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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

What Teriflunomide BOS is

Teriflunomide BOS contains the active substance teriflunomide which is an immunomodulatory agent and adjusts the immune system to limit its attack on the nervous system.

 

What Teriflunomide BOS is used for

Teriflunomide BOS is used in adults to treat relapsing remitting multiple sclerosis (MS).

 

What multiple sclerosis is

Multiple sclerosis (MS) is a long-term illness that affects the central nervous system (CNS). The CNS is made up of the brain and spinal cord. In multiple sclerosis, inflammation destroys the protective sheath (called myelin) around the nerves in the CNS. This loss of myelin is called demyelination. This stops nerves from working properly.

 

People with relapsing form of multiple sclerosis will have repeated attacks (relapses) of physical symptoms caused by their nerves not working properly.

 

These symptoms vary from patient to patient but usually involve:

 

·  difficulty walking.

·  vision problems.

·  balance problems.

 

Symptoms may disappear completely after the relapse is over, but over time, some problems may remain between relapses. This can cause physical disabilities that may interfere with your daily activities.

 

How Teriflunomide BOS works

Teriflunomide BOS helps to protect against attacks on the central nervous system by the immune system by limiting the increase of some white blood cells (lymphocytes). This limits the inflammation that leads to nerve damage in MS.


Do not take Teriflunomide BOS:

 

·  if you are allergic to teriflunomide or any of the other ingredients of this medicine (listed in section 6),

·  if you have severe liver problems,

·  if you are pregnant, think you may be pregnant, or are breast-feeding,

·  if you suffer from a serious problem which affects your immune system e.g. acquired immunodeficiency syndrome (AIDS),

·  if you have a serious problem with your bone marrow, or if you have low numbers of red or white cells in your blood or a reduced number of blood platelets,

·  if you are suffering from a serious infection,

·  if you have severe kidney problems which require dialysis,

·  if you have very low levels of proteins in your blood (hypoproteinemia),

 

If you are not sure, talk to your doctor or pharmacist before taking this medicine.

Warnings and precautions

Talk to your doctor or pharmacist before taking Teriflunomide BOS if:

 

·  you have liver problems; Your doctor will carry out blood tests before and during treatment to check how well your liver is working. If your test results show a problem with your liver, your doctor may stop your treatment with Teriflunomide BOS. Please read section 4.

·  you have high blood pressure (hypertension) whether it is controlled with medicines or not. Teriflunomide BOS can cause an increase in blood pressure. Your doctor will check your blood pressure before the start of treatment and regularly thereafter. Please read section 4.

·  you have an infection. Before you take Teriflunomide BOS, your doctor will make sure you have enough white blood cells and platelets in your blood. As Teriflunomide BOS decreases the number of white cells in the blood this may affect your ability to fight the infection. Your doctor may do blood tests to check your white blood cells if you think you have an infection. Please read section 4.

·  you have severe skin reactions.

·  you have respiratory symptoms.

·  you have weakness, numbness and pain in the hands and feet.

·  you are going to have a vaccination.

·  you take leflunomide with Teriflunomide BOS.

·  you are switching to or from Teriflunomide BOS.

·  you are due to have a specific blood test (calcium level). Falsely low levels of calcium can be detected.

 

Children and adolescents

Teriflunomide should not be used in children and adolescents under 18 years of age. This is because the effects of the medicine in this age group are not known.

 

Other medicines and Teriflunomide BOS

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription.

 

In particular, tell your doctor or pharmacist if you are taking any of the following:

 

·  leflunomide, methotrexate and other medicines that affect the immune system (often called immunosuppressants or immunomodulators)

·  rifampicin (a medicine used to treat tuberculosis and other infections)

·  carbamazepine, phenobarbital, phenytoin for epilepsy

·  St John’s wort (a herbal medicine for depression)

·  repaglinide, pioglitazone, nateglinide, or rosiglitazone for diabetes

·  daunorubicin, doxorubicin, paclitaxel, or topotecan for cancer

·  duloxetine for depression, urinary incontinence or in kidney disease in diabetics

·  alosetron for the management of severe diarrhoea

·  theophylline for asthma

·  tizanidine, a muscle relaxant

·  warfarin, an anticoagulant used to make the blood thinner (i.e. more fluid) in order to avoid blood clots

·  oral contraceptives (containing ethinylestradiol and levonorgestrel)

·  indometacin, ketoprofen for pain or inflammation

·  furosemide for heart disease

·  cimetidine for reducing gastric acid

·  zidovudine for HIV infection

·  rosuvastatin, simvastatin, atorvastatin, pravastatin for hypercholesterolemia (high cholesterol)

·  sulfasalazine for inflammatory bowel disease or rheumatoid arthritis

·  cholestyramine for high cholesterol or relief from itching in liver disease

·  activated charcoal to reduce absorption of medicines or other substances

 

Pregnancy and breast-feeding

Do not take Teriflunomide BOS if you are or think you may be pregnant. If you are pregnant or become pregnant while taking Teriflunomide BOS, the risk of having a baby with birth defects is increased. Women of childbearing potential must not take this medicine without using reliable contraceptive measures.

 

Tell your doctor if you plan to become pregnant after stopping treatment with Teriflunomide BOS, as you need to ensure that most of this medicine has left your body before trying to become pregnant. The elimination of the active substance may take up to 2 years to occur naturally. The time can be reduced to a few weeks by taking certain medicines which speed up removal of Teriflunomide BOS from your body.

 

In either case it should be confirmed by a blood test that the active substance has been sufficiently removed from your body and you need confirmation from your treating physician that the blood level of teriflunomide is low enough to allow you to become pregnant.

 

For further information on the laboratory testing please contact your doctor.

 

If you suspect that you are pregnant while taking Teriflunomide BOS or in the two years after you have stopped treatment, you must contact your doctor immediately for a pregnancy test. If the test confirms that you are pregnant, your doctor may suggest treatment with certain medicines to remove teriflunomide rapidly and sufficiently from your body, as this may decrease the risk to your baby.

 

Contraception

You must use an effective method of contraception during and after treatment with Teriflunomide BOS. Teriflunomide remains in your blood for a long time after you stop taking it. Continue to use effective contraception after you stop treatment.

 

·  Do this until the levels of teriflunomide in your blood are low enough - your doctor will check this.

·  Talk with your doctor about the best method of contraception for you and any potential need for contraception change.

Do not take Teriflunomide BOS when you are breast-feeding, as teriflunomide passes into the breast milk.

 

Driving and using machines

Teriflunomide might make you feel dizzy which may impair your ability to concentrate and react. If you are affected, do not drive or use machines.

 

Teriflunomide BOS contains lactose

Teriflunomide BOS contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

 

Teriflunomide BOS contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’


Treatment with Teriflunomide BOS will be overseen by a doctor who is experienced in the treatment of multiple sclerosis.

 

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

 

The recommended dose is one 14 mg tablet daily.

 

Route/method of administration

Teriflunomide BOS is for oral use. Teriflunomide BOS is taken every day as a single daily dose at any time of the day.

 

You should swallow the tablet whole with some water.

 

Teriflunomide BOS may be taken with or without food.

 

If you take more Teriflunomide BOS than you should

If you have taken too much Teriflunomide BOS, call your doctor straight away. You may experience side effects similar to those described in section 4 below.

 

If you forget to take Teriflunomide BOS

Do not take a double dose to make up for a forgotten tablet. Take your next dose at the scheduled time.

 

If you stop taking Teriflunomide BOS

Do not stop taking Teriflunomide BOS or change your dose without talking to your doctor first.

 

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


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

 

The following side effects may happen with this medicine.

 

 

 

 

Serious side effects

Tell your doctor immediately, if you notice any of the following serious side effects:

·  allergic reactions which might include symptoms of rash, hives, swelling of lips, tongue or face or sudden difficulty breathing

·  severe skin reactions which might include symptoms of skin rash, blistering, fever, or ulcers in your mouth

·  severe infections or sepsis (a potentially life-threatening type of infection) which might include symptoms of high fever, shaking, chills, reduced urine flow, or confusion

·  inflammation of the lungs which might include symptoms of shortness of breath or persistent cough

·  inflammation of the pancreas which might include symptoms of severe pain in the upper abdominal area that may also be felt in your back, nausea, or vomiting

·  Serious liver disease which might include symptoms of yellowing of your skin or the whites of your eyes, darker urine than normal, unexplained nausea and vomiting, or abdominal pain.

 

 

Other side effects can occur with the following frequencies

 

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

 

·  Headache

·  Diarrhoea, feeling sick

·  Increase in ALT (increase in blood levels of certain hepatic enzymes) shown in tests

·  Hair thinning

 

Common (may affect up to 1 in 10 people)

 

·  Influenza, upper respiratory tract infection, urinary tract infection, bronchitis, sinusitis, sore throat and discomfort when swallowing, cystitis, gastroenteritis viral, oral herpes, tooth infection, laryngitis, fungal infection of the foot

·  Laboratory values: a decrease in the number of red blood cells (anaemia), changes in liver and white blood cell test results (see section 2), as well as elevations in a muscle enzyme (creatine phosphokinase) have been observed

·  Mild allergic reactions

·  Feeling anxious

·  Pins and needles, feeling weak, numb, tingling or pain in the lower back or leg (sciatica); feeling numb, burning, tingling or pain in the hands and fingers (carpal tunnel syndrome)

·  Feeling your heartbeat

·  Increase in blood pressure

·  Being sick (vomiting), toothache, upper abdominal pain

·  Rash, acne

·  Pain of the tendons, joints, bones, muscle pain (musculoskeletal pain)

·  Needing to urinate more often than usual

·  Heavy periods

·  Pain

·  Lack of energy or feeling weak (asthenia)

·  Weight loss

 

Uncommon (may affect up to 1 in 100 people)

 

·  Decrease in the number of blood platelets (mild thrombocytopenia)

·  Increased feeling or sensitivity, especially in the skin; stabbing or throbbing pain along one or more nerves, problems in the nerves of the arms or legs (peripheral neuropathy)

·  Nail disorders, severe skin reactions

·  Post-traumatic pain

 

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

· Severe infections (including sepsis)

· Severe allergic reactions (including anaphylaxis)

· Pulmonary reaction (interstitial lung disease, ILD)

· Inflammation of the liver, pancreas, or mouth/lips

· Severe skin reactions

· Abnormal levels of fats (lipids) in the blood


Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister after “EXP”. The expiry date refers to the last day of that month.

Store below 30 ℃

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.


·         The active substance is teriflunomide.

·         Each film-coated tablet contains 14 mg of teriflunomide.

·         The other ingredients are:

-          Tablet core: Lactose monohydrate, pregelatinized starch, hydroxypropyl cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate.

-          Tablet coat: Hypromellose, titanium dioxide, talc, Macrogol/PEG, FD & C Blue #2 and Indigo carmine aluminium lake.


Teriflunomide BOS tablets are pale blue to pastel blue colored, pentagonal shape film coated tablets debossed with “T14” on one side and plain on another side. Teriflunomide BOS tablets are proposed for marketing in Alu-Alu blister pack containing 10 tablets. The carton contains 3 such blister packs i.e. 30 (3x10) tablets.

MAH and Secondary packaging:

Boston Oncology Arabia Limited

Riyadh, Sudair Industrial Area,

Zone A, Road 11, Factory 107,

Saudi Arabia

 

Full Manufacturing and Primary Packaging:

Natco Pharma Limited

 

To report any side effect(s):

·  Saudi Arabia:

·         The National Pharmacovigilance Centre (NPC)

-          SFDA Call Centre: 19999

-          E-mail: npc.drug@sfda.gov.sa

-          Website: https://ade.sfda.gov.sa/

·  Other GCC States:

- Please contact the relevant competent authority.

 

Council of Arab Health Ministers

This is a Medicament

•          Medicament is a product which affects your health and its consumption contrary to instructions is dangerous for you.

•          Follow strictly the doctor’s prescription, the method of use and the instructions of the pharmacist who sold the medicament.

•          The doctor and the pharmacist are the experts in medicines, their benefits and risks.

•          Do not by yourself interrupt the period of treatment prescribed for you.

•          Do not repeat the same prescription without consulting your doctor.

•          Keep all medicaments out of reach of children.

Council of Arab Health Ministers

Union of Arab Pharmacists


07/2022
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

ما هو تيريفلونومايد بي او اس

يحتوي تيريفلونومايد بي او اس على المادة الفعالة تيريفلونومايد التي تعد من العوامل المُعدِّلة للمناعة والتي تضبط عمل الجهاز المناعي لمنع مهاجمته للجهاز العصبي.

 

ما هو استخدام تيريفلونومايد بي او اس

يستخدم تيريفلونومايد بي او اس عند البالغين لعلاج التصلب اللويحي المتعدد المتكرر Multiple sclerosis (MS).

 

ما هو التصلب اللويحي

التصلب اللويحي هو مرض مزمن يصيب الجهاز العصبي المركزي والذي يتكون من الدماغ والنخاع الشوكي. يدمّر الالتهاب الغلاف الواقي للأعصاب في الجهاز العصبي المركزي والذي يدعى المايلين Myelin، وتُدعى خسارة المايلين demyelination هذا يمنع عمل الأعصاب بالشكل المناسب.

 

يعاني مرضى التصلب اللويحي الانتكاسي من نوبات متكررة (انتكاسات) لأعراض جسدية تنجم عن عدم عمل الأعصاب لديهم بالشكل المناسب.

تتفاوت هذه الأعراض من مريض لآخر لكنها تضم غالباً:

·         صعوبة المشي.

·         اضطرابات بصرية.

·         مشاكل في التوازن.

قد تختفي الأعراض كلياً بعد زوال النوبة، لكن بعض الاضطرابات قد تستمر بين النوبات مع مرور الوقت، مما يسبب إعاقات جسدية يمكن أن تؤثر في نشاطاتك اليومية.

كيف يعمل تيريفلونومايد بي او اس

يساعد تيريفلونومايد بي او اس في الوقاية من هجمات الجهاز المناعي على الجهاز العصبي المركزي من خلال الحد من زيادة بعض كريات الدم البيضاء (اللمفاويات)، مما يؤدي للحد من الالتهاب الذي يقود لتلف الأعصاب في التصلب اللويحي

لا تستخدم تيريفلونومايد بي او اس

·         إذا كنت تتحسس من تيريفلونومايد أو أي من المكونات الأخرى لهذا الدواء (مذكورة في القسم 6)

·         إذا كان لديك مشاكل شديدة في الكبد.

·         إذا كنتِ حاملاً، أو تعتقدين بأنك قد تكونين حاملاً، أو كنتِ مرضعةً.

·         إذا كنت تعاني من مشاكل خطيرة تؤثر على جهازك المناعي كمتلازمة نقص المناعة المكتسب (الإيدز AIDS).

·         إذا كانت لديك مشاكل خطيرة في نخاع العظم، أو كان لديك نقص في كريات الدم الحمراء أو البيضاء أو الصفيحات في دمك.

·         إذا كنت تعاني من عدوى خطيرة.

·         إذا كان لديك مشاكل خطيرة في الكلى تتطلب غسيل كلوي.

·         إذا كان لديك مستويات منخفضة من البروتين في دمك.

 

أخبر طبيبك أو الصيدلي قبل استخدامك لهذا الدواء إذا كنت غير متأكد أن ما سبق ينطبق عليك.

 

التحذيرات والاحتياطات

أخبر طبيبك أو الصيدلي قبل تناولك مستحضر تيريفلونومايد بي او اس:  

·         إذا كانت لديك مشاكل في الكبد. سيُجري طبيبك فحوصات دم قبل العلاج وأثناءه للتأكد من عمل ووظيفة الكبد لديك. إذا أظهرت نتائج الفحوصات مشكلة في كبدك فقد يوقف طبيبك العلاج بتيريفلونومايد بي او اس. اقرأ القسم 4 من فضلك.   

·         إذا كان لديك ارتفاع في الضغط سواءً أكان مضبوطاً بالأدوية أم لا، لأن تيريفلونومايد بي او اس قد يسبب زيادة في ضغط الدم، سيقوم طبيبك بالتأكد من ضغط الدم لديك قبل البدء بالعلاج ثم بشكل منتظم بعد ذلك. اقرأ القسم 4 من فضلك.

·         إذا كان لديك عدوى. سيقوم طبيبك بالتأكد من أنك تملك عدداً كافياً من كريات الدم البيضاء والصفيحات في دمك قبل البدء بالعلاج بتيريفلونومايد بي او اس؛ لأن هذا الدواء يخفض عدد الكريات البيضاء في الدم وهو ما يؤثر على قدرة جسمك في الدفاع ضد العدوى. قد يُجري طبيبك بعض الفحوصات الدموية لفحص الكريات البيضاء لديك إذا كنت تعتقد بأنك تعاني من عدوى. اقرأ القسم 4 من فضلك.

·         إذا كانت لديك تفاعلات جلدية خطيرة.

·         إذا كانت لديك أعراض تنفسية.

·         إذا كان لديك ضعف أو خدر أو ألم في يديك أو قدميك.

·         إذا كنت تعتزم أخذ لقاح.

·         إذا كنت تتناول ليفلونومايد مع تيريفلونومايد بي او اس.

·         إذا كان قد تم تحويلك من أو إلى تيريفلونومايد بي او اس.

·         إذا كنت ستخضع لفحوصات دموية محددة (كمستوى الكالسيوم)، فقد يُعطي قيمة منخفضة خاطئة للكالسيوم في الدم.

الأطفال واليافعون

لا ينبغي استخدام تيريفلونومايد بي او اس في الأطفال والمراهقين الذين تقل أعمارهم عن 18 عامًا. وذلك لأن تأثيرات الدواء في هذه الفئة العمرية غير معروفة.

تيريفلونومايد بي او اس مع الأدوية الأخرى

أخبر طبيبك أو الصيدلي عن أي أدوية تتناولها أو الأدوية التي تناولتها مؤخراً أو الأدوية التي ربما تناولتها، ويشمل ذلك الأدوية المأخوذة بدون وصفة طبية.

أخبر طبيبك أو الصيدلي إذا كنت تتناول أياً من الأدوية التالية تحديداً:

·         ليفلونومايد، أو ميثوتركسات، أو أية أدوية أخرى تؤثر في الجهاز المناعي (تُدعى عادةً مثبطات المناعة أو مُعدِّلات المناعة)

·         ريفامبيسين (دواء يستخدم في معالجة السل والتهابات أخرى)

·         كاربامازيبين، فينوباربيتال، فينيتوين لعلاج لصرع

·         عشبة القديس جون (دواء نباتي لعلاج الاكتئاب)

·         ريباغلينايد، بيوغليتازون، ناتيغلينايد، روزيغليتازون لعلاج السكري

·         داونوروبيسين، دوكسوروبيسين، باكليتاكسيل، أو توبوتيكان لعلاج السرطان

·         دولوكسيتين لعلاج الاكتئاب والسلس البولي أو اضطرابات الكلى عند مرضى السكري

·         الوسترون لعلاج الإسهال الشديد

·         ثيوفيللين لعلاج الربو

·         تيزانيدين وهو مرخٍ عضلي

·         وارفارين وهو دواء يستخدم لتمييع الدم للوقاية من تشكل الجلطات

·         موانع الحمل الفموية (التي تحوي إيثينيل إستراديول وليفونورجيستريل)

·         سيفاكلور، بنزيل بنسيلين (بنسلين G)، سيبروفلوكساسين لعلاج الالتهابات

·         إندوميتاسين، كيتوبروفين لعلاج الألم أو الالتهاب

·         فوروسيمايد لعلاج أمراض القلب

·         سيميتيدين لإنقاص الحمض المعدي

·         زيدوفودين لعلاج عدوى ـفيروس نقص المناعة البشري HIV

·         روزوفاستاتين، سيمفاستاتين، أتورفاستاتين، برافاستاتين لعلاج ارتفاع كوليسترول الدم

·         سلفاسالازين لعلاج مرض التهاب الأمعاء أو التهاب المفاصل الروماتويدي

·         كوليستيرامين لعلاج ارتفاع الكوليسترول أو تخفيف الحكة في أمراض الكبد

·         الفحم المفعَّل لتقليل امتصاص أدوية أو مواد أخرى

 

الحمل والرضاعة الطبيعية

لا تستخدمي تيريفلونومايد بي او اس إذا كنتِ حاملاً أو تعتقدين بأن قد تحملين. إذا كنتِ حاملاً أو أصبحتِ حاملاً أثناء استخدامك تيريفلونومايد بي او اس فإن خطر حدوث تشوهات لدى طفلك تزداد. يجب على النساء القادرات على الإنجاب عدم تناول هذا الدواء من دون استخدام وسائل منع حمل موثوقة.

أخبري طبيبك إذا كنتِ تخططين للحمل بعد التوقف عن العلاج بتيريفلونومايد بي او اس، لأنك بحاجة للتأكد من أن معظم هذا الدواء قد زال من جسمك قبل محاولة الحمل. إن إخراج المادة الفعالة قد يستغرق ما يصل لسنتين حتى يحصل بشكل طبيعي، ويمكن اختصار هذه المدة لأسابيع قليلة باستخدام أدوية محددة تسرّع إخراج تيريفلونومايد من جسمك.

يجب في كلتا الحالتين التأكد من أن المادة الفعالة قد زالت بشكلٍ كافٍ من جسمك بإجراء فحص دم، وأنتِ بحاجة لتأكيد من طبيبك المعالج بأن مستوى الدم لتيريفلونومايد هو قليل بما يسمح لكِ بأن تحملي.

تواصلي مع طبيبك من فضلكِ للحصول على معلومات إضافية عن الفحوصات المخبرية.

إذا كنتِ تعتقدين بأنك حامل أثناء علاجك بتيريفلونومايد بي او اس أو خلال السنتين التاليتين بعد إيقاف العلاج فعليكِ لتواصل مع طبيبك فوراً لإجراء اختبار الحمل. سيقترح طبيبكِ العلاج بأدوية معينة لإطراح تيريفلونومايد سريعاً وبشكلٍ كافٍ من جسمك إذا أثبت اختبار الحمل أنك حامل؛ لأن هذا قد يقلل من الخطر على جنينك.

منع الحمل

يجب عليكِ استخدام وسيلة فعالة لمنع الحمل أثناء فترة العلاج بتيريفلونومايد بي او اس وبعدها. يستمر تيريفلونومايد في الدم لفترة طويلة بعد إيقافكِ للدواء؛ ولذا عليكِ الاستمرار باستخدام وسيلة فعالة لمنع الحمل بعد إيقاف العلاج.

·         افعلي ذلك حتى تصبح مستويات تيريفلونومايد في الدم منخفضة بما يكفي، وسيتحرّى طبيبكِ ذلك.

·         استشيري طبيبك حول الطرق الأفضل لكِ لمنع الحمل وعن أي حاجة محتملة لتغيير وسيلة منع الحمل.

لا تستخدمي تيريفلونومايد بي او اس خلال فترة الإرضاع، لأن تيريفلونومايد يصل إلى حليب الثدي.

 

القيادة واستخدام المركبات

يمكن أن يجعلك تيريفلونومايد تشعر بالدوخة مما يؤثر سلباً في قدرتك على التركيز والاستجابة. لا تقُد أو تستخدم الآلات إذا كنت متأثراً.

 

يحتوي تيريفلونومايد بي او اس على اللاكتوز

يحتوي تيريفلونومايد بي او اس على اللاكتوز (نوع من السكريات). تواصل مع طبيبك قبل أخذك للدواء إذا كان قد أخبرك بأن لديك عدم تحمل لبعض السكريات.

 

يحتوي تيريفلونومايد بي او اس على الصوديوم

يحتوي هذا الدواء على أقل من 1 ميلي مول من الصوديوم (ما يُعادل 23 ملغ) للقرص الواحد، لذا يُمكن القول بأنّه خالٍ من الصوديوم.

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سيشرف على العلاج بتيريفلونومايد بي او اس طبيب ذو خبرة في علاج التصلب اللويحي.

تناول هذا الدواء دائماً كما أخبرك طبيبك بالضبط، وراجع هذا الأمر مع طبيبك إذا كنت غير متأكد.

 

الجرعة الموصى بها هي قرص واحد 14 ملغ يومياً.

 

طريقة الإعطاء

تيريفلونومايد بي او اس معد للاستخدام الفموي، ويؤخذ يومياً بجرعة وحيدة في أي وقت من اليوم.

يجب بلع القرص كاملًا مع القليل من الماء.

يمكن أن يؤخذ تيريفلونومايد بي او اس مع الطعام أو بدونه.

 

إذا تناولت من تيريفلونومايد بي او اس كمية أكثر مما ينبغي

اتصل على طبيبك فوراً إذا كنت قد تناولت كمية كبيرة من تيريفلونومايد بي او اس. قد تعاني من أعراض جانبية مشابهة لتلك الموصوفة في القسم 4 أدناه.

إذا نسيت تناول تيريفلونومايد بي او اس

لا تأخذ جرعة مضاعفة لتعوّض الأقراص الفائتة، وتناول جرعتك التالية في وقتها المحدد.

 

إذا توقفت عن تناول تيريفلونومايد بي او اس

لا تتوقف عن تناول تيريفلونومايد بي او اس أو تغيّر جرعته بدون التحدث إلى طبيبك أولاً.

اسألك طبيبك أو الصيدلي إذا كانت لديك أية أسئلة أخرى حول استخدام هذا الدواء.

يمكن لهذا الدواء أن يسبب تأثيرات جانبية كما يحدث مع بقية الأدوية، لكن هذه التأثيرات لا تحدث عند جميع الأشخاص الذين يتلقونه على أية حال.

قد تحصل التأثيرات الجانبية التالية عند استخدام هذا الدواء.

التأثيرات الجانبية الخطيرة

أخبر طبيبك على الفور، إذا لاحظت أيًا من الأعراض الجانبية الخطيرة التالية:

 

·         تفاعلات تحسسية تشمل الطفح الجلدي، والشرى، وتورم الشفتين واللسان والوجه، وصعوبة تنفس مفاجئة

·         تفاعلات جلدية شديدة تشمل ربما أعراضاً كالطفح الجلدي والفقاعات والحمى أو قرحات الفم

·         عدوى شديدة أو تعفن الدم (نوع شديد من العدوى المهددة للحياة) والتي قد تشمل أعراض ارتفاع في درجة الحرارة، رعشة، قشعريرة، قلة تدفق البول، أو ارتباك

·         التهاب الرئتين وقد يعطي أعراضاً تشمل ضيق التنفس والسعال المستمر

·         التهاب البنكرياس الذي قد يشمل أعراض الألم الشديد في منطقة البطن العلوية التي قد تشعر بها أيضًا في الظهر أو الغثيان أو القيء

·         مرض كبدي خطير قد تشمل أعراضه اصفرار الجلد والعينين، وقتامة لون البول، وغثيان وقيء غير مفسريْن، وألم بطن.

يمكن أن تحدث التأثيرات الجانبية الأخرى بالتكرارات التالية:

التأثيرات الجانبية الشائعة جداً (ربما تُؤثر على أكثر من شخص من كل 10 أشخاص):

-           الصداع

-           الإسهال والغثيان

-           يظهر في فحوصات الدم ارتفاع في ALT (زيادة في المستويات الدموية لإنزيمات كبدية محددة)

-           خفة الشعر

التأثيرات الجانبية الشائعة (ربما تُؤثر على شخص واحد من كل 10 أشخاص)

-           انفلوانزا، عدوى الجهاز التنفسي العلوي، عدوى المسالك البولية، التهاب الشعب الهوائية، التهاب الجيوب الأنفية، التهاب حلق وعدم ارتياح عند البلع، التهاب مثانة، التهاب المعدة والأمعاء الفيروسي، الهربس الفموي، عدوى الأسنان، التهاب الحنجرة، عدوى فطرية في القدمين.

-           القيم المخبرية: لوحظ حدوث نقص في عدد كريات الدم الحمراء (فقر دم)، تغيرات في نتائج فحوصات الكبد وكريات الدم البيضاء (انظر القسم 2)، إضافة لارتفاع في الإنزيمات العضلية (كرياتين فوسفوكينار)

-           تفاعلات تحسسية خفيفة

-           الشعور بالقلق

-           خدر وتنميل، الشعور بالضعف والتنميل والوخز والألم في أسفل الظهر أو الساق (عرق النسا أو التهاب العصب الوركي)، الشعور بالخدر والحرق والوخز أو الألم في اليدين والأصابع (متلازمة النفق الرسغي)

-           الشعور بضربات القلب

-           ارتفاع ضغط الدم

-           القيء، وألم الأسنان، وألم أعلى البطن

-           الطفح، وحب الشباب

-           آلام الأوتار، والمفاصل، والعظام، والعضلات (ألم عضلي هيكلي)

-           الحاجة للتبول أكثر من المعتاد

-           دورة طمثية غزيرة

-           الألم

-           قلة الطاقة والشعور بالضعف (وهن)

-           خسارة الوزن

 

 

تأثيرات جانبية غير شائعة (ربما تُؤثر على شخص واحد من كل 100 شخص):

·         نقص خفيف في عدد الصفيحات الدموية

·         زيادة الشعور والحساسية خاصة في الجلد، وألم طاعن أو نابض على مسار عصب واحد أو أكثر، واضطرابات في أعصاب الذراعين والساقين (اعتلال أعصاب محيطي)

·         اضطرابات الأظافر، تفاعلات جلدية شديدة

·         الألم ما بعد الصدمة

 

غير معروف (لا يمكن تقدير التكرار من البيانات المتاحة)

• الالتهابات الشديدة (بما في ذلك تعفن الدم)

• تفاعلات حساسية شديدة (بما في ذلك الحساسية المفرطة)

• رد الفعل الرئوي (مرض الرئة الخلالي)

• التهاب الكبد أو البنكرياس أو الفم / الشفتين

• ردود فعل جلدية شديدة

• مستويات غير طبيعية من الدهون في الدم

حافظ على الدواء بعيداً عن مرأى ومتناول الأطفال.

لا تستخدم هذا الدواء بعد انتهاء تاريخ الصلاحية المدون على العبوة، يشير تاريخ انتهاء الصلاحية إلى اليوم الأخير من نفس الشهر.

قم بتخزينه بدرجة حرارة أقل من  30 درجة مئوية.

لا تتخلص من الأدوية عن طريق مياه الصرف، ونفايات المنزل. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد تستخدمها. وستُساهم تلك الإجراءات بحماية البيئة.

·         المادة الفعالة هي تيريفلونومايد.

·         يحتوي كل قرص ملبس بالفيلم على 14 ملغ من تيريفلونومايد.

·         تشمل المكونات الأخرى:

-           لب القرص: لاكتوز مونوهيدرات، النشاء مسبق التجلتن، هيدروكسي بروبيل سيللوز، غليكولات النشاء الصوديّة، ثنائي أوكسيد السيليكون الغرواني، شمعات المغنيزيوم.

-           غلاف القرص: هايبروميلوز، ثنائي أوكسيد التيتانيوم، تالك، ماكروغول/PEG، ملونات زرقاء FD & C Blue #2 وIndigo carmine aluminium lake. 

أقراص تيريفلونومايد هي أقراص ذات لون أزرق شاحب إلى أزرق فاتح، خماسية الشكل ملبسة بالفيلم منقوش عليها “T14” على أحد جانبيها وملساء على الجانب الآخر.

 

أقراص تيريفلونومايد بي او اس تسوَّق ضمن ظرف من نوع Alu-Alu يحتوي على 10 أقراص، وتحتوي العلبة على 3 أظرف أي 30 قرص (3x10).

مالك حقوق التسويق والتغليف الثانوي:

شركة بوستن اونكولجي العربية

منطقة سدير الصناعية، سدير، المملكة العربية السعودية

 

التصنيع الكامل والتغليف الأولي:

ناتكو فارما المحدودة

 

لإبلاغنا عن أي تأثيرات جانبية عبر:

·         المملكة العربية السعودية:

·         مركز التيقظ الدوائي الوطني The National Pharmacovigilance Centre (NPC)

-          رقم هيئة الغذاء والدواء السعودية: 19999

-          البريد الالكتروني  npc.drug@sfda.gov.sa

-          موقع الشبكة  https://ade.sfda.gov.sa/

·         دول مجلس التعاون الخليجي الأخرى:

-          تواصل رجاءً مع الجهات المختصة ذات الصلة.

 

مجلس وزراء الصحة العرب

هذا الدواء

·         الدواء هو منتج يُؤثر على صحتك، واستخدامه خلافاً للتعليمات يعرضك للخطر.

·         اتبع وصفة الطبيب بدقة، وطريقة الاستخدام وتعليمات الصيدلاني الذي باعك الدواء.

·         الأطباء والصيادلة هم الخبراء في منافع الأدوية ومضارّها.

·         لا توقف الدواء من تلقاء نفسك قبل انتهاء مدة العلاج الموصوفة لك.

·         لا تعاود استخدام نفس الوصفة دون استشارة طبيبك.

·         حافظ على جميع الأدوية بعيداً عن متناول الأطفال.

مجلس وزراء الصحة العرب

اتحاد الصيادلة العرب

07/2022
 Read this leaflet carefully before you start using this product as it contains important information for you

Teriflunomide BOS Teriflunomide Tablets 14 mg

Each film-coated tablet contains 14 mg of teriflunomide. Excipients with known effect: Each film-coated tablet contains 74.7 mg of lactose monohydrate and less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially “sodium free”. For the full list of excipients, see section 6.1.

Film-coated Tablet Teriflunomide BOS tablets are pale blue to pastel blue colored, pentagonal shape film coated tablets debossed with “T14” on one side and plain on another side.

Teriflunomide BOS is indicated for the treatment of adult patients and paediatric patients aged 10 years and older with relapsing remitting multiple sclerosis (MS) (please refer to section 5.1 for important information on the population for which efficacy has been established).


The treatment should be initiated and supervised by a physician experienced in the management of multiple sclerosis.

Posology

Adults
In adults, the recommended dose of teriflunomide is 14 mg once daily.

Paediatric population (10 years and older)
In paediatric patients (10 years of age and above), the recommended dose is dependent on body weight:
- Paediatric patients with body weight >40 kg: 14 mg once daily.
Paediatric patients who reach a stable body weight above 40 kg should be switched to 14 mg once daily.

Film-coated tablets can be taken with or without food.

Special populations

Elderly population
Teriflunomide should be used with caution in patients aged 65 years and over due to insufficient data on safety and efficacy.

Renal impairment
No dose adjustment is necessary for patients with mild, moderate or severe renal impairment not undergoing dialysis.

Patients with severe renal impairment undergoing dialysis were not evaluated. Teriflunomide BOS is contraindicated in this population (see section 4.3).

Hepatic impairment
No dose adjustment is necessary for patients with mild and moderate hepatic impairment.
Teriflunomide BOS is contraindicated in patients with severe hepatic impairment (see section 4.3).

Paediatric population (less than 10 years of age)
The safety and efficacy of teriflunomide in children aged below 10 years have not been established.
No data are available.

Method of administration
The film-coated tablets are for oral use. The tablets should be swallowed whole with some water.


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with severe hepatic impairment (Child-Pugh class C). Pregnant women, or women of childbearing potential who are not using reliable contraception during treatment with teriflunomide and thereafter as long as its plasma levels are above 0.02 mg/l (see section 4.6). Pregnancy must be excluded before start of treatment (see section 4.6). Breast-feeding women (see section 4.6). Patients with severe immunodeficiency states, e.g. acquired immunodeficiency syndrome (AIDS). Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia. Patients with severe active infection until resolution (see section 4.4). Patients with severe renal impairment undergoing dialysis, because insufficient clinical experience is available in this patient group. Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.

Monitoring
Before treatment
Before starting treatment with teriflunomide the following should be assessed:
• Blood pressure
• Alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)
• Complete blood cell count including differential white blood cell and platelet count.

During treatment
During treatment with teriflunomide the following should be monitored: 

• Blood pressure
o Check periodically
• Alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)
o Liver enzymes should be assessed at least every four weeks during the first 6 months of treatment and regularly thereafter.
o Consider additional monitoring when Teriflunomide BOS is given in patients with preexisting liver disorders, given with other potentially hepatotoxic drugs or as indicated by clinical signs and symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. Liver enzymes should be assessed every
two weeks during the first 6 months of treatment, and at least every 8 weeks thereafter for at least 2 years from initiation of treatment.
o For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, monitoring must be performed weekly.
• Complete blood cell counts should be performed based on clinical signs and symptoms (e.g. infections) during treatment.

Accelerated elimination procedure
Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes an average of 8 months to reach plasma concentrations less than 0.02 mg/l, although due to individual variation in substance clearance it may take up to 2 years. An accelerated elimination procedure can be used at any time after discontinuation of teriflunomide (see sections 4.6 and 5.2 for procedural details).

Hepatic effects
Elevations of liver enzymes have been observed in patients receiving teriflunomide (see section 4.8). These elevations occurred mostly within the first 6 months of treatment.

Cases of drug-induced liver injury (DILI) have been observed during treatment with teriflunomide, sometimes life-threatening. Most cases of DILI occurred with time to onset of
several weeks or several months after treatment initiation of teriflunomide, but DILI can also occur with prolonged use.

The risk for liver enzyme increases and DILI with teriflunomide might be higher in patients with pre-existing liver disorder, concomitant treatment with other hepatotoxic drugs, and/or consumption of substantial quantities of alcohol. Patients should therefore be closely monitored for signs and symptoms of liver injury.

Teriflunomide therapy should be discontinued and accelerated elimination procedure considered if liver injury is suspected. If elevated liver enzymes (greater than 3 fold ULN) are
confirmed, teriflunomide therapy should be discontinued.

In case of treatment discontinuation, liver tests should be pursued until normalisation of transaminase levels.

Hypoproteinaemia
Since teriflunomide is highly protein bound and as the binding is dependent upon the concentrations of albumin, unbound plasma teriflunomide concentrations are expected to be
increased in patients with hypoproteinaemia, e.g. in nephrotic syndrome. Teriflunomide should not be used in patients with conditions of severe hypoproteinaemia.

Blood pressure
Elevation of blood pressure may occur during treatment with teriflunomide (see section 4.8).
Blood pressure must be checked before the start of teriflunomide treatment and periodically thereafter. Blood pressure elevation should be appropriately managed before and during treatment with teriflunomide.

Infections
Initiation of treatment with teriflunomide should be delayed in patients with severe active infection until resolution.

In placebo-controlled studies, no increase in serious infections was observed with teriflunomide (see section 4.8). However, based on the immunomodulatory effect of teriflunomide, if a patient develops a serious infection, suspending treatment with Teriflunomide BOS should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Due to the prolonged half-life, accelerated elimination with cholestyramine or charcoal may be considered.

Patients receiving Teriflunomide BOS should be instructed to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment with Teriflunomide BOS until the infection(s) is resolved.

The safety of teriflunomide in individuals with latent tuberculosis infection is unknown, as tuberculosis screening was not systematically performed in clinical studies. Patients tested
positive in tuberculosis screening should be treated by standard medical practice prior to therapy.

Respiratory reactions
Interstitial lung disease (ILD) has been reported with teriflunomide in the post-marketing setting.

ILD and worsening of pre-existing ILD have been reported during treatment with leflunomide, the parent compound of teriflunomide. The risk is increased in patients who had a history of ILD when treated with leflunomide.

ILD may occur acutely at any time during therapy with a variable clinical presentation.

ILD may be fatal. New onset or worsening pulmonary symptoms, such as persistent cough and dyspnoea, may be a reason for discontinuation of the therapy and for further investigation, as appropriate. If discontinuation of the medicinal product is necessary, initiation of an accelerated elimination procedure should be considered.

Haematological effects
A mean decrease less than 15% from baseline affecting white blood cell count has been observed (see section 4.8). As a precaution, a recent complete blood cell count, including
differential white blood cell count and platelets, should be available before the initiation of treatment and the complete blood cell count should be assessed during therapy as indicated by clinical signs and symptoms (e.g., infections).

In patients with pre-existing anaemia, leucopenia, and /or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk of haematological disorders is increased. If such effects occur, the accelerated elimination procedure (see above) to reduce plasma levels of teriflunomide should be considered.

In cases of severe haematological reactions, including pancytopenia, teriflunomide and any concomitant myelosuppressive treatment must be discontinued and a teriflunomide accelerated elimination procedure should be considered.

Skin reactions
Cases of serious skin reactions, sometimes fatal including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with teriflunomide.

If skin and /or mucosal reactions (ulcerative stomatitis) are observed which raise the suspicion of severe generalised major skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis-Lyell's syndrome, or drug reaction with eosinophilia and systemic symptoms), teriflunomide and any other possibly associated treatment must be discontinued, and an accelerated procedure initiated immediately. In such cases patients should not be re-exposed to teriflunomide (see section 4.3).

New onset of psoriasis (including pustular psoriasis) and worsening of pre-existing psoriasis have been reported during the use of teriflunomide. Treatment withdrawal and initiation of an accelerated elimination procedure may be considered taking into account patient's disease and medical history.

Peripheral neuropathy
Cases of peripheral neuropathy have been reported in patients receiving teriflunomide (see section 4.8). Most patients improved after discontinuation of teriflunomide. However, there was a wide variability in final outcome, i.e. in some patients the neuropathy resolved and some patients had persistent symptoms. If a patient taking teriflunomide develops a confirmed peripheral neuropathy, discontinuing teriflunomide therapy and performing the accelerated elimination procedure should be considered.

Vaccination
Two clinical studies have shown that vaccinations to inactivated neoantigen (first vaccination), or recall antigen (reexposure) were safe and effective during teriflunomide treatment. The use of live attenuated vaccines may carry a risk of infections and should therefore be avoided.

Immunosuppressive or immunomodulating therapies
As leflunomide is the parent compound of teriflunomide, co-administration of teriflunomide with leflunomide is not recommended.

Co-administration with antineoplastic or immunosuppressive therapies used for treatment of MS has not been evaluated. Safety studies, in which teriflunomide was concomitantly
administered with interferon beta or with glatiramer acetate for up to one year did not reveal any specific safety concerns, but a higher adverse reaction rate as compared to teriflunomide monotherapy was observed. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.

Switching to or from Teriflunomide BOS
Based on the clinical data related to concomitant administration of teriflunomide with interferon beta or with glatiramer acetate, no waiting period is required when initiating
teriflunomide after interferon beta or glatiramer acetate or when starting interferon beta or glatiramer acetate, after teriflunomide.

Due to the long half-life of natalizumab, concomitant exposure, and thus concomitant immune effects, could occur for up to 2-3 months following discontinuation of natalizumab if
teriflunomide was immediately started. Therefore, caution is required when switching patients from natalizumab to Teriflunomide BOS.

Based on the half-life of fingolimod, a 6-week interval without therapy is needed for clearance from the circulation and a 1 to 2 month period is needed for lymphocytes to return to normal range following discontinuation of fingolimod. Starting Teriflunomide BOS during this interval will result in concomitant exposure to fingolimod. This may lead to an additive effect on the immune system and caution is, therefore, indicated.

In MS patients, the median t1/2z was approximately 19 days after repeated doses of 14 mg. If a decision is made to stop treatment with teriflunomide, during the interval of 5 half-lives (approximately 3.5 months although may be longer in some patients), starting other therapies will result in concomitant exposure to teriflunomide. This may lead to an additive effect on the immune system and caution is, therefore, indicated.

Interference with determination of ionised calcium levels
The measurement of ionised calcium levels might show falsely decreased values under treatment with leflunomide and/or teriflunomide (the active metabolite of leflunomide)
depending on the type of ionised calcium analyser used (e.g. blood gas analyser). Therefore, the plausibility of observed decreased ionised calcium levels needs to be questioned in patients under treatment with leflunomide or teriflunomide. In case of doubtful measurements, it is recommended to determine the total albumin adjusted serum calcium concentration.

Paediatric population

Pancreatitis
In the paediatric clinical trial, cases of pancreatitis, some acute, have been observed in patients receiving teriflunomide (see section 4.8). Clinical symptoms included abdominal pain, nausea and/or vomiting. Serum amylase and lipase were elevated in these patients. The time to onset ranged from a few months up to three years. Patients should be informed of the characteristic symptoms of pancreatitis. If pancreatitis is suspected, pancreatic enzymes and related laboratory parameters should be obtained. If pancreatitis is confirmed, teriflunomide should be discontinued and an accelerated elimination procedure should be initiated (see section 5.2).

Lactose
Since Teriflunomide BOS tablets contain lactose, patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption, should not take this medicinal product.

Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium free”.


Pharmacokinetic interactions of other substances on teriflunomide
The primary biotransformation pathway for teriflunomide is hydrolysis, with oxidation being a minor pathway.

Potent cytochrome P450 (CYP) and transporter inducers
Co-administration of repeated doses (600 mg once daily for 22 days) of rifampicin (a CYP2B6, 2C8, 2C9, 2C19, 3A inducer), as well as an inducer of the efflux transporters P-glycoprotein [P-gp] and breast cancer resistant protein [BCRP] with teriflunomide (70 mg single dose) resulted in an approximately 40% decrease in teriflunomide exposure. Rifampicin and other known potent CYP and transporter inducers such as carbamazepine, phenobarbital, phenytoin and St John's Wort should be used with caution during the treatment with teriflunomide.

Cholestyramine or activated charcoal
It is recommended that patients receiving teriflunomide are not treated with cholestyramine or activated charcoal because this leads to a rapid and significant decrease in plasma concentration unless an accelerated elimination is desired. The mechanism is thought to be by interruption of enterohepatic recycling and/or gastrointestinal dialysis of teriflunomide.

Pharmacokinetic interactions of teriflunomide on other substances

Effect of teriflunomide on CYP2C8 substrate: repaglinide
There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. Therefore, medicinal products metabolised by CYP2C8, such as repaglinide, paclitaxel, pioglitazone or rosiglitazone, should be used with caution during treatment with teriflunomide.

Effect of teriflunomide on oral contraceptives: 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel
There was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0-24 (1.33- and 1.41-fold, respectively) following
repeated doses of teriflunomide. While this interaction of teriflunomide is not expected to adversely impact the efficacy of oral contraceptives, it should be considered when selecting or adjusting oral contraceptive treatment used in combination with teriflunomide.

Effect of teriflunomide on CYP1A2 substrate: caffeine
Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer
of CYP1A2 in vivo. Therefore, medicinal products metabolised by CYP1A2 (such as duloxetin, alosetron, theophylline and tizanidine) should be used with caution during treatment with
teriflunomide, as it could lead to the reduction of the efficacy of these medicinal products.

Effect of teriflunomide on warfarin
Repeated doses of teriflunomide had no effect on the pharmacokinetics of S-warfarin, indicating that teriflunomide is not an inhibitor or an inducer of CYP2C9. However, a 25%
decrease in peak international normalised ratio (INR) was observed when teriflunomide was coadministered with warfarin as compared with warfarin alone. Therefore, when warfarin is coadministered with teriflunomide, close INR follow-up and monitoring is recommended.

Effect of teriflunomide on organic anion transporter 3 (OAT3) substrates
There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of
OAT3 in vivo. Therefore, when teriflunomide is coadministered with substrates of OAT3, such as cefaclor, benzylpenicillin, ciprofloxacin, indometacin, ketoprofen, furosemide, cimetidine, methotrexate, zidovudine, caution is recommended.

Effect of teriflunomide on BCRP and /or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3) substrates
There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively), following repeated doses of teriflunomide. However, there was no apparent impact of this increase in plasma rosuvastatin exposure on the HMG-CoA reductase activity. For rosuvastatin, a dose reduction by 50% is recommended for coadministration with teriflunomide. For other substrates of BCRP (e.g., methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OATP family especially HMG-Co reductase inhibitors (e.g., simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin) concomitant administration of teriflunomide should also be undertaken with caution. Patients should be closely monitored for signs and symptoms of excessive exposure to the medicinal products and reduction of the dose of these medicinal products should be considered.


Use in males
The risk of male-mediated embryo-foetal toxicity through teriflunomide treatment is considered low (see section 5.3).

Pregnancy
There are limited amount of data from the use of teriflunomide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Teriflunomide may cause serious birth defects when administered during pregnancy.
Teriflunomide is contraindicated in pregnancy (see section 4.3).

Women of childbearing potential have to use effective contraception during treatment and after treatment as long as teriflunomide plasma concentration is above 0.02 mg/l. During this period women should discuss any plans to stop or change contraception with the treating physician.
Female children and/or parents/caregivers of female children should be informed about the need to contact the treating physician once the female child under teriflunomide treatment experiences menses. Counselling should be provided to the new patients of child-bearing potential about contraception and the potential risk to the foetus. Referral to a gynaecologist should be considered.

The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must discontinue Teriflunomide BOS and notify the physician
immediately for pregnancy testing, and if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of teriflunomide, by instituting the accelerated elimination procedure described below, at the first delay of menses, may decrease the risk to the foetus.

For women receiving teriflunomide treatment, who wish to become pregnant, the medicinal product should be stopped and an accelerated elimination procedure is recommended in order to more rapidly achieve concentration below 0.02 mg/l (see below).

If an accelerated elimination procedure is not used, teriflunomide plasma levels can be expected to be above 0.02 mg/l for an average of 8 months, however, in some patients it may take up to 2 years to reach plasma concentration below 0.02 mg/l. Therefore, teriflunomide plasma concentrations should be measured before a woman begins to attempt to become pregnant.
Once the teriflunomide plasma concentration is determined to be below 0.02 mg/l, the plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/l, no risk to the foetus is to be expected.

For further information on the sample testing please contact the Marketing Authorization Holder or its local representative (see section 7).

Accelerated elimination procedure

After stopping treatment with teriflunomide:
• cholestyramine 8 g is administered 3 times daily for a period of 11 days, or cholestyramine 4 g three times a day can be used, if cholestyramine 8 g three times a day is not well
tolerated,
• alternatively, 50 g of activated powdered charcoal is administered every 12 hours for a period of 11 days.

However, also following either of the accelerated elimination procedures, verification by 2 separate tests at an interval of at least 14 days and a waiting period of one-and-a-half months between the first occurrence of a plasma concentration below 0.02 mg/l and fertilisation is required.

Both cholestyramine and activated powdered charcoal may influence the absorption of oestrogens and progestogens such that reliable contraception with oral contraceptives may not be guaranteed during the accelerated elimination procedure with cholestyramine or activated powdered charcoal. Use of alternative contraceptive methods is recommended.

Breast-feeding
Animal studies have shown excretion of teriflunomide in milk. Teriflunomide is contraindicated during breast-feeding (see section 4.3).

Fertility
Results of studies in animals have not shown an effect on fertility (see section 5.3). Although human data are lacking, no effect on male and female fertility is anticipated.


Teriflunomide has no or negligible influence on the ability to drive and use machines.

In the case of adverse reactions such as dizziness, which has been reported with leflunomide, the parent compound, the patient's ability to concentrate and to react properly may be impaired. In such cases, patients should refrain from driving and using machines.


Summary of the safety profile
The most frequently reported adverse reactions in the teriflunomide treated (7 mg and 14 mg) patients were: headache (17.8%, 15.7%), diarrhoea (13.1%, 13.6%), increased ALT (13%,
15%), nausea (8%, 10.7%), and alopecia (9.8%, 13.5%). In general, headache, diarrhoea, nausea and alopecia, were mild to moderate, transient and infrequently led to treatment discontinuation.

Teriflunomide is the main metabolite of leflunomide. The safety profile of leflunomide in patients suffering from rheumatoid arthritis or psoriatic arthritis may be pertinent when
prescribing teriflunomide in MS patients.

Tabulated list of adverse reactions
Teriflunomide was evaluated in a total of 2,267 patients exposed to teriflunomide (1,155 on teriflunomide 7 mg and 1,112 on teriflunomide 14 mg) once daily for a median duration of
about 672 days in four placebo-controlled studies (1,045 and 1,002 patients for teriflunomide 7 mg and 14 mg, respectively) and one active comparator study (110 patients in each of the teriflunomide treatment groups) in adult patients with relapsing forms of MS (Relapsing Multiple Sclerosis, RMS).

Listed below are the adverse reactions reported with teriflunomide in placebo-controlled studies in adult patients, reported for teriflunomide 7 mg or 14 mg from clinical studies in adult patients. Frequencies were defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

System Organ Class

Very common

common

Uncommon

Rare

Very rare

Not known

Infections and

infestations

 

Influenza,

Upper respiratory

tract infection,

Urinary tract

infection,

Bronchitis,

Sinusitis,

Pharyngitis,

Cystitis,

Gastroenteritis

viral,

Oral herpes,

Tooth infection,

Laryngitis,

Tinea pedis

Severe

infections

including sepsisa

 

 

 

Blood and

lymphatic

system

disorders

 

Neutropenia b,

Anaemia

Mild

thrombocytop

enia (platelets

<100G/l)

 

 

 

Immune system disorders

 

Mild allergic reactions

Hypersensitivity reactions (immediate or delayed) including anaphylaxis and angioedema

 

 

 

Psychiatric

disorders

 

Anxiety

 

 

 

 

Nervous system

disorders

Headache

Paraesthesia,

Sciatica,

Carpal tunnel syndrome

Hyperaesthesia,

Neuralgia,

Peripheral neuropathy

 

 

 

Cardiac

disorders

 

Palpitations

 

 

 

 

Vascular

disorders

 

Hypertension b

 

 

 

 

Respiratory,

thoracic and

mediastinal

disorders

 

 

Interstitial

lung disease

 

 

 

Gastrointestinal

disorders

Diarrhoea,

Nausea

Pancreatitisb,c,

Abdominal pain

upper,

Vomiting,

Toothache

Stomatitis

 

 

 

Hepatobiliary

disorders

Alanine

aminotransferas

e (ALT) increaseb

Gammaglutamyltransferase (GGT) increaseb,

Aspartate

aminotransferase

increaseb

 

Acute hepatitis

 

Drug induced liver injury (DILI)

Metabolism and

nutrition

disorders

 

 

Dyslipidaemia

 

 

 

Skin and

subcutaneous

tissue disorders

Alopecia

Rash,

Acne

Nail

disorders,

Psoriasis

(including

Pustular)a.b

Severe skin

reactionsa

 

 

 

Musculoskeletal

and connective

tissue disorders

 

Musculoskeletal

pain,

Myalgia,

Arthralgia

 

 

 

 

Renal and

urinary

disorders

 

Pollakiuria

 

 

 

 

Reproductive

system and

breast disorders

 

Menorrhagia

 

 

 

 

General

disorders and

administration site conditions

 

Pain,

Asthenia a

 

 

 

 

Investigations

 

Weight decrease,

Neutrophil count decrease b,

White blood cell

count decrease b,

Blood creatine phosphokinase increased

 

 

 

 

Injury,

poisoning and

procedural

complications

 

 

Posttraumatic pain

 

 

 

a: please refer to the detailed description section
b: see section 4.4
c: frequency is “common” in children based on a controlled clinical study in paediatrics; frequency is “uncommon” in adults

Description of selected adverse reactions

Alopecia
Alopecia was reported as hair thinning, decreased hair density, hair loss, associated or not with hair texture change, in 13.9% of patients treated with 14 mg teriflunomide versus 5.1% in patients treated with placebo. Most cases were described as diffuse or generalised over the scalp (no complete hair loss reported) and occurred most often during the first 6 months and with resolution in 121 of 139 (87.1%) patients treated with teriflunomide 14 mg.
Discontinuation because of alopecia was 1.3% in the teriflunomide 14 mg teriflunomide group, versus 0.1% in the placebo group.

Hepatic effects
During placebo-controlled studies in adult patients the following was detected:

ALT increase (based on laboratory data) according to baseline status - Safety population

in placebo-controlled studies

 

Placebo

(N=997

Teriflunomide

14 mg

(N=1002)

>3 ULN

66/994 (6.6%)

80/999 (8.0%)

>5 ULN

37/994 (3.7%)

31/999 (3.1%)

>10 ULN

16/994 (1.6%)

9/999 (0.9%)

>20 ULN

4/994 (0.4%)

3/999 (0.3%)

ALT >3 ULN and TBILI >2 ULN

5/994 (0.5%)

3/999 (0.3%)

Mild increases in transaminase, ALT below or equal to 3-fold ULN were more frequently seen in teriflunomide-treated groups as compared to placebo. The frequency of elevations above 3-fold ULN and higher was balanced across treatment groups. These elevations in transaminase occurred mostly within the first 6 months of treatment and were reversible after treatment cessation. The recovery time varied between months and years.

Blood pressure effects
In placebo-controlled studies in adult patients the following was established:
- systolic blood pressure was >140 mm Hg in 19.9% of patients receiving 14 mg/day teriflunomide as compared to 15.5% receiving placebo;
- systolic blood pressure was >160 mm Hg in 3.8% of patients receiving 14 mg/day teriflunomide as compared to 2.0% receiving placebo;
- diastolic blood pressure was >90 mm Hg in 21.4% of patients receiving 14 mg/day teriflunomide as compared to 13.6% receiving placebo.

Infections
In placebo-controlled studies in adult patients, no increase in serious infections was observed with teriflunomide 14 mg (2.7%) as compared to placebo (2.2%). Serious opportunistic
infections occurred in 0.2% of each group. Severe infections including sepsis, sometimes fatal have been reported post-marketing.

Haematological effects
A mean decrease affecting white blood cell (WBC) count (<15% from baseline levels, mainly neutrophil and lymphocytes decrease) was observed in placebo-controlled trials with
teriflunomide in adult patients, although a greater decrease was observed in some patients. The decrease in mean count from baseline occurred during the first 6 weeks then stabilised over time while on-treatment but at decreased levels (less than a 15% decrease from baseline). The effect on red blood cell (RBC) (<2%) and platelet counts (<10%) was less pronounced.

Peripheral neuropathy
In placebo-controlled studies in adult patients, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), was reported more
frequently in patients taking teriflunomide than in patients taking placebo. In the pivotal, placebo-controlled studies, the incidence of peripheral neuropathy confirmed by nerve
conduction studies was 1.9% (17 patients out of 898) on 14 mg of teriflunomide, compared with 0.4% (4 patients out of 898) on placebo. Treatment was discontinued in 5 patients with peripheral neuropathy on teriflunomide 14 mg. Recovery following treatment discontinuation was reported in 4 of these patients.

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
There does not appear to be an increased risk of malignancy with teriflunomide in the clinical trial experience. The risk of malignancy, particularly lymphoproliferative disorders, is
increased with use of some other agents that affect the immune system (class effect).

Severe skin reactions
Cases of severe skin reactions have been reported with teriflunomide post-marketing (see section 4.4).

Asthenia
In placebo-controlled studies in adult patients, frequencies for asthenia were 2.0%, 1.6% and 2.2% in the placebo, teriflunomide 7 mg and teriflunomide 14 mg group, respectively.

Psoriasis
In placebo-controlled studies, frequencies for psoriasis were 0.3%, 0.3% and 0.4% in the placebo, teriflunomide 7 mg and teriflunomide 14 mg group, respectively.

Gastrointestinal disorders
Pancreatitis has been reported infrequently in the post-marketing setting with teriflunomide in adults, including cases of necrotising pancreatitis and pancreatic pseudocyst. Pancreatic events may occur at any time during treatment with teriflunomide, which may lead to hospitalisation and/or require corrective treatment.

Paediatric population
The observed safety profile in paediatric patients (from 10 to 17 years-old) receiving teriflunomide daily was overall similar to that seen in adult patients. However, in the paediatric
study (166 patients: 109 in the teriflunomide group and 57 in the placebo group), cases of pancreatitis were reported in 1.8% (2/109) of the teriflunomide-treated patients compared to none in the placebo group, in the double-blind phase. One of these events led to hospitalisation and required corrective treatment. In paediatric patients treated with teriflunomide in the open-label phase of the study, 2 additional cases of pancreatitis (one was reported as a serious event, the other was a nonserious event of mild intensity) and one case of serious acute pancreatitis (with pseudo-papilloma), were reported. In two of these 3 patients, pancreatitis led to hospitalisation. Clinical symptoms included abdominal pain, nausea and/ or vomiting and serum amylase and lipase were elevated in these patients. All patients recovered after treatment discontinuation and accelerated elimination procedure (see section 4.4) and corrective treatment.

The following adverse reactions were more frequently reported in the paediatric population than in the adult population:
• Alopecia was reported in 22.0% of patients treated with teriflunomide versus 12.3% in patients treated with placebo.
• Infections were reported in 66.1% of patients treated with teriflunomide versus 45.6% in patients treated with placebo. Among them, nasopharyngitis and upper respiratory tract infections were more frequently reported with teriflunomide.
• CPK increase was reported in 5.5% of patients treated with teriflunomide versus 0% in patients treated with placebo. The majority of the cases were associated with documented physical exercise.
• Paraesthesia was reported in 11.0% of patients treated with teriflunomide versus 1.8% in patients treated with placebo.
• Abdominal pain was reported in 11.0% of patients treated with teriflunomide versus 1.8% in patients treated with placebo.

To report any side effect(s):
Reporting suspected adverse reactions after authorisation 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 competent authority in Saudi Arabia as per details below:

·         Saudi Arabia

The National Pharmacovigilance Centre (NPC)

·         - SFDA Call Centre: 19999

·         - E-mail: npc.drug@sfda.gov.sa

·         - Website: https://ade.sfda.gov.sa/

 

·         Other GCC States

·         Please contact the relevant competent authority.


Symptoms
There is no experience regarding teriflunomide overdose or intoxication in humans.
Teriflunomide 70 mg daily was administered up to 14 days in healthy subjects. The adverse reactions were consistent with the safety profile for teriflunomide in MS patients.

Management
In the event of relevant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination. The recommended elimination procedure is
cholestyramine 8 g three times a day for 11 days. If this is not well tolerated, cholestyramine 4 g three times a day for 11 days can be used. Alternatively, when cholestyramine is not
available, activated charcoal 50 g twice a day for 11 days may also be used. In addition, if required for tolerability reasons, administration of cholestyramine or activated charcoal does
not need to occur on consecutive days (see section 5.2).


Pharmacotherapeutic group: Immunosuppressants, Selective immunosuppressants, ATC Code: L04AA31

Mechanism of action
Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase
(DHO-DH), which functionally connects with the respiratory chain. As a consequence of the inhibition, teriflunomide generally reduces the proliferation of rapidly dividing cells that depend on de novo synthesis of pyrimidine to expand. The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood, but this is mediated by
a reduced number of lymphocytes.

Pharmacodynamic effects

Immune system
Effects on immune cell numbers in the blood: In the placebo-controlled studies, teriflunomide 14 mg once a day led to a mild mean reduction in lymphocyte count, of less than 0.3 x 109/l, which occurred over the first 3 months of treatment and levels were maintained until the end of the treatment.

Potential to prolong the QT interval
In a placebo-controlled thorough QT study performed in healthy subjects, teriflunomide at mean steady-state concentrations did not show any potential for prolonging the QTcF interval compared with placebo: the largest time matched mean difference between teriflunomide and placebo was 3.45 ms with the upper bound of the 90% CI being 6.45 ms.

Effect on renal tubular functions
In the placebo-controlled studies, mean decreases in serum uric acid at a range of 20 to 30% were observed in patients treated with teriflunomide compared to placebo. Mean decrease in serum phosphorus was around 10% in the teriflunomide group compared to placebo. These effects are considered to be related to increase in renal tubular excretion and not related to changes in glomerular functions.

Clinical efficacy and safety
The efficacy of teriflunomide was demonstrated in two placebo-controlled studies, the TEMSO and the TOWER study, that evaluated once daily doses of teriflunomide 7 mg and 14 mg in adult patients with RMS.

A total of 1,088 patients with RMS were randomised in TEMSO to receive 7 mg (n=366) or 14 mg (n=359) of teriflunomide or placebo (n= 363) for 108 weeks duration. All patients had a
definite diagnosis of MS (based on McDonald criteria (2001)), exhibited a relapsing clinical course, with or without progression, and experienced at least 1 relapse over the year preceding the trial or at least 2 relapses over the 2 years preceding the trial. At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5.

The mean age of the study population was 37.9 years. The majority of patients had relapsing-remitting multiple sclerosis (91.5%), but a subgroup of patients had secondary progressive (4.7%) or progressive relapsing multiple sclerosis (3.9%). The mean number of relapses within the year before study inclusion was 1.4 with 36.2% of patients having gadolinium-enhancing lesions at baseline. The median EDSS score at baseline was 2.50; 249 patients (22.9%) had an EDSS score › 3.5 at baseline. The mean duration of disease, since first symptoms, was 8.7 years. A majority of patients (73%) had not received disease-modifying therapy during the 2 years before study entry. The study results are shown in Table 1.

Long term follow-up results from TEMSO long term extension safety study (overall median treatment duration approximately 5 years, maximum treatment duration approximately 8.5 years) did not present any new or unexpected safety findings.

A total of 1,169 patients with RMS were randomised in TOWER to receive 7 mg (n=408) or 14 mg (n=372) of teriflunomide or placebo (n= 389) for a variable treatment duration ending at 48 weeks after last patient randomised. All patients had a definite diagnosis of MS (based on McDonald criteria (2005)), exhibited a relapsing clinical course, with or without progression, and experienced at least 1 relapse over the year preceding the trial or at least 2 relapses over the 2 years preceding the trial. At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5.

The mean age of the study population was 37.9 years. The majority of patients had relapsing-remitting multiple sclerosis (97.5%), but a subgroup of patients had secondary progressive (0.8%) or progressive relapsing multiple sclerosis (1.7%). The mean number of relapses within the year before study inclusion was 1.4. Gadolinium-enhancing lesions at baseline: no data. The median EDSS score at baseline was 2.50; 298 patients (25.5%) had an EDSS score › 3.5 at baseline. The mean duration of disease, since first symptoms, was 8.0 years. A majority of patients (67.2%) had not received disease-modifying therapy during the 2 years before study entry. The study results are shown in Table 1.

Table 1 - Main results ( for the approved dose, ITT population)

 

TEMSO-study

TOWER-study

 

Teriflunomide14

mg

Placebo

Teriflunomide1

4 mg

Placebo

N

358

363

370

388

Clinical Outcomes

 

 

 

 

 

0.37

0.54

0.32

0.50

 

-0.17 (-0.26, -0.08)***

-0.18 (-0.27, -0.09)****

 

56.5%

45.6%

57.1%

46.8%

 

0.72, (0.58, 0.89)**

0.63, (0.50, 0.79)****

 

20.2%

27.3%

15.8%

19.7%

 

0.70 (0.51, 0.97)*

0.68 (0.47, 1.00)*

 

13.8%

18.7%

11.7%

11.9%

 

0.75 (0.50, 1.11)

0.84 (0.53, 1.33)

MRI endpoints

 

 

Change in BOD week 108(1)

0.72

2.21

Not measured

Change

relative to

placebo

67%***

Mean Number of

Gd-enhancing

lesions at week 108

0.38

1.18

Change

relative to

placebo

(CI95%)

-0.80 (-1.20, -0.39)****

Number of unique

active lesions /scan

0.75

2.46

Change

relative to

placebo

(CI95%)

69%, (59%; 77%)∗∗∗∗

 

∗ ∗ ∗ ∗ p<0.0001 ∗∗∗ p<0.001 ∗∗ p<0.01 ∗ p<0.05 compared to placebo
(1) BOD: burden of disease: total lesion volume (T2 and T1 hypointense) in ml

Efficacy in patients with high disease activity:
A consistent treatment effect on relapses and time to 3-month sustained disability progression in a subgroup of patients in TEMSO (n= 127) with high disease activity was observed. Due to the design of the study, high disease activity was defined as 2 or more relapses in one year, and with one or more Gd-enhancing lesion on brain MRI. No similar subgroup analysis was performed in TOWER as no MRI data were obtained.

No data are available in patients who have failed to respond to a full and adequate course (normally at least one year of treatment) of beta-interferon, having had at least 1 relapse in the previous year while on therapy, and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or patients having an unchanged or increased relapse rate in the prior year as compared to the previous 2 years.

TOPIC was a double-blind, placebo-controlled study that evaluated once daily doses of teriflunomide 7 mg and 14 mg for up to 108 weeks in patients with first clinical demyelinating
event (mean age 32.1 years). The primary endpoint was time to a second clinical episode (relapse). A total of 618 patients were randomised to receive 7 mg (n=205) or 14 mg (n=216) of teriflunomide or placebo (n=197). The risk of a second clinical attack over 2 years was 35.9% in the placebo group and 24.0% in the teriflunomide 14 mg treatment group (hazard ratio: 0.57, 95% confidence interval: 0.38 to 0.87, p=0.0087). The results from the TOPIC study confirmed the efficacy of teriflunomide in RRMS (including early RRMS with first clinical demyelinating event and MRI lesions disseminated in time and space).

Teriflunomide effectiveness was compared to that of a subcutaneous interferon beta-1a (at the recommended dose of 44 μg three times a week) in 324 randomised patients in a study (TENERE) with minimum treatment duration of 48 weeks (maximum 114 weeks). The risk of failure (confirmed relapse or permanent treatment discontinuation whichever came first) was the primary endpoint. The number of patients with permanent treatment discontinuation in the teriflunomide 14 mg group was 22 out of 111 (19.8%), the reasons being adverse events (10.8%), lack of efficacy (3.6%), other reason (4.5%) and lost to follow-up (0.9%). The number of patients with permanent treatment discontinuation in the subcutaneous interferon beta-1a group was 30 out of 104 (28 .8%), the reasons being adverse events (21.2%), lack of efficacy (1.9%), other reason (4.8%) and poor compliance to protocol (1%). Teriflunomide 14 mg/day was not superior to interferon beta-1a on the primary endpoint: the estimated percentage of patients with treatment failure at 96 weeks using the Kaplan-Meier method was 41.1% versus 44.4% (teriflunomide 14 mg versus interferon beta-1a group, p=0.595).

Paediatric population
Children and adolescents (10 to 17 years of age) Study EFC11759/TERIKIDS was an international double-blind, placebo-controlled study in paediatric patients aged 10 to 17 years with relapsing-remitting MS that evaluated once daily doses of teriflunomide (adjusted to reach an exposure equivalent to the dose of 14 mg in adults) for up to 96 weeks followed by an open-label extension. All patients had experienced at least 1 relapse over 1 year or at least 2 relapses over 2 years preceding the study. Neurological evaluations were performed at screening and every 24 weeks until the completion, and at unscheduled visits for suspected relapse. Patients with a clinical relapse or high MRI activity of at least 5 new or enlarging T2 lesions on 2 consecutive scans were switched prior to 96 weeks to the open-label extension to ensure active treatment. The primary endpoint was time to first
clinical relapse after randomisation. Time to first confirmed clinical relapse or high MRI activity, whichever came first, was pre-defined as a sensitivity analysis because it includes both clinical and MRI conditions qualifying for switching into the open-label period.

A total of 166 patients were randomised at a 2:1 ratio to receive teriflunomide (n=109) or placebo (n=57). At entry, study patients had an EDSS score ≤5.5; the mean age was 14.6 years;
the mean weight was 58.1 kg; the mean disease duration since diagnosis was 1.4 years; and the mean T1 Gd-enhancing lesions per MRI scan was 3.9 lesions at baseline. All patients had
relapsing remitting MS with the median EDSS score of 1.5 at baseline. The mean treatment time was 362 days on placebo and 488 days on teriflunomide. Switching from the double-blind period to open-label treatment due to high MRI activity was more frequent than anticipated, and more frequent and earlier in the placebo group than in the teriflunomide group (26% on placebo, 13% on teriflunomide).

Teriflunomide reduced the risk of clinical relapse by 34% relative to placebo, without reaching statistical significance (p = 0.29) (Table 2). In the pre-defined sensitivity analysis,
teriflunomide achieved a statistically significant reduction in the combined risk of clinical relapse or high MRI activity by 43% relative to placebo (p = 0.04) (Table 2).

Teriflunomide significantly reduced the number of new and enlarging T2 lesions per scan by 55% (p=0.0006) (post-hoc analysis also adjusted for baseline T2 counts: 34%, p=0.0446), and the number of Gadolinium-enhancing T1 lesions per scan by 75% (p <0.0001) (Table 2).

Table 2 - Clinical and MRI results of EFC11759/TERIKIDS

EFC11759 ITT population

Teriflunomide

(N=109)

Placebo

(N=57)

Clinical endpoints

Time to first confirmed clinical relapse,

Probability (95%CI) of confirmed relapse at

Week 96

Probability (95%CI) of confirmed relapse at

Week 48

0.39 (0.29, 0.48)

0.30 (0.21, 0.39)

0.53 (0.36, 0.68)

0.39 (0.30, 0.52)

Hazard Ratio (95% CI)

0.66 (0.39, 1.11)^

Time to first confirmed clinical relapse or high

MRI activity, Probability (95%CI) of confirmed

relapse or high MRI activity at Week 96

Probability (95%CI) of confirmed relapse or

high MRI activity at Week 48

0.51 (0.41, 0.60)

0.38 (0.29, 0.47)

0.72 (0.58, 0.82)

0.56 (0.42, 0.68)

Hazard Ratio (95% CI)

0.57 (0.37, 0.87)*

Key MRI endpoints

 

 

Adjusted number of new or enlarged T2 lesions,

Estimate (95% CI)

Estimate (95% CI), post-hoc analysis also

adjusted for baseline T2 counts

4.74 (2.12, 10.57)

3.57 (1.97, 6.46)

10.52 (4.71, 23.50)

5.37 (2.84, 10.16)

Relative risk (95% CI)

Relative risk (95% CI), post-hoc analysis also

adjusted for baseline T2 counts

0.45 (0.29, 0.71)∗∗

0.67 (0.45, 0.99)*

Adjusted number of T1 Gd-enhancing lesions,

Estimate (95% CI)

1.90 (0.66, 5.49)

7.51 (2.48, 22.70)

Relative risk (95% CI)

0.25 (0.13, 0.51)***

^p≥0.05 compared to placebo, ∗ p<0.05, ∗∗ p<0.001, ∗∗∗ p<0.0001

Probability was based on Kaplan-Meier estimator and Week 96 was the end of study treatment (EOT).


Absorption
Median time to reach maximum plasma concentrations occurs between 1 to 4 hours post-dose following repeated oral administration of teriflunomide, with high bioavailability (approximately 100%).

Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.

From the mean predicted pharmacokinetic parameters calculated from the population pharmacokinetic (PopPK) analysis using data from healthy volunteers and MS patients, there is a slow approach to steady-state concentration (i.e., approximately 100 days (3.5 months) to attain 95% of steady-state concentrations) and the estimated AUC accumulation ratio is approximately 34-fold.

Distribution
Teriflunomide is extensively bound to plasma protein (>99%), probably albumin and is mainly distributed in plasma. The volume of distribution is 11 l after a single intravenous (IV)
administration. However, this is most likely an underestimation since extensive organ distribution was observed in rats.

Biotransformation
Teriflunomide is moderately metabolised and is the only component detected in plasma. The primary biotransformation pathway for teriflunomide is hydrolysis with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.

Elimination
Teriflunomide is excreted in the gastrointestinal tract mainly through the bile as unchanged medicinal active substance and most likely by direct secretion. Teriflunomide is a substrate of the efflux transporter BCRP, which could be involved in direct secretion. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After the rapid elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces). Based on individual prediction of pharmacokinetic parameters using the PopPK model of teriflunomide in healthy volunteers and MS patients, median t1/2z was approximately 19 days after repeated doses of 14 mg. After a single intravenous administration, the total body clearance of teriflunomide is 30.5 ml/h.

Accelerated elimination procedure: cholestyramine and activated charcoal
The elimination of teriflunomide from the circulation can be accelerated by administration of cholestyramine or activated charcoal, presumably by interrupting the reabsorption processes at the intestinal level. Teriflunomide concentrations measured during an 11-day procedure to accelerate teriflunomide elimination with either 8 g cholestyramine three times a day, 4 g cholestyramine three times a day or 50 g activated charcoal twice a day following cessation of teriflunomide treatment have shown that these regimens were effective in accelerating teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations, with cholestyramine being faster than charcoal. Following discontinuation of teriflunomide and the administration of cholestyramine 8 g three times a day, the plasma concentration of teriflunomide is reduced 52% at the end of day 1, 91% at the end of day 3, 99.2% at the end of day 7, and 99.9% at the completion of day 11. The choice between the 3 elimination procedures should depend on the patient's tolerability. If cholestyramine 8 g three times a day is not well-tolerated, cholestyramine 4 g three times a day can be used. Alternatively, activated charcoal may also be used (the 11 days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly).

Linearity/non-linearity
Systemic exposure increases in a dose proportional manner after oral administration teriflunomide from 7 to 14 mg.

Characteristics in specific groups of patients

Gender and elderly
Several sources of intrinsic variability were identified in healthy subjects and MS patients based on the PopPK analysis: age, body weight, gender, race, and albumin and bilirubin levels. Nevertheless, their impact remains limited (≤31%).

Hepatic impairment
Mild and moderate hepatic impairment had no impact on the pharmacokinetic of teriflunomide. Therefore no dose adjustment is anticipated in mild and moderate hepatic-impaired patients. However, teriflunomide is contraindicated in patients with severe hepatic impairment (see sections 4.2 and 4.3).

Renal impairment
Severe renal impairment had no impact on the pharmacokinetic of teriflunomide. Therefore no dose adjustment is anticipated in mild, moderate and severe renal-impaired patients.

Paediatric population
In paediatric patients with body weight >40 kg treated with 14 mg once daily, steady state exposures were in the range observed in adult patients treated with the same dosing regimen.

In paediatric patients with body weight ≤40 kg treatment with 7 mg once daily (based on limited clinical data and simulations) led to steady state exposures in the range observed in
adult patients treated with 14 mg once daily.

Observed steady state trough concentrations were highly variable between individuals, as observed for adult MS patients.


Repeated-dose toxicity
Repeated oral administration of teriflunomide to mice, rats and dogs for up to 3, 6, and 12 months, respectively, revealed that the major targets of toxicity were the bone marrow,
lymphoid organs, oral cavity/ gastro intestinal tract, reproductive organs, and pancreas. Evidence of an oxidative effect on red blood cells was also observed. Anemia, decreased
platelet counts and effects on the immune system, including leukopenia, lymphopenia and secondary infections, were related to the effects on the bone marrow and/or lymphoid organs. The majority of effects reflect the basic mode of action of the compound (inhibition of dividing
cells). Animals are more sensitive to the pharmacology, and therefore toxicity, of teriflunomide than humans. As a result, toxicity in animals was found at exposures equivalent or below human therapeutic levels.

Genotoxic and carcinogenic potential
Teriflunomide was not mutagenic in vitro or clastogenic in vivo. Clastogenicity observed in vitro was considered to be an indirect effect related to nucleotide pool imbalance resulting from the pharmacology of DHO-DH inhibition. The minor metabolite TFMA (4- trifluoromethylaniline) caused mutagenicity and clastogenicity in vitro but not in vivo.

No evidence of carcinogenicity was observed in rats and mice.

Reproduction toxicity
Fertility was unaffected in rats despite adverse effects of teriflunomide on male reproductive organs, including reduced sperm count. There were no external malformations in the offspring of male rats administered teriflunomide prior to mating with untreated female rats. Teriflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic range. Adverse effects on the offspring were also seen when teriflunomide was administered to pregnant rats during gestation and lactation. The risk of male-mediated embryo-fetal toxicity through teriflunomide treatment is considered low. The estimated female plasma exposure via the semen of a treated patient is expected to be 100 times lower than the plasma exposure after 14 mg of oral teriflunomide.

Juvenile toxicity
Juvenile rats receiving oral teriflunomide for 7 weeks from weaning through sexual maturity revealed no adverse effects on growth, physical or neurological development, learning and memory, locomotor activity, sexual development, or fertility. Adverse effects comprised anaemia, reduction of lymphoid responsiveness, dose-dependently diminished T cell dependent antibody response and greatly decreased IgM and IgG concentrations, which generally coincided with observations in repeat-dose toxicity studies in adult rats. However, the increase in B cells observed in juvenile rats was not observed in adult rats. The significance of this difference is unknown, but complete reversibility was demonstrated as for most of the other findings. Due to the high sensitivity of animals to teriflunomide, juvenile rats were exposed to lower levels than those in children and adolescents at the maximum recommended human dose (MRHD).


Tablet core
Lactose monohydrate
Pregelatinized starch
Hydroxypropyl cellulose
Sodium starch glycolate
Colloidal silicon dioxide
Magnesium stearate

Tablet coat
Hypromellose
Titanium dioxide
Talc
Macrogol/PEG
FD&C Blue #2/Indigo carmine aluminium lake


Not applicable


36 months

Store below 30°C


Teriflunomide BOS tablets are proposed for marketing in Alu-Alu blister pack containing 10 tablets. The carton contains 3 such blister packs i.e., 30 (3x10) tablets.


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


Boston Oncology Arabia Limited Riyadh, Sudair Industrial Area, Zone A, Road 11, Factory 107, Saudi Arabia

10/2021
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