Protaphane: detailed information

Package leaflet: Information for the user

Protaphane 40 IU/ml (international units/ml) injectable suspension in a vial

human insulin
Read this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Never give it to others. It could be harmful even if their symptoms are the same as yours.
If you experience any side effect, talk to your doctor, pharmacist, or nurse. This includes any side effect not listed in this leaflet. See section 4.

1. What Protaphane is and what it is used for

Protaphane is human insulin with a gradual onset of action and prolonged duration.
Protaphane is used to reduce high blood sugar levels in patients with diabetes mellitus (diabetes).
Diabetes is a disease in which the body does not produce enough insulin to control blood sugar levels. Treatment with Protaphane helps prevent complications of diabetes.
Protaphane begins to lower blood sugar levels about one and a half hours after injection, and its effect lasts for approximately 24 hours. Protaphane is often administered in combination with rapid-acting insulin preparations.

2. What you need to know before using Protaphane

Do not use Protaphane
► If you are allergic to human insulin or to any of the other excipients of this medicine,
see section 6.
► If you experience warning signs of hypoglycemia (low blood sugar),
see the Summary of serious and very common side effects in section 4.
► In insulin infusion pumps.
► If the protective cap is loose or missing. Each vial has a tamper-evident plastic protective cap.
If the cap is not in perfect condition at the time of purchase, return the vial to the supplier.
► If it has not been stored correctly or has been frozen; see section 5.
► If the resuspended insulin does not appear uniformly white and cloudy.
Do not use Protaphane if any of these situations apply. Speak with your doctor, pharmacist, or nurse
for advice.

Before using Protaphane
► Check the label to make sure you are using the correct type of insulin.
► Remove the protective cap.
► Always use a new needle for each injection to prevent contamination.
► Needles and syringes must not be shared.

Warnings and precautions
Certain conditions and activities may affect your insulin requirements. Consult your doctor:
► If you have kidney or liver problems, or disorders of the adrenal glands, pituitary, or thyroid gland.
► If you have increased physical activity or changes in your usual diet, as these may affect your blood sugar levels.
► If you become ill, continue your insulin therapy and consult your doctor.
► If you plan to travel abroad; traveling across different time zones may alter your insulin needs and timing.

Skin changes at the injection site
Rotate your injection sites to help prevent changes in the fatty tissue under the skin, such as thickening, thinning, or the appearance of lumps under the skin.
Insulin may not work as well if you inject into an area with lumps, thinning, or thickening of the skin (see section 3). Inform your doctor if you notice skin changes at the injection site. If you currently inject into one of these affected areas, consult your doctor before switching to a new injection site. Your doctor may advise you to monitor your blood glucose more closely and possibly adjust your insulin dose or that of other antidiabetic medicines.

Other medicines and Protaphane
Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might take any other medicines.
Some medicines affect blood sugar levels, meaning your insulin dose may need to be adjusted. Listed below are the most common medicines that may affect insulin treatment.

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

Other medicines for diabetes
Monoamine oxidase inhibitors (MAOIs) (used to treat depression)
Beta-blockers (used to treat high blood pressure)
Angiotensin-converting enzyme (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 fluid retention)
Glucocorticoids (such as "cortisone" used to treat inflammation)
Thyroid hormones (used to treat thyroid gland disorders)
Sympathomimetics (such as epinephrine [adrenaline], salbutamol, or terbutaline, used to treat asthma)
Growth hormone (a medicine used to stimulate skeletal and somatic growth, significantly affecting the body's metabolic processes)
Danazol (a medicine that affects ovulation)

Octreotide and lanreotide (used to treat acromegaly, a rare hormonal disorder usually occurring in middle-aged adults, caused by excessive production of growth hormone by the pituitary gland) may either increase or decrease blood sugar levels.
Beta-blockers (used to treat high blood pressure) may weaken or completely suppress the warning symptoms that help you recognize low blood sugar.

Pioglitazone (tablets used to treat type 2 diabetes mellitus)
Some patients with long-standing type 2 diabetes and heart problems or a history of stroke who were treated with pioglitazone and insulin have developed heart failure. Inform your doctor immediately if you experience signs of heart failure such as unusual shortness of breath, rapid weight gain, or localized swelling (edema).
If you are taking any of the medicines listed above, inform your doctor, pharmacist, or nurse.

Protaphane and alcohol
► If you consume alcohol, your insulin requirement may change, as blood sugar levels may rise or fall. Careful monitoring is recommended.

Pregnancy and breastfeeding
► If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor before using this medicine. Protaphane can be used during pregnancy. Dose adjustments may be necessary during pregnancy and after delivery. It is important to carefully manage diabetes, particularly to prevent episodes of hypoglycemia, for the health of both mother and child.
► There are no restrictions on the use of Protaphane during breastfeeding.
Consult your doctor, pharmacist, or nurse before taking any medicine during pregnancy or breastfeeding.

Driving and using machines
► Consult your doctor about whether it is safe for you to drive or operate machinery:

If you have frequent episodes of hypoglycemia.
If you have difficulty recognizing the warning signs of hypoglycemia.

High or low blood sugar levels may impair your concentration and reaction ability, and therefore your ability to drive or operate machinery. Be aware that you may put yourself and others at risk.

Protaphane contains sodium
Protaphane contains less than 1 mmol of sodium (23 mg) per dose, i.e., Protaphane is essentially “sodium-free”.

3. How to use Protaphane

Roll the vial between your hands until the liquid appears uniformly white and milky. Resuspension is easier if the insulin has reached room temperature. Draw air into the syringe equal to the dose of insulin to be injected. Inject the air into the vial. Push the needle through the rubber stopper and press the plunger of the syringe.
Turn the vial and syringe upside down and draw the correct dose of insulin into the syringe. Remove the needle from the vial. Expel air from the syringe and check that the drawn insulin dose is correct.

If you need to mix two types of insulin:

Immediately before injection, roll the Protaphane vial between your hands. Continue until the liquid appears uniformly white and milky. Resuspension is easier if the insulin has reached room temperature.
Draw into the syringe an amount of air equal to the dose of Protaphane to be injected. Inject the air into the Protaphane vial and remove the needle.
Draw into the syringe an amount of air equal to the dose of rapid-acting insulin to be injected. Inject the air into the vial containing the rapid-acting insulin. Turn the vial and syringe upside down and draw the prescribed dose of rapid-acting insulin into the syringe. Expel air from the syringe and check that the dose is correct.
Insert the needle into the Protaphane vial, turn the vial and syringe upside down, and draw the prescribed dose. Expel air from the syringe and check that the dose is correct. Inject the mixture immediately.
Always mix Protaphane and rapid-acting insulin in this order.

How to inject Protaphane
► Inject the insulin under your skin. Use the injection technique recommended by your doctor or
nurse.
► Keep the needle under the skin for at least 6 seconds to ensure the full dose has been delivered.
► Dispose of the needle and syringe after each injection.
If you take more insulin than you should
If you take too much insulin, your blood sugar level may drop too low (hypoglycaemia). See
Summary of serious and very common side effects in section 4.
If you forget to take insulin
If you forget to take your insulin, your blood sugar level may become too high (hyperglycaemia).
See Effects of diabetes in section 4.
If you stop treatment with insulin
Do not stop treatment with insulin without first talking to your doctor, who will advise you on what to do. Stopping may lead to high blood sugar levels (severe hyperglycaemia) and ketoacidosis. See Effects of diabetes in section 4.
If you have any further questions about the use of this medicine, ask your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Summary of serious and very common side effects

Low blood sugar level (hypoglycaemia) is a very common side effect. It may occur in more than 1 in 10 people.

You may experience low blood sugar if:

You inject too much insulin.
You eat too little or miss meals.
You are more physically active than usual.
You consume alcohol – see Protaphane with alcohol in section 2.

Warning signs of low blood sugar: cold sweating; cold and pale skin; headache; rapid heartbeat; feeling unwell; hunger; temporary visual disturbances; drowsiness; unusual tiredness and weakness; nervousness or trembling; anxiety; confusion; difficulty concentrating.

Severe hypoglycaemia can lead to loss of consciousness. If severe hypoglycaemia is left untreated, it may cause brain damage (temporary or permanent) and even death. Recovery from unconsciousness may be faster with an injection of the hormone glucagon given by trained personnel who know how to use it. If you are given glucagon, you will need glucose or a sweet snack as soon as you regain consciousness. If you do not respond to glucagon treatment, you must be taken to hospital immediately.

What to do if your blood sugar is low:

► If your blood sugar is too low, eat sugar cubes or another snack high in sugar (sweets, biscuits, fruit juice). Check your blood sugar if possible, then rest. Always carry sugar cubes or snacks high in sugar to use in emergencies.

► When symptoms of hypoglycaemia have disappeared or your blood sugar has stabilised, continue your insulin treatment.

► If you experience low blood sugar, lose consciousness, require a glucagon injection, or have frequent episodes of low blood sugar, contact your doctor. A dose adjustment of insulin, changes in meal times, or physical activity may be necessary.

Inform people close to you that you are diabetic and explain the possible consequences, including the risk of fainting due to hypoglycaemia. Explain that if you faint, they should turn you onto your side and seek immediate medical help. Do not give food or drink, as you could choke.

Severe allergic reaction to Protaphane or one of its excipients (called systemic allergic reaction) is a rare side effect but may be potentially life-threatening. It may occur in fewer than 1 in 10,000 people.

Contact your doctor immediately:

If signs of allergy spread to other parts of the body.
If you suddenly feel unwell and: start sweating; feel sick (vomiting); have difficulty breathing; your heartbeat becomes rapid; or feel dizzy.

► If you notice any of these signs, contact your doctor immediately.

Skin changes at the injection site: If you inject insulin repeatedly into the same spot, fatty tissue may thin (lipoatrophy) or thicken (lipohypertrophy) (may affect fewer than 1 in 100 people). Lumps under the skin may also be caused by the build-up of a protein called amyloid (cutaneous amyloidosis; frequency is unknown). Insulin may not work as effectively if injected into an area with lumps, thinning, or thickening of the skin. Change your injection site with each injection to prevent these skin changes.

List of other side effects

Uncommon side effects
May affect fewer than 1 in 100 people.

Signs of allergy: local allergic reactions (pain, redness, urticaria, inflammation, bruising, swelling, and itching) at the injection site. These symptoms usually disappear within a few weeks of treatment. If symptoms do not disappear or spread to other parts of the body, contact your doctor immediately. See also Severe allergic reaction.

Diabetic retinopathy (an eye disorder related to diabetes that may lead to vision loss): if you have diabetic retinopathy and your blood sugar improves very rapidly, the retinopathy may worsen. Consult your doctor for further information.

Swollen joints: at the beginning of insulin treatment, fluid retention may cause swelling around the ankles and other joints. This is usually a temporary effect that soon disappears. If it does not, contact your doctor.

Very rare side effects
May affect fewer than 1 in 10,000 people.

Visual disturbances: visual disturbances may occur at the beginning of insulin treatment, but these are usually temporary.

Painful neuropathy (pain due to nerve damage): if your blood sugar improves very rapidly, it may cause pain originating in the nerve fibres. This is known as acute painful neuropathy, which is usually transient.

Reporting of side effects

If you experience any of the side effects, tell your doctor, pharmacist, or nurse. This includes any side effect not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

Effects of diabetes

High blood sugar level (hyperglycaemia)

You may have high blood sugar if:

You have not injected enough insulin.
You have forgotten to take insulin or stopped taking it.
You repeatedly take less insulin than required.
You have an infection or fever.
You eat more than usual.
You are less physically active than usual.

Warning signs of high blood sugar:
These symptoms appear gradually and include: increased urination; thirst; loss of appetite; feeling unwell (nausea or vomiting); drowsiness or tiredness; dry, flushed skin; dry mouth and fruity breath (acetone).

What to do if your blood sugar is high:

► If you experience any of these symptoms: check your blood sugar, and if possible, test for ketones in your urine, and contact a doctor immediately.

► These may be symptoms of a very serious condition called diabetic ketoacidosis (build-up of acid in the blood because the body is metabolising fat instead of sugar). If left untreated, it may lead to diabetic coma and possibly death.

5. How to store Protaphane

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the
packaging. The expiry date refers to the last day of the month indicated.
Before opening: store in a refrigerator at 2°C - 8°C. Keep away from cooling elements.
Do not freeze.
During use or when carried as a spare: do not refrigerate or freeze. It may be carried
and kept at room temperature (below 25°C) for up to 4 weeks.
Always keep the vial in its outer packaging to protect it from light.
Dispose of the needle and syringe after each injection.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Protaphane contains

The active substance is human insulin. Protaphane is an isophane (NPH) suspension of human insulin. Each ml contains 40 IU of human insulin. Each vial contains 400 IU of human insulin in 10 ml of injectable suspension.
The other excipients are zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate, sodium hydroxide, hydrochloric acid, protamine sulfate, and water for injections.

Description of the appearance of Protaphane and contents of the pack
Protaphane is a suspension for injection. After resuspension, the liquid should appear uniformly white and cloudy.
Pack sizes of 1 and 5 vials of 10 ml or in a multiple pack of 5 packs of 1 x 10 ml vial. Not all pack sizes may be marketed.
The suspension is aqueous, white and cloudy.
Marketing Authorization Holder and Manufacturer
Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark
This leaflet was last updated on
Other sources of information
More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/.

Package leaflet: Information for the user

Protaphane 100 IU/ml (International Units/ml) injectable suspension in vial

human insulin
Please read this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Never give it to others. It could be harmful even if their symptoms are the same as yours.
If you experience any side effect, talk to your doctor, pharmacist, or nurse. This includes any side effect not listed in this leaflet. See section 4.

1. What Protaphane is and what it is used for

Protaphane is human insulin with a gradual onset of action and prolonged duration.
Protaphane is used to reduce high blood sugar levels in patients with diabetes mellitus (diabetes).
Diabetes is a disease in which the body does not produce enough insulin to control blood sugar levels.
Treatment with Protaphane helps prevent complications of diabetes.
Protaphane begins to lower blood sugar levels about one and a half hours after administration, and its effect lasts for approximately 24 hours. Protaphane is often administered in combination with fast-acting insulin preparations.

2. What you should know before using Protaphane

Do not use Protaphane
► If you are allergic to human insulin or to any of the other excipients of this medicine,
see section 6.
► If you experience warning signs of hypoglycaemia (low blood sugar levels),
see the Summary of serious and very common side effects in section 4.
► In insulin infusion pumps.
► If the protective cap is loose or missing. Each vial has a tamper-evident plastic protective cap. If the cap is not in perfect condition at the time of purchase, return the vial to your supplier.
► If it has not been stored correctly or has been frozen, see section 5.
► If the resuspended insulin does not appear uniformly white and cloudy.
Do not use Protaphane if any of these situations apply. Speak with your doctor, pharmacist, or nurse for advice.

Warnings and precautions
Certain conditions and activities may affect your insulin requirements. Consult your doctor:
► If you have kidney or liver problems, or disorders affecting the adrenal glands, pituitary gland, or thyroid gland.
► If you increase your physical activity or change your usual diet, as this may affect your blood sugar levels.
► If you become ill: you must continue insulin therapy and consult your doctor.
► If you plan to travel abroad: travelling across different time zones may alter your insulin requirements and timing.

Skin changes at the injection site
Injection sites should be rotated to help prevent changes in the fatty tissue under the skin, such as thickening of the skin, thinning of the skin, or the appearance of lumps under the skin.
Insulin may not work as effectively if injected into an area with lumps, thinning, or thickening of the skin (see section 3). Inform your doctor if you notice any skin changes at the injection site. If you currently inject into such an affected area, consult your doctor before switching to another injection site. Your doctor may advise you to monitor your blood glucose more closely and possibly adjust your insulin dose or that of other antidiabetic medicines.

Other medicines and Protaphane
Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might take any other medicines.
Some medicines affect blood sugar levels, meaning that your insulin dose may need to be adjusted. Listed below are the most common medicines that may influence insulin treatment.

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

Other medicines for the treatment of diabetes
Monoamine oxidase inhibitors (MAOIs) (used to treat depression)
Beta-blockers (used to treat high blood pressure)
Angiotensin-converting enzyme (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 (hyperglycaemia) if you take:

Oral contraceptives (birth control pills)
Thiazides (used to treat high blood pressure or fluid retention)
Glucocorticoids (such as "cortisone" used to treat inflammation)
Thyroid hormones (used to treat thyroid gland disorders)
Sympathomimetics (such as epinephrine [adrenaline], salbutamol, or terbutaline, used to treat asthma)
Growth hormone (a medicine used to stimulate skeletal and somatic growth and which significantly affects the body's metabolic processes)
Danazol (a medicine that affects ovulation)

Pioglitazone (tablets used to treat type 2 diabetes mellitus)
Some patients with long-standing type 2 diabetes and heart problems or a history of stroke who were treated with pioglitazone and insulin have developed heart failure. Inform your doctor immediately if you experience signs of heart failure such as unusual shortness of breath, rapid weight gain, or localized swelling (oedema).
If you are taking any of the medicines listed above, inform your doctor, pharmacist, or nurse.

Protaphane and alcohol
► If you consume alcohol, your insulin requirement may change, as alcohol may cause blood sugar levels to rise or fall. Careful monitoring is recommended.

Pregnancy and breastfeeding
► If you are pregnant, think you may be pregnant, or are planning to become pregnant, ask your doctor for advice before taking this medicine. Protaphane can be used during pregnancy. Dose adjustments may be necessary during pregnancy and after delivery. It is important to control diabetes carefully, particularly to prevent episodes of hypoglycaemia, for the health of both mother and baby.
► There are no restrictions on the use of Protaphane during breastfeeding.
Consult your doctor, pharmacist, or nurse before taking any medicine during pregnancy or breastfeeding.

Driving and using machines
► Consult your doctor about whether it is safe for you to drive or operate machinery:

If you have frequent episodes of hypoglycaemia.
If you have difficulty recognizing the warning signs of hypoglycaemia.

High or low blood sugar levels may impair your concentration and reaction ability, and thus your ability to drive or operate machinery. Be aware that you could endanger yourself or others.

Protaphane contains sodium
Protaphane contains less than 1 mmol of sodium (23 mg) per dose, meaning that Protaphane is essentially “sodium-free”.

3. How to use Protaphane

Dose and when to take insulin
Always use insulin and adjust the dose as prescribed by your doctor. If you are unsure, consult your
doctor, pharmacist, or nurse.
Do not change your insulin unless your doctor tells you to. If your doctor has changed the type or brand
of insulin you are using, a dose adjustment may be necessary.

Use in children and adolescents
Protaphane can be used in children and adolescents.

Use in specific patient groups
If you have renal or hepatic impairment, or if you are over 65 years of age, you should monitor your blood
sugar levels regularly and discuss dose adjustments with your doctor.

How and where to inject
Protaphane is administered by subcutaneous injection (injected under the skin). Do not inject the insulin
directly into a vein (intravenous route) or into muscle (intramuscular route).
With each injection, rotate the injection site within the particular area of skin you usually use.
This may reduce the risk of developing lumps or skin depressions; see section 4. The best areas for
injection are: the abdominal area; the buttocks; the front of the thigh; or the upper arm. Insulin will act
more quickly if injected into the abdomen. Always monitor your blood glucose levels regularly.

How to take Protaphane
Protaphane in vials is designed to be used with insulin syringes calibrated in units.

If you need to use only one type of insulin:

Roll the vial gently between your hands until the liquid appears uniformly white and milky. Resuspension is easier if the insulin has reached room temperature. Draw air into the syringe equal to the dose of insulin to be injected. Inject the air into the vial.
Invert the vial and syringe and withdraw the correct dose of insulin into the syringe. Remove the needle from the vial. Expel air from the syringe and check that the dose is correct.

If you need to mix two types of insulin:

Immediately before injection, roll the Protaphane vial gently between your hands until the liquid appears uniformly white and milky. Resuspension is easier if the insulin has reached room temperature.
Draw into the syringe an amount of air equal to the dose of Protaphane to be injected. Inject the air into the Protaphane vial and remove the needle.
Draw into the syringe an amount of air equal to the dose of rapid-acting insulin to be injected. Inject the air into the vial containing the rapid-acting insulin. Invert the vial and syringe, expel air from the syringe, and check that the dose is correct.
Insert the needle into the Protaphane vial, invert the vial and syringe, and withdraw the prescribed dose of rapid-acting insulin. Expel air from the syringe and check that the dose is correct. Inject the mixture immediately.
Always mix Protaphane and rapid-acting insulin in this order.

If you take more insulin than you should
If you take too much insulin, your blood sugar level will drop too low (hypoglycaemia). See
Summary of serious and very common adverse effects in section 4.

If you forget to take insulin
If you forget to take your insulin, your blood sugar level may become too high (hyperglycaemia).
See Effects of diabetes in section 4.

If you stop using insulin
Do not stop using insulin without first talking to your doctor, who will advise you on what to do.
Stopping treatment may lead to high blood sugar levels (severe hyperglycaemia) and ketoacidosis.
See Effects of diabetes in section 4.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Summary of serious and very common side effects
Low blood sugar level (hypoglycaemia) is a very common side effect. It may occur in more than 1 in 10 people.
You may experience low blood sugar level if:

You inject too much insulin.
You eat too little or skip meals.
You do more physical activity than usual.
You consume alcohol – see Protaphane with alcohol in section 2.

Warning signs of low blood sugar level: cold sweating; cold, pale skin; headache; rapid heartbeat; feeling unwell; hunger; temporary visual disturbances; drowsiness; unusual tiredness and weakness; nervousness or trembling; anxiety; confusion; difficulty concentrating.
Severe hypoglycaemia can lead to loss of consciousness. If prolonged severe hypoglycaemia is not treated, it may cause brain damage (transient or permanent) and even death. You may regain consciousness more quickly with an injection of the hormone glucagon given by trained personnel who know how to use it. If glucagon is administered, you will need glucose or a sweet snack as soon as you regain consciousness. If you do not respond to glucagon treatment, you must be taken to hospital.
What to do if your blood sugar level is low:
► If your blood sugar level is too low, eat sugar lumps or another snack high in sugar (candies, biscuits, fruit juice). Check your blood sugar level if possible, then rest. Always carry sugar lumps or snacks high in sugar to use in case of need.
► When symptoms of hypoglycaemia have disappeared or your blood glucose has stabilised, continue your insulin treatment.
► If you have low blood sugar level, you may lose consciousness. If you needed a glucagon injection, or if you have frequent episodes of low blood sugar level, consult your doctor. A dose adjustment of insulin, changes in meal times and physical activity may be necessary.
Inform people close to you that you are diabetic and explain the possible consequences, including the risk of fainting due to hypoglycaemia. Explain that if you faint, they should turn you onto your side and immediately call for medical help. It is important that no food or drink is given, as you could choke.
Severe allergic reaction to Protaphane or to one of its excipients (called systemic allergic reaction) is a rare side effect but may be potentially life-threatening. It may occur in fewer than 1 in 10,000 people.
Contact your doctor immediately:

if signs of allergy spread to other parts of the body.
if you suddenly feel unwell and: start sweating; feel sick (vomiting); have difficulty breathing; have a rapid heartbeat; feel dizzy. ► If you notice any of these signs, contact your doctor immediately.

Skin changes at the injection site: If you inject insulin repeatedly into the same spot, fatty tissue may become thinner (lipoatrophy) or thicker (lipohypertrophy) (affecting fewer than 1 in 100 people). Lumps under the skin may also be caused by the accumulation of a protein called amyloid (cutaneous amyloidosis; frequency unknown). Insulin may not work as well as it should if you inject into an area with lumps, thinning or thickening. Change your injection site with each injection to prevent these skin changes.
List of other side effects
Uncommon side effects
May affect fewer than 1 in 100 people.
Signs of allergy: local allergic reactions (pain, redness, urticaria, inflammation, bruising, swelling and itching) at the injection site. These symptoms usually disappear within a few weeks of treatment. If symptoms do not disappear or spread to other parts of the body, contact your doctor immediately. See also Severe allergic reaction.
Diabetic retinopathy (a diabetes-related eye disorder that may lead to vision loss): if you have diabetic retinopathy and your blood glucose improves very rapidly, the retinopathy may worsen. Consult your doctor for further information.
Swollen joints: at the beginning of insulin treatment, fluid retention may cause swelling around the ankles and other joints. This is usually a temporary phenomenon that soon disappears. If not, contact your doctor.
Very rare side effects
May affect fewer than 1 in 10,000 people.
Visual disturbances: visual disturbances may occur at the beginning of insulin treatment, but these are generally temporary.
Painful neuropathy (pain due to nerve damage): if your blood glucose improves very rapidly, it may cause pain originating from nerve fibres. This is known as acute painful neuropathy and is usually transient.
Reporting of side effects
If you get any of the side effects, tell your doctor, pharmacist or nurse. This includes any side effect not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.
Effects of diabetes
High blood sugar level (hyperglycaemia)
You may have a high blood sugar level if:

You have not injected enough insulin.
You have forgotten to take insulin or stopped taking it.
You repeatedly take less insulin than needed.
You have an infection or fever.
You eat more than usual.
You do less physical activity than usual.

Warning signs of high blood sugar level:
Warning signs appear gradually. They include: passing more urine than normal; thirst; loss of appetite; feeling unwell (nausea or vomiting); drowsiness or tiredness; dry, flushed skin; dry mouth and fruity breath (acetone).
What to do if your blood sugar level is high:
► If you experience any of these symptoms: check your blood glucose, if possible, check for the presence of ketones in your urine and contact a doctor immediately.
► These may be symptoms of a very serious condition called diabetic ketoacidosis (build-up of acid in the blood because the body is metabolising fat instead of sugar).
If left untreated, it may lead to diabetic coma and possibly death.

5. How to store Protaphane

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the
packaging, after 'EXP'. The expiry date refers to the last day of the month.
Before opening: store in a refrigerator at 2°C - 8°C. Keep away from cooling elements.
Do not freeze.
During use or when carried as a spare: do not refrigerate or freeze. It may be carried
and kept at room temperature (below 25°C) for up to 6 weeks.
Always keep the vial in the outer packaging to protect it from light.
Dispose of the needle and syringe after each injection.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer used. This will help protect the environment.

6. Package contents and other information

What Protaphane contains

The active substance is human insulin. Protaphane is an isophane (NPH) suspension of human insulin. Each ml contains 100 IU of human insulin. Each vial contains 1000 IU of human insulin in 10 ml of injectable suspension.
The excipients are zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate, sodium hydroxide, hydrochloric acid, protamine sulfate, and water for injections.

Description of the appearance of Protaphane and contents of the pack
Protaphane is a white, opaque aqueous suspension for injection. After resuspension, the liquid must appear uniformly white and milky.
Pack sizes: 1 or 5 vials of 10 ml or a multiple pack of 5 packs of 1 x 10 ml vial. Not all pack sizes may be marketed.
The suspension is aqueous, white and milky.

Marketing Authorization Holder
Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark

Manufacturer
The manufacturer can be identified by the batch number printed on the carton flap and on the label:

If the second and third characters are S6 or ZF, the manufacturer is Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark.
If the second and third characters are T6, the manufacturer is Novo Nordisk Production SAS, 45 Avenue d’Orléans F-28000 Chartres, France.

This leaflet was last revised on
Other sources of information
More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/.

Package leaflet: Information for the user

Protaphane Penfill 100 IU/ml (international units/ml) injectable suspension in cartridge
human insulin
Please 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 questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Never give it to others. It may be harmful to them, even if their symptoms are the same as yours.
If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet

What Protaphane is and what it is used for
What you need to know before you use Protaphane
How to use Protaphane
Possible side effects
How to store Protaphane
Contents of the pack and other information

1. What Protaphane is and what it is used for

Protaphane is human insulin with a gradual onset of action and prolonged duration.
Protaphane is used to reduce high blood sugar levels in patients with diabetes mellitus (diabetes).
Diabetes is a disease in which the body does not produce enough insulin to control blood sugar levels.
Treatment with Protaphane helps prevent the complications of diabetes.
Protaphane begins to lower blood sugar levels approximately one and a half hours after injection, and its effect lasts for about 24 hours. Protaphane is often administered in combination with rapid-acting insulin preparations.

2. What you need to know before using Protaphane

Do not use Protaphane
► If you are allergic to human insulin or to any of the other excipients of this medicine,
consult section 6.
► If you experience warning signs of hypoglycaemia (low blood sugar levels),
refer to the Summary of serious and very common adverse reactions in section 4.
► In insulin infusion pumps.
► If the cartridge or the device containing the cartridge is leaking, damaged, or cracked.
► If it has not been stored correctly or has been frozen; see section 5.
► If the resuspended insulin does not appear uniformly white and cloudy.
Do not use Protaphane if any of these situations apply. Speak to your doctor, pharmacist, or nurse for
advice.

Before using Protaphane
► Check the label to make sure you are using the correct type of insulin.
► Always inspect the cartridge, including the rubber plunger at the top of the cartridge. Do not use if it appears damaged or if the rubber plunger has been pushed beyond the white band at the top of the cartridge. This could lead to insulin loss.
If you suspect the cartridge is damaged, return it to your supplier. Refer to the pen user manual for further information.
► Always use a new needle for each injection to prevent contamination.
► Needles and Protaphane Penfill must not be shared.
► Protaphane Penfill is intended only for subcutaneous injection with a reusable pen. Speak to your doctor if you need to administer insulin by another method.

Warnings and precautions
Certain conditions and activities may affect your insulin requirements. Consult your doctor:
► If you have kidney or liver problems, or disorders affecting the adrenal glands, pituitary, or thyroid gland.
► If you increase your physical activity or change your usual diet, as this may affect your blood sugar levels.
► If you become ill, continue your insulin therapy.
► If you plan to travel abroad; traveling across different time zones may alter your insulin requirements and timing.

Changes in the skin at the injection site
Rotate your injection sites to help prevent changes in the fatty tissue under the skin, such as skin thickening, skin thinning, or the appearance of lumps under the skin.
Insulin may not work as effectively if injected into an area with lumps, thinning, or thickening (see section 3). Inform your doctor if you notice any skin changes at the injection site. If you are currently injecting into one of these affected areas, consult your doctor before switching to another site. Your doctor may advise you to monitor your blood glucose more closely and adjust your insulin dose or that of other antidiabetic medicines.

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

Other medicines for the treatment of diabetes
Monoamine oxidase inhibitors (MAOIs) (used to treat depression)
Beta-blockers (used to treat high blood pressure)
Angiotensin-converting enzyme (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 (hyperglycaemia) if you take:

Oral contraceptives (birth control pills)
Thiazides (used to treat high blood pressure or fluid retention)
Glucocorticoids (such as "cortisone", used to treat inflammation)
Thyroid hormones (used to treat thyroid gland disorders)
Sympathomimetics (such as epinephrine [adrenaline], salbutamol, or terbutaline, used to treat asthma)
Growth hormone (a medicine used to stimulate skeletal and somatic growth and that significantly affects the body's metabolic processes)
Danazol (a medicine that affects ovulation)

Octreotide and lanreotide (used to treat acromegaly, a rare hormonal disorder usually occurring in middle-aged adults caused by excessive production of growth hormone by the pituitary gland) may either increase or decrease blood sugar levels.
Beta-blockers (used to treat high blood pressure) may weaken or completely suppress the warning symptoms that help you recognize low blood sugar levels.

Pioglitazone (tablets used to treat type 2 diabetes)
Some patients with long-standing type 2 diabetes and heart problems or a history of stroke who were treated with pioglitazone and insulin have developed heart failure.
Inform your doctor immediately if you experience signs of heart failure such as unusual shortness of breath, rapid weight gain, or localized swelling (edema).
If you are taking any of the medicines listed above, inform your doctor, pharmacist, or nurse.

Pregnancy and breastfeeding
► If you are pregnant, think you might be pregnant, or are planning a pregnancy, consult your doctor before using this medicine. Protaphane can be used during pregnancy. Your insulin dose may need to be adjusted during pregnancy and after delivery. It is important to carefully control your diabetes, particularly to prevent episodes of hypoglycaemia, for the health of both you and your baby.
► There are no restrictions on using Protaphane during breastfeeding.
Consult your doctor, pharmacist, or nurse before taking any medicine during pregnancy or breastfeeding.

Driving and using machines
► Consult your doctor about whether it is safe for you to drive or use machines:

If you have frequent episodes of hypoglycaemia.
If you have difficulty recognizing the warning signs of hypoglycaemia.

If your blood sugar is too high or too low, your ability to concentrate and react may be impaired, affecting your ability to drive or operate machinery. Be aware that this could put yourself and others at risk.

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

3. How to use Protaphane

Dosage and timing of insulin administration
Always use insulin and adjust the dose as prescribed by your doctor. If you are unsure, consult your
doctor, pharmacist, or nurse.
Do not change your insulin unless your doctor tells you to do so. If your doctor has changed the type or
brand of insulin you are using, a dose adjustment may be necessary.

Use in children and adolescents
Protaphane can be used in children and adolescents.

Use in specific patient groups
If you have renal or hepatic impairment, or are over 65 years of age, monitor your blood glucose regularly and discuss insulin dose adjustments with your doctor.

How and where to inject
Protaphane is administered by subcutaneous injection (under the skin). Never inject insulin directly into a vein (intravenous route) or into muscle (intramuscular route). Protaphane Penfill is intended only for subcutaneous injections using a reusable insulin pen. Talk to your doctor if you need to administer insulin by another method.
With each injection, rotate the injection site within the general area of skin you usually use.
This can help reduce the risk of developing lumps or skin depressions—see section 4. The best injection sites are: the abdominal area; the buttocks; the front of the thigh; or the upper arm. Insulin will act more quickly if injected into the abdomen. Check your blood glucose levels regularly.
► Do not refill the cartridge. Once empty, it must be discarded.
► Penfill cartridges are designed to be used with Novo Nordisk insulin delivery devices and NovoFine or NovoTwist needles.
► If, in addition to Protaphane Penfill, you have been prescribed another type of insulin in a Penfill cartridge, you must use two separate insulin delivery devices—one for each type of insulin.
► Always carry a spare Penfill cartridge with you in case the one in use is lost or damaged.

Resuspension of Protaphane
Always check that there is enough insulin (at least 12 units) remaining in the cartridge to allow proper resuspension. If there is not enough insulin, use a new cartridge. See the pen user manual for further instructions.
► Always use a new Protaphane Penfill (first place the cartridge into the insulin delivery device).

Allow the insulin to reach room temperature before use. This will make resuspension easier.
Move the cartridge up and down between positions a and b and back again (see figure), ensuring the glass ball moves from one end of the cartridge to the other at least 20 times.
Repeat this movement at least 10 times before each injection.
Always repeat the movement until the liquid appears uniformly white and milky.
Promptly complete the other steps described below.

Blue schematic drawing showing a hand rotating an injector pen from the vertical position indicated with A to the horizontal position indicated with B

How to inject Protaphane
► Inject the insulin under your skin. Use the injection technique recommended by your doctor or nurse and described in the pen instruction manual.
► Keep the needle under the skin for at least 6 seconds. Keep the button fully pressed until you have withdrawn the needle from the skin. This ensures the correct dose is delivered and minimizes the risk of blood flowing back into the needle or insulin reservoir.
► Always remove and dispose of the needle after each injection and store Protaphane with the needle removed. If not, leakage may occur, which could lead to inaccurate dosing.

If you take more insulin than you should
If you take too much insulin, your blood sugar level may drop too low (hypoglycemia). See Summary of serious and very common side effects in section 4.

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

If you stop using insulin
Do not stop using insulin without first talking to your doctor, who will advise you on what to do. Stopping treatment may lead to high blood sugar levels (severe hyperglycemia) and ketoacidosis. See Effects of diabetes in section 4.

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

4. Possible side effects

You inject too much insulin.
You eat too little or miss meals.
You do more physical activity than usual.
You drink alcohol – see Protaphane with alcohol in section 2.

Warning signs of low blood sugar: cold sweating; cold, pale skin; headache; rapid heartbeat; feeling unwell; hunger sensation; temporary visual disturbances; drowsiness; unusual tiredness and weakness; nervousness or trembling; anxiety; confusion; difficulty concentrating.
Severe hypoglycaemia can lead to loss of consciousness. If prolonged severe hypoglycaemia is not treated, it may cause brain damage (transient or permanent) and even death. Recovery of consciousness may be faster with an injection of the hormone glucagon given by trained personnel who know how to use it. If you are given glucagon, you will need glucose or a sweet snack as soon as you regain consciousness. If you do not respond to glucagon treatment, you must be taken to hospital immediately.
What to do if your blood sugar level is low:
► If your blood sugar is too low, eat sugar lumps or another sugary snack (sweets, biscuits, fruit juice). If possible, measure your blood sugar and then rest. Always carry sugar lumps or sugary snacks with you to use in case of need.
► When symptoms of hypoglycaemia have disappeared or your blood sugar has stabilized, continue your insulin treatment.
► If you have low blood sugar, you may lose consciousness. If you have needed a glucagon injection, or if you have had several episodes of low blood sugar, contact your doctor. A dose adjustment of insulin, food intake, and physical activity may be necessary.
Inform people close to you that you have diabetes and what the consequences may be, including the risk of fainting due to hypoglycaemia. Explain that if you should faint, they must turn you onto your side and immediately call for medical help. It is important that food or drink is not given to you, as you could choke.
Severe allergic reaction to Protaphane or to one of its excipients (called systemic allergic reaction) is a rare side effect but may be potentially life-threatening. It may occur in fewer than 1 in 10,000 people.
Contact your doctor immediately:

if signs of allergy spread to other parts of the body.
if you suddenly feel unwell and: start sweating; feel sick (vomiting); have difficulty breathing; your heartbeat becomes rapid; you feel dizzy. ► If you notice any of these signs, contact your doctor immediately.

Skin changes at the injection site: If you inject insulin in the same spot repeatedly, fatty tissue may become thinner (lipoatrophy) or thicker (lipohypertrophy) (may affect fewer than 1 in 100 people). Lumps under the skin may also be caused by the build-up of a protein called amyloid (cutaneous amyloidosis; frequency not known). Insulin may not work as well as it should if you inject into an area with lumps, thinning, or thickening. Change your injection site with each injection to prevent these skin changes.
List of other side effects
Uncommon side effects
May affect fewer than 1 in 100 people.
Signs of allergy: local allergic reactions (pain, redness, urticaria, inflammation, bruising, swelling, or itching). These symptoms usually disappear within a few weeks of treatment. If symptoms do not disappear or spread to other parts of the body, contact your doctor immediately. See also Severe allergic reaction.
Diabetic retinopathy (an eye disorder related to diabetes that may lead to vision loss): if you have diabetic retinopathy and your blood sugar improves very rapidly, your retinopathy may worsen. Consult your doctor for further information.
Swollen joints: at the beginning of insulin treatment, fluid retention may cause swelling around the ankles and other joints. This is normally a temporary phenomenon. If it does not go away, contact your doctor.
Very rare side effects
May affect fewer than 1 in 10,000 people.
Visual disturbances: visual disturbances may occur at the beginning of insulin treatment, but these are usually temporary.
Painful neuropathy (pain due to nerve damage): if your blood sugar improves very rapidly, you may experience pain originating from nerve fibres, known as acute painful neuropathy, which is usually transient.
Reporting of side effects
If you experience any of the side effects, tell your doctor, pharmacist, or nurse. This includes any side effect not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.
Effects of diabetes
High blood sugar level (hyperglycaemia)
You may have a high blood sugar level if:

You have not injected enough insulin.
You have forgotten to take insulin or stopped taking it.
You repeatedly take less insulin than needed.
You have an infection or fever.
You eat more than usual.
You do less physical activity than usual.

Warning signs of high blood sugar:
Warning signs appear gradually. They include: passing more urine than normal; thirst; loss of appetite; feeling unwell (nausea or vomiting); drowsiness or tiredness; dry, flushed skin; dry mouth and fruity breath (acetone).
What to do if your blood sugar level is high:
► If you experience any of these symptoms: check your blood sugar, if possible check for the presence of ketones in your urine, and contact a doctor immediately.
► These may be symptoms of a very serious condition called diabetic ketoacidosis (build-up of acid in the blood because the body is metabolizing fat instead of sugar).
If left untreated, it may lead to diabetic coma and eventually death.

5. How to store Protaphane

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the cartridge label and on the packaging after 'EXP'. The expiry date refers to the last day of the month.
Before opening: store in a refrigerator at 2°C - 8°C. Keep away from cooling elements.
Do not freeze.
During use or when carried as a spare: do not refrigerate or freeze. It may be carried with you and kept at room temperature (below 30°C) for up to 6 weeks.
Always keep the cartridge in the outer packaging to protect it from light.
Dispose of the needle after each injection.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Protaphane contains

The active substance is human insulin. Protaphane is an isophane (NPH) suspension of human insulin. Each ml contains 100 IU of human insulin. Each cartridge contains 300 IU of human insulin in 3 ml of injectable suspension.
The other ingredients are zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate, sodium hydroxide, hydrochloric acid, protamine sulfate, and water for injections.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark

Manufacturer
The manufacturer can be identified by the batch number printed on the side of the pack and on the label:

If the second and third characters are S6, P5, K7, R7 or VG, FG or ZF, the manufacturer is Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark
If the second and third characters are H7 or T6, the manufacturer is Novo Nordisk Production SAS, 45 Avenue d’Orleans, F-28000 Chartres, France.

This leaflet was last updated on
Further information
More detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu/.

Package leaflet: Information for the user

Protaphane InnoLet 100 IU/ml (international units/ml) injectable suspension in pre-filled pen

pre-filled
human insulin
Please read this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Never give it to others. It could be harmful even if their symptoms are the same as yours.
If you experience any side effect, talk to your doctor, pharmacist, or nurse. This includes any side effect not listed in this leaflet. See section 4.

Contents of this leaflet
1 What Protaphane is and what it is used for
2 What you need to know before using Protaphane
3 How to use Protaphane
4 Possible side effects
5 How to store Protaphane
6 Contents of the pack and other information

1. What Protaphane is and what it is used for

Protaphane is a human insulin with a gradual onset of action and prolonged duration.
Protaphane is used to lower high blood sugar levels in patients with diabetes mellitus (diabetes).
Diabetes is a condition in which the body does not produce enough insulin to control blood sugar levels. Treatment with Protaphane helps prevent complications of diabetes.
Protaphane begins to reduce blood sugar levels within about one and a half hours after injection, and its effect lasts for approximately 24 hours. Protaphane is often administered in combination with fast-acting insulin preparations.

2. What you need to know before using Protaphane

Do not use Protaphane
► If you are allergic to human insulin or to any of the other excipients, see section 6
► If you experience warning signs of hypoglycaemia (low blood sugar levels), see the Summary of serious and very common side effects in section 4
► In insulin infusion pumps
► If the InnoLet is leaking, damaged or cracked
► If it has not been stored correctly or has been frozen, see section 5
► If the resuspended insulin does not appear uniformly white and cloudy

Do not use Protaphane if any of these situations apply. Speak to your doctor, pharmacist or nurse for advice.

Before using Protaphane
► Check the label to make sure you are using the correct type of insulin
► Always use a new needle for each injection to prevent contamination
► Needles and Protaphane InnoLet must not be shared
► Protaphane InnoLet is intended only for subcutaneous injection. Speak to your doctor if you need to administer insulin by another route

Warnings and precautions
Certain conditions and activities may affect your insulin requirements. Consult your doctor:
► If you have kidney or liver problems, or disorders affecting the adrenal glands, pituitary gland or thyroid
► If you increase your physical activity or change your usual diet, as this may affect your blood sugar levels
► If you become ill, continue your insulin therapy and consult your doctor
► If you plan to travel abroad: travelling across time zones may alter your insulin requirements and timing of administration

Changes at the injection site
Rotate your injection sites to help prevent changes in the fatty tissue under the skin, such as thickening of the skin, thinning of the skin or the appearance of lumps under the skin.
Insulin may not work as well if you inject into an area with lumps, thinning or thickening of the skin (see section 3). Inform your doctor if you notice any skin changes at the injection site. If you currently inject into such an affected area, consult your doctor before switching to a different injection site. Your doctor may advise you to monitor your blood glucose more closely and possibly adjust your insulin dose or that of other antidiabetic medications.

Other medicines and Protaphane
Inform your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
Some medicines affect blood sugar levels, meaning your insulin dose may need to be adjusted. Listed below are the most common medicines that may affect insulin treatment.

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

Other medicines for the treatment of diabetes
Monoamine oxidase inhibitors (MAOIs) (used to treat depression)
Beta-blockers (used to treat high blood pressure)
Angiotensin-converting enzyme (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 (hyperglycaemia) if you take:

Oral contraceptives (birth control pills)
Thiazides (used to treat high blood pressure or fluid retention)
Glucocorticoids (such as “cortisone”, used to treat inflammation)
Thyroid hormones (used to treat thyroid gland disorders)
Sympathomimetics (such as epinephrine [adrenaline], salbutamol or terbutaline, used to treat asthma)
Growth hormone (a medicine used to stimulate skeletal and somatic growth and that significantly affects the body’s metabolic processes)
Danazol (a medicine that affects ovulation)

Pioglitazone (tablets used to treat type 2 diabetes mellitus)
Some patients with long-standing type 2 diabetes mellitus and with heart problems or a history of stroke who were treated with pioglitazone and insulin have developed heart failure.
Inform your doctor immediately if you experience signs of heart failure such as unusual shortness of breath, rapid weight gain or localized swelling (oedema).
If you are taking any of the medicines listed above, inform your doctor, pharmacist or nurse.

Protaphane and alcohol
► If you consume alcohol, your insulin requirement may change, as blood sugar levels may increase or decrease. Careful monitoring is recommended.

Pregnancy and breastfeeding
► If you are pregnant, think you may be pregnant or are planning to become pregnant, ask your doctor for advice before taking this medicine. Protaphane can be used during pregnancy. Your insulin dose may need to be adjusted during pregnancy and after delivery. It is important to carefully control diabetes, particularly to prevent episodes of hypoglycaemia, for the health of both mother and child.
► There are no restrictions on the use of Protaphane during breastfeeding.
Consult your doctor, pharmacist or nurse before taking any medicine during pregnancy or breastfeeding.

Driving and using machines
► Consult your doctor about whether it is safe for you to drive or operate machinery:

If you have frequent episodes of hypoglycaemia
If you have difficulty recognizing the warning signs of hypoglycaemia

If your blood sugar is too high or too low, your ability to concentrate and react may be impaired, which could affect your ability to drive or operate machinery. Be aware that you could put yourself and others at risk.

Protaphane contains sodium
Protaphane contains less than 1 mmol of sodium (23 mg) per dose, i.e. Protaphane is essentially “sodium-free”.

3. How to use Protaphane

Dosage and when to take insulin
Always use insulin and adjust the dose as prescribed by your doctor. If you are unsure, consult your
doctor, pharmacist, or nurse.
Do not change your insulin unless your doctor tells you to do so. If your doctor has changed the type or
brand of insulin you are using, a dose adjustment may be necessary.
Use in children and adolescents
Protaphane can be used in children and adolescents.
Use in specific patient groups
If you have kidney or liver impairment, or if you are over 65 years of age, monitor your blood sugar
regularly and discuss insulin dose adjustments with your doctor.
How and where to inject
Protaphane is administered by subcutaneous injection (under the skin). Never inject insulin directly
into a vein (intravenous route) or into muscle (intramuscular route). Protaphane Innolet is intended
only for subcutaneous injections. Speak with your doctor if you need to administer insulin by another
route.
With each injection, always rotate the injection site within the particular area of skin you usually use.
This can reduce the risk of developing lumps or skin depressions; see section 4. The best areas for
injection are: the abdomen; buttocks; front of the thigh; or upper arm. Your insulin will act more quickly
if injected into the abdomen. Always monitor your blood glucose regularly.
How to inject Protaphane InnoLet
Protaphane InnoLet is a pre-filled pen containing human insulin isophane (NPH).
Read carefully the Instructions for Use provided in this package leaflet. You must use the pen exactly as
described in the Instructions for Use for Protaphane InnoLet.
Always make sure you are using the correct pen before injecting your insulin.
If you take more insulin than you should
If you take too much insulin, your blood sugar level will drop too low (hypoglycaemia). See Summary
of serious and very common adverse reactions in section 4.
If you forget to take insulin
If you forget to take your insulin, your blood sugar level will become too high (hyperglycaemia). See
Effects of diabetes in section 4.
If you stop using insulin
Do not stop treatment with insulin without first discussing it with your doctor, who will advise you on
what to do. Stopping treatment may lead to high blood sugar levels (severe hyperglycaemia) and
ketoacidosis. See Effects of diabetes in section 4.
If you have any further questions about the use of this medicine, ask your doctor, pharmacist, or nurse.

4 Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.

Summary of serious and very common side effects
Low blood sugar (hypoglycaemia) is a very common side effect. It may affect more than 1 in 10 people.
You may experience low blood sugar if:

You inject too much insulin.
You eat too little or skip meals.
You are more physically active than usual.
You consume alcohol; see Protaphane with alcohol in section 2.

Warning signs of low blood sugar: cold, clammy sweat; cold, pale skin; headache; rapid heartbeat; feeling unwell; hunger; temporary visual disturbances; drowsiness; unusual tiredness or weakness; nervousness or trembling; anxiety; confusion; difficulty concentrating.
Severe hypoglycaemia can lead to loss of consciousness. If prolonged severe hypoglycaemia is not treated, it may cause brain damage (transient or permanent) and may even lead to death. Recovery may be faster with an injection of the hormone glucagon given by trained personnel who know how to use it. If glucagon is administered, you will need glucose or a sweet snack as soon as you regain consciousness. If you do not respond to glucagon treatment, you must be taken to hospital immediately.
What to do if your blood sugar is low:
► If your blood sugar is too low, eat sugar lumps or another high-sugar snack (candy, biscuits, fruit juice). If possible, measure your blood sugar and then rest. Always carry sugar lumps, candy, biscuits, or fruit juice with you to use in emergencies.
► When symptoms of hypoglycaemia have disappeared or when your blood glucose has stabilized, continue your insulin treatment.
► If you experience low blood sugar, lose consciousness, require a glucagon injection, or have frequent episodes of low blood sugar, contact your doctor. A dose adjustment may be needed, as well as changes to your insulin timing, diet, or physical activity.
Inform people close to you that you have diabetes and explain the possible consequences, including the risk of fainting due to hypoglycaemia. Explain that if you faint, they should turn you onto your side and seek immediate medical help. It is important that no food or drink is given, as you could choke.

Severe allergic reaction to Protaphane or one of its excipients (called a systemic allergic reaction) is a side effect that may be potentially life-threatening. It may affect fewer than 1 in 10,000 people.
Contact your doctor immediately:

If signs of allergy spread to other parts of the body.
If you suddenly feel unwell and: start sweating; feel sick (vomiting); have difficulty breathing; your heartbeat becomes rapid; or feel dizzy. ► If you notice any of these signs, contact your doctor immediately.

Skin changes at the injection site: If you inject insulin repeatedly into the same spot, fatty tissue may thin (lipoatrophy) or thicken (lipohypertrophy) (may affect fewer than 1 in 100 people). Lumps under the skin may also be caused by the buildup of a protein called amyloid (cutaneous amyloidosis; frequency unknown). Insulin may not work as effectively if injected into an area with lumps, thinning, or thickening. Rotate your injection site with each injection to prevent these skin changes.

List of other side effects
Uncommon side effects
May affect fewer than 1 in 100 people.
Signs of allergy: Local allergic reactions (pain, redness, hives, inflammation, bruising, swelling, or itching) at the injection site. These symptoms usually disappear within a few weeks of treatment. If symptoms do not disappear or spread to other parts of the body, contact your doctor immediately. See also Severe allergic reaction.
Diabetic retinopathy (a diabetes-related eye disorder that may lead to vision loss): if you have diabetic retinopathy and your blood glucose improves rapidly, the condition may worsen. Consult your doctor for further information.
Swollen joints: At the start of insulin treatment, fluid retention may cause swelling around the ankles and other joints. This usually resolves quickly. If it does not, contact your doctor.

Very rare side effects
May affect fewer than 1 in 10,000 people.
Visual disturbances: Visual disturbances may occur at the beginning of insulin treatment, but these are usually temporary.
Painful neuropathy (pain due to nerve damage): if blood glucose improves very rapidly, it may cause pain originating from nerve fibres. This is known as acute painful neuropathy, which is usually transient.

Reporting of side effects
If you experience any side effects, inform your doctor, pharmacist, or nurse. This includes any side effect not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

Other effects of diabetes
High blood sugar (hyperglycaemia)
You may have high blood sugar if:

You have not injected enough insulin.
You have forgotten to take insulin or stopped taking it.
You repeatedly take less insulin than required.
You have an infection or fever.
You eat more than usual.
You are less physically active than usual.

Warning signs of high blood sugar:
Symptoms develop gradually and include: increased urination; thirst; loss of appetite; feeling unwell (nausea or vomiting); drowsiness or fatigue; dry, flushed skin; dry mouth; fruity breath (acetone).
What to do if your blood sugar is high:
► If you experience any of these symptoms: check your blood glucose, test your urine for ketones if possible, and contact a doctor immediately.
► These may be symptoms of a serious condition called diabetic ketoacidosis (build-up of acid in the blood due to the body metabolizing fat instead of sugar).
If left untreated, this may lead to diabetic coma and possibly death.

5. How to store Protaphane

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the InnoLet label and on the packaging after 'EXP'. The expiry date refers to the last day of the month.
Before opening: store in a refrigerator at 2°C - 8°C. Keep away from cooling elements.
Do not freeze.
During use or when carried as a spare: do not refrigerate or freeze. It may be carried with you and stored at room temperature (below 30°C) for up to 6 weeks.
Always keep the pen cap on the InnoLet when not in use to protect it from light.
Dispose of the needle after each injection.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package Contents and Other Information

What Protaphane Contains

The active substance is human insulin. Protaphane is a human insulin isophane (NPH) suspension. Each ml contains 100 IU of human insulin. Each pre-filled pen contains 300 IU of human insulin in 3 ml of injectable suspension.
The other excipients are zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate, sodium hydroxide, hydrochloric acid, protamine sulfate, and water for injections.

Description of the Appearance of Protaphane and Contents of the Pack
Protaphane is a suspension for injection. After resuspension, the liquid should appear uniformly white and milky.
Packs of 1, 5 or 10 pre-filled pens of 3 ml. Not all pack sizes may be marketed.
The suspension is aqueous, white and milky.

Marketing Authorisation Holder and Manufacturer
Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark

This leaflet was last updated on
Other Sources of Information
More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/.
For instructions on how to use your InnoLet, please turn the page.
Instructions for using Protaphane injectable suspension in InnoLet.
Read carefully the following instructions before using your InnoLet. If you do not follow these instructions carefully, you may inject too much or too little insulin, which could lead to blood sugar levels that are too high or too low.
Protaphane InnoLet is a simple and compact pre-filled pen capable of delivering from 1 to 50 units of insulin in 1-unit increments. InnoLet is designed to be used with NovoFine or NovoTwist disposable needles up to 8 mm in length. As a precaution, always carry a spare insulin delivery device in case your InnoLet is lost or damaged.

Blue technical diagram on white background of a medical device with numbered dial, graduated scale, separated components, and directional arrow

Getting Started
Check the name and the colored label of your InnoLet to ensure it contains the correct type of insulin. This is particularly important if you use more than one type of insulin. Using the wrong type of insulin may cause your blood sugar level to become too high or too low. Remove the pen cap. It is easier to resuspend the insulin if it has reached room temperature.

Resuspending the Insulin
Before each injection:

To ensure uniform resuspension, verify that at least 12 units of insulin remain in the cartridge. If less than 12 units remain, use a new Protaphane InnoLet.
Move the pen up and down between positions A and B and vice versa so that the glass ball moves from one end to the other of the insulin cartridge (Figure 1A) at least 20 times before first use. Repeat the movement at least 10 times before subsequent uses. Always repeat the movement until the liquid appears uniformly white and milky.
Always resuspend the insulin before each injection. Failure to resuspend the insulin may lead to inaccurate dosing, which could cause blood sugar levels to become too high or too low. After resuspending, proceed immediately to the next steps described below.

Illustration showing a hand rotating a medical device from a vertical position labeled A to a horizontal position labeled B

Attaching the Needle
Always use a new needle for each injection. This reduces the risk of contamination, infection, insulin leakage, needle blockage, and incorrect dosing.

Be careful not to bend or damage the needle before use.
Remove the protective seal from a new disposable needle.
Screw the needle perpendicularly and firmly onto the InnoLet (Figure 1B).
Remove the outer large needle cap and the inner needle cap. It may be helpful to keep the outer large needle cap in its designated compartment.
Never try to reattach the inner needle cap onto the needle. You may injure yourself with the needle.

Technical illustration of a medical device with a curved blue arrow indicating counterclockwise rotation of the upper part

Preparing to Remove Air Before Each Injection
During normal use, small amounts of air may accumulate in the needle and insulin cartridge.
To avoid injecting air and to ensure the correct dose of insulin is delivered:

Select 2 units by turning the dose selector clockwise.
Hold the InnoLet with the needle pointing upwards and tap the insulin cartridge gently several times with your fingers (Figure 1C), so that air bubbles collect at the top of the cartridge (Figure 1C).
While keeping the needle pointing upwards, press the injection button and the dose selector will return to 0.
Always ensure a drop of insulin appears at the tip of the needle ( Figure 1C) before injection. This confirms insulin flow. If no drop appears, change the needle and repeat the procedure no more than 6 times.

If no drop of insulin appears after repeated attempts, the device is faulty and must not be used.

If no drop appears, insulin will not be injected, even if the dose selector moves. This may indicate a blocked or damaged needle.
Always check your InnoLet before injection. If you do not check it, you may inject too little insulin or none at all, which could lead to blood sugar levels that are too high.

Medical illustration of a hand holding a syringe with liquid and a graduated scale from 12 to 300 units on a light blue background

Selecting the Dose

Always ensure the injection button is fully pressed and the dose selector is set to 0.
Select the number of units to be injected by turning the dose selector clockwise (Figure 2).
You will hear a click for each single unit selected. The dose can be corrected by turning the selector in either direction. Make sure not to turn the knob or correct the dose once the needle is inserted into the skin. This may lead to inaccurate dosing, which could cause blood sugar levels to become too high or too low.

Always use the dose scale and dose selector to verify how many units you have selected before injecting insulin. Do not count the clicks of the pen. If you select and inject the wrong dose, your blood sugar level may become too high or too low. Do not use the residual scale—it only approximately indicates how much insulin remains in the pen.
You cannot select a dose greater than the number of units remaining in the cartridge.

Diagram of a timer with numbers from 0 to 50 and two curved blue arrows indicating clockwise rotational movement

Injecting the Insulin
Insert the needle into the skin. Use the injection technique recommended by your doctor.
Administer the insulin dose by fully pressing the injection button ( Figure 3). You will hear clicks as the dose selector returns to 0.
After injection, wait at least 6 seconds before removing the needle to ensure complete dose delivery.

Ensure you do not block the dose selector during injection, as it must be free to return to 0 when the injection button is pressed. Always confirm that the dose selector returns to 0 after injection. If the dose selector stops before reaching 0, the full dose has not been delivered, which may result in blood sugar levels that are too high.
Remove the needle after each injection.

Two hands holding a medical device with a numbered dial from 0 to 50 and a blue arrow pointing downward at the top button

Removing the Needle

Replace the outer large protective cap and unscrew the needle (Figure 4). Dispose of the needle carefully.
Replace the pen cap on your InnoLet to protect the insulin from light.

Always use a new needle for each injection.
Always remove and discard the needle after each injection, and store the InnoLet without the needle attached. This reduces the risk of contamination, infection, insulin leakage, needle blockage, and inaccurate dosing.
Important Additional Information
Anyone caring for you must take great care when handling used needles to reduce the risk of needlestick injuries and cross-infections.
Dispose of used InnoLet pens carefully, ensuring the needle has been removed.
Never share the pen or needles with other people. This could lead to cross-infections.
Never share the pen with other people. The medicine may be dangerous to their health.
Always keep InnoLet and needles out of sight and reach of others, especially children.

Pen Maintenance
InnoLet is designed to function accurately and safely. Handle it with care. If it has been dropped, damaged or impaired, insulin leakage may occur. This could lead to incorrect dosing, which may cause blood sugar levels to become too high or too low.
You may clean the exterior of the Protaphane InnoLet by wiping it with a disinfectant swab. Do not immerse, wash or lubricate it, as this may damage the mechanism and lead to incorrect dosing, which could cause blood sugar levels to become too high or too low.
Do not refill the InnoLet. Once empty, it must be discarded.

Package leaflet: Information for the user

Protaphane FlexPen 100 IU/ml (international units/ml) injectable suspension in pre-filled pen

human insulin
Please read all of this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Never give it to other people, even if their symptoms appear to be the same as yours. It could be harmful to them.
If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet

What Protaphane is and what it is used for
What you need to know before using Protaphane
How to use Protaphane
Possible side effects
How to store Protaphane
Contents of the pack and other information

1. What Protaphane is and what it is used for

Protaphane is human insulin with a gradual onset of action and prolonged duration.
Protaphane is used to reduce high blood sugar levels in patients with diabetes mellitus (diabetes).
Diabetes is a disease in which the body does not produce enough insulin to control blood sugar levels.
Treatment with Protaphane helps prevent complications of diabetes.
Protaphane begins to lower blood sugar levels about one and a half hours after injection, and its effect lasts for approximately 24 hours. Protaphane is often administered in combination with rapid-acting insulin preparations.

2. What you should know before using Protaphane

Do not use Protaphane
► If you are allergic to human insulin or to any of the other excipients of this medicine,
see section 6.
► If you experience warning signs of hypoglycemia (low blood sugar),
see the Summary of serious and very common side effects in section 4.
► In insulin infusion pumps.
► If the FlexPen is leaking, damaged, or cracked.
► If it has not been stored correctly or has been frozen, see section 5.
► If the resuspended insulin does not appear uniformly white and cloudy.
Do not use Protaphane if any of these situations apply. Speak to your doctor, pharmacist, or nurse
for advice.

Before using Protaphane
► Check the label to make sure you are using the correct type of insulin.
► Always use a new needle for each injection to prevent contamination.
► Needles and Protaphane FlexPen must not be shared.
► Protaphane FlexPen is intended only for subcutaneous injection. Speak to your doctor if you need
to administer insulin by another route.

Warnings and precautions
Certain conditions and activities may affect your insulin requirements. Consult your doctor:
► If you have kidney or liver problems, or disorders of the adrenal glands, pituitary, or thyroid.
► If you increase your physical activity or change your usual diet, as this may affect your blood sugar levels.
► If you become ill, continue your insulin therapy and consult your doctor.
► If you plan to travel abroad: traveling across different time zones may alter your insulin requirements and timing.

Skin changes at the injection site
Rotate your injection sites to help prevent changes in the fatty tissue under the skin, such as thickening or thinning of the skin, or the appearance of lumps under the skin.
Insulin may not work as effectively if injected into an area with lumps, thinning, or thickening of the skin (see section 3). Inform your doctor if you notice any skin changes at the injection site. If you currently inject into one of these affected areas, consult your doctor before switching to another site. Your doctor may advise you to monitor your blood glucose more closely and possibly adjust your insulin dose or that of other antidiabetic medicines.

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

Other medicines for the treatment of diabetes
Monoamine oxidase inhibitors (MAOIs) (used to treat depression)
Beta-blockers (used to treat high blood pressure)
Angiotensin-converting enzyme (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 fluid retention)
Glucocorticoids (such as "cortisone" used to treat inflammation)
Thyroid hormones (used to treat thyroid gland disorders)
Sympathomimetics (such as epinephrine [adrenaline], salbutamol, or terbutaline, used to treat asthma)
Growth hormone (a medicine used to stimulate skeletal and somatic growth and that significantly affects the body's metabolic processes)
Danazol (a medicine that affects ovulation)

Pioglitazone (tablets used to treat type 2 diabetes mellitus)
Some patients with long-standing type 2 diabetes mellitus and with heart problems or a history of stroke who were treated with pioglitazone and insulin have developed heart failure.
Inform your doctor immediately if you experience signs of heart failure such as unusual shortness of breath, rapid weight gain, or localized swelling (edema).
If you are taking any of the medicines listed above, inform your doctor, pharmacist, or nurse.

Protaphane and alcohol
► If you consume alcohol, your insulin requirement may change because blood sugar levels may increase or decrease. Careful monitoring is recommended.

Pregnancy and breastfeeding
► If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor before taking this medicine. Protaphane can be used during pregnancy. Dose adjustments may be necessary during pregnancy and after delivery. It is important to carefully control diabetes, particularly to prevent episodes of hypoglycemia, for the health of both mother and child.
► There are no restrictions on the use of Protaphane during breastfeeding.
Consult your doctor, pharmacist, or nurse before taking any medicine during pregnancy or breastfeeding.

Driving and using machines
► Consult your doctor about whether it is safe for you to drive or operate machinery:

If you have frequent episodes of hypoglycemia.
If you have difficulty recognizing the warning signs of hypoglycemia.

High or low blood sugar levels may impair your concentration and reaction ability, and therefore your ability to drive or operate machinery. Be aware that this could endanger yourself or others.

Protaphane contains sodium
Protaphane contains less than 1 mmol of sodium (23 mg) per dose, i.e., Protaphane is essentially “sodium-free”.

3. How to use Protaphane

Dose and when to take insulin
Always use insulin and adjust the dose as prescribed by your doctor. If you are unsure, consult your doctor, pharmacist, or nurse.
Do not change your insulin unless your doctor tells you to do so. If your doctor changes the type or brand of insulin you are using, your dose may need to be adjusted by your doctor.

Use in children and adolescents
Protaphane can be used in children and adolescents.

Use in specific patient groups
If you have kidney or liver impairment, or if you are over 65 years old, your blood sugar levels should be monitored regularly and you should discuss insulin dose adjustments with your doctor.

How to inject with Protaphane FlexPen
Protaphane FlexPen is a pre-filled pen containing human isophane insulin (NPH).
Carefully read the Instructions for Use for Protaphane FlexPen included in this package leaflet. You must use the pen exactly as described in the Instructions for Use for Protaphane FlexPen.
Always make sure you are using the correct pen before injecting your insulin.

If you take more insulin than you should
If you take too much insulin, your blood sugar level will drop too low (hypoglycaemia). See Summary of serious and very common side effects in section 4.

If you forget to take insulin
If you forget to take your insulin, your blood sugar level will become too high (hyperglycaemia). See Effects of diabetes in section 4.

If you stop using insulin
Do not stop treatment with insulin without first talking to your doctor, who will advise you on what to do. Stopping insulin treatment may lead to high blood sugar levels (severe hyperglycaemia) and ketoacidosis. See Effects of diabetes in section 4.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Summary of serious and very common side effects
Low blood sugar level (hypoglycaemia) is a very common side effect. It may occur in more than 1 in 10 people.
You may experience low blood sugar if:

You inject too much insulin.
You eat too little or skip meals.
You do more physical activity than usual.
You consume alcohol; see Protaphane with alcohol in section 2.

Warning signs of low blood sugar: cold sweating; cold, pale skin; headache; rapid heartbeat; feeling unwell; hunger; temporary visual disturbances; drowsiness; unusual tiredness and weakness; nervousness or trembling; anxiety; confusion; difficulty concentrating.
Severe hypoglycaemia can lead to loss of consciousness. If severe prolonged hypoglycaemia is not treated, it can cause brain damage (transient or permanent) up to death. You may regain consciousness more quickly with an injection of the hormone glucagon administered by trained personnel who know how to use it. If glucagon is administered to you, you will need glucose or a sweet snack as soon as you regain consciousness. If you do not respond to glucagon treatment, you must be taken to hospital.
What to do if blood sugar is low:
► If blood sugar is too low, eat sugar lumps or another sugary snack (candies, biscuits, fruit juice). Measure your blood sugar if possible, then rest. Always carry sugar lumps, candies, biscuits, or fruit juice with you to use in case of need.
► When symptoms of hypoglycaemia have disappeared or when your blood glucose has stabilized, continue your insulin treatment.
► If you have low blood sugar, you may lose consciousness. If you required a glucagon injection, or if you have frequent episodes of low blood sugar, consult your doctor. Dose adjustment and timing of insulin, food intake, and physical activity may be necessary.
Inform people close to you that you are diabetic and explain the possible consequences, including the risk of fainting due to hypoglycaemia. Explain that if you faint, they should turn you onto your side and immediately call for medical help. It is important not to give you food or drink as you could choke.
Severe allergic reaction to Protaphane or one of its excipients (called systemic allergic reaction) is a rare side effect but can be potentially life-threatening. It may occur in fewer than 1 in 10,000 people.
Contact your doctor immediately:

if signs of allergy spread to other parts of the body.
if you suddenly feel unwell, and: start sweating; feel sick (vomiting); have difficulty breathing; your heartbeat becomes rapid; you feel dizzy. ► If you notice any of these signs, contact your doctor immediately.

Skin changes at the injection site: If you inject insulin in the same spot repeatedly, fatty tissue may thin (lipoatrophy) or thicken (lipohypertrophy) (may affect fewer than 1 in 100 people). Lumps under the skin may also be caused by the buildup of a protein called amyloid (cutaneous amyloidosis; frequency is unknown). Insulin may not work as effectively if injected into an area with lumps, thinning, or thickening. Change your injection site with each injection to prevent these skin changes.
List of other side effects
Uncommon side effects
May affect fewer than 1 in 100 people.
Signs of allergy: Local allergic reactions (pain, redness, hives, inflammation, bruising, swelling, or itching at the injection site). These symptoms usually disappear within a few weeks of treatment. If symptoms do not disappear or spread to other parts of the body, consult your doctor. See also Severe allergic reaction.
Diabetic retinopathy (a diabetes-related eye disorder that may lead to vision loss): if you have diabetic retinopathy and your blood glucose improves very rapidly, the retinopathy may worsen. Consult your doctor for further information.
Swollen joints: at the beginning of insulin treatment, fluid retention may cause swelling around the ankles and other joints. This is usually a temporary phenomenon that soon resolves. If not, contact your doctor.
Very rare side effects
May affect fewer than 1 in 10,000 people.
Visual disturbances: visual disturbances may occur at the beginning of insulin treatment, but this is generally a temporary reaction.
Painful neuropathy (pain due to nerve damage): if blood glucose improves very rapidly, it may cause pain originating in the nerve fibers. This is known as acute painful neuropathy and is usually transient.
Reporting of side effects
If you get any side effects, inform your doctor, pharmacist, or nurse. This includes any side effect not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.
Other effects of diabetes
High blood sugar level (hyperglycaemia)
You may have high blood sugar if:

You have not injected enough insulin.
You forgot to take insulin or stopped taking it.
You repeatedly take less insulin than needed.
You have an infection or fever.
You eat more than usual.
You do less physical activity than usual.

Warning signs of high blood sugar:
Warning signs appear gradually. They include: increased urination; thirst; loss of appetite; feeling unwell (nausea or vomiting); drowsiness or tiredness; dry, flushed skin; dry mouth and fruity breath (acetone).
What to do if blood sugar is high:
► If you experience any of these symptoms: check your blood glucose, if possible check for ketones in your urine, and contact a doctor immediately.
► These may be symptoms of a very serious condition called diabetic ketoacidosis (build-up of acid in the blood because the body is metabolizing fat instead of sugar).
If left untreated, it could lead to diabetic coma and possibly death.

5. How to store Protaphane

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 FlexPen label and on the
packaging after 'EXP'. The expiry date refers to the last day of the month.
Before opening: store in a refrigerator at 2°C - 8°C. Keep away from cooling elements.
Do not freeze.
During use or when carried as a spare: do not refrigerate or freeze. It may be carried with you
and stored at room temperature (below 30°C) for up to 6 weeks.
Always keep the pen cap on the FlexPen when not in use to protect it from light.
Dispose of the needle after each injection.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. This will help protect the environment.

6. Package Contents and Other Information

What Protaphane Contains

The active substance is insulin. Protaphane is an isophane (NPH) suspension of human insulin. Each ml contains 100 IU of human insulin. Each pre-filled pen contains 300 IU of human insulin in 3 ml of injectable suspension.
The other excipients are zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate, sodium hydroxide, hydrochloric acid, protamine sulfate, and water for injections.

Description of the Appearance of Protaphane and Contents of the Package
Protaphane is a white, opaque suspension for injection. After resuspension, the liquid will appear uniformly white and cloudy.
Pack sizes: 1, 5, and 10 pre-filled pens of 3 ml. Not all pack sizes may be marketed.
The suspension is aqueous, white, and cloudy.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark

Manufacturer
The manufacturer can be identified by the batch number printed on the carton flap and on the label:

If the second and third characters are S6, P5, K7, R7, VG, FG or ZF, the manufacturer is Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark
If the second and third characters are H7 or T6, the manufacturer is Novo Nordisk Production SAS, 45 Avenue d’Orleans, F-28000 Chartres, France.

This leaflet was last updated on
Further Information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/.
For instructions on how to use your FlexPen, please turn the page.
Instructions for using Protaphane injectable suspension in FlexPen.
Read these instructions carefully before using your FlexPen. If you do not follow these instructions exactly, you may inject too much or too little insulin, which could lead to blood sugar levels that are too high or too low.
The FlexPen is a pre-filled insulin pen for variable dose administration. You can select a dose between 1 and 60 units in 1-unit increments. The FlexPen has been designed and tested for use with NovoFine or NovoTwist disposable needles up to 8 mm in length.
As a precaution, always carry a spare insulin delivery device in case your FlexPen is lost or damaged.

Technical diagram of a blue and transparent injection pen with cap, separated components, and reference lines for device parts

Cannot generate alternative text because the

Pen Maintenance
Handle your FlexPen with care. If it leaks or has been dropped, it may be damaged and insulin may be lost. This could lead to incorrect dosing, which may result in blood sugar levels that are too high or too low.
You may clean the outside of your FlexPen with a disinfectant wipe. Do not immerse, wash, or lubricate the pen, as this may damage the mechanism.
Do not refill your FlexPen. Once empty, it must be discarded.

Preparing Protaphane FlexPen
A
Check the name and the colored label on your pen to make sure it contains the correct type of insulin. This is very important if you use more than one type of insulin. If you inject the wrong type of insulin, your blood sugar level may become too high or too low.
Each time you use a new pen,
Allow the insulin to reach room temperature before use. This makes resuspension easier. Remove the pen cap (see A).

A hand grasping and pulling to the right the upper part of a blue and white cylindrical medical device, indicated by a blue arrow

B
Before each injection with a new FlexPen, you must resuspend the insulin:
Move the pen up and down 20 times as shown, ensuring the glass ball moves from one end of the cartridge to the other. Repeat this procedure until the liquid appears uniformly white and cloudy.
For each subsequent injection, move the pen up and down at least 10 times until the liquid appears uniformly white and cloudy.
Always resuspend the insulin before each injection. This reduces the risk of high or low blood sugar levels. After resuspension, proceed quickly with the following steps.

Blue illustration showing an arm rotating an injection pen from a horizontal to a vertical position following a curved arrow

Always check that there are at least 12 units of insulin remaining in the cartridge after resuspension. If there are fewer than 12 units, use a new FlexPen. 12 units are indicated on the scale. See the large figure at the top of the instructions.
Do not use the pen if the resuspended insulin does not appear uniformly white and cloudy.

Attaching the Needle
C
Remove the protective seal from a new disposable needle.
Screw the needle firmly and perpendicularly onto your FlexPen.

Technical illustration of a hand rotating the upper part of a medical injection pen upward

D
Remove the outer needle cap and keep it for later use.

Technical illustration showing a hand rotating the upper part of an injection pen to the right following the direction of a blue arrow

E
Remove the inner needle cap and discard it.
Never try to reinsert the inner needle cap onto the needle, as you may injure yourself.

A hand holding an injection pen and pushing it forward toward the skin following the direction indicated by a thick blue arrow

Always use a new needle for each injection. This reduces the risk of contamination, infection, insulin leakage, needle blockage, and incorrect dosing.
Be careful not to bend or damage the needle before use.

Checking Insulin Flow
F
During normal use, small amounts of air may accumulate in the cartridge before each injection. Before each injection, to ensure you are injecting insulin and to deliver the correct dose:
Turn the dose selector to 2 units.

A hand rotating the dial of a blue medical device to adjust the dosage, with an inset showing the number 2 on the display

G
Hold the FlexPen with the needle pointing upward and gently tap the cartridge several times with your finger so that air bubbles collect at the top of the cartridge.

Blue technical drawing of a hand holding a medical device with an exposed needle next to vibration or signal symbols

H
With the needle pointing upward, press the injection button fully. The dose selector will return to 0.
A drop of insulin should appear at the tip of the needle. If it does not, change the needle and repeat the procedure no more than 6 times.
If no drop appears after 6 attempts, the pen is defective and you must use a new one.

Medical illustration showing a hand holding a blue and green device with an arrow pointing upward

Always ensure a drop appears at the needle tip before injecting. This ensures insulin is flowing. If no drop appears, you will not inject insulin, even if the dose selector moves. This may indicate a blocked or damaged needle.
Always check the flow before injecting. If you do not check the flow, you may inject too little insulin or none at all, which could lead to high blood sugar levels.

Selecting the Dose
I
Ensure the dose selector is at 0.
Turn the dose selector to select the number of units to be injected.
You can increase or decrease the dose by turning the selector in either direction until the correct dose is aligned with the indicator. While turning the dose selector, be careful not to press the injection button, as this may cause insulin to leak.
You cannot select a dose greater than the number of units remaining in the cartridge.

Two hands holding a blue injection pen with an arrow indicating rotation of the dial to adjust the dosage between 4 and 26 units

Before injecting insulin, always use the dose selector and indicator to confirm how many units have been selected.
Do not count the clicks of the pen. If you select and inject the wrong dose, your blood sugar level may become too high or too low. Do not use the scale on the pen, which only approximately indicates how much insulin remains in the pen.

Injection
J
Insert the needle into the skin. Use the injection technique shown by your doctor or nurse.
Administer the insulin dose by pressing the injection button fully until the indicator reaches 0. Make sure to press only the button.
Rotating the dose selector will not inject insulin.

A hand pressing the green cap of a blue vial downward, indicated by a downward arrow, with a close-up detail of the dosage marked on the container

K
Keep the injection button fully pressed and leave the needle under the skin for at least 6 seconds. This ensures complete delivery of the dose.
Remove the needle from the skin and release pressure on the injection button.
Always ensure the dose selector returns to 0 after injection. If the dose selector stops before reaching 0, the full dose has not been delivered, which may result in high blood sugar levels.

Technical illustration of a pre-filled syringe placed vertically above a flat surface, indicating the tip of the

L
Place the needle tip into the outer needle cap without touching the cap. Once covered, press the outer cap firmly and then unscrew the needle.
Dispose of the used needle carefully and replace the pen cap.

Two illustrations showing how to connect and disconnect a medical device using lateral movements indicated by dark blue arrows

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

Other Important Information
Anyone caring for you should handle used needles with extreme care to reduce the risk of needle-stick injuries and cross-infections.
Dispose of used FlexPens carefully, ensuring the needle has been removed.
Never share your pen or needles with other people. This could lead to cross-infections.
Never share your pen with other people. The medicine may be harmful to their health.
Always keep the pen and needles out of sight and reach of others, especially children.