Active ingredients: Cyclosporine
Sandimmun Neoral 10 mg soft capsules
Sandimmun Neoral 25 mg soft capsules
Sandimmun Neoral 50 mg soft capsules
Sandimmun Neoral 100 mg soft capsules
Why is Sandimmun Neoral used? What is it for?
What is Sandimmun Neoral
The name of the medicine is Sandimmun Neoral. Contains the active ingredient cyclosporine. Ciclosporin belongs to a group of medicines known as immunosuppressive agents. These medicines are used to decrease the body's immune reactions.
What Sandimmun Neoral is used for and how Sandimmun Neoral works
- If you have had an organ transplant, bone marrow or stem cell transplant, the function of Sandimmun Neoral is to control the body's immune system. Sandimmun Neoral prevents the rejection of transplanted organs by blocking the development of certain cells that should usually attack the transplanted tissue.
- If you have an autoimmune disease, in which your body's immune response attacks the body's cells, Sandimmun Neoral blocks the immune response. These diseases include eye problems that endanger vision (endogenous uveitis, including Behçet's uveitis), severe cases of certain skin conditions (atopic dermatitis or eczema and psoriasis), severe rheumatoid arthritis and a kidney disease known as syndrome nephrotic.
Contraindications When Sandimmun Neoral should not be used
Do not take Sandimmun Neoral:
- if you are allergic to cyclosporine or any of the other ingredients of this medicine
- with products containing Hypericum perforatum (St. John's wort). - with medicines containing dabigatran etexilate (used to prevent blood clots after surgery) or bosentan and aliskiren (used to lower high blood pressure).
Do not take Sandimmun Neoral and tell your doctor if any of the above apply to you. If you are not sure, ask your doctor before taking Sandimmun Neoral.
Precautions for use What you need to know before taking Sandimmun Neoral
If you are taking Sandimmun Neoral following a transplant, the medicine will only be prescribed for you by a doctor with experience in transplantation and / or autoimmune diseases.
The warning in this leaflet may vary depending on whether you are taking the medicine for a transplant or for an autoimmune disease.
Follow all the doctor's instructions carefully. This may differ from the general information contained in this leaflet.
Before and during treatment with Sandimmun Neoral, tell your doctor immediately:
- if you have any signs of infection, such as fever or sore throat. Sandimmun Neoral suppresses the immune system and can also affect the body's ability to fight infections.
- if you have liver problems.
- if you have kidney problems. Your doctor will carry out regular blood tests and may change the dose if necessary.
- if you develop high blood pressure. Your doctor will check your blood pressure regularly and, if necessary, may give you a medicine to lower your blood pressure.
- if you have low levels of magnesium in your body. Your doctor may prescribe magnesium supplements, especially just after your transplant surgery.
- if you have high levels of potassium in your blood.
- if you have gout.
- if you need a vaccination.
If any of the above apply to you before or during treatment with Sandimmun Neoral, tell your doctor immediately.
Sun exposure and sun protection
Sandimmun Neoral suppresses the immune system. This increases the risk of developing cancer, particularly of the skin and lymphoid system. Must limit exposure to the sun and UV light:
- Wearing appropriate protective clothing.
- Often applying a sunscreen with a high protection factor.
Tell your doctor before taking Sandimmun Neoral:
- if you have or have had alcohol problems.
- if you have epilepsy.
- if you have any liver problems.
- if you are pregnant.
- if you are breastfeeding.
- if this medicine is being prescribed to a child.
If you have any of the above conditions (or you are not sure), tell your doctor before taking Sandimmun Neoral. This is because this medicine contains alcohol (see section below "Sandimmun Neoral contains ethanol").
Monitoring during treatment with Sandimmun Neoral
The doctor will check:
- blood levels of cyclosporine, especially if you have had a transplant,
- blood pressure before starting treatment and regularly during treatment,
- how the liver and kidneys are functioning,
- blood lipids (fats).
If you have any questions about how Sandimmun Neoral works or why this medicine has been prescribed for you, ask your doctor.
Also, if you are taking Sandimmun Neoral for a disease other than transplantation (intermediate uveitis or posterior uveitis and Behçet's uveitis, atopic dermatitis, severe rheumatoid arthritis or nephrotic syndrome), do not take Sandimmun Neoral:
- if you have kidney problems (except nephrotic syndrome).
- if you have an infection that is not controlled with therapy.
- if you have any type of cancer.
- if you have high blood pressure (hypertension) which is not controlled with therapy.
If problems with high blood pressure develop during treatment and cannot be kept under control, Sandimmun Neoral should be stopped by your doctor.
If any of the above apply to you, do not take Sandimmun Neoral. If you are not sure, tell your doctor or pharmacist before taking Sandimmun Neoral.
If you are being treated for Behçet's uveitis, your doctor will carefully check if you have any neurological symptoms (for example: increased forgetfulness, personality changes observed over time, psychiatric or mood disorders, burning sensation in the limbs, decreased sensation of the limbs, tingling sensation in the limbs, weakness in the limbs, gait disturbance, headache with or without nausea and vomiting, visual disturbances including limited movements of the eyeball).
If you are elderly and are being treated for psoriasis or atopic dermatitis, your doctor will monitor you carefully. If you have been prescribed Sandimmun Neoral for the treatment of psoriasis or atopic dermatitis, you should not be exposed to UVB radiation or phototherapy during treatment.
Children and adolescents
Sandimmun Neoral should not be given to children for diseases other than transplantation, except for the treatment of nephrotic syndrome.
Elderly (65 years of age and older)
There is limited experience with Sandimmun Neoral in elderly patients. The doctor must check that the kidneys are functioning properly. If you are over 65 years of age and suffer from psoriasis or atopic dermatitis, you should only be treated with Sandimmun Neoral if the condition is particularly severe.
Interactions Which drugs or foods may change the effect of Sandimmun Neoral
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. In particular, tell your doctor or pharmacist if you are taking any of the following medicines before or during treatment with Sandimmun Neoral:
- Medicines that can affect potassium levels. These include medicines that contain potassium, potassium supplements, urinating tablets (diuretics) called potassium-sparing diuretics and some medicines that lower blood pressure.
- Methotrexate. It is a medicine used to treat cancer, severe psoriasis and severe rheumatoid arthritis.
- Medicines that can increase or decrease the level of cyclosporine (the active substance in Sandimmun Neoral) in the blood. Your doctor may check the level of cyclosporine in your blood when starting or stopping treatment with other medicines.
- Medicines that may increase the level of cyclosporine in the blood include: antibiotics (such as erythromycin or azithromycin), antifungals (voriconazole, itraconazole), medicines used for heart problems or high blood pressure (diltiazem, nicardipine, verapamil, amiodarone), metoclopramide (used against nausea), oral contraceptives, danazol (used to treat menstrual problems), medicines used to treat gout (allopurinol), cholic acid and derivatives (used to treat gallstones), protease inhibitors used to treat " HIV, imatinib (used to treat leukemia or cancer), colchicine, telaprevir (used to treat "hepatitis C).
- Medicines that may decrease the level of cyclosporine in the blood include: barbiturates (used to promote sleep), some anticonvulsant medicines (such as carbamazepine or phenytoin), octreotide (used to treat acromegaly or neuroendocrine tumors of the intestine), medicines antibacterials used to treat tuberculosis, orlistat (used to promote weight loss), herbal medicines containing St. John's wort, ticlopidine (used after a stroke), certain medicines that lower blood pressure (bosentan ) and terbinafine (an antifungal medicine used to treat infections of the toes and nails).
- Medicines that can affect the kidneys. These include: antibacterial medicines (gentamicin, tobramycin, ciprofloxacin), antifungal medicines that contain amphotericin B, medicines used for urinary tract infections that contain trimethoprim, medicines for cancer that contain melphalan, medicines used to lower the amount of acid in the stomach (inhibitors of acid secretion of the H2-receptor antagonist type), tacrolimus, pain relievers (non-steroidal anti-inflammatory medicines such as diclofenac), fibric acid medicines (used to lower the amount of fat in the blood).
- Nifedipine. It is used to treat high blood pressure and heart pain. If you are taking nifedipine while taking cyclosporine, you may experience swelling of the gums which thicken around the teeth.
- Digoxin (used to treat heart problems), cholesterol-lowering medicines (HMG-CoA reductase inhibitors also called statins), prednisolone, etoposide (used to treat cancer), repaglinide (an antidiabetic medicine), immunosuppressants (everolimus , sirolimus), ambrisentan and specific cancer medicines called anthracyclines (e.g. doxorubicin).
If you get any of the above conditions (or you are not sure), tell your doctor or pharmacist before taking Sandimmun Neoral.
Sandimmun Neoral with food and drink
Do not take Sandimmun Neoral with grapefruit or grapefruit juice. This is because they may affect the action of Sandimmun Neoral.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking this medicine. Your doctor will discuss with you the potential risks of taking Sandimmun Neoral during pregnancy.
- Tell your doctor if you are pregnant or planning to become pregnant. There is limited experience with Sandimmun Neoral in pregnancy. In general Sandimmun Neoral should not be taken during pregnancy. If this medicine is required, your doctor will discuss with you the benefits and potential risks of taking it during pregnancy.
- Tell your doctor if you are breastfeeding. Breastfeeding is not recommended during treatment with Sandimmun Neoral. This is because cyclosporine, the active substance, passes into breast milk. This can affect the baby.
Driving and using machines
Sandimmun Neoral contains alcohol. This can affect the ability to drive and use machines.
Sandimmun Neoral contains ethanol
Sandimmun Neoral contains approximately 12.0 vol. Ethanol (alcohol). %, which corresponds to up to 500 mg per dose used in transplant patients. This is equivalent to nearly 15ml of beer or 5ml of wine per serving.
Alcohol can be harmful if you have alcohol-related problems, epilepsy, brain damage, liver problems or if you are pregnant or breastfeeding. It can also be harmful if the medicine is given to children.
Sandimmun Neoral contains castor oil
Sandimmun Neoral contains castor oil which can cause stomach pain and diarrhea.
Dose, Method and Time of Administration How to use Sandimmun Neoral: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor.
Do not take more than the recommended dose.
The dose of this medicine will be carefully adjusted to your personal needs by your doctor. Too much medicine can affect how your kidneys work. You will have regular blood tests and hospital visits, especially after a transplant. This will give you a chance to talk to your doctor about your treatment and any problems you may have.
How much Sandimmun Neoral to take
Your doctor will work out the correct dose of Sandimmun Neoral for you. It depends on your body weight and why you are taking the medicine. Your doctor will also tell you how often to take the medicine.
- In adults:
Organ, bone marrow or stem cell transplant
- The total daily dose is usually between 2 mg and 15 mg per kilogram of body weight. It should be divided into two doses.
- The higher doses are usually used before and just after the transplant. Lower doses are used once the transplanted organ or bone marrow has stabilized.
- Your doctor will adjust the dose to the one that is appropriate for you. To do this, your doctor may need to do some blood tests.
Endogenous uveitis
- The total daily dose is usually between 5 mg and 7 mg per kilogram of body weight. It should be divided into two doses.
Nephrotic syndrome
- For adults, the total daily dose is usually 5 mg per kilogram of body weight. It should be divided into two doses. In patients with kidney problems, the starting dose taken each day should not exceed 2.5 mg per kilogram of body weight.
Severe rheumatoid arthritis
- The total daily dose is usually between 3 mg per kilogram of body weight and 5 mg per kilogram of body weight. It should be divided into two doses.
Psoriasis and atopic dermatitis
- The total daily dose is usually between 2.5 mg per kilogram of body weight and 5 mg per kilogram of body weight. It should be divided into two doses.
- In children:
Nephrotic syndrome
- For children, the total daily dose is usually 6 mg per kilogram of body weight. It should be divided into two doses.In patients with kidney problems, the starting dose taken each day should not exceed 2.5 mg per kilogram of body weight.
Follow your doctor's instructions exactly and never change the dose yourself, even if you feel well.
Switching from Sandimmun to Sandimmun Neoral
You may have already taken another medicine called Sandimmun soft gelatin capsules or Sandimmun oral solution. Your doctor may decide to switch to this medicine, Sandimmun Neoral oral solution.
- All these medicines contain cyclosporine as the active ingredient.
- Compared to Sandimmun, Sandimmun Neoral is a different, improved formulation of cyclosporine. With Sandimmun Neoral cyclosporine is better absorbed into the blood and absorption is less likely to be affected by taking the medicine with food. This means that cyclosporine levels in the blood will remain more constant with Sandimmun Neoral than with Sandimmun.
If your doctor changes your medicine from Sandimmun to Sandimmun Neoral:
- Do not go back to taking Sandimmun unless your doctor tells you to.
- Following the switch from Sandimmun to Sandimmun Neoral, your doctor will monitor you more closely for a short time. This is due to the modification of how cyclosporine is absorbed into the blood. Your doctor will make sure you take the right dose for your individual needs.
- It may experience some unwanted effects. If this happens, contact your doctor or pharmacist. The dose may need to be reduced. Never reduce the dose yourself, unless your doctor tells you to.
If your doctor switches you from one oral formulation of cyclosporine to another
After switching from one oral formulation of cyclosporine to another:
- Your doctor will monitor you more closely for a short time.
- It may experience some unwanted effects. If this happens, contact your doctor or pharmacist. Your dose may need to be adjusted. Never change your dose on your own unless your doctor tells you to.
When to take Sandimmun Neoral
Take Sandimmun Neoral at the same time each day. This is very important if you have had a transplant.
How to take Sandimmun Neoral
Daily doses should always be taken in 2 divided doses.
Remove the capsules from the blister. Swallow the capsules whole with water.
How long to take Sandimmun Neoral
Your doctor will tell you how long to take Sandimmun Neoral. This depends on whether you are taking the medicine after a transplant or to treat a severe skin condition, rheumatoid arthritis, uveitis or nephrotic syndrome. For severe rash, the treatment duration is usually 8 weeks.
Keep taking Sandimmun Neoral until your doctor tells you to.
If you have any questions about how long to take Sandimmun Neoral, talk to your doctor or pharmacist.
Overdose What to do if you have taken an overdose of Sandimmun Neoral
If you take more Sandimmun Neoral than you should
If you have accidentally taken too much medicine, tell your doctor immediately or go to the emergency room of the nearest hospital. You may need medical attention.
If you forget to take Sandimmun Neoral
- If you forget to take a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose. Then continue as before.
- Do not take a double dose to make up for a forgotten dose.
If you stop taking Sandimmun Neoral
Do not stop taking Sandimmun Neoral unless your doctor tells you to.
Continue to take Sandimmun Neoral even if you feel well. Stopping treatment with Sandimmun Neoral may increase the risk of rejection of the organ that was transplanted to you.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Sandimmun Neoral
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some side effects can be serious
Tell your doctor immediately if you experience any of the following serious side effects:
- Like other medicines that affect the immune system, cyclosporine can affect the body's ability to fight infections and can cause tumors or other cancers, especially of the skin. Signs of infection could be fever or sore throat.
- Impaired vision, loss of coordination, awkwardness, memory loss, difficulty speaking or understanding what others are saying and muscle weakness. These could be signs of a brain infection called progressive multifocal leukoencephalopathy.
- Brain problems with signs such as seizures, confusion, feeling disoriented, unresponsive, personality changes, feeling agitated, insomnia, vision changes, blindness, coma, paralysis of part or all of the body, stiff neck, loss of coordination with or without unusual speech or eye movements.
- Swelling in the back of the eye. This may be associated with blurred vision. It can also affect vision due to the increased pressure inside the head (benign intracranial hypertension).
- Liver problems and damage with or without yellow skin and eyes, nausea, loss of appetite and dark urine.
- Kidney problems which can greatly reduce the amount of urine produced.
- Low levels of red blood cells or platelets. The signs include paleness, feeling tired, difficulty breathing, dark urine (this is a sign of a breakdown of red blood cells), bruising or bleeding for no obvious reason, feeling confused, feeling disoriented, reduced alertness and kidney problems.
Other side effects include:
Very common side effects: These side effects may affect more than 1 in 10 people.
- Kidney problems.
- High blood pressure.
- Headache.
- Body agitation that cannot be controlled. Excessive growth of body and facial hair.
- High levels of lipids in the blood.
If any of these effects occur severely, please tell your doctor.
Common side effects: These side effects may affect between 1 and 10 in 100 people.
- Fits (convulsions).
- Liver problems.
- High blood sugar levels.
- Tiredness.
- Loss of appetite.
- Nausea (feeling sick), vomiting, abdominal pain, constipation, diarrhea.
- Excessive hair growth.
- Acne, hot flashes.
- Fever.
- Low levels of white blood cells in the blood.
- Feeling numb or tingling.
- Muscle pain, muscle spasms.
- Stomach ulcer.
- Overgrowth of the gums and covering of the teeth.
- High levels of uric acid or potassium in the blood, low levels of magnesium in the blood.
If any of these effects occur severely, please tell your doctor.
Uncommon side effects: These side effects may affect between 1 and 10 in 1,000 people.
- Symptoms of brain disorders including sudden attacks, mental confusion, insomnia, disorientation, visual disturbances, loss of consciousness, feeling of limb weakness, reduced movement.
- Rash.
- Generalized swelling.
- Weight gain.
- Low levels of red blood cells, low levels of platelets in the blood which can increase the risk of bleeding.
If any of these effects occur severely, please tell your doctor.
Rare side effects: These side effects may affect between 1 and 10 in 10,000 people.
- Nerve problems with numbness or tingling in the fingers and toes.
- Inflammation of the pancreas with severe pain in the upper stomach.
- Muscle weakness, loss of muscle strength, pain in the muscles of the legs or hands or in any part of the body.
- Destruction of red blood cells, leading to kidney problems with symptoms such as swelling of the face, stomach, hands and / or feet, decreased urine volume, difficulty breathing, chest pain, seizures, loss of consciousness.
- Changes in the menstrual cycle, enlargement of the mammary gland in men.
If any of these effects occur severely, please tell your doctor.
Very rare side effects: These side effects may affect between 1 and 10 in 100,000 people.
- Swelling in the back of the eye which may be associated with increased pressure in the head and visual disturbances. If this occurs severely, please tell your doctor.
Other undesirable effects with frequency not known: Frequency cannot be estimated from the available data.
- Severe liver problems with and without yellow skin or eyes, nausea (feeling sick), loss of appetite, dark urine, swelling of the face, feet, hands and / or the whole body.
- Bleeding under the skin or purple spots, sudden bleeding with no apparent cause.
- Migraine or severe headache often with malaise (nausea, vomiting) and sensitivity to light.
- Pain in the legs and feet
If any of these effects occur severely, please tell your doctor.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Additional side effects in children and adolescents
There are no additional side effects to be expected in children and adolescents compared to adults.
Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also directly report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- 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.
- Do not store the capsules in a warm place (maximum temperature 25 ° C).
- Leave the capsules in the blister. Only take the capsules out when it is time to take your medicine.
- A characteristic odor may be detected when the blister is opened. This is normal and does not affect the use of the medicine.
- Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Sandimmun Neoral contains
- The active ingredient is cyclosporine. Each capsule contains 10 mg of cyclosporine.
- The other ingredients are:
Capsule contents: alpha-tocopherol, absolute ethanol, propylene glycol, corn oil monodi-triglycerides, macrogolglycerol hydroxystearate / hydrogenated polyoxyl castor oil.
Capsule shell: titanium dioxide (E 171), glycerol 85%, propylene glycol, gelatin.
Impression: carminic acid (E 120).
- The active ingredient is cyclosporine. Each capsule contains 25 mg of cyclosporine.
- The other ingredients are:
Capsule contents: alpha-tocopherol, absolute ethanol, propylene glycol, corn oil monodi-triglycerides, macrogolglycerol hydroxystearate / hydrogenated polyoxyl castor oil.
Capsule shell: black iron oxide (E172), titanium dioxide (E171), glycerol 85%, propylene glycol, gelatin.
Impression: carminic acid (E 120).
- The active ingredient is cyclosporine. Each capsule contains 50 mg of cyclosporine.
- The other ingredients are:
Capsule contents: alpha-tocopherol, absolute ethanol, propylene glycol, corn oil monodi-triglycerides, macrogolglycerol hydroxystearate / hydrogenated polyoxyl castor oil.
Capsule shell: titanium dioxide (E 171), glycerol 85%, propylene glycol, gelatin.
Impression: carminic acid (E 120).
- The active ingredient is cyclosporine. Each capsule contains 100 mg of cyclosporine.
- The other ingredients are:
Capsule contents: alpha-tocopherol, absolute ethanol, propylene glycol, corn oil monodi-triglycerides, macrogolglycerol hydroxystearate / hydrogenated polyoxyl castor oil.
Capsule shell: black iron oxide (E172), titanium dioxide (E171), glycerol 85%, propylene glycol, gelatin.
Impression: carminic acid (E 120).
Description of what Sandimmun Neoral looks like and contents of the pack
Sandimmun Neoral 10 mg soft capsules are oval-shaped yellow-white and imprinted with "NVR 10" in red.
Sandimmun Neoral 25 mg soft capsules are blue-gray oval shaped and imprinted with "NVR 25mg" in red.
Sandimmun Neoral 50 mg soft capsules are elongated yellow-white and imprinted with "NVR 50mg" in red.
Sandimmun Neoral 100 mg soft capsules are elongated blue-gray in color and imprinted with "NVR 100mg" in red.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SANDIMMUN NEORAL SOFT CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 10 mg of cyclosporine.
Excipients with known effect:
Ethanol: 10 mg / capsule.
Sandimmun Neoral soft capsules contain 11.8% v / v ethanol (9.4% m / v).
Propylene Glycol: 10 mg / capsule.
Macrogolglycerol hydroxystearate / polyoxyl-40 hydrogenated castor oil: 40.5 mg / capsule.
Each capsule contains 25 mg of cyclosporine.
Excipients with known effect:
Ethanol: 25 mg / capsule.
Sandimmun Neoral soft capsules contain 11.8% v / v ethanol (9.4% m / v).
Propylene Glycol: 25mg / capsule.
Macrogolglycerol hydroxystearate / polyoxyl-40 hydrogenated castor oil: 101.25 mg / capsule.
Each capsule contains 50 mg of cyclosporine.
Excipients with known effect:
Ethanol: 50 mg / capsule.
Sandimmun Neoral soft capsules contain 11.8% v / v ethanol (9.4% m / v).
Propylene Glycol: 50mg / capsule.
Macrogolglycerol hydroxystearate / polyoxyl-40 hydrogenated castor oil: 202.5 mg / capsule.
Each capsule contains 100 mg of cyclosporine.
Excipients with known effect:
Ethanol: 100 mg / capsule.
Sandimmun Neoral soft capsules contain 11.8% v / v ethanol (9.4% m / v).
Propylene Glycol: 100mg / capsule.
Macrogolglycerol hydroxystearate / polyoxyl-40 hydrogenated castor oil: 405.0 mg / capsule.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Soft capsule.
Soft gelatin capsules, oval, yellow-white in color, imprinted with "NVR 10" in red.
Blue-gray, oval-shaped soft gelatin capsules, imprinted with "NVR 25 mg" in red.
Soft gelatin capsules, elongated, yellow-white in color, imprinted with "NVR 50 mg" in red.
Blue-gray, elongated soft gelatin capsules, imprinted with "NVR 100 mg" in red.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Indications for transplantation
Organ transplant
Prevention of solid organ transplant rejection.
Treatment of transplant cell rejection in patients who have previously received other immunosuppressive therapies.
Bone marrow transplant
Prevention of rejection of allogeneic bone marrow and stem cell transplantation.
Prophylaxis or treatment of graft-versus-host disease (GVHD).
Indications other than transplantation
Endogenous uveitis
Treatment of posterior or intermediate uveitis of non-infectious origin at risk of severe loss of visual function, in patients in whom conventional therapies have not been effective or cause unacceptable side effects.
Treatment of Behçet uveitis with repeated inflammatory attacks of the retina in patients without neurological manifestations.
Nephrotic syndrome
Steroid-dependent and steroid-resistant nephrotic syndrome due to primary glomerulopathies such as minimal change nephropathy, focal and segmental glomerulosclerosis or membranous glomerulonephritis.
Sandimmun Neoral can be used to induce and maintain disease remission.It can also be used to maintain corticosteroid-induced remission by allowing it to be withdrawn.
Rheumatoid arthritis
Treatment of severe active rheumatoid arthritis.
Psoriasis
Treatment of severe psoriasis in patients in whom conventional therapy is inappropriate or ineffective.
Atopic dermatitis
Sandimmun Neoral is indicated in patients with severe atopic dermatitis when systemic therapy is required.
04.2 Posology and method of administration
Dosage
The reported dosing ranges for oral administration are intended for reference only.
The daily doses of Sandimmun Neoral should be administered in two divided doses distributed equally throughout the day. It is recommended that Sandimmun Neoral be administered on a regular schedule with regard to time and in relation to meals.
Sandimmun Neoral should only be prescribed by or in close collaboration with a physician experienced in immunosuppressive therapy and / or organ transplantation.
Transplant
Solid organ transplant
Treatment with Sandimmun Neoral should begin within 12 hours prior to surgery by administering a dose of 10-15 mg / kg administered in 2 divided doses. This dose should be maintained as a daily dose for 1-2 weeks after surgery. intervention and be gradually reduced according to local immunosuppression protocols based on blood levels, until a recommended maintenance dose of approximately 2-6 mg / kg administered in 2 divided doses is reached.
When Sandimmun Neoral is given with other immunosuppressants (e.g. with corticosteroids or as part of triple or quadruple therapy), lower doses (e.g. 3-6 mg / kg divided into 2 divided doses for initial treatment) may be used.
Bone marrow transplant
The starting dose should be administered the day before the transplant. In most cases, Sandimmun concentrate for solution for infusion is preferred for this purpose. The recommended intravenous dose is 3-5 mg / kg / day. The infusion is maintained at the same dose level in the immediate post-transplant period for no longer than 2 weeks, before switching to oral maintenance therapy with Sandimmun Neoral at a daily dose of approximately 12.5 mg / kg in 2 refracted administrations.
Maintenance treatment should be continued for at least 3 months (and preferably 6 months) before reducing the dose gradually to zero within 1 year after transplantation.
If initial therapy is performed with Sandimmun Neoral, the recommended daily dose is 12.5-15 mg / kg divided into 2 divided doses, starting the day before transplantation.
In the presence of gastrointestinal disturbances that could reduce drug absorption, higher doses of Sandimmun Neoral or the use of intravenous Sandimmun may be necessary.
In some patients, GVHD may develop after discontinuation of ciclosporin treatment, but usually a favorable response is obtained upon resumption of therapy. In these cases, an initial loading dose of 10-12.5 mg / kg should be administered, followed by daily oral administration of the previously adequate maintenance dose. Low doses of Sandimmun Neoral should be used for the treatment of chronic mild GVHD.
Indications other than transplantation
When Sandimmun Neoral is used in known indications other than transplantation, the following general precautions should be observed:
Before starting treatment, the pretreatment value of renal function should be accurately determined by at least two determinations. Estimated glomerular filtration rate (eGFR), calculated using the MDRD formula, can be used in adults to estimate renal function and an appropriate formula should be used to evaluate eGFR in pediatric patients. As Sandimmun Neoral can impair renal function, renal function should be evaluated frequently. If the eGFR decreases by more than 25% from baseline in more than one measurement, the Sandimmun Neoral dose should be reduced by 25-50%. If eGFR decreases from at baseline exceeds 35%, further reduction of the Sandimmun Neoral dose should be considered. These recommendations apply even if patient values remain within the laboratory normal range. If dose reduction is not effective in improving eGFR within one month, Sandimmun Neoral treatment should be discontinued (see section 4.4).
Regular monitoring of blood pressure is necessary.
Determination of bilirubin and parameters that evaluate liver function is necessary before starting therapy, and careful monitoring is recommended during treatment. Determinations of serum lipids, potassium, magnesium and uric acid are advisable before treatment and periodically during treatment.
Occasional monitoring of cyclosporine blood levels may be important in indications other than transplantation, eg. when Sandimmun Neoral is administered in combination with substances that may interfere with the pharmacokinetics of cyclosporine or in the event of an unusual clinical response (e.g. lack of efficacy or increased intolerance to the drug resulting in renal dysfunction).
The oral route is the normal route of administration. If concentrate for solution for infusion is used, particular attention should be paid to intravenous administration of an adequate dosage corresponding to the dose administered orally. Consultation with a physician experienced in the use of cyclosporine is recommended.
With the exception of patients with endogenous uveitis at risk for vision and children with nephrotic syndrome, the total daily dose should never exceed 5 mg / kg.
For maintenance treatment, the lowest effective and well tolerated dose should be determined on an individual basis.
Sandimmun Neoral treatment should be discontinued in patients who, within a given time interval (see below for specific information), do not achieve an adequate response or whose effective dose is not compatible with treatment safety standards.
Endogenous uveitis
To induce remission it is recommended to start with 5 mg / kg / day orally divided into 2 administrations until remission of the active inflammation of the uvea and improvement of visual acuity are achieved. In refractory cases, the dose may be increased to 7 mg / kg / day for a limited period.
To achieve initial remission or to control inflammatory ocular attacks, systemic corticosteroids may be administered concomitantly at daily doses of 0.2-0.6 mg / kg prednisone or other corticosteroids if Sandimmun Neoral alone is not sufficient to check the situation. After 3 months the dosage of corticosteroids can be reduced to the lowest effective dose.
For maintenance therapy the dose should be gradually decreased to the lowest effective dose. During the remission phase the dose should not exceed 5 mg / kg / day.
Infectious causes of uveitis must be ruled out before immunosuppressants can be used.
Nephrotic syndrome
To induce remission, the recommended daily dose is administered in 2 divided oral doses.
If renal function (except for proteinuria) is normal, the recommended daily dose is as follows:
- adults: 5 mg / kg
- children: 6 mg / kg
In patients with impaired renal function, the starting dose should not exceed 2.5 mg / kg / day.
The use of Sandimmun Neoral in combination with low dose oral corticosteroids is recommended if the effect of Sandimmun Neoral alone is unsatisfactory, particularly in steroid-resistant patients.
The time to improve varies from 3 to 6 months depending on the type of glomerulopathy. If no improvement has been observed after this time for improvement, Sandimmun Neoral therapy should be discontinued.
Doses should be adjusted on an individual basis according to efficacy (proteinuria) and safety, but not to exceed 5 mg / kg / day in adults and 6 mg / kg / day in children.
For maintenance therapy the dose should be gradually decreased to the lowest effective dose.
Rheumatoid arthritis
For the first 6 weeks of treatment the recommended dose is 3 mg / kg / day orally divided into 2 doses. If the effect is insufficient, the daily dose can be gradually increased, in the absence of tolerability problems, but should not exceed 5 mg / kg. To achieve full efficacy, up to 12 weeks of treatment with Sandimmun Neoral may be required. .
For maintenance therapy the dose should be titrated on an individual basis to the lowest effective dose according to tolerability.
Sandimmun Neoral can be administered in combination with low dose corticosteroids and / or non-steroidal anti-inflammatory drugs (NSAIDs) (see section 4.4). Sandimmun Neoral can also be administered in combination with low weekly doses of methotrexate in patients with unsatisfactory response to methotrexate monotherapy, starting with a Sandimmun Neoral dose of 2.5 mg / kg divided into 2 daily doses, with the option of increase the dose according to the tolerability shown by the patient.
Psoriasis
Sandimmun Neoral treatment should be prescribed by physicians experienced in the diagnosis and treatment of psoriasis. Due to the variability of this disease, therapy must be individualized. To induce remission, the recommended starting dose is 2.5 mg / kg / day administered orally in 2 divided doses. If no improvement is observed within 1 month, the daily dose can be gradually increased but should not exceed 5 mg / kg. Treatment should be discontinued in patients who do not show sufficient psoriatic lesion response within 6 weeks of therapy at a dose of 5 mg / kg / day, or in patients whose effective dose is not compatible with treatment safety standards. (see section 4.4).
Initial doses of 5 mg / kg / day are warranted in patients whose clinical condition requires rapid improvement. Once a satisfactory response is achieved, treatment with Sandimmun Neoral can be stopped and a subsequent relapse can be treated again with Sandimmun Neoral at the previously effective dose. Continued maintenance of therapy may be necessary in some patients.
For maintenance therapy, the dose should be titrated on an individual basis to the lowest effective dose and should not exceed 5 mg / kg / day.
Atopic dermatitis
Sandimmun Neoral treatment should be prescribed by physicians experienced in the diagnosis and treatment of atopic dermatitis. Due to the variability of this disease, therapy must be individualized. The recommended dose range is 2.5-5 mg / kg / day in 2 divided oral doses. If an initial dose of 2.5 mg / kg / day does not result in a satisfactory response within 2 weeks of therapy, the daily dose can be rapidly increased to a maximum of 5 mg / kg. In very severe cases, rapid and adequate disease control is more likely to occur with an initial dose of 5 mg / kg / day. Once a satisfactory response is achieved , the dose should be reduced gradually and, if possible, treatment with Sandimmun Neoral should be stopped.A subsequent relapse can be treated with a further course of Sandimmun Neoral.
Although an 8-week course of therapy may be sufficient to achieve remission, treatment for up to 1 year has been shown to be effective and well tolerated as long as monitoring guidelines are followed.
Switching from Sandimmun to Sandimmun Neoral
Available data indicate that after switching from Sandimmun to Sandimmun Neoral at the same dose (1: 1), the trough concentrations of ciclosporin in whole blood are comparable. In many patients, however, an increase in maximum concentration (Cmax) and an increase in exposure to the active substance (AUC) can be observed. In a small percentage of patients these changes are more marked and may be clinically relevant. cyclosporin from the Sandimmun Neoral formulation is less variable and the correlation between minimum cyclosporin concentrations and drug exposure (in terms of AUC) is greater than with the Sandimmun formulation.
Since switching from Sandimmun to Sandimmun Neoral may result in increased exposure to cyclosporine, the following precautions should be observed:
In transplant patients, Sandimmun Neoral should be started at the same daily dose that was previously used with Sandimmun. Trough whole blood levels of ciclosporin should be checked within 4-7 days of switching to Sandimmun Neoral. In addition, clinical parameters indicative of the drug's safety, such as renal function and blood pressure, should be monitored in the first 2 months after switching. If the minimum blood levels of cyclosporine are outside the therapeutic range and / or worsening of clinical parameters indicative of safety occurs, the dosage of the drug should be adjusted accordingly.
In patients treated for indications other than transplantation, Sandimmun Neoral should be started at the same daily dose that was previously used with Sandimmun. Two, 4, and 8 weeks after the switch, kidney function and blood pressure should be checked. If blood pressure rises significantly above the pre-switch value or if the eGFR decreases by more than 25% of the value measured before Sandimmun therapy in more than one measurement, the dose should be reduced (see also "Additional Precautions" in the paragraph 4.4). In the event of unexpected toxicity or lack of efficacy of cyclosporine, minimum blood levels should also be monitored.
Switching between oral formulations of cyclosporine
Switching from one oral formulation of cyclosporine to another should be done under physician supervision, including monitoring the blood levels of cyclosporine for transplant patients.
Special populations
Patients with renal insufficiency
All indications
Ciclosporin undergoes minimal renal elimination and its pharmacokinetics are not largely affected by renal insufficiency (see section 5.2). However, due to its nephrotoxic potential (see section 4.8), careful monitoring of renal function is recommended (see section 4.8). paragraph 4.4).
Indications other than transplantation
With the exception of patients being treated for nephrotic syndrome, patients with impaired renal function should not take cyclosporine (see subsection on additional precautions in indications other than transplantation in section 4.4). In patients with nephrotic syndrome with impaired renal function, the starting dose should not exceed 2.5 mg / kg / day.
Patients with hepatic impairment
Ciclosporin is extensively metabolised by the liver. An approximately 2 to 3-fold increase in ciclosporin exposure may be observed in patients with hepatic impairment. Dosage may need to be reduced in patients with severe hepatic impairment to maintain blood levels within the recommended target range (see sections 4.4 and 5.2) and it is recommended that cyclosporine blood levels be monitored until stable levels are reached.
Pediatric population
Clinical studies have included children aged 1 year and older. In several studies, pediatric patients required and tolerated higher doses of cyclosporine per kg of body weight than those used in adults.
The use of Sandimmun Neoral in children in non-transplant indications is not recommended with the exception of nephrotic syndrome (see section 4.4).
Elderly (65 years and over)
Experience with Sandimmun Neoral in the elderly is limited.
In clinical trials with cyclosporine in rheumatoid arthritis, patients aged 65 years and older were more likely to develop systolic hypertension during treatment and to show ≥50% increase in serum creatinine from baseline after 3-4 months of treatment. therapy.
In elderly patients, the dose should be carefully identified, usually starting with the lowest level of the therapeutic range, given the greater frequency of decreased hepatic, renal or cardiac function, of concomitant diseases or therapies and of an increase in susceptibility. for infections.
Method of administration
Oral use
Sandimmun Neoral capsules should be swallowed whole.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Association with products containing Hypericum perforatum (St. John's wort) (see section 4.5).
Combination with medicinal products which are substrates for the multidrug efflux pump, P-glycoprotein or organic anion transport peptides (OATP) and for which high plasma concentrations are associated with serious and / or life-threatening adverse events, eg. bosentan, dabigatran etexilate and aliskiren (see section 4.5).
04.4 Special warnings and appropriate precautions for use
Supervision of the doctor
Sandimmun Neoral should only be prescribed by medical specialists who have experience with immunosuppressive therapy and can ensure adequate follow-up, which includes regular comprehensive medical examinations, blood pressure measurements and laboratory safety checks.Transplant patients receiving this medicine should be followed up by centers equipped with suitable laboratories and adequate medical support staff. The physician responsible for maintenance therapy should be provided with complete information for patient monitoring.
Lymphomas and other neoplasms
Like other immunosuppressants, cyclosporine increases the risk of developing lymphomas and other malignancies, particularly those of the skin. The increased risk appears to be related to the degree and duration of immunosuppression rather than to the use of specific agents.
For this reason, a treatment regimen comprising various immunosuppressants (including cyclosporine) should be used with caution as it can lead to lymphoproliferative and organ malignancies, some of which are fatal.
Due to the potential risk of cutaneous malignancies, patients being treated with Sandimmun Neoral, particularly those being treated for psoriasis or atopic dermatitis, should be advised to avoid excessive sun exposure without protection and should not be exposed to simultaneous radiation. ultraviolet B or photochemotherapy with PUVA.
Infections
Like other immunosuppressants, cyclosporine predisposes patients to the development of various bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens. Activation of latent polyomavirus infections that can lead to polyomavirus associated nephropathy (PVAN), especially BK virus nephropathy (BKVN) or JC virus associated progressive multifocal leukoencephalopathy (PML) has been observed in patients treated with cyclosporine. are often related to a high total immunosuppressive burden and should be considered in the differential diagnosis of immunosuppressed patients with deteriorating renal function or neurological symptoms. Serious and / or fatal outcomes have been reported. Effective prophylactic and therapeutic strategies should be employed in particularly in patients undergoing multiple long-term immunosuppressive therapy.
Renal toxicity
A frequent and potentially serious complication, an increase in serum creatinine and urea, may arise during Sandimmun Neoral therapy. These functional changes are dose-dependent and are initially reversible, usually responding to a reduction in dose. During treatment. In the long term, some patients may develop structural changes in the kidney (eg interstitial fibrosis), for which a differential diagnosis with kidney transplant rejection must be made in patients undergoing kidney transplantation. frequency of renal function according to local guidelines for the indication in question (see sections 4.2 and 4.8).
Hepatotoxicity
Sandimmun Neoral can also cause dose-dependent, reversible increases in bilirubin and liver enzymes (see section 4.8). There have been cases from clinical trials and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and hepatic infarction in patients treated with cyclosporine. Most of the reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and concomitant therapies with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section 4.8). Careful control of liver function assessment parameters is required and abnormal values may require dose reduction (see sections 4.2 and 5.2).
Elderly (65 years and over)
Renal function should be monitored with particular care in elderly patients.
Monitoring of cyclosporine blood levels (see section 4.2)
When Sandimmun Neoral is used in transplant patients, routine monitoring of cyclosporine blood levels is an important safety measure. For monitoring the blood levels of cyclosporine in whole blood, the use of methods based on specific monoclonal antibodies (determination of the unchanged drug) is preferable; an HPLC method, which is also capable of determining the unchanged drug, can also be used. If plasma or serum is used, a standard separation protocol (time and temperature) must be followed. For initial monitoring of liver transplant patients, to ensure a dosage that provides adequate immunosuppression, specific monoclonal antibody should be used, or simultaneous determinations using both specific and non-specific monoclonal antibody should be performed.
Occasional monitoring of cyclosporine blood levels is recommended in non-transplant patients, eg. when Sandimmun Neoral is administered in combination with substances that may interfere with the pharmacokinetics of cyclosporine or in case of an unusual clinical response (eg lack of efficacy or increased intolerance to the drug which also manifests itself as renal dysfunction).
It should be borne in mind that the concentration of cyclosporine in blood, plasma or serum is only one of many contributing factors to the patient's clinical status. The results should therefore only be used as a guide to dosage determination, together with other parameters. clinical and laboratory.
Hypertension
During Sandimmun Neoral therapy, blood pressure should be checked regularly. If hypertension occurs, "adequate antihypertensive therapy should be used. An antihypertensive medicinal product that does not interfere with cyclosporine pharmacokinetics, eg isradipine, should be preferred (see section 4.5).
Increased blood lipids
Since Sandimmun Neoral has been reported to induce a reversible slight increase in blood lipids, it is advisable to evaluate lipid levels before treatment and after the first month of therapy. In the event of an increase, a low-fat diet should be considered and, if necessary, a reduction in the dose of cyclosporine should be considered.
Hyperkalemia
Ciclosporin increases the risk of hyperkalaemia, especially in patients with renal dysfunction. Particular caution is also recommended when cyclosporine is administered concomitantly with potassium-sparing medicinal products (eg potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) or medicinal products containing potassium, as well as in patients on a potassium-rich diet, in which case a monitoring of potassium levels is recommended.
Hypomagnesemia
Ciclosporin increases the clearance of magnesium. This can lead to symptomatic hypomagnesaemia especially in the period immediately following the transplant. Monitoring of serum magnesium levels in the immediate post-transplant period is therefore recommended, especially in the presence of neurological symptoms / signs. Magnesium supplements should be administered if deemed necessary.
Hyperuricemia
Caution is required in the treatment of patients with hyperuricaemia.
Live attenuated vaccines
During cyclosporine treatment, vaccinations may be less effective. The use of live attenuated vaccines should be avoided (see section 4.5).
Interactions
Caution should be exercised when cyclosporine is administered concomitantly with drugs that substantially increase or decrease plasma concentrations of cyclosporine by inhibition or induction of CYP3A4 and / or P-glycoprotein (see section 4.5).
Renal toxicity should be monitored when initiating the use of ciclosporin with active substances that increase ciclosporin levels or with substances exhibiting nephrotoxic synergy (see section 4.5).
Concomitant use of cyclosporine and tacrolimus should be avoided (see section 4.5).
Ciclosporin is an inhibitor of CYP3A4, P-glycoprotein multidrug efflux pump, organic anion transport proteins (OATP) and may increase plasma levels of concomitantly administered drugs that are substrates of this enzyme and / or transporter. Caution should be exercised when cyclosporine is administered concomitantly with these medicinal products or concomitant use should be avoided (see sections 4.5). Cyclosporine increases exposure to HMG-CoA reductase inhibitors (statins). In case of concomitant administration with cyclosporine, the dosage of statins should be reduced and the concomitant use of some statins should be avoided according to the recommendations in their respective package leaflets. Statin therapy needs to be temporarily suspended or discontinued in patients with signs and symptoms of myopathy or in those with risk factors predisposing to severe renal injury secondary to rhabdomyolysis, including renal failure (see section 4.5).
Following concomitant administration of ciclosporin e lercanidipine, a three-fold increase in the AUC of lercanidipine and a 21% increase in the AUC of cyclosporine was observed. Therefore, the simultaneous combination of cyclosporine and lercanidipine should be avoided. Administration of cyclosporine 3 hours after that of lercanidipine did not result in any change in the AUC of lercanidipine but the AUC of cyclosporine was increased by 27%. Therefore this combination should be administered with caution with an interval of at least 3 hours.
Special excipients: Polyoxyl castor oil 40
Sandimmun Neoral contains polyoxyl 40 castor oil which can cause stomach upset and diarrhea.
Special excipients: Ethanol
Sandimmun Neoral contains approximately 12 vol% ethanol. A 500 mg dose of Sandimmun Neoral contains 500 mg of ethanol equivalent to approximately 15 ml of beer or 5 ml of wine. It can be harmful to alcoholic patients and should be taken into consideration in pregnant or lactating women, in patients with liver disease or epilepsy, or if the patient is a child.
Additional precautions in indications other than transplantation
Patients with impaired renal function (except nephrotic syndrome patients with an acceptable degree of renal insufficiency), uncontrolled hypertension, uncontrolled infections or any type of malignancy should not take cyclosporine.
Baseline renal function should be carefully assessed by at least two eGFR determinations prior to initiation of treatment. Renal function should be evaluated frequently during therapy to allow for dosage adjustments (see section 4.2).
Additional precautions for endogenous uveitis
Sandimmun should be administered with caution to patients with Behcet's syndrome with neurological involvement. The neurological status of these patients must be carefully monitored.
There is only limited experience of the use of Sandimmun Neoral in children with endogenous uveitis.
Additional precautions for nephrotic syndrome
Patients with abnormal renal function at baseline should be treated initially with the dose of 2.5 mg / kg / day and should be monitored very carefully.
In some patients it may be difficult to diagnose Sandimmun Neoral-induced renal dysfunction due to changes in renal function related to the nephrotic syndrome itself. This explains why, in rare cases, structural renal changes associated with Sandimmun Neoral have been observed without increases in serum creatinine. Renal biopsy should be considered for patients with steroid-dependent mild renal lesions in whom Sandimmun Neoral has been administered for more than 1 year.
Cases of malignancies (including Hodgkin's lymphoma) have occasionally been reported in patients with nephrotic syndrome treated with immunosuppressants (including cyclosporine).
Additional precautions for rheumatoid arthritis
After 6 months of therapy, renal function should be evaluated every 4-8 weeks in relation to the stability of the disease, concomitant drugs and concomitant diseases. More frequent monitoring is required if the dose of Sandimmun Neoral is increased or concomitant treatment with an NSAID is initiated or its dosage is increased. , "hypertension that cannot be controlled with" appropriate therapy develops.
As with other long-term treatments with immunosuppressive drugs, the possibility of an increased risk of developing lymphoproliferative diseases should be borne in mind. Particular care should be taken when Sandimmun Neoral is administered in combination with methotrexate due to synergistic nephrotoxic effects.
Additional precautions for psoriasis
Discontinuation of Sandimmun Neoral therapy is recommended if "hypertension that cannot be controlled with" appropriate therapy develops during treatment.
Elderly patients should only be treated for disabling psoriasis and renal function should be carefully monitored.
There is only limited experience of using Sandimmun Neoral in children with psoriasis.
Malignant neoplasms (mainly cutaneous) have been reported in patients with psoriasis treated with cyclosporine, as well as in those treated with conventional immunosuppressive therapies. Skin lesions not typical of psoriasis, which could suggest neoplastic or pre-neoplastic malignant lesions, should be biopsied before starting treatment with Sandimmun Neoral. Patients presenting with neoplastic or pre-malignant skin changes should start treatment with Sandimmun Neoral only after adequate treatment of these lesions and only if there are no effective therapeutic alternatives.
Lymphoproliferative disorders have occurred in a few psoriatic patients treated with Sandimmun Neoral. These were sensitive to prompt discontinuation of treatment.
Patients treated with Sandimmun Neoral should not be exposed to ultraviolet B light or photochemotherapy with PUVA at the same time.
Additional precautions for atopic dermatitis
Discontinuation of Sandimmun Neoral therapy is recommended if "hypertension that cannot be controlled with" appropriate therapy develops during treatment.
Experience with Sandimmun Neoral in children with atopic dermatitis is limited.
Elderly patients should only be treated for disabling atopic dermatitis and renal function should be carefully monitored.
Benign lymphadenopathy is usually associated with a flare-up of atopic dermatitis and always disappears spontaneously or with general improvement of the disease.
Lymphadenopathy observed during cyclosporine treatment should be checked regularly.
If lymphadenopathy persists, despite improvement in atopic dermatitis, a biopsy should be performed as a precautionary measure to ascertain the absence of lymphoma.
Active herpes simplex infections should be allowed to resolve before starting treatment with Sandimmun Neoral; however, if they occur during therapy, these infections are not necessarily a reason for treatment discontinuation, unless they are severe
Skin infections from Staphylococcus aureus they are not an absolute contraindication to Sandimmun Neoral therapy, but should be controlled with suitable antibacterial agents. Oral administration of erythromycin, which has the potential to increase the blood concentration of ciclosporin, should be avoided (see section 4.5). In the absence of a therapeutic alternative, it is recommended to closely monitor cyclosporine blood levels, renal function, as well as any undesirable effects of cyclosporine.
Patients treated with Sandimmun Neoral should not be exposed to ultraviolet B light or photochemotherapy with PUVA at the same time.
Pediatric use in indications other than transplantation
Except for the treatment of nephrotic syndrome, there is no adequate experience with Sandimmun Neoral. Use in children under 16 years of age in indications other than transplantation is not recommended with the exception of nephrotic syndrome.
04.5 Interactions with other medicinal products and other forms of interaction
Interactions with Medicines
Of the various drugs that interact with cyclosporine, those for which interactions have been adequately proven and which have clinical consequences are listed below.
It is known that various drugs are able to increase or decrease the plasma or blood concentrations of cyclosporine, acting by competitive inhibition or induction of the enzymes involved in its metabolism, in particular CYP3A4.
Ciclosporin is also an inhibitor of CYP3A4, multidrug efflux transporter P-glycoprotein and organic anion transporter proteins (OATP), and may increase plasma levels of concomitant drugs that are substrates of the same enzyme and / or transporter.
Medicinal products known to reduce or increase the bioavailability of ciclosporin: In transplant patients, ciclosporin levels should be frequently measured and, if necessary, their dosage adjusted, particularly during initiation or discontinuation of concomitantly administered medicinal products. at transplant, the relationship between blood levels and clinical effects is less well established.When medicinal products known to increase levels are administered concomitantly with cyclosporine, frequent assessment of renal function and careful monitoring of cyclosporin-related side effects may be more appropriate than determination of blood levels.
Medicines that decrease cyclosporine levels
All inducers of CYP3A4 and / or P-glycoprotein are expected to decrease cyclosporin levels. Examples of drugs that decrease cyclosporin levels are:
Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine i.v; probucol, orlistat, hypericum perforatum (St. John's wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan.
Products containing Hypericum perforatum (St. John's wort) should not be used concomitantly with Sandimmun Neoral due to the risk of decreased blood levels of cyclosporine and therefore decreased effect (see section 4.3).
Rifampicin induces the intestinal and hepatic metabolism of cyclosporine. Doses of cyclosporine may need to be increased 3-5 times during concomitant administration.
Octreotide oral absorption of cyclosporine decreases therefore a 50% increase in the dose of cyclosporine or a switch to intravenous administration may be required.
Medicines that increase cyclosporine levels
All inhibitors of CYP3A4 and / or P-glycoprotein can lead to an increase in cyclosporine levels.
Examples are:
Nicardipine, metoclopramide, oral contraceptives, methylprednisolone (high doses), allopurinol, cholic acid and derivatives, protease inhibitors, imatinib, colchicine, nefazodone.
Macrolide antibiotics: Erythromycin exposure to cyclosporine may increase 4-7 times, sometimes causing nephrotoxicity. It has been reported that clarithromycin double exposure to cyclosporine. Azithromycin increases cyclosporine levels by about 20%.
Azole antibiotics: Ketoconazole, fluconazole, itraconazole and voriconazole they can increase cyclosporine exposure by more than double.
Verapamil increases the blood concentrations of cyclosporine by 2-3 times.
Concomitant administration of telaprevir resulted in an approximately 4.64-fold increase in normalized cyclosporine dose exposure (AUC).
Amiodarone significantly increases the plasma concentration of cyclosporine simultaneously with an increase in serum creatinine. This interaction can occur long after amiodarone is discontinued due to its very long half-life (approximately 50 days).
It has been reported that danazol increases the blood concentrations of cyclosporine by approximately 50%.
Diltiazem (at doses of 90 mg / day) can increase cyclosporine plasma concentrations by up to 50%.
Imatinib may increase ciclosporin exposure and Cmax by approximately 20%.
Interactions with food
The concomitant intake of grapefruit and grapefruit juice has been reported to increase the bioavailability of cyclosporine.
Associations with increased risk of nephrotoxicity
Care should be taken when administering cyclosporine in combination with other active ingredients with synergistic nephrotoxic effects, such as: aminoglycosides (including gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); fibric acid derivatives (e.g. bezafibrate, fenofibrate); NSAIDs (including diclofenac, naproxen, sulindac); melphalan; H2 receptor antagonists (e.g. cimetidine, ranitidine); methotrexate (see section 4.4).
During concomitant use of a drug that may exhibit nephrotoxic synergy, careful monitoring of renal function should be performed. If significant renal impairment occurs, the dose of the concomitantly administered medicinal product should be reduced or an alternative treatment considered.
The concomitant use of cyclosporine and tacrolimus should be avoided due to the risk of nephrotoxicity and pharmacokinetic interaction via CYP3A4 and / or P-gp (see section 4.4).
Effects of cyclosporine on other drugs
Ciclosporin is an inhibitor of CYP3A4, P-glycoprotein multidrug efflux pump (P-gp) and organic anion transport proteins (OATP). Concomitant administration of cyclosporine and drugs that are substrates of CYP3A4, P-gp and OATP may increase the plasma levels of concomitantly administered drugs that are substrates of this enzyme and / or transporter.
Some examples are listed below:
Ciclosporin may reduce the clearance of digoxin, colchicine, HMG-CoA reductase inhibitors (statins) and etoposide. If any of these medicinal products are administered concomitantly with cyclosporine, careful clinical observation is required to allow for early detection of the toxic manifestations of the medicinal products, followed by dose reduction or discontinuation of the medicinal products. When administered concomitantly with ciclosporin, the dosage of statins should be reduced and the concomitant use of some statins should be avoided according to the recommendations in their respective package leaflets. Exposure changes of commonly used statins with ciclosporin are summarized in Table 1. Statin therapy should be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or in those who have risk factors predisposing to severe renal damage secondary to rhabdomyolysis, including renal failure.
Table 1. Summary of changes in exposure of commonly used statins with cyclosporine
Caution is recommended when cyclosporine is co-administered with lercanidipine (see section 4.4).
Following concomitant administration of ciclosporin e aliskiren, a substrate of P-gp, aliskiren Cmax was increased approximately 2.5-fold and AUC approximately 5-fold. However, the pharmacokinetic profile of ciclosporin was not significantly altered. Concomitant administration of ciclosporin and aliskiren was not recommended (see section 4.3).
Co-administration of dabigatran etexilate is not recommended due to cyclosporine's P-gp inhibitor activity (see section 4.3).
The simultaneous administration of nifedipine and cyclosporine can cause an increase in the incidence of gingival hyperplasia, compared to what occurs with cyclosporine alone.
It has been observed that the concomitant administration of diclofenac and cyclosporine causes a significant increase in the bioavailability of diclofenac with the possible consequence of a reversible alteration of renal function. The increased bioavailability of diclofenac is most likely caused by the reduction of the intense first pass effect to which the molecule is subjected. In the event that a NSAIDs with reduced first pass effect (e.g. acetylsalicylic acid) is administered together with cyclosporine, an increase in their bioavailability is not expected.
In clinical trials with everolimus or sirolimus in combination with cyclosporine in full dose microemulsion elevations in serum creatinine have been observed. This effect was often reversible with a reduction in the dose of cyclosporine. Everolimus and sirolimus only minimally affected cyclosporine pharmacokinetics. Concomitant administration of cyclosporine significantly increases the blood levels of everolimus and sirolimus.
Caution is required in concomitant use of potassium-sparing drugs (e.g. potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or drugs containing potassium as they could lead to significant increases in serum potassium (see section 4.4).
Ciclosporin can increase plasma concentrations of repaglinide and therefore increase the risk of hypoglycemia.
In healthy volunteers the co-administration of bosentan and cyclosporine increased bosentan exposure several times and there was a 35% decrease in cyclosporine exposure. Co-administration of ciclosporin with bosentan is not recommended (see above sub-section "Medicinal products that lower cyclosporine levels" and section 4.3).
In healthy volunteers the administration of multiple doses of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure, while cyclosporine exposure increased marginally (approximately 10%).
In cancer patients with concomitant administration of intravenous anthracyclines and very high doses of cyclosporine, a significant increase in exposure to anthracyclines (ex. doxorubicin, mitoxantrone, daunorubicin).
During treatment with cyclosporine, vaccination may be less effective and the use of live attenuated vaccines should be avoided.
Pediatric population
Interaction studies have only been performed in adults.
04.6 Pregnancy and lactation
Pregnancy
Animal studies have shown reproductive toxicity in rats and rabbits.
Experience with Sandimmun Neoral in pregnant women is limited. Pregnant transplant women treated with immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at risk of premature birth (
A limited series of observations is available on children up to about 7 years of age who have been exposed to cyclosporine in the stage of uterine life. In these children, renal function and blood pressure were found to be normal. However, no studies have been conducted. adequate and controlled in pregnant women and therefore, Sandimmun Neoral should not be used in pregnancy unless the potential benefit to the mother justifies the potential fetal risk. The ethanol content of the Sandimmun Neoral formulations should also be taken into account in the pregnant women (see section 4.4).
Feeding time
Cyclosporine passes into breast milk. The ethanol content of Sandimmun Neoral formulations should also be taken into account in breastfeeding women (see section 4.4). Mothers being treated with Sandimmun Neoral should not breastfeed due to the potential of Sandimmun Neoral to cause serious adverse reactions in breastfed infants / children. A decision must be made whether to abstain from breastfeeding or from using the medicinal product taking into account the importance of the medicinal product to the mother.
Fertility
There are limited data on the effect of Sandimmun Neoral on human fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
There are no data on the effects of Sandimmun Neoral on the ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
The main adverse reactions observed in clinical trials and associated with cyclosporine administration include renal dysfunction, tremor, hirsutism, hypertension, diarrhea, anorexia, nausea and vomiting.
Many undesirable effects associated with cyclosporine therapy are dose dependent and respond to dose reduction. In the different indications the overall profile of the side effects is essentially the same; however, there are differences in incidence and severity. Due to the higher starting doses and the longer duration of maintenance therapy required after transplantation, undesirable effects are more frequent and commonly more severe in transplant patients than in patients treated for other indications.
Anaphylactoid reactions have been observed after intravenous administration (see section 4.4).
Infections and infestations
Patients treated with immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic) (see section 4.4). Generalized and localized infections can arise. Pre-existing infections can also worsen, and reactivation of polyomavirus infections can lead to polyomavirus associated nephropathy (PVAN) or JC virus associated progressive multifocal leukoencephalopathy (PML). Serious and / or fatal outcomes have been reported.
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Patients treated with immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at increased risk of developing lymphoma or lymphoproliferative disorders and other cancers, particularly of the skin. The frequency of tumors increases with the intensity and duration of therapy (see section 4.4). Some tumors can be fatal.
Summary table of adverse drug reactions observed in clinical trials
Adverse drug reactions observed in clinical trials (Table 1) are listed based on MedDRA system organ class. Within each system organ class, adverse drug reactions are listed by frequency, with the most frequent first. Within each frequency class, adverse drug reactions are listed in descending order of severity. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1 / 10); common (≥1 / 100,
Table 1: Adverse drug reactions observed in clinical studies
Other adverse reactions based on post-marketing experience
There have been cases from clinical trials and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and hepatic infarction in patients treated with cyclosporine. Most of the reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and concomitant therapies with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section 4.4).
Acute and chronic nephrotoxicity
Patients being treated with calcineurin inhibitor (CNI) therapies, including cyclosporin and cyclosporin-containing regimens, are at increased risk of acute or chronic nephrotoxicity. There have been reports from clinical and post-marketing studies associated with the use of Sandimmun Neoral. Cases of acute nephrotoxicity have reported disturbances of ion homeostasis, such as hyperkalaemia, hypomagnesaemia and hyperuricaemia. Cases reporting chronic morphological changes include arteriolar hyalinosis, tubular atrophy and interstitial fibrosis (see section 4.4).
Pediatric population
Clinical trials included children aged 1 year and above who received standard dose cyclosporine with a safety profile comparable to that of adults.
04.9 Overdose
The oral LD of cyclosporine is 2,329 mg / kg in mice, 1,480 mg / kg in rats and> 1,000 mg / kg in rabbits. The intravenous LD of cyclosporine is 148 mg / kg in mice, 104 mg / kg in rats and 46 mg / kg in rabbits.
Symptoms
Experience with acute cyclosporine overdose is limited.Oral doses of cyclosporine up to 10 g (approximately 150 mg / kg) have been tolerated with relatively minor clinical consequences such as vomiting, somnolence, headache, tachycardia and, in a few patients, moderately severe and reversible renal impairment. However, severe symptoms of intoxication have been reported following accidental overdose with cyclosporine after parenteral administration in premature infants.
Treatment
In all cases of overdose, general supportive measures should be followed and symptomatic treatment instituted. Forced emesis and gastric lavage may be useful within the first hours of oral intake. Cyclosporine is poorly dialyzable and cannot be effectively eliminated by the carbon filters of hemoperfusion.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: immunosuppressive substances, calcineurin inhibitor.
ATC code: L04AD01.
Cyclosporine (also called cyclosporine A) is a cyclic polypeptide made up of 11 amino acids. It is a potent immunosuppressant capable of prolonging the survival of allogeneic transplants of skin, heart, kidney, pancreas, bone marrow, small intestine or lung in animals. Studies have shown that cyclosporine inhibits the development of immune reactions cell-mediated, including allogeneic transplant immunity, delayed skin hypersensitivity reactions, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft versus host reaction (GVHD) and also the production of T lymphocytes At the cellular level, it inhibits the production and release of lymphokines, including interleukin 2 (T-cell growth factor, TCGF). Ciclosporin is found to block quiescent lymphocytes in the G0 or G1 phase of the cell cycle and inhibits the release , triggered by the antigen, of lymphokines by activated T cells.
All available evidence indicates that cyclosporine acts on lymphocytes in a specific and reversible way. Unlike cytostatic agents, it does not depress hematopoiesis and does not alter the function of phagocytes.
In humans, organ and bone marrow transplants have been successfully performed using cyclosporine for the prevention and treatment of rejection and GVHD. Ciclosporin has also been used successfully in liver transplant patients positive or negative for hepatitis C virus (HCV). The beneficial effects of cyclosporine therapy have also been observed in a number of diseases of autoimmune origin or which may be considered as such.
Pediatric population: Ciclosporin has been shown to be effective in steroid-dependent nephrotic syndrome.
05.2 "Pharmacokinetic properties
Absorption
After oral administration of Sandimmun Neoral the peak blood concentration of cyclosporine is reached within 1-2 hours. After administration of Sandimmun Neoral the absolute oral bioavailability of cyclosporine is 20-50%. A decrease in AUC and Cmax of approximately 13 and 33% was observed when Sandimmun Neoral was administered with a high-fat meal. The relationship between administered dose and cyclosporine exposure (AUC) is linear over the therapeutic dose range. Individual and intra-subject variability in AUC and Cmax is approximately 10-20%. Sandimmun Neoral oral solution and soft gelatin capsules are bioequivalent.
Compared to Sandimmun, administration of Sandimmun Neoral results in a 59% higher Cmax and 29% higher bioavailability. Available data indicate that when switching from Sandimmun soft gelatin capsules to Sandimmun Neoral soft gelatin capsules with a 1: 1 dose ratio, the trough concentrations in whole blood are comparable and remain within the desired therapeutic range. Administration of Sandimmun Neoral it improves the linearity of the cyclosporine exposure dose (AUCB). Compared to Sandimmun, it guarantees a more constant absorption profile, less influenced by concomitant food intake or daily rhythm.
Distribution
Ciclosporin is largely distributed outside the blood volume with a mean apparent volume of distribution of 3.5 l / kg. In the blood, 33-47% is found in plasma, 4-9% in lymphocytes, 5-12% in granulocytes and 41-58% in erythrocytes. About 90% of it is bound to proteins in plasma, mainly to lipoproteins.
Biotransformation
Ciclosporin is metabolised to a large extent giving rise to approximately 15 metabolites. Metabolism takes place mainly in the liver via cytochrome P450 3A4 (CYP3A4) and the main metabolic pathways are mono- and dihydroxylation and N-demethylation in different positions of the molecule. All the metabolites identified so far contain the unaltered peptide structure of the compound from which they derive, some possess a weak immunosuppressive activity (up to a tenth of the original drug).
Elimination
Elimination occurs mainly via the biliary route, only 6% of the oral dose is excreted in the urine, of which only 0.1% in unchanged form.
There was a high variability of the reported data on the terminal half-life of cyclosporine, this depends on the analytical method adopted and the type of population. The terminal half-life varies from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe hepatic insufficiency (see sections 4.2 and 4.4). The elimination half-life in kidney transplant patients was approximately 11 hours, ranging from 4 to 25 hours.
Special populations
Patients with renal insufficiency
In a study in patients with end stage renal insufficiency, systemic clearance was approximately two thirds of the mean systemic clearance in patients with normal renal function. Less than 1% of the administered dose is eliminated by dialysis.
Patients with hepatic impairment
An approximately 2 to 3-fold increase in cyclosporine exposure can be observed in patients with hepatic impairment. In a study in patients with severe liver disease with biopsy-proven cirrhosis, the terminal half-life was 20.4 hours ( range between 10.8 and 48.0 hours) compared to 7.4-11.0 hours in healthy subjects.
Pediatric population
Pharmacokinetic data from pediatric patients treated with Sandimmun Neoral and Sandimmun are very limited. In 15 kidney transplant patients aged 3-16 years, the total blood clearance of ciclosporin following intravenous administration of Sandimmun was 10.6 ± 3.7 ml / min / kg (assay: Ciclo-trac specific RIA). In a study with 7 kidney transplant patients aged 2-16 years, the clearance of ciclosporin ranged from 9.8 to 15.5 ml / min / kg. In 9 liver transplant patients aged 0.6-5.6 years, clearance was 9.3 ± 5.4 ml / min / kg (assay: HPLC). Compared to adult transplant populations, the differences in bioavailability between Sandimmun Neoral and Sandimmun in the pediatric population are comparable to those seen in adults.
05.3 Preclinical safety data
Ciclosporin did not give any evidence of mutagenic or teratogenic effects in standard tests performed with oral administration (up to 17 mg / kg / day in rats and up to 30 mg / kg / day in rabbits orally). At toxic doses (30 mg / kg / day in rats and 100 mg / kg / day in rabbits orally), ciclosporin was found to be embryo and foetotoxic, as evidenced by the "increase in pre and postnatal mortality and the reduction fetal weight associated with delays in the development of the skeletal system.
In two published studies, rabbits exposed to ciclosporin (10 mg / kg / day subcutaneously) in the uterine life stage showed reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal failure up to the age of 35 weeks. Pregnant rats that received intravenous cyclosporine 12 mg / kg / day (double the recommended intravenous dose in humans) produced fetuses with an increased incidence of ventricular septal defect. These findings have not been confirmed in other species and their relevance to humans is unknown. Impairment of fertility has not been demonstrated in male and female rat studies.
Ciclosporin has been studied in a series of tests in vitro And in vivo for genotoxicity without any evidence of a clinically relevant mutagenic potential.
Carcinogenicity studies were conducted in male and female rats and mice. In the 78-week study conducted in mice, at doses of 1, 4 and 16 mg / kg / day, there was a statistically significant trend in the development of lymphocytic lymphomas in females, and an incidence of hepatocellular carcinomas in males treated with mean dose, significantly higher than controls. In the 24-month study in the rat treated with 0.5, 2 and 8 mg / kg / day, pancreatic islet cell adenomas appeared at the lowest dose at a significantly higher frequency than controls. Hepatocellular carcinomas and pancreatic islet cell adenomas are not dose related.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sandimmun Neoral 10 mg soft capsules
Capsule contents
Alpha-tocopherol
Absolute ethanol
Propylene glycol
Corn oil mono-di-triglycerides
Macrogolglycerol hydroxystearate / polyoxyl-40 hydrogenated castor oil.
Capsule shell
Titanium dioxide (E 171)
Glycerol 85%
Propylene glycol
Jelly
Impression
Carminic acid (E 120)
Sandimmun Neoral 25 mg soft capsules
Capsule contents
Alpha-tocopherol
Absolute ethanol
Propylene glycol
Corn oil mono-di-triglycerides
Macrogolglycerol hydroxystearate / polyoxyl-40 hydrogenated castor oil
Capsule shell
Black iron oxide (E172)
Titanium dioxide (E171)
Glycerol 85%
Propylene glycol
Jelly
Impression
Carminic acid (E120)
Sandimmun Neoral 50 mg soft capsules
Capsule contents
Alpha tocopherol
Absolute ethanol
Propylene glycol
Corn oil mono-di-triglycerides
Macrogolglycerol hydroxystearate / polyoxyl-40 hydrogenated castor oil
Capsule shell
Titanium dioxide (E171)
Glycerol 85%
Propylene glycol
Jelly
Impression
Carminic acid (E120)
Sandimmun Neoral 100 mg soft capsules
Capsule contents
Alpha-tocopherol
Absolute ethanol
Propylene glycol
Corn oil mono-di-triglycerides
Macrogolglycerol hydroxystearate / polyoxyl-40 hydrogenated castor oil
Capsule shell
Black iron oxide (E172)
Titanium dioxide (E 171)
Glycerol 85%
Propylene glycol
Jelly
Impression
Carminic acid (E 120)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Sandimmun Neoral capsules can be stored at room temperature not exceeding 25 ° C. Increases in temperature up to 30 ° C for a total of up to 3 months do not affect the quality of the medicine. Sandimmun Neoral capsules should be left in the blister until taken. A characteristic odor may be detected when the blister is opened. This is normal and does not affect the use of the medicine.
06.5 Nature of the immediate packaging and contents of the package
Double-sided aluminum blister consisting of aluminum foil on the underside and aluminum foil on the top.
Sandimmun Neoral 10 mg soft capsules - 50 capsules
Sandimmun Neoral 25 mg soft capsules - 50 capsules
Sandimmun Neoral 50 mg soft capsules - 50 capsules
Sandimmun Neoral 100 mg soft capsules - 30 capsules
06.6 Instructions for use and handling
No special instructions.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
UK
08.0 MARKETING AUTHORIZATION NUMBER
Sandimmun Neoral 10 mg soft capsules - A.I.C. n. 029453053
Sandimmun Neoral 25 mg soft capsules - A.I.C. n. 029453014
Sandimmun Neoral 50 mg soft capsules - A.I.C. n. 029453026
Sandimmun Neoral 100 mg soft capsules - A.I.C. n. 029453038
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Sandimmun Neoral 10 mg soft capsules
First authorization: 27.06.2001
Renewal: 09.09.2010
Sandimmun Neoral 25 mg soft capsules
Sandimmun Neoral 50 mg soft capsules
Sandimmun Neoral 100 mg soft capsules
First authorization: 31.08.1995
Renewal: 09.09.2010
10.0 DATE OF REVISION OF THE TEXT
04.11.2013
