Allergic symptoms:: Local allergic reactions (pain, redness, urticaria, inflammation, hematomas, swelling and itching) can occur at the injection site. These usually disappear after a few weeks of treatment. If symptoms do not disappear, consult your doctor.

Visual problems:: You may have visual problems when starting insulin treatment, but this alteration is usually temporary.

Joint inflammation:: When starting insulin treatment, fluid retention can cause joint inflammation, particularly in the ankles and other joints. This effect usually disappears quickly. If it does not, consult your doctor.

Diabetic retinopathy:(a diabetes-related eye disease that can lead to vision loss):If you have diabetic retinopathy and your blood sugar level improves rapidly, the retinopathy may worsen.Consult your doctor.

Rare side effects

They can affect up to 1 in 1,000 people.

Painful neuropathy:(pain due to nerve damage):If your blood sugar level improves rapidly, you may experience nerve pain. This is called acute painful neuropathy and is usually temporary.

Reporting side effects

Inform your doctor, pharmacist or nurse if you experience any type of side effect, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

c)Diabetes effects

High blood sugar (hyperglycemia)

Symptoms of high blood sugar may appear if:

•Not enough insulin is injected.

•Insulin is forgotten or treatment is interrupted.

•Less insulin than needed is repeatedly injected.

•An infection and/or fever is present.

•More food is eaten than usual.

•Less physical exercise than usual is done.

Symptoms of high blood sugar:

The warning symptoms appear gradually. These include: increased need to urinate, thirst, loss of appetite, feeling dizzy (nausea or vomiting), drowsiness or fatigue, dry and red skin, feeling of dryness in the mouth and breath with a fruity odor (acetone).

What to do if your blood sugar level is high::

• If you notice any of the described symptoms: check your blood sugar level, check your urine ketone level if possible and consult your doctor immediately.
• These may be symptoms of a severe condition called diabetic ketoacidosis (acid accumulates in the blood because the body breaks down fat instead of sugar). If not treated, it can cause diabetic coma and death.

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

Do not use this medication after the expiration date that appears on the packaging and on the FlexPen label, after CAD. The expiration date is the last day of the month indicated.

Always keep the cap on FlexPen when not in use, to protect it from light. NovoMix 50 must be protected from excessive heat and light.

Before opening: NovoMix 50 FlexPen not in usemust be stored in the refrigerator between 2°C and 8°C, away from the refrigerator element. Do not freeze.

Before using NovoMix 50 FlexPen, take it out of the refrigerator. It is recommended to resuspend the insulin as instructed each time you use a new pen. See usage instructions.

During use or when carrying as a spare:NovoMix 50 FlexPen in use or being carried as a sparemust not be stored in the refrigerator. It can be carried and stored at room temperature (below 30°C) for 4weeks.

Medications should not be thrown away through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications you no longer need. This will help protect the environment.

Composition of NovoMix 50

• The active principle is insulin aspart. NovoMix 50 is a mixture composed of 50% soluble insulin aspart and 50% insulin aspart crystallized with protamine. 1ml contains 100units of insulin aspart. Each pre-filled pen contains 300units of insulin aspart in 3ml of injectable suspension.
• The other components are glycerol, phenol, metacresol, zinc chloride, disodium phosphate dihydrate, sodium chloride, protamine sulfate, hydrochloric acid, sodium hydroxide, and water for injectable preparations.

Appearance of NovoMix 50 and contents of the package

NovoMix 50 is presented as an injectable suspension in a pre-filled pen. The cartridge contains a glass bead to facilitate resuspension. After resuspension, the liquid should have a uniformly white, turbid, and aqueous appearance. Do not use the pen if the resuspended insulin does not appear uniformly white, turbid, and aqueous.

Package sizes of 1, 5, and 10pre-filled pens of 3ml. Not all presentations may be marketed.

The suspension is turbid, white, and aqueous.

Holder of the marketing authorization and responsible manufacturer

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd, Denmark

Instructions for use are found on the back of the FlexPen.

Last review date of this leaflet:

Other sources of information

The detailed information on this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu.

Instructions for use of NovoMix 50 injectable suspension in FlexPen.

Read these instructions carefully before using your FlexPen.If you do not follow the instructions carefully, you may administer too little or too much insulin, which could result in a level of blood sugar that is too high or too low.

FlexPen is a pre-filled pen injector.

• You can select doses from 1 to 60units, in increments of 1unit.
• FlexPen is designed to be used with the disposable needles NovoFine or NovoTwist up to 8mm in length.
• Always carry a spare insulin delivery device in case your FlexPen is lost or damaged.

Care of the pen

• You must handle your FlexPen with care. If it falls, is damaged, or is hit, there is a risk of insulin loss. This could result in an inaccurate dose, which may cause a level of blood sugar that is too high or too low.

• You can clean the outer part of your FlexPen with an alcohol-impregnated cotton swab. Do not submerge it, wash it, or lubricate it, as the pen may be damaged.

• Do not refillyour FlexPen.

Resuspension of insulin

A

Check the name and color of the labelof your pento ensure that it contains the correct type of insulin. This is especially important if you use more than one type of insulin. If you use the wrong type of insulin, your level of blood sugar may become too high or too low.

Each time you use a new pen

Allow the insulin to reach room temperature before using it. This makes it easier to resuspend.

Remove the pen cap.

B

Before administering the first injection with a new FlexPen, you must resuspend the insulin:

Turn the pen between your palms 10times, making sure the pen remains in ahorizontalposition (parallel to the floor).

C

Move the pen from top to bottom 10times between the two positions, so thatthe glass beadmovesfrom one end of the cartridge to the other.

Repeat both movements until the liquid appears uniformly white, turbid, and aqueous.

For each subsequent injection

Move the pen from top to bottom between the two positions at least 10times until the liquid appears uniformly white, turbid, and aqueous. If this movement alone is not enough to achieve a uniformly white, turbid, and aqueous appearance, repeat the procedure described above (see Figures B and C) until the liquid appears with this appearance.

• Always ensure that you have resuspended the insulin before each injection. This reduces the risk of having a level of blood sugar that is too high or too low.After resuspending the insulin, complete the following injection steps without delay.

Check always that there are at least12unitsof insulinleft in the cartridge to be able to resuspend it. If there are less than 12units, use a new FlexPen. On the insulin scale remaining, you can see if there are 12units. See the large drawing at the beginning of these instructions.

Do not use the pen if the resuspended insulin does not appearuniformly white, turbid, and aqueous.

Insertion of the needle

D

Take a new needle and remove the paper clip.

Insert the straight needle firmly into your FlexPen.

E

Remove the large outer needle cap and store it for later use.

F

Remove the small inner needle cap and discard it.

Do not attempt to put the small inner needle cap back on the needle. You could prick yourself with the needle.

• Always use a new needle for each injection.This reduces the risk of contamination, infection, insulin loss, needle blockage, and inaccurate dosing.

• Be careful not to bend or damage the needle before use.

Check the insulin flow

Before each injection, small amounts of air may be present in the cartridge during normal use. To avoid injecting air and ensure proper dosing:

G

Turn the dose selector to select 2units.

H

Hold your FlexPen with the needle pointing upwards and gently tap the cartridge a few times with your finger to deposit the air bubbles at the top of the cartridge.

I

Keeping the needle pointing upwards, press the plunger all the way down. The dose selector returns to 0.

A drop of insulin should appear at the needle tip. If not, change the needle and repeat the procedure up to a maximum of 6times.

If a drop of insulin still does not appear, the pen is defective and you must use a new one.

Always ensure that a drop appears at the needle tip before injecting. This ensures that the insulin flows. If no drop appears, no insulin will be injected, although the dose selector may move. This may indicate that the needle is blocked or damaged.

Always check the flow before injecting. If you do not check the flow, you may receive an insufficient or non-existent dose of insulin, which could result in a level of blood sugar that is too high.

Selecting the dose

Check that the dose selector marks 0.

J

Turn the dose selector to select the number of units you need to inject.

Thedose can beadjustedforward and backward by turning the dose selector in either direction until the correct dose is aligned with the dose marker. When turning the dose selector, be careful not to press the plunger, as insulin may leak out.

You cannot select a dose greater than the number of units remaining in the cartridge.

Before injecting insulin, always use the dose selector and dose marker to see how many units you have selected.

Do not count the clicks of the pen. If you select an incorrect dose and inject it, your level of blood sugar may become too high or too low. Do not use the remaining insulin scale, as it only shows the approximate amount of insulin remaining in the pen.

Injection

Insert the needle under the skin. Use the injection technique recommended by your doctor or nurse.

K

Inject the dose by pressing the plunger all the way down so that the 0 is aligned with the dose marker. Be careful to press the plunger only when injecting.

Turning the dose selector will not inject insulin.

L

• Keepthe plunger completely pressedand keep the needle under the skin forat least 6seconds. This ensures that the full dose is injected.

• Remove the needle from the skin and once you have done so, stop pressing the plunger.

• Always ensure that the dose selector returns to 0 after injection. If the dose selector stops before reaching 0, the full dose has not been administered, which could result in a level of blood sugar that is too high.

M

Put the needle cap back on the pen without touching it. When the needle is covered, press the needle cap firmly and then twist it off.

Dispose of the needle carefully and put the pen cap back on the FlexPen.

Always remove the needle after each injection and store your FlexPen without the needle attached.This reduces the risk of contamination, infection, insulin loss, needle blockage, and inaccurate dosing.

Other important information

People who care for these patients must be very careful when handling used needlesto reduce the risk of accidental punctures and infections.

Dispose of your used FlexPen carefully without leaving the needle attached.

Never share the pen or needles with others. This could result in infections.

Never share the pen with others. Your medicine could be harmful to their health.

Always keep the pen and needles out of sight and reach of others, especially children.