Signifor

Package leaflet: Information for the user

Signifor 0.3 mg solution for injection, 0.6 mg solution for injection, 0.9 mg solution for injection

pasireotide
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, nurse, or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any adverse reaction, including those not listed in this leaflet, talk to your doctor, nurse, or pharmacist. See section 4.

Contents of this leaflet

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

1. What Signifor is and what it is used for

Signifor is a medicine containing the active substance pasireotide. It is used to treat Cushing's disease in adult patients for whom surgery is not indicated or has proven ineffective.
Cushing's disease is caused by enlargement of the pituitary gland (a gland at the base of the brain), called a pituitary adenoma. This leads to excessive production of a hormone called adrenocorticotropic hormone (ACTH), which in turn results in overproduction of another hormone called cortisol.
The human body naturally produces a substance called somatostatin, which inhibits the production of certain hormones, including ACTH. Pasireotide works in a very similar way to somatostatin.
Therefore, Signifor is able to inhibit the production of ACTH, helping to control cortisol overproduction and improve the symptoms of Cushing's disease.
If you have any questions about how Signifor works or why this medicine has been prescribed for you, please consult your doctor.

2. What you should know before using Signifor

Do not use Signifor

• if you are allergic to pasireotide or to any of the other ingredients of this medicine (listed in section 6);
• if you have severe liver problems.

Warnings and precautions
Talk to your doctor before using Signifor if you currently have or have ever had:

• problems with blood sugar levels, either too high (such as hyperglycaemia/diabetes) or too low (hypoglycaemia);
• heart problems such as a recent heart attack, congestive heart failure (a type of heart disease in which the heart cannot pump blood adequately throughout the body), or sudden, severe chest pain (typically felt as pressure, heaviness, tightness, squeezing, or persistent pain in the chest);
• a heart rhythm disorder, such as irregular heartbeat or an abnormal electrical signal called "prolongation of the QT interval", or "QT prolongation";
• low levels of potassium or magnesium in the blood;
• gallstones.

During treatment with Signifor

• Signifor controls excessive cortisol production. This control may become excessive and signs or symptoms associated with cortisol deficiency may occur, such as extreme weakness, fatigue, weight loss, nausea, vomiting, or low blood pressure. If this happens, inform your doctor immediately.
• Signifor may cause increased blood sugar levels. Your doctor may decide to monitor your blood sugar and may start or adjust your antidiabetic therapy.
• Signifor may reduce your heart rate. Your doctor may decide to monitor your heart rate using a device that measures heart activity (an "ECG", or electrocardiogram). If you are taking medicines for heart conditions, your doctor may consider adjusting their dosage.
• Your doctor may also decide to periodically monitor gallstones, liver enzymes, and pituitary hormones, as all of these may be affected by this medicine.

Children and adolescents
This medicine must not be used in children and adolescents under 18 years of age, as there are no available data in this age group.
Other medicines and Signifor
Signifor may interact with the way other medicines work. If you are taking other medicines at the same time as Signifor (including medicines without a prescription), your doctor may need to monitor your heart very closely or adjust the dose of Signifor or the other medicines. Inform your doctor or pharmacist if you are using, have recently used, or might use any other medicine. In particular, inform your doctor if you are taking:

• medicines to treat irregular heartbeat, such as those containing disopyramide, procainamide, quinidine, sotalol, dofetilide, ibutilide, amiodarone, or dronedarone;
• medicines to treat bacterial infections (oral: clarithromycin, moxifloxacin; injectable: erythromycin, pentamidine);
• medicines to treat fungal infections (ketoconazole, except in shampoo);
• medicines to treat certain psychiatric disorders (chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, tiapride, amisulpride, sertindole, methadone);
• medicines to treat hay fever and other allergies (terfenadine, astemizole, mizolastine);
• medicines used for prevention or treatment of malaria (chloroquine, halofantrine, lumefantrine);
• medicines to control blood pressure such as:
  • beta-blockers (metoprolol, carteolol, propranolol, sotalol);
  • calcium channel blockers (bepridil, verapamil, diltiazem);
  • cholinesterase inhibitors (rivastigmine, physostigmine);
• medicines to control the balance of electrolytes in the body (potassium, magnesium).

It is particularly important to mention the following medicines:

• cyclosporine (used in organ transplantation to reduce immune system activity);
• medicines to control blood sugar levels when they are too high (as in diabetes) or too low (hypoglycaemia), including:
  • insulin;
  • metformin, liraglutide, vildagliptin, nateglinide (antidiabetic medicines).

Pregnancy, breastfeeding and fertility
Ask your doctor or pharmacist for advice before taking any medicine.

• You must not use Signifor during pregnancy unless strictly necessary. If you are pregnant or think you may be pregnant, it is important to inform your doctor, who will evaluate with you whether using Signifor during pregnancy is appropriate.
• You must not breastfeed while using Signifor. It is not known whether Signifor passes into breast milk.
• If you are a woman of childbearing potential, you must use a contraceptive method during treatment. Ask your doctor about the need for contraception before taking this medicine.

Driving and using machines
Signifor may have a minor effect on the ability to drive vehicles or operate machinery, because some of the side effects that may occur during treatment with Signifor—such as dizziness, headache, and fatigue—may reduce your ability to drive or operate machinery safely.
Important information about some of the excipients of Signifor
Signifor contains less than 1 mmol (23 mg) of sodium per dose, i.e. it is practically "sodium-free".

3. How to use Signifor

Use this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor or pharmacist. This medicine comes in a vial, which is a small glass container.

How much Signifor to use
The recommended dose is one vial of Signifor 0.6 mg twice daily. Taking Signifor at the same time each day will help you remember when to take the medicine. After you have started treatment, your doctor may decide to increase your dose to one vial of Signifor 0.9 mg twice daily.

If you experience side effects, your doctor may temporarily reduce the dose to 0.3 mg per injection.

If you have liver disease before starting treatment with Signifor, your doctor may decide to start treatment with a dose of one vial of Signifor 0.3 mg twice daily.

Vials of Signifor are available in different strengths (0.3 mg, 0.6 mg and 0.9 mg) to meet the specific dose prescribed by your doctor.

Your doctor will regularly monitor your response to treatment with Signifor and determine the best dose for you.

How to use Signifor
Your doctor or nurse will teach you how to self-administer the injection with Signifor. It is also recommended that you read the instructions at the end of this leaflet. If you have any questions, ask your doctor, nurse or pharmacist.

Signifor is for subcutaneous use. This means it is injected through a short needle into the fatty tissue under the skin. The thighs and abdomen are suitable injection sites. To help avoid pain and skin irritation, choose a different injection site each time. You should also avoid injecting into areas that are tender or where the skin is irritated.

Do not use Signifor if you notice that the solution is not clear or contains particles. The solution should be free from visible particles, clear and colourless.

How long to use Signifor
You must continue using Signifor for the length of time prescribed by your doctor.

If you use more Signifor than you should
If you accidentally use more Signifor than prescribed by your doctor, contact your doctor, nurse or pharmacist immediately.

If you forget to use Signifor
Do not inject a double dose of Signifor to make up for a forgotten dose. If you forget to inject a dose of Signifor, simply inject the next dose at the scheduled time.

If you stop using Signifor
If you stop treatment with Signifor, cortisol levels may rise again and symptoms may worsen. Therefore, do not stop using Signifor unless your doctor tells you to.

If you have any questions about how to use this medicine, consult your doctor, nurse or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Some side effects may be serious. Immediately inform your doctor if you experience any of the
following:
Very common (may affect more than 1 in 10 people)

• Changes in blood sugar levels. Symptoms may include excessive thirst, increased urination, increased appetite with weight loss, fatigue, nausea, vomiting, abdominal pain.
• Gallstones or associated complications. Symptoms may include fever, chills, yellowing of the skin/eyes, back pain or pain in the right side of the abdomen.
• Excessive tiredness.

Common (may affect up to 1 in 10 people)

• Low cortisol levels. Symptoms may include excessive tiredness, weakness, weight loss, nausea, vomiting, and low blood pressure.
• Slow heart rate.
• Low blood pressure. Symptoms may include dizziness, lightheadedness, vertigo, or fainting when standing up.
• Problems with bile flow (cholestasis). Symptoms may include yellowing of the skin, dark urine, pale stools, and itching.
• Inflammation of the gallbladder (cholecystitis).

Other side effects of Signifor may include:
Very common (may affect more than 1 in 10 people)

• Diarrhoea
• Nausea
• Stomach pain
• Pain at the injection site

Common (may affect up to 1 in 10 people)

• Prolongation of the QT interval (an abnormal electrical signal in the heart that can be seen on tests)
• Loss of appetite
• Vomiting
• Headache
• Dizziness
• Hair loss
• Itching
• Muscle pain (myalgia)
• Joint pain (arthralgia)
• Abnormal liver function test results
• Abnormal pancreatic function test results
• Abnormal blood coagulation parameters

Uncommon (may affect up to 1 in 100 people)

• Low levels of red blood cells (anaemia)

Not known (frequency cannot be estimated from the available data)

• Increased levels of ketone bodies (a group of substances produced in the liver) in urine or blood (diabetic ketoacidosis) as a complication of increased blood sugar levels. Symptoms may include fruity-smelling breath, difficulty breathing, and confusion.
• Oily or fatty stools
• Altered stool colour

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

5. How to store Signifor

• 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 label of the vial and on the carton after “EXP” or “Scad”. The expiry date refers to the last day of that month.
• Store in the original packaging to protect the medicine from light.
• Do not dispose of any medicine 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 Signifor contains

• The active substance is pasireotide.
  Signifor 0.3 mg: One 1 ml vial of solution contains 0.3 mg of pasireotide (as pasireotide diacetate).
  Signifor 0.6 mg: One 1 ml vial of solution contains 0.6 mg of pasireotide (as pasireotide diacetate).
  Signifor 0.9 mg: One 1 ml vial of solution contains 0.9 mg of pasireotide (as pasireotide diacetate).
• The other components are mannitol, tartaric acid, sodium hydroxide and water for injections.

Description of the appearance of Signifor and contents of the pack
Signifor injectable solution is a clear, colourless solution in a vial. Each vial contains 1 ml of injectable solution.
Signifor is available in packs containing 6 vials or in multiple packs containing 18 (3 packs of 6), 30 (5 packs of 6) or 60 (10 packs of 6) vials.
It is possible that not all strengths or pack sizes are marketed.

Marketing Authorisation Holder
Recordati Rare Diseases
Tour Hekla
52 avenue du Général de Gaulle
92800 Puteaux
France

Manufacturer
Recordati Rare Diseases
Tour Hekla
52 avenue du Général de Gaulle
92800 Puteaux
France
Recordati Rare Diseases
Eco River Parc
30 rue des Peupliers
92000 Nanterre
France

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Recordati
Tél/Tel: +32 2 46101 36
Tel: +46 8 545 80 230
Švedija

България Luxembourg/Luxemburg
Recordati Rare Diseases
Tel: +33 (0)1 47 73 64 58
Tél/Tel: +32 2 46101 36
France Belgique/Belgien

Česká republika Magyarország
Recordati Rare Diseases
Tel: +33 (0)1 47 73 64 58
Tel: +33 (0)1 47 73 64 58
France Franciaország

Danmark Malta
Recordati AB
Tlf.: +46 8 545 80 230
Tel: +33 1 47 73 64 58
Sverige Franza

Deutschland Nederland
Recordati Rare Diseases Germany GmbH
Tel: +49 731 140 554 0
Tel: +32 2 46101 36
België

Eesti Norge
Recordati AB
Tel: +46 8 545 80 230
Tlf: +46 8 545 80 230
Rootsi Sverige

Ελλάδα Österreich
Recordati Hellas
Τηλ: +30 210 6773822
Recordati Rare Diseases Germany GmbH
Tel: +49 731 140 554 0
Deutschland

España Polska
Recordati Rare Diseases Spain S.L.U.
Tel: +34 91 659 28 90
Recordati Rare Diseases
Tel: +33 (0)1 47 73 64 58
Francja

France Portugal
Recordati Rare Diseases
Tél: +33 (0)1 47 73 64 58
Recordati Rare Diseases SARL
Tel: +351 21 432 95 00

Hrvatska România
Recordati Rare Diseases
Tél: +33 (0)1 47 73 64 58
Recordati Rare Diseases
Tel: +33 (0)1 47 73 64 58
Francuska Franţa

Ireland Slovenija
Recordati Rare Diseases
Tél: +33 (0)1 47 73 64 58
Tel: +33 (0)1 47 73 64 58
France Francija

Ísland Slovenská republika
Recordati AB
Simi: +46 8 545 80 230
Recordati Rare Diseases
Tel: +33 (0)1 47 73 64 58
Svíþjóð Francúzsko

Italia Suomi/Finland
Recordati Rare Diseases Italy Srl
Tel: +39 02 487 87 173
Recordati AB
Puh/Tel: +46 8 545 80 230
Sverige

Κύπρος Sverige
Recordati Rare Diseases
Τηλ: +33 1 47 73 64 58
Recordati AB
Tel: +46 8 545 80 230
Γαλλία

Latvija
Recordati AB
Tel: +46 8 545 80 230
Zviedrija

Further information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu. Links to other websites on rare diseases and their treatments are also provided.

INSTRUCTIONS FOR USE OF SIGNIFOR INJECTABLE SOLUTION

This medicine is contained in a vial, a small glass container. Signifor must be administered using a sterile disposable syringe and injection needles.
Your doctor or nurse will teach you how to use Signifor vials. However, before using the vial, please read the following information carefully. If you are unsure about how to perform the self-injection or have any doubts, consult your doctor or nurse.
The injection can be prepared either by using two different needles—one for drawing up the solution and another for injecting—or by using a single short, thin needle for both steps. Your doctor or nurse will advise you which method to use. Please follow their instructions.
Store Signifor vials according to the storage conditions described on the carton.

Important safety information
Warning: Keep vials out of the reach of children.

What you need
To perform the self-injection, you will need:

1. One vial of Signifor
2. An alcohol swab or similar
3. One sterile syringe
4. One sterile, long, thick, blunt needle for drawing up the solution (your doctor or nurse will advise if needed)
5. One sterile, short, thin needle
6. A sharps container or another rigid, closed container for disposal

Injection site
The injection site is the area on the body where the injection is given. Signifor is for subcutaneous use. This means it must be injected into the fatty tissue beneath the skin using a short needle. The thighs and abdomen are suitable areas for subcutaneous injection. To avoid pain and skin irritation, choose a different site for each injection compared to the previous one. Avoid injecting into areas that are tender or where the skin is irritated.

Getting started
When you are ready to perform the self-injection, carefully follow the steps below:

• Wash your hands thoroughly with soap and water.
• Use new, sterile disposable syringes and needles for each injection. Never use a syringe or needle more than once. Never share needles or syringes.
• Remove the vial from the carton.
• Inspect the vial. DO NOT USE if it is broken or if the liquid appears cloudy or contains particles. In any of these cases, return the entire pack to the pharmacy.

To reduce local discomfort, it is recommended to bring the solution to room temperature before administration.
Vials should be opened only immediately before use, and any unused portion must be discarded.

Check the expiry date and dose
Check the expiry date printed on the vial label (after “EXP”) and ensure the vial contains the dose prescribed by your doctor.
DO NOT USE if the medicine is expired or if the dose is incorrect. In either case, return the entire pack to the pharmacy.

How to inject Signifor

Step 1:
Signifor injectable solution is contained in a break-open vial. The coloured mark on the top indicates the break line on the neck of the vial. Tap the vial gently with your fingers to ensure no liquid remains in the upper part where it will be opened.

Step 2:
Recommended procedure: Hold the vial vertically with the coloured mark facing you. Hold the base of the vial in one hand. Place one thumb above and one below the neck of the vial, and snap off the top at the break line. Once opened, place the vial upright on a clean, flat surface.

Step 3:
Take the sterile syringe and attach the needle. If you have been instructed to use two needles, use the long, thick, blunt needle for this step.
Before proceeding to Step 4, clean the injection site with an alcohol swab.

Step 4:
Remove the cap from the needle. Insert the needle into the vial and pull back the plunger to draw the entire contents of the vial into the syringe.
If you have been instructed to use two needles, you must now replace the long needle with the short one.

Step 5:
Hold the syringe in one hand between two fingers, with your thumb on the base of the plunger. Tap the syringe gently with your fingers to remove any air bubbles.
Ensure there are no air bubbles in the syringe by pushing the plunger gently until a small drop of liquid appears at the tip of the needle.
Do not allow the needle to touch any surface. You are now ready for injection.

Step 6:
Gently pinch the skin at the injection site and, holding the needle at an angle of approximately 45 degrees (as shown in the figure), insert it into the injection site.
Gently pull back on the plunger to check whether a blood vessel has been punctured. If you see blood in the syringe, first remove the needle from the skin, then replace the short needle with a new one, and inject at a different site.

Step 7:
While continuing to hold the skin pinched, slowly push the syringe plunger all the way down to inject the full dose. Keep pressing on the plunger and maintain the syringe in position for 5 seconds.

Step 8:
Slowly release the pinched skin and gently withdraw the needle. Replace the cap on the needle.

Step 9:
Immediately dispose of the used syringe and needle in a sharps container or another rigid, closed container. Any unused product or waste must be disposed of in accordance with local regulations.

Package leaflet: information for the user

Signifor 10 mg powder and solvent for injectable suspension, 20 mg powder and solvent for injectable suspension, 40 mg powder and solvent for injectable suspension, 60 mg powder and solvent for injectable suspension

pasireotide
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, nurse or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor, nurse or pharmacist. See section 4.

Contents of this leaflet

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

1. What Signifor is and what it is used for

Signifor is a medicine that contains the active substance pasireotide. It is used for the treatment of acromegaly in adults. It is also used for the treatment of Cushing’s disease in adults for whom surgery is not indicated or has proven ineffective.

Acromegaly
Acromegaly is caused by a type of tumour called a pituitary adenoma that develops in the pituitary gland (at the base of the brain). The adenoma causes excessive production of hormones that control the growth of tissues, organs, and bones, resulting in an increase in the size of bones and tissues, especially in the hands and feet.
Signifor reduces the production of these hormones and may also reduce the size of the adenoma. As a result, it reduces the symptoms of acromegaly, which include headache, increased sweating, numbness in the hands and feet, fatigue, and joint pain.

Cushing’s disease
Cushing’s disease is caused by enlargement of the pituitary gland (a gland at the base of the brain) called a pituitary adenoma. This causes excessive production of a hormone called adrenocorticotropic hormone (ACTH), which in turn leads to overproduction of another hormone called cortisol.
The human body naturally produces a substance called somatostatin, which inhibits the production of certain hormones, including ACTH. Pasireotide works in a way very similar to somatostatin.
Signifor is therefore able to block the production of ACTH, helping to control the overproduction of cortisol and improve the symptoms of Cushing’s disease.

If you have any questions about how Signifor works or why this medicine has been prescribed for you, please consult your doctor.

2. What you need to know before using Signifor

Do not use Signifor

• if you are allergic to pasireotide or to any of the other ingredients of this medicine (listed in section 6).
• if you have severe liver problems.

Warnings and precautions
Talk to your doctor before using Signifor if you currently have or have ever had:

• problems with blood sugar levels, either too high (such as hyperglycaemia/diabetes) or too low (hypoglycaemia);
• heart problems such as a recent heart attack, congestive heart failure (a type of heart disease in which the heart cannot pump blood sufficiently throughout the body), or sudden, severe chest pain (usually felt as pressure, heaviness, tightness, constriction, or persistent pain in the chest);
• a heart rhythm disorder, such as irregular heartbeat or an abnormal electrical signal called “prolongation of the QT interval”, or “QT prolongation”;
• low levels of potassium or magnesium in the blood;
• gallstones;
• or if you are taking anticoagulants (medicines used to reduce the blood’s ability to clot), your doctor will monitor your blood clotting parameters and may adjust the dose of your anticoagulant.

During treatment with Signifor:

• Signifor may cause an increase in blood sugar levels. Your doctor may decide to monitor your blood sugar and may start or adjust your antidiabetic therapy.
• Signifor controls the overproduction of cortisol. This control may be excessive, leading to signs or symptoms associated with cortisol deficiency, such as extreme weakness, fatigue, weight loss, nausea, vomiting, or low blood pressure. If this occurs, inform your doctor immediately.
• Signifor may lower your heart rate. Your doctor may decide to monitor your heart rate using a device that measures heart activity (an “ECG”, or electrocardiogram). If you are taking medicines for heart conditions, your doctor may consider adjusting their doses.
• Your doctor may also periodically monitor gallstones, liver enzymes, and pituitary hormones, as all of these may be affected by this medicine.

Children and adolescents
This medicine must not be used in children and adolescents under 18 years of age, as there are no available data in this age group.
Other medicines and Signifor
Signifor may interact with other medicines. If you are taking other medicines at the same time as Signifor (including non-prescription medicines), your doctor may need to monitor your heart very closely or adjust the dose of Signifor or the other medicines. Inform your doctor or pharmacist if you are using, have recently used, or might use any other medicine. In particular, inform your doctor if you are taking:

• medicines used in organ transplantation to reduce immune system activity (cyclosporine);

• medicines to treat high or low blood sugar levels (such as in diabetes or hypoglycaemia), such as:

  • insulin
  • metformin, liraglutide, vildagliptin, nateglinide (antidiabetic medicines);

• medicines to treat irregular heartbeat, such as those containing disopyramide, procainamide, quinidine, sotalol, dofetilide, ibutilide, amiodarone, or dronedarone;

• medicines to treat bacterial infections (orally: clarithromycin, moxifloxacin; by injection: erythromycin, pentamidine);

• medicines to treat fungal infections (ketoconazole, except when contained in shampoo);

• medicines to treat certain psychiatric disorders (chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, tiapride, amisulpride, sertindole, methadone);

• medicines to treat hay fever and other allergies (terfenadine, astemizole, mizolastine);

• medicines used for prevention or treatment of malaria (chloroquine, halofantrine, lumefantrine);

• medicines to control blood pressure such as:

  • beta-blockers (metoprolol, carteolol, propranolol, sotalol)
  • calcium channel blockers (bepridil, verapamil, diltiazem)
  • cholinesterase inhibitors (rivastigmine, physostigmine);

• medicines to control the body’s electrolyte balance (potassium, magnesium).

Pregnancy, breastfeeding and fertility
Ask your doctor or pharmacist for advice before taking any medicine.

• You must not use Signifor during pregnancy unless strictly necessary. If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor before taking this medicine.
• If you are breastfeeding, consult your doctor before taking this medicine. It is not known whether Signifor passes into breast milk.
• If you are a woman of childbearing potential, you must use a contraceptive method during treatment. Ask your doctor about the need for contraception before taking this medicine.

Driving and using machines
Signifor may have a minor effect on the ability to drive vehicles or operate machinery, as some of the side effects associated with its use—such as headache, dizziness, and fatigue—may reduce the ability to drive or operate machinery safely.
Important information about some of the excipients of Signifor
Signifor contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially “sodium-free”.

3. How to use Signifor

This medicine will be administered to you by a qualified healthcare professional.
How much Signifor to use
Acromegaly
The recommended starting dose of Signifor in acromegaly is 40 mg every 4 weeks. After you have started treatment, your doctor will reassess the dose. This may involve measuring levels of growth hormone and other hormones in your blood. Depending on the results and how you feel, the dose of Signifor given with each injection may need to be reduced or increased. The dose must not exceed 60 mg. If you have liver disease before starting treatment with Signifor for acromegaly, your doctor may decide to start treatment with a dose of 20 mg.
Cushing’s disease
The usual starting dose of Signifor in Cushing’s disease is 10 mg every 4 weeks. After you have started treatment, your doctor may reassess the dose. This may involve measuring cortisol levels in your blood or urine. Depending on the results and how you feel, the dose of Signifor given with each injection may need to be reduced or increased. The dose must not exceed 40 mg.
Your doctor will regularly monitor your response to treatment with Signifor and determine the best dose for you.
How to use Signifor
Signifor will be injected by a doctor or nurse. If you have any doubts about how to use this medicine, consult your doctor, nurse, or pharmacist.
Signifor is for intramuscular use. This means it is injected through a needle into the muscles of the buttocks.
How long to use Signifor
This is a long-term treatment which may last for years. Your doctor will regularly monitor your condition to ensure the treatment is having the desired effect. Treatment with Signifor should continue for as long as your doctor considers it necessary.
If you stop treatment with Signifor
If you stop treatment with Signifor, your symptoms may return. Therefore, do not stop using Signifor unless your doctor tells you to.
If you have any questions about how to use this medicine, consult your doctor, nurse, or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Some side effects can be serious. Immediately inform your doctor if you experience any of the
following:

Very common (may affect more than 1 in 10 people)

• High blood sugar levels. This may cause excessive thirst, increased urination, increased appetite with weight loss, fatigue, nausea, vomiting, abdominal pain
• Gallstones or related complications. These may cause fever, chills, yellowing of the skin/eyes, back pain or pain in the right side of the abdomen.

Common (may affect up to 1 in 10 people)

• Low cortisol levels. These may cause excessive fatigue, weakness, weight loss, nausea, vomiting and low blood pressure.
• Slow heart rate.
• Prolongation of the QT interval (an abnormal electrical signal in the heart that may be seen on tests).
• Problems with bile flow (cholestasis). This may cause yellowing of the skin, dark urine, pale stools and itching.
• Inflammation of the gallbladder (cholecystitis).

Other side effects of Signifor may include:
Very common (may affect more than 1 in 10 people)

• Diarrhoea
• Nausea
• Abdominal pain
• Fatigue

Common (may affect up to 1 in 10 people)

• Fatigue, tiredness, pale skin (signs of low red blood cell levels)
• Loss of appetite
• Headache
• Swelling
• Vomiting
• Dizziness
• Pain, discomfort, itching and swelling at the injection site
• Changes in liver function test results
• Abnormal blood test results (signs of high levels of creatine phosphokinase, glycated haemoglobin and lipase in the blood)
• Hair loss

Uncommon (may affect up to 1 in 100 people)

• Changes in blood test results for pancreatic function (amylase)
• Abnormal blood clotting

Not known (frequency cannot be estimated from the available data)

• Increased levels of ketone bodies (a group of substances produced in the liver) in urine or blood (diabetic ketoacidosis) as a complication of increased blood sugar levels. You may notice fruity-smelling breath, difficulty breathing and confusion.
• Oily or fatty stools
• Change in stool colour

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

5. How to store Signifor

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the carton, vial, and pre-filled syringe after “EXP”/“Scad”. The expiry date refers to the last day of that month.
• Store in a refrigerator (2°C-8°C). Do not freeze.
• Do not dispose of any medicine 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 Signifor contains

• The active substance is pasireotide.
  Signifor 10 mg: each vial contains 10 mg of pasireotide (as pasireotide pamoate).
  Signifor 20 mg: each vial contains 20 mg of pasireotide (as pasireotide pamoate).
  Signifor 30 mg: each vial contains 30 mg of pasireotide (as pasireotide pamoate).
  Signifor 40 mg: each vial contains 40 mg of pasireotide (as pasireotide pamoate).
  Signifor 60 mg: each vial contains 60 mg of pasireotide (as pasireotide pamoate).

• The other ingredients are:

  • In the powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50).
  • In the solvent: sodium carmellose, mannitol, poloxamer 188, water for injections.

Description of the appearance of Signifor and contents of the pack
Signifor powder is a slightly yellowish to yellowish powder contained in a vial; the solvent is a clear solution ranging in colour from slightly yellow to slightly brown, supplied in a pre-filled syringe.

Signifor 10 mg is available in single packs containing one vial of powder with 10 mg of pasireotide and one pre-filled syringe with 2 ml of solvent.
Signifor 20 mg is available in single packs containing one vial of powder with 20 mg of pasireotide and one pre-filled syringe with 2 ml of solvent.
Signifor 30 mg is available in single packs containing one vial of powder with 30 mg of pasireotide and one pre-filled syringe with 2 ml of solvent.
Signifor 40 mg is available in single packs containing one vial of powder with 40 mg of pasireotide and one pre-filled syringe with 2 ml of solvent.
Signifor 60 mg is available in single packs containing one vial of powder with 60 mg of pasireotide and one pre-filled syringe with 2 ml of solvent.

Each single pack contains the vial and a pre-filled syringe in a sealed blister tray, together with a vial adapter and a safety needle for injection.
Signifor 40 mg and Signifor 60 mg are also available in multiple packs containing 3 intermediate packs.

It is possible that not all strengths or pack sizes are marketed.

Marketing Authorisation Holder
Recordati Rare Diseases
Tour Hekla
52 avenue du Général de Gaulle
92800 Puteaux
France

Manufacturer
Recordati Rare Diseases
Tour Hekla
52 avenue du Général de Gaulle
92800 Puteaux
France
Recordati Rare Diseases
Eco River Parc
30 rue des Peupliers
92000 Nanterre
France

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Recordati Recordati AB.
Tél/Tel: +32 2 46101 36 Tel: + 46 8 545 80 230
Švedija

България Luxembourg/Luxemburg
Recordati Rare Diseases Recordati
Teл.: +33 (0)1 47 73 64 58 Tél/Tel: +32 2 46101 36
Франция Belgique/Belgien

Česká republika Magyarország
Recordati Rare Diseases Recordati Rare Diseases
Tel: +33 (0)1 47 73 64 58 Tel: +33 (0)1 47 73 64 58
Francie Franciaország

Danmark Malta
Recordati AB. Recordati Rare Diseases
Tlf.: + 46 8 545 80 230 Tel: +33 1 47 73 64 58
Sverige Franza

Deutschland Nederland
Recordati Rare Diseases Germany GmbH Recordati
Tel: +49 731 140 554 0 Tel: +32 2 46101 36
België

Eesti Norge
Recordati AB. Recordati AB.
Tel: + 46 8 545 80 230 Tlf: + 46 8 545 80 230
Rootsi Sverige

Ελλάδα Österreich
Recordati Hellas Recordati Rare Diseases Germany GmbH
Τηλ: +30 210 6773822 Tel: +49 731 140 554 0
Deutschland

España Polska
Recordati Rare Diseases Spain S.L.U. Recordati Rare Diseases
Tel: + 34 91 659 28 90 Tel: +33 (0)1 47 73 64 58
Francja

France Portugal
Recordati Rare Diseases Recordati Rare Diseases SARL
Tél: +33 (0)1 47 73 64 58 Tel: +351 21 432 95 00

Hrvatska România
Recordati Rare Diseases Recordati Rare Diseases
Tél: +33 (0)1 47 73 64 58 Tel: +33 (0)1 47 73 64 58
Francuska Franţa

Ireland Slovenija
Recordati Rare Diseases Recordati Rare Diseases
Tél: +33 (0)1 47 73 64 58 Tel: +33 (0)1 47 73 64 58
France Francija

Ísland Slovenská republika
Recordati AB. Recordati Rare Diseases
Simi: + 46 8 545 80 230 Tel: +33 (0)1 47 73 64 58
Svíþjóð Francúzsko

Italia Suomi/Finland
Recordati Rare Diseases Italy Srl Recordati AB.
Tel: +39 02 487 87 173 Puh/Tel: +46 8 545 80 230
Sverige

Κύπρος Sverige
Recordati Rare Diseases Recordati AB.
Τηλ: +33 1 47 73 64 58 Tel: +46 8 545 80 230
Γαλλία

Latvija
Recordati AB.
Tel: + 46 8 545 80 230
Zviedrija

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu. Links to other websites on rare diseases and their therapeutic treatments are also provided.

The following information is intended exclusively for healthcare professionals:

INSTRUCTIONS FOR USE OF SIGNIFOR POWDER AND SOLVENT FOR INJECTABLE SUSPENSION

FOR INJECTION ONLY
FOR DEEP INTRAMUSCULAR INJECTION ONLY
WARNING:
There are two critical steps in the reconstitution of Signifor. Failure to perform them may compromise
the success of the injection.

• The injection kit must reach room temperature. Before reconstitution, remove the injection kit from the refrigerator and allow it to sit at room temperature for at least 30 minutes, but no longer than 24 hours.
• After adding the solvent, gently agitate the vial for at least 30 seconds until a uniform suspension is formed.

Contents of the injection kit:

a One vial containing powder
b One pre-filled syringe containing solvent
c One vial adapter for reconstitution of the medicine
d One injection needle (20G x 1.5″) with safety device

Carefully follow the instructions below to ensure proper reconstitution of Signifor powder and solvent for injectable suspension prior to deep intramuscular injection.
The Signifor suspension must be prepared only immediately before administration.
Signifor must be administered only by a qualified healthcare professional.

Step 1

Remove the Signifor injection kit from the
refrigerator.
WARNING: It is essential to begin the
reconstitution procedure only after the kit has
reached room temperature. Before
reconstitution, allow the kit to remain at room
temperature for at least 30 minutes, but do not
exceed 24 hours.
Note: The injection kit may be returned to the
refrigerator if not used within 24 hours.

Step 2

Remove the plastic cap from the vial and
clean the vial’s rubber stopper with an alcohol-
soaked swab.
Peel off the seal from the vial adapter package,
but DO NOT remove the adapter from its
package.
Holding the vial adapter package, place it onto
the top of the vial and push it down completely
until it clicks into place.
Remove the vial adapter package by lifting it
upwards as shown in the figure.