Clefirem

Patient Information Leaflet

CLEFIREM, 14 mg, coated tablets
teriflunomide
Please read this leaflet carefully before taking this medicine, as it contains
important information for you.

• Keep this leaflet so that you can read it again if necessary.
• If you have any further questions, please consult your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm someone else, even if their symptoms are the same.
• If you experience any adverse effects, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Table of Contents

1. What Clefirem is and what it is used for
2. Important information before taking Clefirem
3. How to take Clefirem
4. Possible side effects
5. How to store Clefirem
6. Contents of the pack and other information

1. What Clefirem is and what it is used for

What is Clefirem?
Clefirem contains the active substance teriflunomide, which is an immunomodulatory medicine that regulates the immune system to reduce its attack on the nervous system.

What is Clefirem used for?
Clefirem is used to treat adults, children, and adolescents (aged 10 years and older, weighing more than 40 kg) with relapsing-remitting multiple sclerosis.

What is multiple sclerosis?
Multiple sclerosis is a chronic disease that affects the central nervous system. The central nervous system consists of the brain and spinal cord. In multiple sclerosis, inflammation damages the protective covering around nerves (called myelin) in the central nervous system. This process is known as demyelination. This damage prevents nerves from functioning properly.

In people with relapsing-remitting multiple sclerosis, there are repeated attacks (relapses) of physical symptoms caused by improper nerve function. Symptoms vary between individuals but usually include:

• difficulty walking,
• vision problems,
• problems with balance.

These symptoms may completely disappear after a relapse ends, but over time some problems may persist between relapses. This may lead to physical disability that makes it difficult to perform daily activities.

How Clefirem works
Clefirem helps protect the central nervous system from the immune system by reducing the increase in certain white blood cells (lymphocytes). This reduces the inflammation that, in patients with multiple sclerosis, leads to nerve damage.

2. Important information before taking Clefirem

When not to take Clefirem:

• if the patient is allergic to teriflunomide or any of the other ingredients of this medicine (listed in section 6);
• if the patient has ever experienced severe skin rash, skin peeling, blisters, and/or oral ulceration after taking teriflunomide or leflunomide;
• if the patient has severe liver disease;
• if the patient is pregnant, suspects she may be pregnant, or is breastfeeding;
• if the patient has any severe diseases affecting the immune system, e.g. acquired immunodeficiency syndrome (AIDS);
• if the patient has any severe bone marrow disorders or has low numbers of red or white blood cells or reduced platelet count;
• if the patient has severe infection;
• if the patient has severe kidney disease requiring dialysis;
• if the patient has very low levels of proteins in the blood (hypoproteinemia).
  If in doubt, consult a doctor or pharmacist before taking this medicine.

Warnings and precautions
Before starting Clefirem, discuss with your doctor or pharmacist if:

• the patient has liver function disorders and/or drinks large amounts of alcohol; the doctor may perform blood tests to check liver function before and during treatment. If test results indicate liver dysfunction, the doctor may discontinue Clefirem. Refer to section 4.
• the patient has high blood pressure (hypertension), regardless of whether it is controlled with medication or not. Clefirem may increase blood pressure. The doctor will monitor blood pressure before starting treatment and regularly thereafter. Refer to section 4.
• the patient has an infection. Before taking Clefirem, the doctor will ensure the patient has adequate levels of white blood cells and platelets. Since Clefirem reduces white blood cell count, it may impair the ability to fight infections. The doctor may perform blood tests if the patient suspects an infection. Viral infections such as herpes virus (including cold sores or shingles) may occur during treatment with teriflunomide. In some cases, serious complications have occurred. Immediately inform the doctor if any symptoms suggestive of herpes virus infection are suspected. Refer to section 4.
• the patient has severe skin reactions.
• the patient has respiratory symptoms.
• the patient experiences weakness, numbness, or pain in the hands and feet.
• the patient plans to be vaccinated.
• the patient is taking leflunomide together with Clefirem.
• the patient is switching from another medication to Clefirem or from Clefirem to another medication.
• the patient is scheduled for a specific blood test (calcium level measurement). Calcium test results may be falsely low.

Respiratory system reactions
Inform the doctor if the patient develops unexplained cough or shortness of breath (difficulty breathing). The doctor may perform additional tests.

Children and adolescents
Clefirem is not intended for use in children under 10 years of age, as it has not been studied in pediatric patients with multiple sclerosis.
The warnings and precautions listed above also apply to children. The following information is important for children and their caregivers:

• cases of pancreatitis have been observed in patients receiving teriflunomide. The doctor may perform blood tests if pancreatitis is suspected.

Clefirem with other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take, including over-the-counter medicines.
In particular, inform the doctor or pharmacist if the patient is taking any of the following medicines:

• leflunomide, methotrexate, and other medicines affecting the immune system (often called immunosuppressants or immunomodulators);
• rifampicin (used to treat tuberculosis and other infections);
• carbamazepine, phenobarbital, phenytoin (used to treat epilepsy);
• St. John’s wort (a herbal remedy for depression);
• repaglinide, pioglitazone, nateglinide, or rosiglitazone (used to treat diabetes);
• daunorubicin, doxorubicin, paclitaxel, or topotecan (used to treat cancer);
• duloxetine (used to treat depression, urinary incontinence, or kidney disease in diabetic patients);
• alosetron (used to treat severe diarrhea);
• theophylline (used to treat asthma);
• tizanidine (a muscle relaxant);
• warfarin (an anticoagulant used to thin the blood to prevent clots);
• oral contraceptives (containing ethinylestradiol and levonorgestrel);
• cefaclor, benzylpenicillin (penicillin G), ciprofloxacin (used to treat infections);
• indomethacin, ketoprofen (used to treat inflammation or pain);
• furosemide (used to treat heart conditions);
• cimetidine (used to reduce gastric acid secretion);
• zidovudine (used to treat HIV infection);
• rosuvastatin, simvastatin, atorvastatin, pravastatin (used to treat hypercholesterolemia, i.e. high blood cholesterol);
• sulfasalazine (used for inflammatory bowel disease and rheumatoid arthritis);
• cholestyramine (used for high blood cholesterol or itching in liver disease);
• activated charcoal (used to reduce absorption of medicines or other substances).

Pregnancy and breastfeeding
Do not take Clefirem if the patient is pregnant or suspects she may be pregnant. Women who are pregnant or who become pregnant while taking Clefirem have an increased risk of congenital malformations in the baby. Women of childbearing potential who do not use effective contraception must not take this medicine. If a girl starts menstruating while taking Clefirem, inform the doctor, who will provide specialist advice regarding contraception and potential risks in case of pregnancy.
If a woman plans to become pregnant after stopping Clefirem, she should inform her doctor, because it is essential to ensure the medicine is no longer in the body before attempting pregnancy. Elimination of the active substance may take up to 2 years. This period can be shortened to several weeks by taking specific medicines that accelerate the removal of Clefirem from the body.
In both cases, blood testing must confirm that the active substance has been sufficiently eliminated from the body. The doctor should confirm that the blood level of Clefirem is low enough to allow pregnancy.
More information about laboratory tests can be obtained from the treating doctor.
If a woman suspects she became pregnant while taking Clefirem or within two years after stopping treatment, she must stop taking Clefirem immediately and contact her doctor for a pregnancy test. If pregnancy is confirmed, the doctor may recommend appropriate treatment to rapidly and adequately eliminate Clefirem from the body to reduce risk to the baby.

Contraception
Women must use effective contraception during treatment with Clefirem and after stopping treatment. Teriflunomide remains in the blood for a long time after stopping treatment. Therefore, effective contraception must continue after stopping treatment.

• This method should be used until the blood level of teriflunomide is sufficiently low (confirmed by the doctor).
• Discuss with the doctor the most suitable contraceptive method for the patient and any need to change the contraceptive method.

Do not take Clefirem while breastfeeding, as teriflunomide passes into human milk.

Driving and operating machinery
Clefirem may cause dizziness, which may impair concentration and reaction ability. Patients experiencing these symptoms should not drive or operate machinery.

Clefirem contains lactose
Clefirem contains lactose (a type of sugar). If the patient has previously been diagnosed with intolerance to certain sugars, consult a doctor before taking this medicine.

Clefirem contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e. the medicine is considered "sodium-free".

3. How to take Clefirem

Treatment with Clefirem will be supervised by a physician experienced in the management of multiple sclerosis.
This medicine should always be taken exactly as prescribed by your doctor. If in doubt, consult your doctor.
Adults, children and adolescents (aged 10 years and older, with body weight greater than 40 kg)
The recommended dose is one 14 mg tablet once daily.
Route and method of administration
Clefirem is administered orally. Clefirem should be taken every day at any time as a single daily dose.
Tablets must be swallowed whole with water. Tablets must not be divided, crushed, or chewed, as this may alter the amount of medicine absorbed.
Clefirem may be taken with food or independently of meals.
Overdose of Clefirem
In case of taking more than the prescribed dose of Clefirem, contact your doctor immediately. Adverse effects similar to those described in section 4 below may occur.
Missed dose of Clefirem
Do not take a double dose to make up for a missed tablet. Take the next dose according to the prescribed dosing schedule.
Stopping treatment with Clefirem
Do not stop taking Clefirem or change the dose without first consulting your doctor.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
The following adverse reactions may occur after using this medicine.
Severe adverse reactions
Some adverse reactions may be severe or may become severe. If any of the following symptoms occur, contact your doctor immediately.
Common (may occur in up to 1 in 10 people)

• pancreatitis, which may cause symptoms such as abdominal pain, nausea or vomiting (frequency is common in children and adolescents and uncommon in adult patients).

Uncommon (may occur in up to 1 in 100 people)

• allergic reactions, which may cause symptoms including rash, hives, swelling of the lips, tongue or face, or sudden breathing difficulties;
• severe skin reactions, which may cause symptoms including skin rash, blisters on the skin, fever or mouth ulcers;
• severe infections or sepsis (a type of infection potentially life-threatening to the patient), which may cause symptoms including high fever, seizures, chills, reduced urine output or confusion;
• pneumonia, which may cause symptoms including shortness of breath or persistent cough.

Frequency not known (frequency cannot be estimated from the available data):

• severe liver disease, which may cause symptoms including yellowing of the skin or whites of the eyes, darker than usual urine, unexplained nausea and vomiting, or abdominal pain.

Other adverse reactions may occur with the following frequency:
Very common (may occur in more than 1 in 10 people)

• headache;
• diarrhoea, nausea;
• increased AlAT activity (elevated activity of certain liver enzymes in blood) observed in laboratory tests;
• hair thinning.

Common (may occur in up to 1 in 10 people)

• herpes virus infections, including cold sores and shingles, with symptoms such as blisters, burning, itching, tingling, numbness or pain of the skin, usually on one side of the upper body or face, and other symptoms such as fever and fatigue;
• influenza, upper respiratory tract infection, urinary tract infection, bronchitis, sinusitis, sore throat and discomfort during swallowing, cystitis, viral gastroenteritis, dental infection, laryngitis, fungal foot infection;
• laboratory findings: decreased number of red blood cells (anaemia), changes in the liver and white blood cell test results (see section 2), increased activity of muscle enzymes (creatine kinase) has also been observed;
• mild allergic reactions;
• feeling of restlessness;
• tingling sensation, feeling of weakness, numbness, tingling or pain in the lower back or leg (sciatica), tingling, burning, numbness or pain in the hands and fingers (carpal tunnel syndrome);
• sensation of "pounding heartbeat";
• increased blood pressure;
• vomiting, toothache, epigastric pain;
• rash, acne;
• tendon, joint, bone pain, muscle pain (musculoskeletal pain);
• need to urinate more frequently than usual;
• heavy menstrual bleeding;
• pain;
• lack of energy or feeling of weakness (asthenia);
• weight loss.

Uncommon (may occur in up to 1 in 100 people)

• decreased number of platelets (mild thrombocytopenia);
• increased sensitivity (especially of the skin), stabbing or pulsating pain along one or more nerves, nerve disorders of arms or legs (peripheral neuropathy);
• changes in nails, severe skin reactions;
• injury-related pain;
• psoriasis;
• inflammation of the mucous membrane of the mouth/lips;
• abnormal levels of fats (lipids) in the blood;
• inflammation of the large intestine.

Rare (may occur in up to 1 in 1000 people)

• inflammation or damage to the liver.

Frequency not known (frequency cannot be estimated from the available data)

• pulmonary hypertension.

Children (aged 10 years and older) and adolescents
The adverse reactions listed above also apply to children and adolescents. The following additional information is important for children, adolescents and their caregivers:
Common (may occur in up to 1 in 10 people)

• pancreatitis.

Reporting of adverse reactions
If any adverse reactions occur, including any adverse reactions not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Reactions of Medicinal Products at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl.
Adverse reactions can also be reported to the responsible entity.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Clefirem

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the cardboard box and folding carton after "EXP". The expiry date refers to the last day of the stated month.
No special storage instructions are required for this medicine.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What Clefirem contains
The active substance is teriflunomide.
Clefirem 14 mg film-coated tablets

• Each tablet contains 14 mg of teriflunomide.
• The other ingredients are: lactose monohydrate, corn starch, microcrystalline cellulose (E 460), sodium carboxymethyl starch (type A), hydroxypropylcellulose (E 463), magnesium stearate (E 407B), colloidal anhydrous silica, hypromellose, titanium dioxide (E 171), indigo carmine, aluminium lake of indigo carmine (E132), triacetin (E 1518) (see section 2 "Clefirem contains lactose").

What Clefirem looks like and contents of the pack
Clefirem 14 mg film-coated tablets are light blue, round, biconvex film-coated tablets with a diameter of approximately 7.1 mm, smooth on both sides.
Clefirem 14 mg film-coated tablets are available in aluminum blisters packed in cardboard boxes containing 28 or 84 film-coated tablets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Bausch Health Ireland Limited
3013 Lake Drive, Citywest Business Campus
Dublin 24, D24PPT3
Ireland
Tel.: +48 17 865 51 00

Importer
Bausch Health Poland Sp. z o.o.
Kosztowska Street 21
41-409 Myslowice
Poland