SANDIMMUN NEORAL 100 MGML ORAL SOLUTION

Ciclosporin

Sandimmun Neoral

®

Ciclosporin

לרואינ ןומיאדנס ﻝﺍﺭﻮﺌﻴﻧ ﻥﻮﻤﻳﺪﻧﺎﺳ

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS’ REGULATIONS

(PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

Sandimmun

Sandimmun

Sandimmun

Neoral

®

25 mg

Neoral

®

50 mg

Neoral

®

100 mg

Capsules

Capsules

Capsules

Each capsule contains:

Ciclosporin 25 mg

Ciclosporin 50 mg

Ciclosporin 100 mg

Sandimmun Neoral

®

100 mg/ml Oral Solution

Oral solution: Each 1 ml contains: Ciclosporin 100 mg

Inactive ingredients: see section 6 “Further information”. Also see section “Important information regarding some of the

ingredients of the medicine”.

Read this leaflet carefully in its entirety before using the medicine. This leaflet contains concise information about the

medicine. If you have further questions, refer to the doctor or pharmacist.

This medicine has been prescribed for the treatment of your ailment. Do not pass it on to others. It may harm them even if it

seems to you that their ailment is similar.

1. WHAT IS THE MEDICINE INTENDED FOR?

1. Prophylactic treatment for graft rejection in kidney, liver and heart transplantation, in combination with corticosteroids.

2. Treatment during a bone marrow transplantation.

3. Treatment of uveitis that is not from an infectious origin (Endogenous uveitis).

4. Treatment of nephrotic syndrome (Minimal Change Disease MCD type) when conventional therapy has failed.

5. Treatment of severe cases of rheumatoid arthritis when standard treatment is ineffective or inappropriate.

6. Treatment of severe cases of psoriasis in patients above 16 years of age that do not respond to other treatment.

7. Treatment of severe cases of atopic dermatitis in adults, for up to 8 weeks only, when conventional therapy is ineffective or

inappropriate.

If you have undergone an organ or bone marrow transplantation, the function of Sandimmun Neoral is to control your body’s

immune system. Sandimmun Neoral prevents rejection of transplanted organs by blocking the development of special cells

which would normally attack the transplanted tissue.

If you suffer from a non-transplant disease, where your body’s own immune response attacks the cells in your body (autoimmune

disease), Sandimmun Neoral suppresses immunoreactions in these diseases.

Therapeutic group: Immunosuppressants.

2. BEFORE USING THE MEDICINE

If you are taking Sandimmun Neoral after a transplant, the medicine will only be prescribed for you by a specialist experienced

in transplants and/or autoimmune diseases. The information in this leaflet may change in accordance with the reason for which

the medicine is being taken - after a transplant or for treatment of autoimmune diseases.

Follow your doctor’s instructions exactly. They may be different than the general information in this leaflet.

X

Do not use the medicine if:

∙ you are allergic to ciclosporin or to any of the other ingredients of the medicine, listed in section 6.

∙ you are taking preparations containing Hypericum perforatum (St. John’s wort).

∙ you are taking preparations containing dabigatran etexilate (to prevent blood clots after surgery) or bosentan and aliskiren

(to treat hypertension).

If these conditions apply to you, inform the doctor without taking Sandimmun Neoral. If you are unsure, consult the

doctor before starting treatment with Sandimmun Neoral.

Special warnings regarding use of the medicine:

!

Before and during treatment with Sandimmun Neoral, inform the doctor immediately:

∙ If you have signs of infection, such as fever or a sore throat. Sandimmun Neoral suppresses the immune system and may

affect the ability of the body to fight infections.

∙ If you suffer from liver problems.

∙ If you suffer from kidney problems. Your doctor will carry out regular blood tests and may adjust the dosage if necessary.

∙ If you develop high blood pressure. Your doctor will check your blood pressure regularly and may give you a medicine to lower

blood pressure if necessary.

∙ If you have low magnesium levels. Your doctor may give you magnesium supplements, especially after an organ transplant

operation.

∙ If you have high blood potassium levels.

∙ If you suffer from gout.

∙ If you need to be vaccinated.

If these conditions apply to you before or during treatment with Sandimmun Neoral, refer to the doctor immediately.

!

Protection from sun exposure

Sandimmun Neoral suppresses the immune system. This increases the risk of developing cancers, particularly cancer of the

skin and lymphatic system. Limit exposure to sunlight and UV light by wearing protective clothes and frequently applying

sunscreen with a high protection factor.

!

Inform the doctor before starting treatment, if:

∙ you have or had problems related to alcohol dependence

∙ you have epilepsy

∙ you have any liver problems

∙ you are pregnant

∙ you are breastfeeding

∙ the medicine is given to a child

If these conditions apply to you (or if you are unsure), refer to the doctor before taking Sandimmun Neoral. This is because the

medicine contains alcohol (ethanol). See section “Use of the medicine and alcohol consumption”.

!

Tests during the course of treatment with Sandimmun Neoral

Your doctor will perform the following tests:

∙ levels of ciclosporin in your blood - especially if you have undergone a transplant.

∙ blood pressure before starting treatment and regularly during treatment.

∙ liver and kidney function.

∙ blood lipid levels.

If you have questions regarding how to use this medicine, or why this medicine has been prescribed for you, refer to the

doctor.

!

If you are taking Sandimmun Neoral for a non-transplant disease (such as: uveitis, intermediary or posterior uveitis

or Behçet’s uveitis, atopic dermatitis, severe rheumatoid arthritis or nephrotic syndrome), do not take Sandimmun Neoral if

you have:

∙ kidney problems (except for nephrotic syndrome)

∙ infections which are not under control with medication

∙ any type of cancer

∙ high blood pressure which is not under control with medication. If you develop high blood pressure during treatment and it

cannot be controlled, your doctor must stop treatment with Sandimmun Neoral.

Do not take Sandimmun Neoral if any of the above conditions apply to you. If you are unsure, refer to the doctor or pharmacist

before taking Sandimmun Neoral.

If you are being treated for Behçet’s uveitis, the doctor will monitor the course of treatment with Sandimmun Neoral particularly

carefully if you have neurological symptoms (for example: increased forgetfulness, personality changes noticed over time,

psychiatric or mood disorders, “burning” sensation in the limbs, decreased sensation in the limbs, tingling sensation in the

limbs, weakness of the limbs, walking disorders, headache with or without nausea and vomiting, vision disorders, including

restricted movement of the eye).

If you are elderly and are being treated with Sandimmun Neoral for psoriasis or atopic dermatitis, avoid exposure to any type

of UVB rays or phototherapy during the course of treatment. The doctor will closely monitor the course of treatment.

!

Children and adolescents

Do not give Sandimmun Neoral to children for a non-transplant disease, except for treatment of nephrotic syndrome.

!

Elderly population (65 years of age and older)

There is limited experience with administration of Sandimmun Neoral in elderly patients. Your doctor should monitor your kidney

function. If you are over the age of 65 and have psoriasis or atopic dermatitis, you will only be treated with Sandimmun Neoral

if your condition is particularly severe.

!

Drug interactions:

If you are taking, or have recently taken, other medicines, including non-prescription medicines or nutritional

supplements, tell the doctor or pharmacist.

Inform the doctor or pharmacist before taking Sandimmun Neoral, particularly if you are taking:

∙ Medicines that may affect your potassium levels, such as medicines which contain potassium, potassium supplements,

potassium-sparing diuretics and some medicines which lower your blood pressure.

∙ Methotrexate. This medicine is used to treat tumors, severe psoriasis and severe rheumatoid arthritis.

Medicines which may increase or decrease the levels of ciclosporin (the active substance of Sandimmun Neoral) in the blood. The

doctor might check the concentration of ciclosporin in your blood when starting or stopping treatment with other medicines.

Medicines which may increase the level of ciclosporin in your blood: antibiotics (such as erythromycin, azythromycin),

anti-fungals (voriconazole, itraconazole), medicines used for heart problems or high blood pressure (such as: diltiazem,

nicardipine, verapamil, amiodarone), metoclopramide (used to stop nausea), oral contraceptives, danazol (used to treat menstrual

disorders), medicines used to treat gout (allopurinol), cholic acid and its derivatives (used to treat gallstones), protease inhibitors

used to treat AIDS, imatinib (used to treat leukemia or tumors), colchicine, telaprevir (used to treat hepatitis C).

∎ Medicines which may decrease the level of ciclosporin in your blood: barbiturates (medicines used to induce sleep), some

anti-convulsants (such as carbamazepine, phenytoin), octreotide (used to treat acromegaly or neuroendocrine tumors in

the gut), anti-bacterial medicines used to treat tuberculosis, orlistat (helps weight loss), herbal medicines containing St.

John’s wort, ticlopidine (used after a stroke), certain medicines which lower blood pressure (bosentan), and terbinafine (an

anti-fungal medicine used to treat infections of the toes and nails).

∙ Other medicines which may affect the kidneys, such as: anti-bacterial medicines (gentamycin, tobramycin, ciprofloxacin),

anti-fungal medicines which contain amphotericin B, medicines used for urinary tract infections which contain trimethoprim,

medicines used to treat cancer which contain melphalan, medicines used to lower the amount of acid in the stomach (acid

secretion inhibitors of the H2-receptor antagonist type), tacrolimus, pain killers (non-steroidal anti-inflammatory medicines

such as diclofenac), fibric acid (used to lower fat in the blood).

∙ Nifedipine, used to treat high blood pressure and angina. Gum swelling that might spread toward the teeth may occur when

taking nifedipine during the course of treatment with ciclosporin.

∙ Digoxin (used to treat heart problems), medicines which lower cholesterol (HMG-CoA reductase inhibitors also called statins),

prednisolone, etoposide (used to treat cancer), repaglinide (an oral anti-diabetic preparation), immunosuppressants (everolimus,

sirolimus), ambrisentan and specific anti-cancer medicines called anthracyclines (such as doxorubicin).

If any of these conditions apply to you (or you are unsure), refer to the doctor before taking Sandimmun Neoral.

!

Use of the medicine and food

Do not take Sandimmun Neoral with grapefruit or grapefruit juice, since this may affect the activity of the medicine.

!

Pregnancy and breastfeeding

Consult the doctor or pharmacist before taking this medicine. The doctor will discuss with you the potential risks of taking

Sandimmun Neoral during pregnancy.

Tell the doctor if you are pregnant or intend to become pregnant. Experience with Sandimmun Neoral in pregnancy is

limited. In general, Sandimmun Neoral should not be taken during pregnancy. If you must take this medicine, the doctor will

discuss with you the benefits and potential risks associated with taking the medicine during pregnancy.

Tell the doctor if you are breastfeeding. Breastfeeding is not recommended during treatment with Sandimmun Neoral,

since ciclosporin, the active substance in Sandimmun Neoral, passes into breast milk and may affect your baby.

Hepatitis C

Tell your doctor if you have hepatitis C. Your liver functions may change during hepatitis C treatment, which may affect the

ciclosporin levels in your blood. Your doctor may have to carefully monitor the ciclosporin levels in your blood and adjust the

dosage after you start hepatitis C treatment.

!

Driving and using machines

Sandimmun Neoral contains alcohol. This may affect your ability to drive or use machines.

In regards to children, they should be cautioned against riding bicycles or playing near the road, and the like.

!

Use of the medicine and alcohol consumption

Sandimmun Neoral contains approximately 12.0% ethanol (alcohol). For example, a 500 mg dose given to transplant patients

has alcohol equivalent to approximately 15 ml beer or 5 ml wine per dose.

Alcohol may be harmful if you have problems related to alcohol dependence, epilepsy, brain injury, liver problems, and in

pregnant or breastfeeding women and in children.

!

Important information regarding some of the ingredients of the medicine

Sandimmun Neoral contains castor oil, which may cause stomach discomfort and diarrhea.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions. Check with the doctor or pharmacist if you are uncertain about the dosage

and treatment regimen of the preparation.

Do not exceed the recommended dose.

The dosage of the medicine will be adjusted for you by the doctor only, according to your specific needs. A too high dosage may

affect the kidneys. Therefore, undergo blood tests and visit a hospital regularly, especially after a transplant. This will enable

you to discuss the treatment with the doctor and to indicate the problems you experience.

The dosage and frequency of administration

The doctor will adjust the right dosage of Sandimmun Neoral for you, depending on your body weight and the reason you are

taking the medicine. The doctor will also tell you how often to take the medicine.

Follow the doctor’s instructions exactly, and never change the dosage on your own, even if you feel well.

If you were previously taking a different dosage form of oral ciclosporin:

The doctor will monitor the ciclosporin levels in your blood very closely for a short time following the switch from one oral

dosage form to another.

When you switch from one oral ciclosporin dosage form to another, you may experience side effects. If this happens, please

tell the doctor or pharmacist, as the dosage you are taking will have to be adjusted. Never change the dosage on your own,

unless instructed to do so by the doctor.

Directions for use:

When to take Sandimmun Neoral

It is important to take the medicine at the same time every day, especially if you have undergone a transplant.

How to take Sandimmun Neoral

The daily dosage should always be taken in two separate doses.

Sandimmun Neoral capsules: remove the capsule from the blister. Swallow the capsules whole with a glass of water.

Sandimmun Neoral Oral Solution:

Initial use of Sandimmun Neoral Oral Solution:

1. Raise the cap in the center of the metal sealing ring.

2. Completely remove the sealing ring.

3. Take out the black stopper and throw it away.

4. Push the tube unit with the white stopper firmly into the neck of the bottle.

Measuring the dose

5. Choose a syringe depending on the volume prescribed by the doctor. For a volume less than 1 ml or

equal to 1 ml, use the 1-ml syringe. For a volume greater than 1 ml, use the 4-ml syringe. Insert the

nozzle of the syringe into the white stopper.

6. Pull out the plunger until the volume of solution prescribed by the doctor has been drawn up (position

the lower part of the plunger in front of the graduation corresponding to the volume prescribed by the

doctor).

7. Expel large bubbles by depressing and withdrawing the plunger a few times before removing the

syringe containing the prescribed dosage from the bottle. The presence of a few tiny bubbles is of no

importance and will not affect the dosage in any way.

Make sure that the syringe has the right amount of medicine and then remove the syringe from the

bottle.

8. Pour the solution from the syringe into a small glass that contains a bit of liquid, preferably orange

juice or apple juice (but not grapefruit juice). Avoid any contact between the syringe and the liquid in

the glass. Stir and drink the entire mixture right away.

9. After use, wipe the syringe on the outside only with a dry tissue and put it back in its cover. The tube

and the white stopper should remain in the bottle. Close the bottle with the separately provided

cap.

Subsequent use of the oral solution:

Start from step 5.

Duration of treatment

The doctor will tell you how long you will need to take Sandimmun Neoral. This depends on whether the reason for the treatment

is after a transplant or for the treatment of a severe skin disease, rheumatoid arthritis, uveitis or nephrotic syndrome. For severe

rash, the treatment usually lasts for 8 weeks.

Keep taking Sandimmun Neoral for as long as your doctor tells you.

If you have questions about how long to take Sandimmun Neoral, refer to the doctor or pharmacist.

Overdose

If you took an overdose, or if a child has accidentally swallowed the medicine, refer immediately to a doctor or proceed to a

hospital emergency room, and bring the package of the medicine with you. You may need medical treatment.

If you forgot to take the medicine

If you forgot to take this medicine at the scheduled time, take a dose as soon as you remember, unless it is almost time for the

next dose. Continue taking the medicine as usual. Never take two doses together!

If you stop taking the medicine

Adhere to the treatment regimen as recommended by the doctor.

Do not stop treatment with Sandimmun Neoral without instruction from the doctor. Continue treatment even if you feel well.

Stopping Sandimmun Neoral treatment may increase the risk of rejection of the transplanted organ.

Do not take medicines in the dark! Check the label and the dose each time you take the medicine. Wear glasses

if you need them.

If you have further questions regarding use of the medicine, consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Sandimmun Neoral may cause side effects in some users. Do not be alarmed when reading the

list of side effects. You may not suffer from any of them.

Some side effects could be serious:

Refer to a doctor immediately if you notice any of the following serious side effects:

∙ Like other medicines that suppress the immune system, ciclosporin may influence your body’s ability to fight against infections

and may cause tumors or other cancers, particularly of the skin. Signs of infection might be fever or sore throat.

∙ If you experience changes in vision, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what

other people say, and muscle weakness; these might be symptoms of an infection of the brain called progressive multifocal

leukoencephalopathy (PML).

∙ Brain disorders with signs such as: seizures, confusion, disorientation, reduced responsiveness, personality changes, agitation,

sleeplessness, vision disorders, blindness, coma, paralysis of part or all of the body, stiff neck, loss of coordination with or

without abnormal speech or eye movements.

∙ Swelling at the back of the eye that may be associated with blurred vision and may cause a vision disorder because of

increased pressure inside the head (benign intracranial hypertension).

∙ Liver problems and damage with or without yellowing of the skin and eyes, nausea, loss of appetite and dark urine.

∙ Kidney disorders, which may greatly reduce urine output.

∙ Low level of red blood cells or platelets. The signs include pale skin, tiredness, breathlessness, dark urine (a sign of the

breakdown of red blood cells), bruising or bleeding for no obvious reason, confusion, disorientation, reduced alertness and

kidney problems.

Additional side effects

Very common side effects - may affect more than 1 in every 10 patients:

Kidney disorders, high blood pressure, headache, involuntary shaking of the body, excessive growth of body and facial hair,

high level of lipids in the blood.

If any of these side effects affect you severely, refer to the doctor.

Common side effects - may affect between 1 and 10 in every 100 patients:

Seizures, liver disorders, high level of sugar in the blood, tiredness, loss of appetite, nausea, vomiting, abdominal pain,

constipation, diarrhea, excessive hair growth, acne, hot flushes, fever, low level of white blood cells, numbness or tingling,

muscle pain, muscle spasm, stomach ulcer, overgrowth (swelling) of the gums until they cover the teeth, high level of uric acid

or potassium in the blood, low level of magnesium in the blood.

If any of these side effects affect you severely, refer to the doctor.

Uncommon side effects - may affect between 1 and 10 in every 1,000 patients:

Symptoms of brain disorders including sudden fits, mental confusion, sleeplessness, disorientation, vision disorders,

unconsciousness, weakness in the limbs, impaired movements.

In addition, rash, general swelling, weight gain, low level of red blood cells, low level of platelets in the blood that may increase

the risk of bleeding.

If any of these side effects affect you severely, refer to the doctor.

Rare side effects - may affect between 1 and 10 in every 10,000 patients:

Nerve disorder, with feeling of numbness or tingling in the fingers and toes, inflammation of the pancreas with severe upper

stomach pain, muscle weakness, loss of muscle strength, pain in muscles of the legs, hands or anywhere in the body, destruction

of red blood cells, involving kidney problems with symptoms such as swelling of the face, stomach, hands and/or feet; decreased

urination, breathing difficulties, chest pain, fits (seizures), unconsciousness, abnormal changes in the menstrual cycle, breast

enlargement in men.

If any of these side effects affect you severely, refer to the doctor.

Very rare side effects - may affect between 1 and 10 in every 100,000 patients:

Swelling at the back of the eye which may be associated with an increase in pressure inside the head and vision disorders.

If this side effect affects you severely, refer to the doctor.

Side effects of unknown frequency - the frequency cannot be estimated from the available data:

Serious liver problems, with or without yellowing of the eyes or skin, nausea, loss of appetite, dark colored urine, swelling of the

face, stomach, feet, hands or the whole body; bleeding underneath the skin or purple skin patches, sudden bleeding with no

apparent cause; migraine or severe headache often with nausea, vomiting and sensitivity to light; pain in the legs and feet.

If any of these side effects affect you severely, refer to the doctor.

If a side effect occurs, if one of the side effects worsens or if you suffer from a side effect not mentioned in the

leaflet, consult with the doctor.

Additional side effects in children and adolescents:

There are no additional side effects expected in children and adolescents when compared with adults.

Reporting side effects

Side effects can be reported to the Ministry of Health by clicking on the link “Report Side Effects of Drug Treatment” found

on the Ministry of Health homepage (www.health.gov.il) that directs you to the online form for reporting side effects, or by

entering the link:

https://sideeffects.health.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

∙ Avoid poisoning! This medicine and any other medicine must be kept in a safe place out of the reach and sight of children

and/or infants in order to avoid poisoning. Do not induce vomiting without explicit instruction from the doctor.

∙ Do not use this medicine after the expiry date (exp. date) that appears on the package. The expiry date refers to the last day

of that month.

∙ Do not use the medicine if you notice that the package is damaged or has signs of tampering.

∙ Do not discard the medicine in the waste bin or sink. Consult with the pharmacist regarding how to dispose of a medicine

you no longer need. This will help to protect the environment.

Sandimmun Neoral Oral Solution:

Store the oral solution at room temperature, between 15°C-30°C and not in the refrigerator, as it contains oils, which solidify

at low temperatures. Below 20°C, a jelly-like formation may occur. If the jelly-like appearance does not disappear after warming

up to 30°C, do not use Sandimmun Neoral oral solution. Small flakes or small amounts of sediment may still be observed. If

the oral solution is stored by mistake in the refrigerator, it should reach room temperature before it can be used again. Flakes

or sediment are of no importance to the medicine’s effectiveness or safety, and measuring with the dosing syringe will still

be accurate.

After opening the bottle, use the solution within 2 months.

Sandimmun Neoral Capsules:

Store at a temperature that does not exceed 25°C. Keep in the original package in order to protect from moisture.

Keep the capsules in the package and only remove them immediately before use.

When a package is opened, a characteristic smell is noticeable. This is normal and does not indicate that there is any problem

with the capsules.

6. FURTHER INFORMATION

Capsules:

Capsules content:

macrogolglycerol hydroxystearate / polyoxyl 40 hydrogenated castor oil, corn oil–mono–di–triglycerides, ethanol anhydrous /

alcohol dehydrated, propylene glycol, alpha–tocopherol.

Sandimmun Neoral soft gelatin capsules contain 11.8% v/v ethanol (9.4% w/v).

Capsule shell:

gelatin, propylene glycol, glycerol 85%, titanium dioxide (E 171), iron oxide black (E 172) (25- and 100-mg capsules).

Capsule color:

carminic acid (E 120), aluminium chloride hexahydrate, sodium hydroxide, propylene glycol, hypromellose / hydroxypropyl

methylcellulose 2910, isopropanol / isopropyl alcohol, water, purified.

Oral Solution:

polyoxyl 40 hydrogenated castor oil, corn oil-mono–di–triglycerides, propylene glycol, ethanol absolute, DL–alpha–tocopherol.

Sandimmun Neoral oral solution contains 12% v/v ethanol (9.5% w/v).

What the medicine looks like and the contents of the package

Capsules:

Sandimmun Neoral 25 mg - a soft gelatin, oval, blue-gray capsule, with imprint NVR 25mg in red ink.

Sandimmun Neoral 50 mg - a soft gelatin, oblong, yellow-white capsule, with imprint NVR 50mg in red ink.

Sandimmun Neoral 100 mg - a soft gelatin, oblong, blue-gray capsule, with imprint NVR 100mg in red ink.

Each pack contains 50 capsules.

Oral Solution:

Sandimmun Neoral 100 mg/ml Oral Solution - a clear, yellow to light yellow or brown-yellow to light brown-yellow

solution.

The oral solution pack contains:

1. An oral solution in a glass bottle.

2. Two plastic oral dispenser sets:

∙ A set containing a tubing unit with a white cap and a 1 ml syringe for measuring the dose. The 1 ml syringe is used to measure

doses smaller than or equal to 1 ml (each 0.05 ml mark is equivalent to 5 mg ciclosporin).

∙ A set containing a tubing unit with a white cap and a 4 ml syringe for measuring the dose. The 4 ml syringe is used to measure

doses larger than 1 ml, and up to 4 ml (each 0.1 ml mark is equivalent to 10 mg ciclosporin).

3. A black cap for closing the bottle again after first opening.

Manufacturer:

Capsules: Catalent Germany Eberbach GmbH, Eberbach/Baden, Germany for Novartis Pharma AG, Basel, Switzerland.

Oral Solution: Delpharm Huningue SAS, Huningue, France for Novartis Pharma AG, Basel, Switzerland.

This leaflet was revised in June 2020.

Registration Holder:

Novartis Israel Ltd., .P.O.B 7126, Tel Aviv.

Registration numbers of the medicine:

Sandimmun Neoral 25 mg Capsules

066 67 28138

Sandimmun Neoral 50 mg Capsules

066 77 28139

Sandimmun Neoral 100 mg Capsules

066 78 28140

Sandimmun Neoral 100 mg/ml Oral Solution

066 79 28141

SH SAN NEO APL June 20 V1

SAN NEO API June 20 V1

REF UK PI 27-Feb-2020

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

SANDIMMUN

NEORAL

25mg Capsules

SANDIMMUN

NEORAL

50mg Capsules

SANDIMMUN

NEORAL

100mg Capsules

SANDIMMUN

NEORAL

100mg/ml Oral Solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

SANDIMMUN NEORAL 25mg Capsules

Each capsule contains 25 mg ciclosporin.

Excipients with known effect:

Ethanol: Sandimmun Neoral Capsules 25mg contain 11.8% v/v ethanol (9.4% m/v).

Propylene glycol: 25 mg/capsule.

Macrogolglycerol hydroxystearate/Polyoxyl 40 hydrogenated castor oil: 101.25 mg/capsule.

SANDIMMUN NEORAL 50mg Capsules

Each capsule contains 50 mg ciclosporin.

Excipients with known effect:

Ethanol: Sandimmun Neoral Capsules 50mg contain 11.8% v/v ethanol (9.4% m/v).

Propylene glycol: 50 mg/capsule.

Macrogolglycerol hydroxystearate/Polyoxyl 40 hydrogenated castor oil: 202.5 mg/capsule.

SANDIMMUN NEORAL 100mg Capsules

Each capsule contains 100 mg ciclosporin.

Excipients with known effect:

Ethanol: Sandimmun Neoral Capsules 100mg contain 11.8% v/v ethanol (9.4% m/v).

Propylene glycol: 100 mg/capsule.

Macrogolglycerol hydroxystearate/Polyoxyl 40 hydrogenated castor oil: 405.0 mg/capsule.

SANDIMMUN NEORAL 100mg/ml Oral Solution

The oral solution contains 100 mg of ciclosporin per ml. Each bottle of 50 ml contains 5000 mg of

ciclosporin.

Excipients with known effect:

Ethanol: 94.70 mg/ml. Neoral Oral Solution contains 12% v/v ethanol (9.5% m/v).

Propylene glycol: 94.70 mg/ml.

Macrogolglycerol hydroxystearate / polyoxyl 40 hydrogenated castor oil: 383.70 mg/ml.

For the full list of excipients see section 6.1.

3

PHARMACEUTICAL FORM

Sandimmun Neoral soft-gelatin capsules:

25 mg: blue-grey, oval soft gelatin capsules, imprinted with “NVR 25mg” in red.

50 mg: yellow-white oblong soft gelatin capsules, imprinted with "NVR 50 mg" in red.

100 mg: blue-grey oblong soft gelatin capsules, imprinted with "NVR 100 mg" in red.

Sandimmun Neoral oral solution:

Clear, yellow to faintly yellow resp. brownish yellow to faintly brownish yellow solution.

SAN NEO API 10June20 V1 Clean

REF UK SmPC 27 Feb 20

The formulation of Sandimmun Neoral is a microemulsion preconcentrate.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Transplantation indications

Solid organ transplantation

Prophylaxis of organ rejection in kidney, liver, heart allogeneic transplants in conjunction with

corticosteroids. May also be used in the treatment of chronic rejection in patients previously treated

with other immunosuppressive agents.

Bone marrow transplantation

Non-transplantation indications

Endogenous uveitis

Nephrotic syndrome

Nephritic syndrome type MCD (minimal change disease) in cases where conventional therapy has

failed.

Rheumatoid arthritis

Severe cases in which standard treatments are ineffective or inappropriate

Psoriasis

Severe psoriasis above age 16 that did not respond to other treatment.

Atopic dermatitis

Atopic dermatitis in adults only up to 8 weeks, for severe cases in which conventional therapy is

ineffective or inappropriate.

4.2

Posology and method of administration

Posology

The dose ranges given for oral administration are intended to serve as guidelines only.

The daily doses of Sandimmun Neoral should always be given in two divided doses equally

distributed throughout the day.

It is recommended that Sandimmun Neoral be administered on a

consistent schedule with regard to time of day and in relation to meals.

Sandimmun Neoral should only be prescribed by, or in close collaboration with, a physician with

experience of immunosuppressive therapy and/or organ transplantation.

Transplantation

Solid organ transplantation

Treatment with Sandimmun Neoral should be initiated within 12 hours before surgery at a dose of 10

to 15 mg/kg given in 2 divided doses. This dose should be maintained as the daily dose for 1 to

2 weeks post-operatively, being gradually reduced in accordance with blood levels according to local

immunosuppressive protocols until a recommended maintenance dose of about 2 to 6 mg/kg given in

2 divided doses is reached.

SAN NEO API 10June20 V1 Clean

REF UK SmPC 27 Feb 20

When Sandimmun Neoral is given with other immunosuppressants (e.g. with corticosteroids or as part

of a triple or quadruple medicinal product therapy), lower doses (e.g. 3 to 6 mg/kg given in 2 divided

doses for the initial treatment) may be used.

Bone marrow transplantation

The initial dose should be given on the day before transplantation. In most cases, Sandimmun

concentrate for solution for infusion is preferred for this purpose. The recommended intravenous dose

is 3 to 5 mg/kg/day. Infusion is continued at this dose level during the immediate post-transplant

period of up to 2 weeks, before a change is made to oral maintenance therapy with Sandimmun Neoral

at daily doses of about 12.5 mg/kg given in 2 divided doses.

Maintenance treatment should be continued for at least 3 months (and preferably for 6 months) before

the dose is gradually decreased to zero by 1 year after transplantation.

If Sandimmun Neoral is used to initiate therapy, the recommended daily dose is 12.5 to 15 mg/kg

given in 2 divided doses, starting on the day before transplantation.

Higher doses of Sandimmun Neoral, or the use of Sandimmun intravenous therapy, may be necessary

in the presence of gastrointestinal disturbances which might decrease absorption.

In some patients, GVHD (Graft versus host disease) occurs after discontinuation of ciclosporin

treatment, but usually responds favourably to re-introduction of therapy. In such cases an initial oral

loading dose of 10 to 12.5 mg/kg should be given, followed by daily oral administration of the

maintenance dose previously found to be satisfactory. Low doses of Sandimmun Neoral should be

used to treat mild, chronic GVHD.

Non-transplantation indications

When using Sandimmun Neoral in any of the established non-transplantation indications, the

following general rules should be adhered to:

Before initiation of treatment a reliable baseline level of renal function should be established by at

least two measurements. The estimated glomerular filtration rate (eGFR) by the MDRD formula can

be used for estimation of renal function in adults and an appropriate formula should be used to assess

eGFR in paediatric patients. Since Sandimmun Neoral can impair renal function, it is necessary to

assess renal function frequently. If eGFR decreases by more than 25% below baseline at more than

one measurement, the dosage of Sandimmun Neoral should be reduced by 25 to 50%. If the eGFR

decrease from baseline exceeds 35%, further reduction of the dose of Sandimmun Neoral should be

considered. These recommendations apply even if the patient`s values still lie within the laboratory`s

normal range. If dose reduction is not successful in improving eGFR within one month, Sandimmun

Neoral treatment should be discontinued (see section 4.4).

Regular monitoring of blood pressure is required.

The determination of bilirubin and parameters that assess hepatic function are required prior to

starting therapy and close monitoring during treatment is recommended. Determinations of serum

lipids, potassium, magnesium and uric acid are advisable before treatment and periodically during

treatment.

Occasional monitoring of ciclosporin blood levels may be relevant in non-transplant indications, e.g.

when Sandimmun Neoral is co-administered with substances that may interfere with the

pharmacokinetics of ciclosporin, or in the event of unusual clinical response (e.g. lack of efficacy or

increased drug intolerance such as renal dysfunction).

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The normal route of administration is by mouth. If the concentrate for solution for infusion is used,

careful consideration should be given to administering an adequate intravenous dose that corresponds

to the oral dose. Consultation with a physician with experience of use of ciclosporin is recommended.

Except in patients with sight-threatening endogenous uveitis and in children with nephrotic syndrome,

the total daily dose must never exceed 5 mg/kg.

For maintenance treatment the lowest effective and well tolerated dosage should be determined

individually.

In patients in whom within a given time (for specific information see below) no adequate response is

achieved or the effective dose is not compatible with the established safety guidelines, treatment with

Sandimmun Neoral should be discontinued.

Endogenous uveitis

For inducing remission, initially 5 mg/kg/day orally given in 2 divided doses are recommended until

remission of active uveal inflammation and improvement in visual acuity are achieved. In refractory

cases, the dose can be increased to 7 mg/kg/day for a limited period.

To achieve initial remission, or to counteract inflammatory ocular attacks, systemic corticosteroid

treatment with daily doses of 0.2 to 0.6 mg/kg prednisone or an equivalent may be added if

Sandimmun Neoral alone does not control the situation sufficiently. After 3 months, the dose of

corticosteroids may be tapered to the lowest effective dose.

For maintenance treatment, the dose should be slowly reduced to the lowest effective level. During the

remission phases, this should not exceed 5 mg/kg/day.

Infectious causes of uveitis should be ruled out before immunosuppressants can be used.

Nephrotic syndrome

For inducing remission, the recommended daily dose is given in 2 divided oral doses.

If the renal function (except for proteinuria) is normal, the recommended daily dose is the following:

- adults: 5 mg/kg

- children: 6 mg/kg

In patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day.

The combination of Sandimmun Neoral with low doses of oral corticosteroids is recommended if the

effect of Sandimmun Neoral alone is not satisfactory, especially in steroid-resistant patients.

Time to improvement varies from 3 to 6 months depending on the type of glomerulopathy. If no

improvement has been observed after this time to improvement period, Sandimmun Neoral therapy

should be discontinued.

The doses need to be adjusted individually according to efficacy (proteinuria) and safety (primarily

serum creatinine), but should not exceed 5 mg/kg/day in adults and 6 mg/kg/day in children.

For maintenance treatment, the dose should be slowly reduced to the lowest effective level.

Rheumatoid arthritis

For the first 6 weeks of treatment the recommended dose is 2.5 mg/kg/day orally given in 2 divided

doses. If the effect is insufficient, the daily dose may then be increased gradually as tolerability

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permits, but should not exceed 4 mg/kg. To achieve full effectiveness, up to 12 weeks of Sandimmun

Neoral therapy may be required.

For maintenance treatment the dose has to be titrated individually to the lowest effective level

according to tolerability.

Sandimmun Neoral can be given in combination with low-dose corticosteroids and/or non-steroidal

anti-inflammatory drugs (NSAIDs) (see section 4.4). Sandimmun Neoral can also be combined with

low-dose weekly methotrexate in patients who have insufficient response to methotrexate alone, by

using 2.5 mg/kg Sandimmun Neoral in 2 divided doses per day initially, with the option to increase

the dose as tolerability permits.

Psoriasis

Sandimmun Neoral treatment should be initiated by physicians with experience in the diagnosis and

treatment of psoriasis. Due to the variability of this condition, treatment must be individualised. For

inducing remission, the recommended initial dose is 2.5 mg/kg/day orally given in 2 divided doses. If

there is no improvement after 1 month, the daily dose may be gradually increased, but should not

exceed 5 mg/kg. Treatment should be discontinued in patients in whom sufficient response of

psoriatic lesions cannot be achieved within 6 weeks on 5 mg/kg/day, or in whom the effective dose is

not compatible with the established safety guidelines (see section 4.4).

Initial doses of 5 mg/kg/day are justified in patients whose condition requires rapid improvement.

Once satisfactory response is achieved, Sandimmun Neoral may be discontinued and subsequent

relapse managed with re-introduction of Sandimmun Neoral at the previous effective dose. In some

patients, continuous maintenance therapy may be necessary.

For maintenance treatment, doses have to be titrated individually to the lowest effective level, and

should not exceed 5 mg/kg/day given orally in two divided doses.

Atopic dermatitis

Sandimmun Neoral treatment should be initiated by physicians with experience in the diagnosis and

treatment of atopic dermatitis. Due to the variability of this condition, treatment must be individualised.

The recommended dose range in adults is 2.5 to 5 mg/kg/day given in 2 divided oral doses for a

maximum of 8 weeks. If a starting dose of 2.5 mg/kg/day does not achieve a satisfactory response

within 2 weeks, the daily dose may be rapidly increased to a maximum of 5 mg/kg. In very severe cases,

rapid and adequate control of the disease is more likely to occur with a starting dose of 5 mg/kg/day.

Once satisfactory response is achieved, the dose should be reduced gradually and, if possible,

Sandimmun Neoral should be discontinued. Subsequent relapse may be managed with a further course

of Sandimmun Neoral.

Switching between oral ciclosporin formulations

The switch from one oral ciclosporin formulation to another should be made under physician

supervision, including monitoring of blood levels of ciclosporin for transplantation patients

to ensure

that pre-conversion levels are attained

Special populations

Patients with renal impairment

All indications

Ciclosporin undergoes minimal renal elimination and its pharmacokinetics are not extensively

affected by renal impairment (see section 5.2). However, due to its nephrotoxic potential (see section

4.8), careful monitoring of renal function is recommended (see section 4.4).

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Non-transplantation indications

With the exception of patients being treated for nephrotic syndrome, patients with impaired renal

function should not receive ciclosporin (see subsection on additional precautions in non-

transplantation indications in section 4.4). In nephrotic syndrome patients with impaired renal

function, the initial dose should not exceed 2.5 mg/kg/day.

Patients with hepatic impairment

Ciclosporin is extensively metabolised by the liver. An approximate 2- to 3-fold increase in

ciclosporin exposure may be observed in patients with hepatic impairment

.

Dose reduction may be

necessary in patients with severe liver impairment to maintain blood levels within the recommended

target range (see sections 4.4 and 5.2) and it is recommended that ciclosporin blood levels are

monitored until stable levels are reached.

Paediatric population

Clinical studies have included children from 1 year of age. In several studies, paediatric patients

required and tolerated higher doses of ciclosporin per kg body weight than those used in adults.

Use of Sandimmun Neoral in children for non-transplantation indications other than nephrotic

syndrome cannot be recommended (see section 4.4).

Elderly population (age 65 years and above)

Experience with Sandimmun Neoral in the elderly is limited.

In rheumatoid arthritis clinical trials with oral ciclosporin, patients aged 65 or older were more likely

to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥50%

above the baseline after 3 to 4 months of therapy.

Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing

range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of

concomitant disease or medication

and increased susceptibility for infections.

Method of administration

Oral use

Sandimmun Neoral capsules should be swallowed whole.

Sandimmun Neoral Oral Solution should be diluted, preferably with orange or apple juice. However,

other drinks, such as soft drinks, can be used accordingly to individual taste. The solution should be

stirred well immediately before it is taken. Owing to its possible interference with the cytochrome

P450-dependent enzyme system, grapefruit or grapefruit juice should be avoided for dilution (see

section 4.5). The syringe should not come in contact with the diluent. If the syringe is to be cleaned,

do not rinse it but wipe the outside with a dry tissue (see section 6.6).

Precautions to be taken before handling or administering the medicinal product

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Combination with products containing

Hypericum perforatum

(St John´s Wort) (see section 4.5).

Combination with medicines that are substrates for the multidrug efflux transporter P-glycoprotein or

the organic anion transporter proteins (OATP) and for which elevated plasma concentrations are

associated with serious and/or life-threatening events, e.g. bosentan, dabigatran etexilate and aliskiren

(see section 4.5).

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4.4

Special warnings and precautions for use

Medical supervision

Sandimmun Neoral should be prescribed only by physicians who are experienced in

immunosuppressive therapy and can provide adequate follow-up, including regular full physical

examination, measurement of blood pressure and control of laboratory safety parameters.

Transplantation patients receiving this medicinal product should be managed in facilities with

adequate laboratory and supportive medical resources. The physician responsible for maintenance

therapy should receive complete information for the follow-up of the patient.

Lymphomas and other malignancies

Like other immunosuppressants, ciclosporin 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.

A treatment regimen containing multiple immunosuppressants (including ciclosporin) should

therefore be used with caution as this could lead to lymphoproliferative disorders and solid organ

tumours, some with reported fatalities.

In view of the potential risk of skin malignancy, patients on Sandimmun Neoral, in particular those

treated for psoriasis or atopic dermatitis, should be warned to avoid excess unprotected sun exposure

and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

Infections

Like other immunosuppressants, ciclosporin predisposes patients to the development of a variety of

bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens. Activation of

latent polyomavirus infections that may lead to polyomavirus associated nephropathy (PVAN),

especially to BK virus nephropathy (BKVN), or to JC virus associated progressive multifocal

leukoencephalopathy (PML), have been observed in patients receiving ciclosporin. These conditions

are often related to a high total immunosuppressive burden and should be considered in the

differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological

symptoms. Serious and/or fatal outcomes have been reported. Effective pre-emptive and therapeutic

strategies should be employed, particularly in patients on multiple long-term immunosuppressive

therapy.

Renal toxicity

A frequent and potentially serious complication, an increase in serum creatinine and urea, may occur

during Sandimmun Neoral therapy. These functional changes are dose-dependent and are initially

reversible, usually responding to dose reduction. During long-term treatment, some patients may

develop structural changes in the kidney (e.g. interstitial fibrosis) which, in renal transplant patients,

must be differentiated from changes due to chronic rejection. Frequent monitoring of renal function is

therefore required according to local guidelines for the indication in question (see sections 4.2 and

4.8).

Hepatotoxicity

Sandimmun Neoral may also cause dose-dependent, reversible increases in serum bilirubin and in

liver enzymes (see section 4.8). There have been solicited and spontaneous reports of hepatotoxicity

and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with

ciclosporin. Most reports included patients with significant co-morbidities, underlying conditions and

other confounding factors including infectious complications and co-medications with hepatotoxic

potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section

4.8). Close monitoring of parameters that assess hepatic function is required and abnormal values may

necessitate dose reduction (see sections 4.2 and 5.2).

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Elderly population (age 65 years and above)

In elderly patients, renal function should be monitored with particular care.

Monitoring ciclosporin levels (see section 4.2)

When Sandimmun Neoral is used in transplant patients, routine monitoring of ciclosporin blood levels

is an important safety measure. For monitoring ciclosporin levels in whole blood, a specific

monoclonal antibody (measurement of parent compound) is preferred; a high-performance liquid

chromatography (HPLC) method, which also measures the parent compound, can be used as well. If

plasma or serum is used, a standard separation protocol (time and temperature) should be followed.

For the initial monitoring of liver transplant patients, either the specific monoclonal antibody should

be used, or parallel measurements using both the specific monoclonal antibody and the non-specific

monoclonal antibody should be performed, to ensure a dosage that provides adequate

immunosuppression.

In non-transplant patients, occasional monitoring of ciclosporin blood levels is recommended, e.g.

when Sandimmun Neoral is co-administered with substances that may interfere with the

pharmacokinetics of ciclosporin, or in the event of unusual clinical response (e.g. lack of efficacy or

increased drug intolerance such as renal dysfunction).

It must be remembered that the ciclosporin concentration in blood, plasma, or serum is only one of

many factors contributing to the clinical status of the patient. Results should therefore serve only as a

guide to dosage in relationship to other clinical and laboratory parameters.

Hypertension

Regular monitoring of blood pressure is required during Sandimmun Neoral therapy. If hypertension

develops, appropriate antihypertensive treatment must be instituted. Preference should be given to an

antihypertensive agent that does not interfere with the pharmacokinetics of ciclosporin, e.g. isradipine

(see section 4.5).

Blood lipids increased

Since Sandimmun Neoral has been reported to induce a reversible slight increase in blood lipids, it is

advisable to perform lipid determinations before treatment and after the first month of therapy. In the

event of increased lipids being found, restriction of dietary fat and, if appropriate, a dose reduction,

should be considered.

Hyperkalaemia

Ciclosporin enhances the risk of hyperkalaemia, especially in patients with renal dysfunction. Caution

is also required when ciclosporin is co-administered with potassium-sparing drugs (e.g. potassium-

sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor

antagonists) or potassium-containing medicinal products as well as in patients on a potassium rich

diet. Control of potassium levels in these situations is advisable.

Hypomagnesaemia

Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia,

especially in the peri-transplant period. Control of serum magnesium levels is therefore recommended

in the peri-transplant period, particularly in the presence of neurological symptom/signs. If considered

necessary, magnesium supplementation should be given.

Hyperuricaemia

Caution is required when treating patients with hyperuricaemia.

Live-attenuated vaccines

During treatment with ciclosporin, vaccination may be less effective. The use of live attenuated

vaccines should be avoided (see section 4.5).

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Interactions

Caution should be observed when co-administering ciclosporin with drugs that substantially increase

or decrease ciclosporin plasma concentrations, through inhibition or induction of CYP3A4 and/or P-

glycoprotein (see section 4.5).

Renal toxicity should be monitored when initiating ciclosporin use together with active substances

that increase ciclosporin levels or with substances that exhibit nephrotoxic synergy (see section 4.5).

Concomitant use of ciclosporin and tacrolimus should be avoided (see section 4.5).

Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein and organic

anion transporter proteins (OATP) and may increase plasma levels of co-medications that are

substrates of this enzyme and/or transporter.

Caution should be observed while co-administering

ciclosporin with such drugs or concomitant use should be avoided (see section 4.5). Ciclosporin

increases the exposure to HMG-CoA reductase inhibitors (statins). When concurrently administered

with ciclosporin, the dosage of the statins should be reduced and concomitant use of certain statins

should be avoided according to their label recommendations. Statin therapy needs to be temporarily

withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors

predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis (see section

4.5).

Following concomitant administration of ciclosporin and

lercanidipine

, the AUC of lercanidipine was

increased three-fold and the AUC of ciclosporin was increased 21%. Therefore the simultaneous

combination of ciclosporin and lercanidipine should be avoided. Administration of ciclosporin 3 hours

after lercanidipine yielded no change of the lercanidipine AUC, but the ciclosporin AUC was

increased by 27%. This combination should therefore be given with caution with an interval of at least

3 hours.

Special excipients: Polyoxyl 40 hydrogenated castor oil

Sandimmun Neoral contains polyoxyl 40 hydrogenated castor oil, which may cause stomach upsets

and diarrhoea.

Special excipients: Ethanol

Sandimmun Neoral contains around 12% vol. ethanol. A 500 mg dose of Sandimmun Neoral contains

500 mg ethanol, equivalent to nearly 15 ml beer or 5 ml wine. This may be harmful in alcoholic

patients and should be taken into account in pregnant or breast-feeding women, in patients presenting

with liver disease or epilepsy, or if the patients is a child.

Additional precautions in non-transplantation indications

Patients with impaired renal function (except nephrotic syndrome patients with a permissible degree

of renal impairment), uncontrolled hypertension, uncontrolled infections, or any kind of malignancy

should not receive ciclosporin.

Before initiation of treatment a reliable baseline assessment of renal function should be established by

at least two measurements of eGFR. Renal function must be assessed frequently throughout therapy to

allow dosage adjustment (see section 4.2).

Additional precautions in endogenous uveitis

Sandimmun Neoral should be administered with caution in patients with neurological Behcet`s

syndrome. The neurological status of these patients should be carefully monitored.

There is only limited experience with the use of Sandimmun Neoral in children with endogenous

uveitis.

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Additional precautions in nephrotic syndrome

Patients with abnormal baseline renal function should initially be treated with 2.5 mg/kg/day and must

be monitored very carefully.

In some patients, it may be difficult to detect Sandimmun Neoral-induced renal dysfunction because

of changes in renal function related to the nephrotic syndrome itself. This explains why, in rare cases,

Sandimmun Neoral-associated structural kidney alterations have been observed without increases in

serum creatinine. Renal biopsy should be considered for patients with steroid-dependent minimal-

change nephropathy, in whom Sandimmun Neoral therapy has been maintained for more than 1 year.

In patients with nephrotic syndrome treated with immunosuppressants (including ciclosporin), the

occurrence of malignancies (including Hodgkin's lymphoma)

has occasionally been reported.

Additional precautions in rheumatoid arthritis

After 6 months of therapy, renal function needs to be assessed every 4 to 8 weeks depending on the

stability of the disease, its co- medication, and concomitant diseases. More frequent checks are

necessary when the Sandimmun Neoral dose is increased, or concomitant treatment with an NSAID is

initiated or its dosage increased. Discontinuation of Sandimmun Neoral may also become necessary if

hypertension developing during treatment cannot be controlled by appropriate therapy.

As with other long-term immunosuppressive treatments, an increased risk of lymphoproliferative

disorders must be borne in mind. Special caution should be observed if Sandimmun Neoral is used in

combination with methotrexate due to nephrotoxic synergy.

Additional precautions in psoriasis

Discontinuation of Sandimmun Neoral therapy is recommended if hypertension developing during

treatment cannot be controlled with appropriate therapy.

Elderly patients should be treated only in the presence of disabling psoriasis, and renal function

should be monitored with particular care.

There is only limited experience with the use of Sandimmun Neoral in children with psoriasis.

In psoriatic patients on ciclosporin, as in those on conventional immunosuppressive therapy,

development of malignancies (in particular of the skin) has been reported. Skin lesions not typical for

psoriasis, but suspected to be malignant or pre-malignant should be biopsied before Sandimmun

Neoral treatment is started. Patients with malignant or pre-malignant alterations of the skin should be

treated with Sandimmun Neoral only after appropriate treatment of such lesions, and if no other

option for successful therapy exists.

In a few psoriatic patients treated with Sandimmun Neoral, lymphoproliferative disorders have

occurred. These were responsive to prompt discontinuation.

Patients on Sandimmun Neoral should not receive concomitant ultraviolet B irradiation or PUVA

photochemotherapy.

Additional precautions in atopic dermatitis

Discontinuation of Sandimmun Neoral is recommended if hypertension developing during treatment

cannot be controlled with appropriate therapy.

Experience with Sandimmun Neoral in children with atopic dermatitis is limited.

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Elderly patients should be treated only in the presence of disabling atopic dermatitis and renal

function should be monitored with particular care.

Benign lymphadenopathy is commonly associated with flares in atopic dermatitis and invariably

disappears spontaneously or with general improvement in the disease.

Lymphadenopathy observed on treatment with ciclosporin should be regularly monitored.

Lymphadenopathy which persists despite improvement in disease activity should be examined by

biopsy as a precautionary measure to ensure the absence of lymphoma.

Active herpes simplex infections should be allowed to clear before treatment with Sandimmun Neoral

is initiated, but are not necessarily a reason for treatment withdrawal if they occur during therapy

unless infection is severe.

Skin infections with

Staphylococcus aureus

are not an absolute contraindication for Sandimmun

Neoral therapy, but should be controlled with appropriate antibacterial agents. Oral erythromycin,

which is known to have the potential to increase the blood concentration of ciclosporin (see section

4.5), should be avoided. If there is no alternative, it is recommended to closely monitor blood levels of

ciclosporin, renal function, and for side effects of ciclosporin.

Patients on Sandimmun Neoral should not receive concomitant ultraviolet B irradiation or PUVA

photochemotherapy.

Paediatric use in non-transplantation indications

Except for the treatment of nephrotic syndrome, there is no adequate experience available with

Sandimmun Neoral. Its use in children for non-transplantation indications other than nephrotic

syndrome cannot be recommended.

4.5

Interaction with other medicinal products and other forms of interaction

Drug interactions

Of the many drugs reported to interact with ciclosporin, those for which the interactions are

adequately substantiated and considered to have clinical implications are listed below.

Various agents are known to either increase or decrease plasma or whole blood ciclosporin levels

usually by inhibition or induction of enzymes involved in the metabolism of ciclosporin, in particular

CYP3A4.

Ciclosporin is also an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein and

organic anion transporter proteins (OATP) and may increase plasma levels of co-medications that are

substrates of this enzyme and/or transporters.

Medicinal products known to reduce or increase the bioavailability of ciclosporin: In transplant

patients frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment

is required, particularly during the introduction or withdrawal of the co-administered medication. In

non-transplant patients the relationship between blood level and clinical effects is less well

established. If medicinal products known to increase ciclosporin levels are given concomitantly,

frequent assessment of renal function and careful monitoring for ciclosporin-related side effects may

be more appropriate than blood level measurement.

Drugs that decrease ciclosporin levels

All inducers of CYP3A4 and/or P-glycoprotein are expected to decrease ciclosporin levels. Examples

of drugs that decrease ciclosporin levels

are:

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Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, intravenous sulfadimidine,

probucol, orlistat, hypericum perforatum (St. John’s wort), ticlopidine, sulfinpyrazone, terbinafine,

bosentan

Products containing

Hypericum perforatum

(St John´s Wort) must not be used concomitantly with

Sandimmun Neoral due to the risk of decreased blood levels of ciclosporin and thereby reduced effect

(see section 4.3).

Rifampicin

induces ciclosporin intestinal and liver metabolism. Ciclosporin doses may need to be

increased 3- to 5-fold during co-administration.

Octreotide

decreases oral absorption of ciclosporin and a 50% increase in the ciclosporin dose or a

switch to intravenous administration could be necessary.

Drugs that increase ciclosporin levels

All inhibitors of CYP3A4 and/or P-glycoprotein may lead to increased levels of cyclosporine.

Examples are:

Nicardipine, metoclopramide, oral contraceptives, methylprednisolone (high dose), allopurinol,

cholic acid and derivatives, protease inhibitors, imatinib, colchicine, nefazodone

Macrolide antibiotics: Erythromycin

can increase ciclosporin exposure 4- to 7-fold, sometimes

resulting in nephrotoxicity.

Clarithromycin

has been reported to double the exposure of ciclosporin

.

Azitromycin

increases ciclosporin levels by around 20%.

Azole antibiotics: Ketoconazole, fluconazole, itraconazole and voriconazole

could more than double

ciclosporin exposure.

Verapamil

increases ciclosporin blood concentrations 2- to 3-fold.

Co-administration with

telaprevir

resulted in approximately 4.64-fold increase in ciclosporin dose

normalised exposure (AUC).

Amiodarone

substantially increases the plasma ciclosporin concentration concurrently with an

increase in serum creatinine. This interaction can occur for a long time after withdrawal of

amiodarone, due to its very long half-life (about 50 days).

Danazol

has been reported to increase ciclosporin blood concentrations by approximately 50%.

Diltiazem

(at doses of 90 mg/day)

can increase ciclosporin plasma concentrations by up to 50%.

Imatinib

could increase ciclosporin exposure and C

by around 20%.

Food interactions

The concomitant intake of grapefruit and grapefruit juice has been reported to increase the

bioavailability of ciclosporin.

Combinations with increased risk for nephrotoxicity

Care should be taken when using ciclosporin together with other active substances that exhibit

nephrotoxic synergy such as:

aminoglycosides (including gentamycin, tobramycin), amphotericin B,

ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); fibric acid derivatives (e.g.

bezafibrate, fenofibrate); NSAIDs (including diclofenac, naproxen, sulindac); melphalan, histamine

H

2

-receptor antagonists (e.g. cimetidine, ranitidine); methotrexate (see section 4.4).

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During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal

function should be performed. If a significant impairment of renal function occurs, the dosage of the

co-administered medicinal product should be reduced or alternative treatment considered.

Concomitant use of ciclosporin and tacrolimus should be avoided due to the risk for nephrotoxicity

and pharmacokinetic interaction via CYP3A4 and/or P-gp (see section 4.4).

Impact of DAA therapy

The pharmacokinetics of ciclosporin may be impacted by changes in liver function during DAA

therapy, related to clearance of HCV virus. A close monitoring and potential dose adjustment of

ciclosporin is warranted to ensure continued efficacy.

Effects of ciclosporin on other drugs

Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein (P-gp) and

organic anion transporter proteins (OATP). Co-administration of drugs that are substrates of CYP3A4,

P-gp and OATP with ciclosporin

may increase plasma levels of co-medications 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 drugs are used concurrently with ciclosporin, close clinical observation

is required in order to enable early detection of toxic manifestations of the medicinal products,

followed by reduction of its dosage or its withdrawal. When concurrently administered with

ciclosporin, the dosage of the statins should be reduced and concomitant use of certain statins should

be avoided according to their label recommendations. Exposure changes of commonly used statins

with ciclosporin are summarised in Table 1. Statin therapy needs to be temporarily withheld or

discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing

to severe renal injury, including renal failure, secondary to rhabdomyolysis.

Table 1

Summary of exposure changes of commonly used statins with ciclosporin

Statin

Doses available

Fold change in

exposure with

ciclosporin

Atorvastatin

10-80 mg

8-10

Simvastatin

10-80 mg

Fluvastatin

20-80 mg

Lovastatin

20-40 mg

Pravastatin

20-80 mg

5-10

Rosuvastatin

5-40 mg

5-10

Pitavastatin

1-4 mg

Caution is recommended when co-administering ciclosporin with lercanidipine (see section 4.4).

Following concomitant administration of ciclosporin and

aliskiren

, a P-gp substrate, the C

aliskiren was increased approximately 2.5-fold and the AUC approximately 5-fold. However, the

pharmacokinetic profile of ciclosporin was not significantly altered. Co-administration of ciclosporin

and aliskiren is not recommended (see section 4.3).

Concomitant administration of dabigatran extexilate is not recommended due to the P-gp inhibitory

activity of ciclosporin (see section 4.3).

The concurrent administration of

nifedipine

with ciclosporin may result in an increased rate of

gingival hyperplasia compared with that observed when ciclosporin is given alone.

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The concomitant use of

diclofenac

and ciclosporin has been found to result in a significant increase in

the bioavailability of diclofenac, with the possible consequence of reversible renal function

impairment. The increase in the bioavailability of diclofenac is most probably caused by a reduction

of its high first-pass effect. If

NSAIDs

with a low first-pass effect (e.g. acetylsalicylic acid) are given

together with ciclosporin, no increase in their bioavailability is to be expected.

Elevations in serum creatinine were observed in the studies using

everolimus

sirolimus

combination with full-dose ciclosporin for microemulsion. This effect is often reversible with

ciclosporin dose reduction. Everolimus and sirolimus had only a minor influence on ciclosporin

pharmacokinetics. Co-administration of ciclosporin significantly increases blood levels of everolimus

and sirolimus.

Caution is required with concomitant use of

potassium-sparing medicinal products (e.g. potassium-

sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists

) or

potassium-containing

medicinal products

since they may lead to significant increases in serum potassium (see section 4.4).

Ciclosporin may increase the plasma concentrations of

repaglinide

and thereby increase the risk of

hypoglycaemia.

Co-administration of

bosentan

and ciclosporin in healthy volunteers increases the bosentan exposure

several-fold and there was a 35% decrease in ciclosporin exposure. Co-administration of ciclosporin

with bosentan is not recommended (see above subsection “Drugs that decrease ciclosporin levels” and

section 4.3).

Multiple dose administration of

ambrisentan

and ciclosporin in healthy volunteers resulted in an

approximately 2-fold increase in ambrisentan exposure, while the ciclosporin exposure was

marginally increased (approximately 10%).

A significantly increased exposure to

anthracycline antibiotics (e.g. doxorubicine, mitoxanthrone,

daunorubicine

) was observed in oncology patients with the intravenous co-administration of

anthracycline antibiotics and very high doses of ciclosporin.

During treatment with ciclosporin, vaccination may be less effective and the use of live attenuated

vaccines should be avoided.

Paediatric population

Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation

Pregnancy

Animal studies have shown reproductive toxicity in rats and rabbits.

Experience with Sandimmun Neoral in pregnant women is limited. Pregnant women receiving

immunosuppressive therapies after transplantation, including ciclosporin and ciclosporin-containing

regimens, are at risk of premature delivery (<37 weeks).

A limited number of observations in children exposed to ciclosporin

in utero

are available, up to an

age of approximately 7 years. Renal function and blood pressure in these children were normal.

However, there are no adequate and well-controlled studies in pregnant women and therefore

Sandimmun Neoral should not be used during pregnancy unless the potential benefit to the mother

justifies the potential risk to the foetus. The ethanol content of the Sandimmun Neoral formulations

should also be taken into account in pregnant women (see section 4.4).

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Breast-feeding

Ciclosporin passes into breast milk. The ethanol content of the Sandimmun Neoral formulations

should also be taken into account in women who are breast-feeding (see section 4.4). Mothers

receiving treatment with Sandimmun Neoral should not breast-feed because of the potential of

Sandimmun Neoral to cause serious adverse drug reactions in breast-fed newborns/infants. A decision

should be made whether to abstain from breast-feeding or to abstain from using the medicinal drug,

taking into account the importance of the medicinal product to the mother.

Fertility

There is limited data on the effect of Sandimmun Neoral on human fertility (see section 5.3).

4.7

Effects on ability to drive and use machines

No data exist on the effects of Sandimmun Neoral on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

The principal adverse reactions observed in clinical trials and associated with the administration of

ciclosporin include renal dysfunction, tremor, hirsutism, hypertension, diarrhoea, anorexia, nausea

and vomiting.

Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose

reduction. In the various indications the overall spectrum of side effects is essentially the same; there

are, however, differences in incidence and severity. As a consequence of the higher initial doses and

longer maintenance therapy required after transplantation, side effects are more frequent and usually

more severe in transplant patients than in patients treated for other indications.

Infections and infestations

Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin-containing

regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic) (see section 4.4). Both

generalised and localised infections can occur. Pre-existing infections may also be aggravated and

reactivation of polyomavirus infections may lead to polyomavirus-associated nephropathy (PVAN) or

to 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 receiving immunosuppressive therapies, including ciclosporin and ciclosporin containing

regimens, are at increased risk of developing lymphomas or lymphoproliferative disorders and other

malignancies, particularly of the skin. The frequency of malignancies increases with the intensity and

duration of therapy (see section 4.4). Some malignancies may be fatal.

Tabulated summary of adverse drug reactions from clinical trials

Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class.

Within each system organ class, the adverse drug reactions are ranked by frequency, with the most

frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order

of decreasing seriousness. 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,

<1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000) very rare (<1/10,000), not known

(cannot be estimated from the available data).

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Table 1: Adverse drug reactions from clinical trials

Blood and lymphatic system disorders

Common

Leucopenia

Uncommon

Thrombocytopenia, anaemia

Rare

Haemolytic uraemic syndrome, microangiopathic haemolytic anaemia

Not known*

Thrombotic microangiopathy, thrombotic thrombocytopenic purpura

Metabolism and nutrition disorders

Very common

Hyperlipidaemia

Common

Hyperglycaemia, anorexia, hyperuricaemia, hyperkalaemia, hypomagnesaemia

Nervous system disorders

Very common

Tremor, headache

Common

Convulsions, paraesthesia

Uncommon

Encephalopathy including Posterior Reversible Encephalopathy Syndrome

(PRES), signs and symptoms such as convulsions, confusion, disorientation,

decreased responsiveness, agitation, insomnia, visual disturbances, cortical

blindness, coma, paresis and cerebellar ataxia

Rare

Motor polyneuropathy

Very rare

Optic disc oedema, including papilloedema, with possible visual impairment

secondary to benign intracranial hypertension

Not known*

Migraine

Vascular disorders

Very common

Hypertension

Common

Flushing

Gastrointestinal disorders

Common

Nausea, vomiting, abdominal discomfort/pain, diarrhoea, gingival hyperplasia,

peptic ulcer

Rare

Pancreatitis

Hepatobiliary disorders

Common

Hepatic function abnormal (see section 4.4)

Not known*

Hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and

liver failure with some fatal outcome (see section 4.4)

Skin and subcutaneous tissue disorders

Very common

Hirsutism

Common

Acne, hypertrichosis

Uncommon

Allergic rashes

Musculoskeletal and connective tissue disorders

Common

Myalgia, muscle cramps

Rare

Not known*

Muscle weakness, myopathy

Pain of lower extremities

Renal and urinary disorders

Very common

Renal dysfunction (see section 4.4)

Reproductive system and breast disorders

Rare

Menstrual disturbances, gynaecomastia

General disorders and administration site conditions

Common

Pyrexia, fatigue

Uncommon

Oedema, weight increase

* Adverse events reported from post marketing experience where the ADR frequency is not known

due to the lack of a real denominator.

Other adverse drug reactions from post-marketing experience

Hepatotoxicity and liver injury

There have been solicited and spontaneous reports of hepatotoxicity and liver injury including

cholestasis, jaundice hepatitis and liver failure in patients treated with ciclosporin. Most reports

included patients with significant co-morbidities, underlying conditions and other confounding factors

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including infectious complications and co-medications with hepatotoxic potential. In some cases,

mainly in transplant patients, fatal outcomes have been reported (see section 4.4).

Acute and chronic nephrotoxicity

Patients receiving calcineurin inhibitor (CNI) therapies, including ciclosporin and ciclosporin-

containing regimens, are at increased risk of acute or chronic nephrotoxicity. There have been reports

from clinical trials and from the post-marketing setting associated with the use of Sandimmun Neoral.

Cases of acute nephrotoxicity reported disorders of ion homeostasis, such as hyperkalaemia,

hypomagnesaemia, and hyperuricaemia. Cases reporting chronic morphological changes included

arteriolar hyalinosis, tubular atrophy and interstitial fibrosis (see section 4.4).

Pain of lower extremities

Isolated cases of pain of lower extremities have been reported in association with ciclosporin. Pain of

lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS).

Paediatric population

Clinical studies have included children from 1 year of age using standard ciclosporin dosage with a

comparable safety profile to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions to the Ministry of Health according

to the National Regulation by using an online form https://sideeffects.health.gov.il

4.9

Overdose

The oral LD

of ciclosporin is 2,329 mg/kg in mice, 1,480 mg/kg in rats and > 1,000 mg/kg in rabbits.

The intravenous LD

is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.

Symptoms

Experience with acute overdosage of ciclosporin is limited. Oral doses of ciclosporin of up to 10 g

(about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting,

drowsiness, headache, tachycardia and in a few patients moderately severe, reversible impairment of

renal function. However, serious symptoms of intoxication have been reported following accidental

parenteral overdosage with ciclosporin in premature neonates.

Treatment

In all cases of overdosage, general supportive measures should be followed and symptomatic

treatment applied. Forced emesis and gastric lavage may be of value within the first few hours after

oral intake. Ciclosporin is not dialysable to any great extent, nor is it well cleared by charcoal

haemoperfusion.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressive agents, calcineurin inhibitors, ATC code: L04AD01

Ciclosporin (also known as ciclosporin A) is a cyclic polypeptide consisting of 11 amino acids. It is a

potent immunosuppressive agent, which in animals prolongs survival of allogeneic transplants of skin,

heart, kidney, pancreas, bone marrow, small intestine or lung. Studies suggest that ciclosporin inhibits

the development of cell-mediated reactions, including allograft immunity, delayed cutaneous

hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft-versus-

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host disease (GVHD), and also T-cell dependent antibody production. At the cellular level it inhibits

production and release of lymphokines including interleukin 2 (T-cell growth factor, TCGF).

Ciclosporin appears to block the resting lymphocytes in the G

or G

phase of the cell cycle, and

inhibits the antigen-triggered release of lymphokines by activated T-cells.

All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes.

Unlike cytostatic agents, it does not depress haemopoiesis and has no effect on the function of

phagocytic cells.

Successful solid organ and bone marrow transplantations have been performed in man using

ciclosporin to prevent and treat rejection and GVHD. Ciclosporin has been used successfully both in

hepatitis C virus (HCV) positive and HCV negative liver transplants recipients. Beneficial effects of

ciclosporin therapy have also been shown in a variety of conditions that are known, or may be

considered to be of autoimmune origin.

Paediatric population: Ciclosporin has been shown to be efficacious in steroid-dependent nephrotic

syndrome.

5.2

Pharmacokinetic properties

Absorption

Following oral administration of Sandimmun Neoral peak blood concentrations of ciclosporin are

reached within 1-2 hours. The absolute oral bioavailability of ciclosporin following administration of

Sandimmun Neoral is 20 to 50%. About 13 and 33% decrease in AUC and C

was observed when

Sandimmun Neoral was administered with a high-fat meal. The relationship between administered

dose and exposure (AUC) of ciclosporin is linear within the therapeutic dose range. The intersubject

and intrasubject variability for AUC and C

is approximately 10-20%. Sandimmun Neoral Oral

Solution and Capsules are bioequivalent.

Distribution

Ciclosporin is distributed largely outside the blood volume, with an average apparent distribution

volume of 3.5 l/kg. In the blood, 33 to 47% is present in plasma, 4 to 9% in lymphocytes, 5 to 12% in

granulocytes, and 41 to 58% in erythrocytes. In plasma, approximately 90% is bound to proteins,

mostly lipoproteins.

Biotransformation

Ciclosporin is extensively metabolised to approximately 15 metabolites.

Metabolism mainly takes

place in the liver via cytochrome P450 3A4 (CYP3A4), and the main pathways of metabolism consist

of mono- and dihydroxylation and N-demethylation at various positions of the molecule. All

metabolites identified so far contain the intact peptide structure of the parent compound; some possess

weak immunosuppressive activity (up to one-tenth that of the unchanged drug).

Elimination

The excretion is primarily biliary, with only 6% of the oral dose excreted in the urine; only 0.1% is

excreted in the urine as unchanged parent compound.

There is a high variability in the data reported on the terminal half-life of ciclosporin depending on the

assay applied and on the target population. The terminal half-life ranged from 6.3 hours in healthy

volunteers to 20.4 hours in patients with severe liver disease (see sections 4.2 and 4.4). The

elimination half-life in kidney-transplanted patients was approximately 11 hours, with a range

between 4 and 25 hours.

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Special populations

Patients with renal impairment

In a study performed in patients with terminal renal failure, the systemic clearance was approximately

two thirds of the mean systemic clearance in patients with normally functioning kidneys. Less than

1% of the administered dose is removed by dialysis.

Patients with hepatic impairment

An approximate 2- to 3-fold increase in ciclosporin exposure may be observed in patients with hepatic

impairment. In a study performed in severe liver disease patients with biopsy-proven cirrhosis, the

terminal half-life was 20.4 hours (range between 10.8 to 48.0 hours) compared to 7.4 to 11.0 hours in

healthy subjects.

Paediatric population

Pharmacokinetic data from paediatric patients given Sandimmun Neoral

or Sandimmun

are very

limited. In 15 renal transplant patients aged 3 -16 years, ciclosporin whole blood clearance after

intravenous administration of Sandimmun

was 10.6±3.7 ml/min/kg (assay: Cyclo-trac specific RIA).

In a study of 7 renal transplant patients aged 2-16 years, the ciclosporin clearance ranged from 9.8

to15.5 ml/min/kg. In 9 liver transplant patients aged 0.65-6 years, clearance was 9.3±5.4 ml/min/kg

(assay: HPLC). In comparison to adult transplant populations, the differences in bioavailability

between Sandimmun Neoral and Sandimmun in paediatrics are comparable to those observed in

adults.

5.3

Preclinical safety data

Ciclosporin gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral

application (rats up to 17 mg/kg/day and rabbits up to 30 mg/kg/day orally). At toxic doses (rats at

30 mg/kg/day and rabbits at 100 mg/kg/day orally), ciclosporin was embryo- and foetotoxic as

indicated by increased prenatal and postnatal mortality, and reduced foetal weight together with

related skeletal retardations.

In two published research studies, rabbits exposed to ciclosporin

in utero

(10 mg/kg/day

subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic

hypertension, and progressive renal insufficiency up to 35 weeks of age. Pregnant rats which received

12 mg/kg/day of ciclosporin intravenously (twice the recommended human intravenous dose) had

foetuses with an increased incidence of ventricular septal defect. These findings have not been

demonstrated in other species and their relevance for humans is unknown. No impairment in fertility

was demonstrated in studies in male and female rats.

Ciclosporin was tested in a number of

in vitro

in vivo

tests for genotoxicity with no evidence for a

clincally relevant mutagenic potential.

Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse

study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for

lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose

males significantly exceeded the control value. In the 24-month rat study conducted at 0.5, 2, and

8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate at the low dose

level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related.

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6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsules

Capsule content: macrogolglycerol hydroxystearate / polyoxyl 40 hydrogenated castor oil, corn oil–

mono–di–triglycerides, ethanol anhydrous / alcohol dehydrated, propylene glycol, alpha–tocopherol.

Capsule shell: gelatin, propylene glycol, glycerol 85%, titanium dioxide (E 171), iron oxide black (E

172) (25- and 100-mg capsules)

Imprint: carminic acid (E 120), aluminium chloride hexahydrate, sodium hydroxide, propylene glycol,

hypromellose / Hydroxypropyl methylcellulose 2910, isopropanol / Isopropyl alcohol, water, purified.

Oral solution

polyoxyl 40 hydrogenated castor oil , corn oil-mono–di–triglycerides, propylene glycol, ethanol

absolute, DL–alpha–tocopherol.

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is printed on the package materials

6.4

Special precautions for storage

Sandimmun Neoral Capsules may be stored at room temperature not exceeding 25°C. Sandimmun

Neoral Capsules should be left in the blister pack until required for use in order to protect from

moisture. When a blister is opened, a characteristic smell is noticeable. This is normal and does not

mean that there is anything wrong with the capsule.

Sandimmun Neoral oral solution should be stored between 15 and 30°C. Below 20°C a jelly-like

formation may occur as Sandimmun Neoral oral solution contains oily components of natural origin

which tend to solidify at low temperatures. If a jelly-like appearance does not disappear after warming

up, up to 30°C, Sandimmun Neoral oral solution should not be used. Minor flakes or slight sediment

may still be observed. These phenomena do not affect the efficacy and safety of the product and the

dosing by means of the pipette remains accurate.

After opening, Sandimmun Neoral oral solution should be used within 2 months

Sandimmun Neoral must be kept out of the reach and sight of children.

6.5

Nature and contents of container

Sandimmun Neoral Capsules are available in 10 x 5 and 2 x 25 blister packs of double-sided

aluminium consisting of an aluminium foil on the bottom side and an aluminium foil on the upper

side. Not all pack sizes may be marketed.

Sandimmun Neoral Oral Solution is available in 50 mL amber glass bottle closed with a rubber

stopper and aluminium tear-off cap. The tear-off cap indicates if the bottle has been previously

opened. A cap is provided for closure of the bottle during the in-use period.

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6.6

Special precautions for disposal

Sandimmun Neoral capsules: No special requirements.

Sandimmun Neoral Oral Solution is provided with two syringes for measuring the doses.

The 1 ml syringe is used to measure doses less than or equal to 1 ml (each graduation of 0.05 ml

corresponds to 5 mg of ciclosporin).

The 4 ml syringe is used to measure doses greater than 1 ml, and up to 4 ml (each graduation of 0.1 ml

corresponds to 10 mg of ciclosporin).

Initial use of Sandimmun Neoral Oral Solution

Raise the flap in the centre of the metal sealing ring.

Tear off the sealing ring completely.

Remove the black stopper

and throw it away

Push the tube unit with the white stopper firmly into the neck of

the bottle.

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Choose the syringe depending on the prescribed volume. For

volume less than 1 ml or equal to 1 ml, use the 1-ml syringe. For

volume greater than 1 ml, use the 4-ml syringe. Insert the nozzle

of the syringe into the white stopper.

Draw up the prescribed volume of solution (position the lower

part of the plunger ring in front of the graduation corresponding

to the prescribed volume).

Expel any large bubbles by depressing and withdrawing the

plunger a few times before removing the syringe containing the

prescribed dose from bottle. The presence of a few tiny bubbles

is of no importance and will not affect the dose in any way.

Push the medicine out of the syringe into a small glass with

some liquid (not grapefruit juice). Avoid any contact between

the syringe and the liquid in the glass. The medicine can be

mixed just before it is taken. Stir and drink the entire mixture

right away. Once mixed it should be taken immediately after

preparation.

After use, wipe the syringe on the outside only with a dry tissue

and replace it in its cover. The white stopper and tube should

remain in the bottle. Close the bottle with the separately

provided black cap.

Subsequent use

Commence at point 5.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

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7

MANUFACTURERS

Manufacturer:

Sandimmun Neoral capsules:

Catalent Germany Eberbach GmbH, Eberbach/Baden, Germany

Sandimmun Neoral oral solution:

Delpharm Huningue SAS, Huningue, France

For:

Novartis Pharma AG, Switzerland

CH-4002, Basel, Switzerland

8

REGISTRATION HOLDER

Novartis Israel Ltd

P.O.B 7126, Tel Aviv, Israel

9

REGISTRATION NUMBER(S)

SANDIMMUN

®

NEORAL

®

25 mg Capsules: 066-67-28138

SANDIMMUN

®

NEORAL

®

50 mg Capsules: 066-77-28139

SANDIMMUN

®

NEORAL

®

100 mg Capsules: 066-78-28140

SANDIMMUN NEORAL 100 mg/ml Oral Solution: 066-79-28141

Revised in June 2020.