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What Rezurock is
The active substance is called belumosudil.
Belumosudil belongs to a group of medicines called immunosuppresants. It works by blocking an enzyme called ROCK2 that is involved in how your immune system works.
What Rezurock is used for
Rezurock is used to treat adults and adolescents aged 12 years and older with chronic graft-versus-host disease who have received at least two previous treatments.
What chronic graft-versus-host disease is
Chronic graft-versus-host disease can happen after you have a bone marrow or stem cell (blood) transplant. The cells transplanted from the donor (the graft) attack your body (the host). This disease can cause damage to many organs like your skin, liver or digestive system.
Do not take Rezurock
· if you are pregnant since Rezurock can harm your unborn baby (see section “Pregnancy, breast-feeding and fertility”).
· if you are allergic to belumosudil or any of the other ingredients of this medicine (listed in section 6).
If you are uncertain whether the conditions above apply to you, talk to your doctor, pharmacist or nurse before taking Rezurock.
Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Rezurock, if you:
· plan to become pregnant, since Rezurock can harm your unborn baby (see section “Pregnancy, breast-feeding and fertility”).
· are breast-feeding or plan to breast-feed, since Rezurock may potentially cause serious side effects in a breast-fed child (see section “Pregnancy, breast-feeding and fertility”).
· have any kidney problems.
· have any liver problems.
· are taking other medicines (see section “Other medicines and Rezurock”).
You should have blood tests before and during treatment with Rezurock including tests to monitor how well your liver is working.
Children
Rezurock is not recommended for use in children under 12 years old.
Other medicines and Rezurock
Tell your doctor, pharmacist or nurse if you are taking, have recently taken, or might take any other medicines, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Rezurock may affect the way other medicines work, and other medicines may affect the way Rezurock works.
Especially tell your doctor if you are taking any of the medicines in the table below as your doctor may need to change the dose of these medicines or the dose of Rezurock:
Medicine | Purpose of the medicine | Potential effect |
rifampicin | for tuberculosis | These medicines might decrease the concentration of belumosudil. |
dexamethasone | for allergies or inflammation | |
carbamazepine, phenytoin | for seizures | |
efavirenz | for HIV | |
benzodiazepines like midazolam | to cause drowsiness | |
proton pump inhibitors like omeprazole or rabeprazole | to lower acid production in the stomach | |
other gastric acid reducing agents like ranitidine | ||
statins like atorvastatin | to lower cholesterol | Belumosudil might increase the concentration of these medicines since it slows their breakdown in your body.
|
beta blockers like carvedilol | to lower blood pressure
| |
calcium channel blockers like diltiazem | ||
ciclosporin | to suppress the immune system | |
antibiotics like amoxicillin or clarithromycin | for bacterial infections | |
digoxin | to regulate the heart beat | |
docetaxel | for chemotherapy | |
antifungals like clotrimazole | for fungal infections |
If you are not sure if any of the above apply to you, talk to your doctor before taking Rezurock.
While you are taking Rezurock you should never start a new medicine without checking first with your doctor. This includes prescription medicines, non-prescription medicines (over-the-counter medicines) and herbal or alternative medicines.
Keep a list of all the medicines you take to show your doctor and pharmacist when you get a new medicine.
Rezurock with food
Rezurock should be taken with food. See section 3.
Pregnancy, breast-feeding and fertility
Tell your doctor immediately if you are pregnant, think you may be pregnant, or if you are breast-feeding. If you are planning to have a baby, ask your doctor for advice before taking this medicine.
Pregnancy
Do not take Rezurock during pregnancy because Rezurock can harm your unborn baby. Your doctor will check if you are pregnant before starting the treatment. If you become pregnant whilst taking Rezurock, speak to your doctor immediately.
If you are a woman who is able to become pregnant, your doctor will check if you are pregnant before starting treatment with Rezurock. This is because Rezurock can harm an unborn baby. You must use a reliable and highly effective method of contraception during your entire treatment with Rezurock and for at least one week after the last dose.
If you are a man with a female partner who is able to become pregnant, your partner should avoid becoming pregnant whilst you are taking Rezurock. You must use a highly effective method of contraception during your entire treatment with Rezurock and for at least one week after the last dose.
Talk to your doctor about how to take appropriate measures of contraception during your treatment with Rezurock.
Breast-feeding
You should not breast-feed during treatment with Rezurock and for at least one week after the last dose because Rezurock may be harmful to a breast-fed child.
Fertility
Based on animal studies, Rezurock may cause temporary infertility. Effects were reversible.
Driving and using machines
Rezurock may affect your ability to drive or use machines. You may feel tired or dizzy while taking Rezurock. Do not drive or operate machines if you have these side effects.
Rezurock contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say it is essentially ‘sodium-free’.
Rezurock is prescribed to you by a doctor with experience of treating chronic graft-versus-host-disease.
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.
The recommended dose for adults and adolescents (12 years of age or over) is one tablet (containing 200 mg of belumosudil) taken once daily orally at about the same time each day.
Your doctor may increase your dose of Rezurock if you are also taking certain drugs that can affect how belumosudil works.
Swallow the tablet whole with a glass of water with a meal.
Do not cut, crush or chew Rezurock tablets.
Your doctor may tell you to stop taking Rezurock for a while or permanently stop treatment depending on how you tolerate the treatment.
If you take more Rezurock than you should
If you take too much Rezurock, tell your doctor or go to the nearest hospital right away. Take the medicine pack with you.
If you forget to take Rezurock
If you miss a dose of Rezurock, take it as soon as you remember on the same day if it is less than 12 hours since your dose was due. Take your next dose of Rezurock at your regular time on the next day. If it is more than 12 hours since your dose was due, do not take the dose and take your next dose of Rezurock at your regular time on the next day. Do not take extra doses of Rezurock to make up for a missed dose.
If you are sick after taking Rezurock
If you are sick (vomit) after taking Rezurock, do not take another dose of Rezurock. Take your next dose of Rezurock at your regular time on the next day.
Duration of treatment with Rezurock
You should continue treatment until your doctor tells you to stop.
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. Some side effects can be serious.
Tell your doctor straight away if you experience any of the following rare serious side effects which may affect less than 1 in 10,000 people:
· Cough, chest pain, difficulty breathing, fever and sweating/chills. These could be symptoms of pneumonia.
· Painful, hot, swollen or blistering skin.
· Bloody diarrhoea.
Other side effects
Other possible side effects include the following listed below. If these side effects become severe, tell your doctor.
Very common (may affect more than 1 in 10 people)
· Extreme tiredness
· Feeling sick (nausea)
Common (may affect up to 1 in 10 people):
· Headache
· Increase in aspartate aminotransferase (a liver enzyme)
· Increase in alanine aminotransferase (a liver enzyme)
· Diarrhoea
· Muscle or joint pain
· Being sick (vomiting)
· Increase in gamma glutamyl transferase (a liver enzyme)
· Low white blood cell count (cells that fight infection)
· Swelling
· Muscle spasms
· Upper respiratory tract infections (such as common cold, sinus infection)
· Sudden shortness of breath or difficulty breathing (dyspnea)
· Cough
· High blood sugar (hyperglycaemia)
· Decrease in appetite
· Increase in alkaline phosphatase in the blood (a muscle enzyme)
· Decrease in weight
· Low red blood cell count (anaemia)
· Pain, tingling or numbness in the hands or feet (neuropathy peripheral)
· High blood pressure
· Low platelet count (cells that fight bleeding)
· Lower respiratory tract infections (such as pneumonia, bronchitis)
· Pain in the stomach
· Constipation
· Itching
· Dizziness
· Increase in creatinine phosphokinase in the blood (a muscle enzyme)
· Increase in creatinine in the blood (a muscle waste product)
· Fever
Your doctor may change your dose of Rezurock, temporarily stop, or permanently stop treatment with Rezurock if you have certain side effects.
Reporting of side effects
To report any side effect(s):
· Saudi Arabia: |
- The National Pharmacovigilance and Drug Safety Centre (NPC) |
· SFDA call center : 19999 |
· E-mail: npc.drug@sfda.gov.sa |
· Website: https://ade.sfda.gov.sa/ |
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com |
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and bottle after “EXP”. The expiry date refers to the last day of that month.
Do not store above 30°C.
Store in the original container to protect from moisture.
Tightly close the bottle of Rezurock after you take your dose.
The Rezurock bottle contains a desiccant packet to help keep your tablets dry (protect from moisture). Keep the desiccant in the bottle.
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.
What Rezurock contains
The active substance is belumosudil mesilate. Each tablet contains 200 mg belumosudil.
The other ingredients are:
Tablet core: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.
Tablet coating: polyvinyl alcohol (E1203), polyethylene glycol (E1521), talc (E553b), titanium dioxide (E171), yellow iron oxide (E172).
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Sanofi Winthrop Industrie
82 avenue Raspail
94250 Gentilly
France
Manufacturer:
UPM pharmaceuticals Inc.
501 Fifth Street
Bristol, TN 37620
United States
Secondary packaging:
Packaging Solutions LLC Pharma
37716 United StatesUSA ,Clinton
Tennessee TN Industrial Parkway 341
JD Yarnell
ما هو ريزوروك
تُسمّى المادة الفعالة بيلوموسوديل.
ينتمي بيلوموسوديل إلى مجموعة من الأدوية تُسمّى مثبّطات المناعة. وهو يعمل عن طريق حصر إنزيم يُسمّى ROCK2 له علاقة بكيفيّة عمل جهاز المناعة لديك.
لماذا يُستعمل ريزوروك
يُستعمل ريزوروك لعلاج المرضى البالغين والمراهقين الذين تبلغ أعمارهم 12 عامًا وما فوق المصابين بمرض عدم توافق خلايا المضيف المزمن والذين تلقّوا علاجين سابقين على الأقلّ.
ما هو مرض عدم توافق خلايا المضيف
يمكن أن يحدث مرض عدم توافق خلايا المضيف المزمن بعد خضوعك لعمليّة زرع نخاع العظم أو الخلايا الجذعيّة (الدم). الخلايا المزروعة من المتبرّع (الزرع) تهاجم جسمك (المضيف). يمكن أن يسبّب هذا المرض ضررًا للكثير من الأعضاء مثل الجلد أو الكبد أو الجهاز الهضمي.
لا ينبغي بك أخذ ريزوروك
· إذا كنتِ حاملاً لأن ريزوروك يمكن أن يؤذي طفلك الذي لم يولد بعد (أنظري فقرة "الحمل والرضاعة والخصوبة").
· إذا كنت تعاني من حساسية تجاه البيلوموسوديل أو تجاه أيّ من المكوّنات الأخرى لهذا الدواء (المدرجة في الفقرة رقم 6).
إذا كنت غير متأكّد ما إذا كانت الحالات المذكورة أعلاه تنطبق عليك، تحدّث مع طبيبك أو الصيدلي أو الممرضة قبل تناول ريزوروك.
تحذيرات واحتياطات
يجب عليك التحدّث إلى طبيبك أو الصيدلي أو الممرّضة قبل تناول ريزوروك إذا كنت:
· تخططين للحمل، لأنّ ريزوروك يمكن أن يؤذي طفلك الذي لم يولد بعد (أنظري فقرة "الحمل والرضاعة والخصوبة").
· مرضعة أو تخططين للإرضاع، لأنّ ريزوروك قد يسبب أعراضًا جانبيّة خطيرة لدى الطفل الرضيع (أنظري فقرة "الحمل والرضاعة والخصوبة").
· تعاني من أي مشاكل في الكلى.
· تعاني من أي مشاكل في الكبد.
· تتناول أدوية أخرى (أنظر قسم "أدوية أخرى وريزوروك").
ينبغي عليك إجراء فحوصات دم قبل العلاج بريزورك وأثناءه، بما في ذلك فحوصات لمراقبة مدى كفاءة عمل الكبد.
الأطفال
لا يُنصح باستخدام ريزوروك للأطفال ما دون 12 عامًا.
أدوية أخرى وريزوروك
أخبر طبيبك أو الصيدلي أو الممرّضة إذا كنت تتناول، أو تناولت مؤخرًا، أو قد تتناول أيّ أدوية أخرى، بما في ذلك الأدوية التي تُصرف بدون وصفة طبيّة والفيتامينات والمكمّلات العشبيّة.
قد يؤثر ريزوروك على طريقة عمل أدوية أخرى، وقد تؤثر أدوية أخرى على طريقة عمل ريزوروك.
أخبر طبيبك بشكل خاص إذا كنت تتناول أيًا من الأدوية المذكورة في الجدول أدناه فقد يحتاج طبيبك إلى تغيير جرعة هذه الأدوية أو جرعة ريزوروك:
الدواء | غرض الدواء | التأثير المحتمل |
ريفامبيسين | لمرض السلّ |
قد تقلل هذه الأدوية من تركيز البيلوموسوديل. |
ديكساميثازون | للحساسيات أو الالتهاب | |
كاربامازيبين، فينيتوين | لنوبات الصرع | |
إيفافيرنز | لفيروس نقص المناعة البشريّة | |
البنزوديازيبينات مثل الميدازولام | للتسبب في النعاس | |
مثبّطات مضخة البروتون مثل أوميبرازول أو رابيبرازول |
لخفض إنتاج الحمض في المعدة | |
أدوية أخرى لخفض حمض المعدة مثل رانيتيدين | ||
الستاتينات مثل أتورفاستاتين | لخفض الكولسترول |
قد يزيد البيلوموسوديل من تركيز هذه الأدوية لأنّه يبطئ تحللها في الجسم. |
حاصرات بيتا مثل كارفيديلول |
لخفض ضغط الدم | |
حاصرات قنوات الكالسيوم مثل ديلتيازيم | ||
سيكلوسبورين | لقمع جهاز المناعة | |
المضادات الحيويّة مثل أموكسيسيلين أو كلاريثروميسين | للالتهابات البكتيريّة | |
ديجوكسين | لتنظيم ضربات القلب | |
دوسيتاكسيل | للعلاج الكيميائي | |
مضادات الفطريّات مثل كلوتريمازول | للالتهابات الفطريّة |
إذا لم تكن متأكّدًا مما إذا كان أيّ مما سبق ينطبق عليك، تحدث مع طبيبك قبل تناول ريزوروك.
أثناء تناولك ريزوروك، يجب ألا تبدأ أبدًا بتناول دواء جديد من دون استشارة طبيبك أولاً. وهذا يشمل الأدوية الموصوفة طبيًا والأدوية التي لا تستلزم وصفة طبية (الأدوية التي تُصرف من دون وصفة طبيّة) والأدوية العشبيّة أو البديلة.
احتفظ بقائمة بجميع الأدوية التي تتناولها لتعرضها على طبيبك والصيدلي عندما تحصل على دواء جديد.
ريزوروك مع الطعام
ينبغي تناول ريزوروك مع الطعام. انظر الفقرة 3.
الحمل والرضاعة والخصوبة
أخبري طبيبك فورًا إذا كنت حاملاً، أو تعتقدين أنّك قد تكونين حاملاً، أو إذا كنت مرضعة. إذا كنت تخططين لإنجاب طفل، استشيري طبيبك قبل تناول هذا الدواء.
الحمل
لا تتناولي ريزوروك أثناء الحمل لأنّ ريزوروك يمكن أن يؤذي طفلك الذي لم يولد بعد. سوف يتحقق طبيبك مما إذا كنت حاملاً قبل بدء العلاج. إذا أصبحت حاملاً أثناء تناول ريزوروك، تحدثي إلى طبيبك على الفور.
إذا كنت امرأة قادرة على الحمل، فسوف يتحقق طبيبك مما إذا كنت حاملاً قبل بدء العلاج بريزوروك. وذلك لأنّ ريزوروك يمكن أن يؤذي الجنين. يجب عليك استخدام وسيلة موثوقة وفعّالة للغاية لمنع الحمل خلال فترة علاجك بريزوروك بالكامل ولمدّة أسبوع واحد على الأقلّ بعد الجرعة الأخيرة.
إذا كنت رجلاً ولديك شريكة قادرة على الحمل، فيجب على شريكتك تجنّب الحمل أثناء تناولك ريزوروك. يجب عليك استخدام وسيلة فعالة للغاية لمنع الحمل خلال فترة العلاج بريزوروك بأكملها ولمدّة أسبوع واحد على الأقلّ بعد الجرعة الأخيرة.
ينبغي التحدّث إلى طبيبك حول كيفيّة اتخاذ التدابير المناسبة لمنع الحمل أثناء العلاج بريزوروك.
الرضاعة
لا ينبغي أن تُرضِعي أثناء العلاج بريزوروك ولمدّة أسبوع واحد على الأقلّ بعد الجرعة الأخيرة لأنّ ريزوروك قد يؤذي الطفل الرضيع.
الخصوبة
بناءً على الدراسات التي أجريت على الحيوانات، قد يسبّب ريزوروك عقمًا مؤقتًا. كانت التأثيرات قابلة للعكس.
القيادة واستخدام الآلات
قد يؤثر ريزوروك على قدرتك على القيادة أو استخدام الآلات. قد تشعر بالتعب أو الدوار أثناء تناول ريزوروك. لا تقد سيّارة ولا تشغّل آلات إذا أُصبت بالآثار الجانبيّة هذه.
يحتوي ريزوروك على الصوديوم
يحتوي هذا الدواء على أقل من 1 مليمول صوديوم (23 ملغ) لكل قرص، ويعني هذا أنّه "خالٍ من الصوديوم" بشكل أساسي.
يصف لك ريزوروك طبيب لديه خبرة في علاج مرض عدم توافق خلايا المضيف المزمن.
تناول هذا الدواء دائمًا حسب تعليمات طبيبك تمامًا. استشر طبيبك إذا لم تكن متأكدًا.
الجرعة الموصى بها للبالغين والمراهقين (12 عامًا أو أكثر) هي قرص واحد (يحتوي على 200 ملغ من البيلوموسوديل) يؤخذ مرة واحدة يوميًا عن طريق الفم في الوقت نفسه تقريبًا كلّ يوم.
قد يزيد طبيبك جرعتك من ريزوروك إذا كنت تتناول أيضًا أدوية معيّنة يمكن أن تؤثر على كيفية عمل البيلوموسوديل.
يجب بلع القرص كاملاً مع كوب من الماء مع الطعام.
لا تقطع أقراص ريزوروك أو تسحقها أو تمضغها.
قد يطلب منك طبيبك التوقّف عن تناول ريزوروك لفترة من الوقت أو إيقاف العلاج بشكل دائم حسب كيفيّة تحمّلك العلاج.
إذا تناولت جرعة من ريزوروك أكثر مما ينبغي
إذا تناولت جرعة زائدة من ريزوروك، أعلم طبيبك أو اذهب إلى أقرب مستشفى على الفور. خذ علبة الدواء معك.
إذا نسيت تناول ريزوروك
إذا فاتتك جرعة من ريزوروك، تناولها بمجرد أن تتذكرها في اليوم نفسه إذا مرّ أقل من 12 ساعة على موعد تناول الجرعة. تناول جرعتك التالية من ريزوروك في وقتك المعتاد في اليوم التالي. إذا مرّ أكثر من 12 ساعة منذ موعد تناول الجرعة، لا تتناول الجرعة وتناول الجرعة التالية من ريزوروك في وقتك المعتاد في اليوم التالي. لا تأخذ جرعات إضافيّة من ريزوروك لتعويض الجرعة المنسية.
إذا تقيّأت بعد تناول ريزوروك
إذا تقيّأت بعد تناول ريزوروك، لا تتناول جرعة أخرى من ريزوروك. تناول جرعتك التالية من ريزوروك في وقتك المعتاد في اليوم التالي.
مدّة العلاج بريزوروك
يجب عليك مواصلة العلاج حتى يطلب منك طبيبك إيقافه.
إذا كان لديك أيّ أسئلة أخرى حول استعمال هذا الدواء، اسأل طبيبك أو الصيدلي.
كما هو الحال مع سائر الأدوية، يمكن أن يسبّب هذا الدواء أعراضًا جانبیّة، وإن كانت لا تحدث مع الجمیع. قد تكون بعض الأعراض الجانبيّة خطيرة.
أخبر طبيبك على الفور إذا واجهت أيًا من الأعراض الجانبيّة الخطيرة النادرة التالية التي قد تصيب أقل من شخص من كلّ 10000 شخص:
· سعال، ألم في الصدر، صعوبة في التنفّس، حمى وتعرّق/قشعريرة. يمكن أن تكون هذه أعراض الالتهاب الرئوي.
· جلد مؤلم، ساخن، متورّم أو متقرّح.
· إسهال دموي.
أعراض جانبيّة أخرى
تشمل الأعراض الجانبيّة المحتملة الأخرى تلك المذكورة أدناه. إذا أصبحت الأعراض الجانبيّة هذه شديدة، أخبر طبيبك.
شائعة جدًا (قد تُصيب أكثر من شخص واحد من كلّ 10 أشخاص):
· تعب شديد
· شعور بالغثيان (غثيان)
شائعة (قد تُصيب لغاية شخص واحد من كلّ 10 أشخاص):
· صداع
· زيادة في ناقلة أمين الأسبارتات (إنزيم في الكبد)
· زيادة في ناقلة أمين الألانين (إنزيم في الكبد)
· إسهال
· آلام في العضلات أو المفاصل
· تقيّؤ (قيء)
· زيادة في إنزيم غاما جلوتاميل ترانسفيراز (إنزيم في الكبد)
· انخفاض عدد خلايا الدم البيضاء (الخلايا التي تقاوم العدوى)
· تورّم
· تشنّجات عضليّة
· التهابات في الجهاز التنفسي العلوي (مثل نزلات البرد والتهاب الجيوب الأنفيّة)
· ضيق مفاجئ في التنفّس أو صعوبة في التنفّس (ضيق التنفّس)
· سعال
· ارتفاع نسبة السكر في الدم (فرط سكر الدم)
· انخفاض الشهيّة
· زيادة في الفوسفاتيز القلوي في الدم (إنزيم عضلي)
· انخفاض في الوزن
· انخفاض عدد خلايا الدم الحمراء (فقر الدم)
· ألم أو وخز أو تنميل في اليدين أو القدمين (الاعتلال العصبي المحيطي)
· ضغط دم مرتفع
· انخفاض عدد الصفائح الدمويّة (الخلايا التي تقاوم النزيف)
· التهابات الجهاز التنفّسي السفلي (مثل الالتهاب الرئوي والتهاب الشعب الهوائيّة)
· ألم في المعدة
· إمساك
· حكّة
· دوخة
· زيادة في فوسفوكيناز الكرياتينين في الدم (إنزيم عضلي)
· زيادة الكرياتينين في الدم (منتج الفضلات العضليّة)
· حمى
قد يغير طبيبك جرعتك من ريزوروك، أو يوقف العلاج مؤقتًا، أو يوقف العلاج بريزوروك بشكل دائم إذا أُصبت بأعراض جانبيّة معيّنة.
الإبلاغ عن الأعراض الجانبيّة
إذا ظهرت عليك أي أعراض جانبيّة، تحدّث إلى طبيبك أو الصيدلي أو الممرّضة. وهذا يشمل أي أعراض جانبيّة محتملة غير مدرجة في هذه النشرة. يمكنك أيضًا الإبلاغ عن الأعراض الجانبيّة مباشرةً عبر نظام البطاقة الصفراء. يمكنك العثور على معلومات حول هذا الأمر على www.mhra.gov.uk/yellowcard أو البحث عن البطاقة الصفراء لهيئة تنظيم الأدوية ومنتجات الرعاية الصحيّة MHRA في جوجل بلاي Google Play أو متجر تطبيقات أبل Apple App Store. من خلال الإبلاغ عن الأعراض الجانبية، يمكنك المساعدة على تقديم المزيد من المعلومات حول سلامة هذا الدواء.
للإبلاغ عن الأعراض الجانبيّة:
· المملكة العربيّة السعوديّة: |
- المركز الوطني للتیقّظ والسّلامة الدوائیّة (NPC) |
· مركز الاتصال التابع للهيئة العامة للغذاء والدواء: 19999 |
· البريد الإلكتروني: npc.drug@sfda.gov.sa |
· الموقع الإلكتروني: https://ade.sfda.gov.sa/ |
· سانوفي – التيقّظ الدوائي: KSA_Pharmacovigilance@sanofi.com |
يُحفظ هذا الدواء بعیدًا عن مرأى الأطفال ومتناولهم.
لا تستخدم هذا الدواء بعد تاريخ انتهاء الصلاحیة المذكور على علبة الكرتون الخارجيّة والزجاجة بعد كلمة “EXP” . يشير تاريخ انتهاء الصلاحیة إلى الیوم الأخیر من ذلك الشهر.
لا يُحفظ في درجة حرارة تتخطّى 30 درجة مئويّة.
يُحفظ في عبوته الأصليّة لحمايته من الرطوبة.
أغلق زجاجة ريزوروك بإحكام بعد تناول جرعتك.
تحتوي زجاجة ريزوروك على عبوة مجففة للمساعدة على الحفاظ على جفاف الأقراص (الحماية من الرطوبة). احتفظ بالمادة المجففة في الزجاجة.
لا تتخلص من أي أدوية عن طريق مياه الصرف الصحي أو النفايات المنزليّة. اسأل الصيدلي عن كيفية التخلّص من الأدوية التي لم تعد تستخدمها. سوف تساعد هذه التدابير في حماية البيئة.
ماذا يحتوي ريزوروك
المادة الفعالة هي بيلوموسوديل ميسيلات. يحتوي كلّ قرص على 200 ملغ بيلوموسوديل.
المكوّنات الأخرى هي:
قلب القرص: سليلوز دقيق البلوريّة، هيبروميلوز، كروسكارميلوز الصوديوم، ثاني أكسيد السيليكون الغروي، ستيرات المغنيسيوم.
غلاف القرص:
كحول بولي فينيل (E1203)، بولي إيثيلين جلايكول (E1521)، تلك (E553b)، ثاني أكسيد التيتانيوم (E171)، أكسيد الحديد الأصفر (E172).
الشكل الصیدلاني لريزوروك ومحتويات عبوته
أقراص ريزوروك المغلفة عبارة عن أقراص مستطيلة ذات لون أصفر شاحب ومنقوش عليها "KDM" على جانب واحد و"200" على الجانب الآخر.
ريزوروك متوفر في زجاجة بلاستيكية مع سدادة مقاومة للأطفال في عبوة تحتوي على 30 قرصًا مغلفًا.
حامل رخصة التسويق والمصنّع
حامل رخصة التسويق:
Sanofi Winthrop Industrie
82 avenue Raspail
94250 Gentilly
France
المصنّع:
UPM pharmaceuticals Inc.
501 Fifth Street
Bristol, TN 37620
United States
التغليف الثانوي:
Packaging Solutions LLC Pharma
37716 United StatesUSA ,Clinton
Tennessee TN Industrial Parkway 341
JD Yarnell
Rezurock is indicated for the treatment of patients aged 12 years and older with chronic graft-versus-host disease (chronic GVHD) who have received at least two prior lines of systemic therapy.
Rezurock treatment should be initiated and supervised by physicians experienced in the management of chronic GVHD.
Posology
The recommended dose of Rezurock is 200 mg administered orally once daily at approximately the same time with a meal.
Treatment should continue until disease progression or unacceptable toxicity.
A complete blood cell count and liver function test must be performed before initiating therapy with Rezurock.
Dose modification due to adverse reactions
Perform liver function tests at least monthly throughout treatment (see section 4.4).
The recommended Rezurock dose modifications for hepatotoxicity and other adverse reactions are provided in Table 1.
Table 1: Dose modifications for adverse reactionsDose modification due to drug interactions
Strong CYP3A4 inducers and Proton Pump Inhibitors decrease the exposure of belumosudil (see section 4.5).
Co-administration of belumosudil with drugs transported by OATP1B1 and BCRP substrates can lead to an increase in exposure of these concomitant drugs (e.g. rosuvastatin) (see section 4.5).
Strong CYP3A Inducers
Increase the dosage of Rezurock to 200 mg twice daily when co-administered with strong CYP3A inducers.
Proton Pump Inhibitors
Increase the dosage of Rezurock to 200 mg twice daily when co-administered with proton pump inhibitors.
OATP1B1/BCRP substrates
Consider switching to a drug less sensitive to OATP1B1 and BCRP inhibition when possible. If used together the dose of rosuvastatin should not exceed 5 mg once daily. Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 and BCRP.
Delayed or missed dose
If a dose is missed or delayed for less than 12 hours after the scheduled dose, the dose should be taken as soon as possible on the same day with a return to the normal schedule the following day.
If a dose is missed or delayed for more than 12 hours after the scheduled dose, the dose should be taken at the usual time the following day.
If a patient vomits following the intake of a dose, the next dose should be taken at the usual time the following day.
Patients should not take extra doses to make up the missed dose.
Special populations
Hepatic impairment
Dose modification is not recommended when administering belumosudil to patients with mild or moderate hepatic impairment (Child-Pugh A and B).
Belumosudil is not recommended in patients with severe hepatic impairment. The safety and efficacy of belumosudil in severe (Child-Pugh C) hepatic impairment has not been evaluated. For patients with pre-existing severe hepatic impairment (Child-Pugh C), consider the risks and potential benefits before initiating treatment with belumosudil (see section 5.2).
Monitor patients frequently for adverse reactions.
Renal impairment
No dose modification of Rezurock is required in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min).
No data are available for patients with severe renal impairment (creatinine clearance < 30 mL/min) or for patients with end-stage renal disease on dialysis (see sections 5.1 and 5.2). Use with caution.
Elderly patients (≥65 years)
No additional dose adjustments are recommended for elderly patients (see sections 5.1 and 5.2).
Paediatric population
The posology is the same in adults and adolescents aged 12 to 18 years.
The safety and efficacy of Rezurock in children and adolescents aged below 12 years of age have not been established. No data are available (see section 5.1).
Method of administration
For oral use.
Rezurock should be taken at approximately the same time each day with a meal (see section 5.2).
The film-coated tablet should not be broken, crushed or chewed.
Women of childbearing potential
Women of childbearing potential should be advised to avoid becoming pregnant while taking belumosudil and of the potential risk to a foetus, and to have a pregnancy test prior to starting treatment with belumosudil.
Women of childbearing potential must use a highly effective method of contraception during treatment with belumosudil and for at least one week after the last dose of belumosudil (see sections 4.6 and 5.3).
Male patients
Male patients with female partners of childbearing potential should be advised that their female partners should avoid becoming pregnant while taking belumosudil and of the potential risk to a foetus.
Males with female partners of childbearing potential must use a highly effective method of contraception during treatment with belumosudil and for at least a week after the last dose of belumosudil (see sections 4.6 and 5.3).
Breast-feeding
Breast-feeding is not recommended during treatment with belumosudil and for at least one week after the last dose (see section 4.6).
Hepatotoxicity
Increases in liver function tests were observed in clinical studies with belumosudil and generally occurred early during treatment with the incidence decreasing thereafter (see section 4.8). Liver function tests should be performed prior to the initiation of treatment with belumosudil and monitored at least monthly during treatment with belumosudil and the dose should be adjusted for ≥ Grade 2 toxicities (see section 4.2)
Effect of CYP3A inhibitors on belumosudil
The co-administration of multiple doses of itraconazole (a strong CYP3A inhibitor) did not alter exposure to belumosudil to any clinically relevant extent.
Effect of CYP3A inducers on belumosudil
The co-administration of multiple doses of rifampin (a strong CYP3A4 inducer) decreased belumosudil Cmax by 59% and AUC by 72%. The co-administration of strong CYP3A4 inducers with belumosudil may decrease belumosudil exposure. Increase the dose of belumosudil to 200 mg twice daily (see section 4.2).
The co-administration of moderate CYP3A4 inducers e.g., efavirenz is predicted to have a reduced effect on belumosudil as compared to strong CYP3A4 inducers. The co-administration of moderate CYP3A4 inducers with belumosudil may decrease belumosudil exposure. No dose adjustment is recommended.
Effect of proton pump inhibitors on belumosudil
The co-administration of multiple doses of rabeprazole decreased belumosudil Cmax by 87% and AUC by 80%. The co-administration of multiple doses of omeprazole decreased belumosudil Cmax by 68% and AUC by 47%. The co-administration of proton pump inhibitors with belumosudil may decrease belumosudil exposure. Increase the dose of belumosudil to 200 mg twice daily (see section 4.2).
Effect of other gastric acid reducing agents on belumosudil The co-administration of belumosudil with gastric acid reducing agents other than proton pump inhibitors may decrease belumosudil exposure. No dose adjustment is recommended, however belumosudil and the gastric acid reducing agent should be taken 12 hours apart.
In vitro studies
Effect of belumosudil on CYP3A substrates
The co-administration of belumosudil is predicted to increase midazolam (a sensitive CYP3A substrate) Cmax and AUC approximately 1.3- and 1.5-fold, respectively. No dose adjustment is recommended.
The co-administration of belumosudil may increase exposure of sensitive CYP3A4 substrates with a narrow therapeutic index such as ciclosporin and tacrolimus. No dose adjustment is recommended.
Effect of belumosudil on CYP2C9 substrates
The co-administration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C9 substrates (such as warfarin).
Effect of belumosudil on CYP2C8 substrates
The co-administration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C8 substrates that are not an OATP1B1 substrate.
Effect of belumosudil on UGT1A1 substrates
Belumosudil is a weak inhibitor of UGT1A1, the clinical consequences are not known.
Transporters
Belumosudil is a substrate of P-gp. Belumosudil inhibits BCRP, P-gp, and OATP1B1. The co-administration of oral BCRP, P-gp and OATP1B1 substrates with belumosudil may increase the concentrations of the substrate drugs (such as digoxin and docetaxel).
The co-administration of belumosudil with drugs transported by OATP1B1 and BCRP can lead to an increase in exposure of these concomitant drugs (e.g. rosuvastatin) which may increase the risk of these substrate-related toxicities. Co-administration of belumosudil increases rosuvastatin Cmax and AUC by 3.6 and 4.6-fold, respectively.
Pregnancy
There are no data on the use of belumosudil in pregnant women.
Belumosudil can cause foetal harm based on findings from animal studies (see section 5.3) and its mechanism of action. In pregnant rats and rabbits, oral administration of belumosudil resulted in maternal and/or foetal toxicity at doses below the recommended human dose. As a precautionary measure, belumosudil is contraindicated in pregnancy (see section 4.3).
Women of childbearing potential/Contraception in males and females
Women of childbearing potential should be informed that animal studies show belumosudil to be harmful to the developing foetus. Women of childbearing potential must have their pregnancy status verified prior to initiating treatment with belumosudil, and must use a reliable and highly effective
method of contraception during treatment with belumosudil and for at least one week after the last dose of belumosudil. In case pregnancy should occur during treatment with belumosudil, a risk/benefit evaluation must be carried out on an individual basis with careful counselling regarding potential risks to the foetus (see sections 4.4 and 5.3).
Male patients with female partners of childbearing potential should be advised that their female partners should avoid becoming pregnant while taking belumosudil and of the potential risks to a foetus.
Male patients with female partners of childbearing potential must use a highly effective method of contraception during treatment and for at least one week after the last dose of belumosudil (see section 4.4).
Breast-feeding
It is unknown whether belumosudil or its metabolites are excreted in human milk. No data are available regarding the presence of belumosudil or its metabolites in animal or human milk or its effects on the breast-fed child, or on milk production. A risk to the infant cannot be excluded. Because of the potential for serious adverse reactions in a breast-fed child, breast-feeding should be discontinued during treatment with belumosudil and for at least one week after the last dose (see section 4.4).
Fertility
There are no human data on the effect of belumosudil on fertility. Based on findings from animal studies, belumosudil may impair male and female fertility at dose levels above the recommended clinical dose. The effects on fertility are reversible (see section 5.3).
Belumosudil may cause fatigue and dizziness (see section 4.8). Patients should be advised not to drive or operate machines if they experience these symptoms.
Summary of safety profile
The overall safety profile of belumosudil in chronic graft-versus-host-disease is based on data from 186 patients from two clinical trials, KD025-208 and KD025-213.
The most common adverse reactions (≥5%) were asthenia (21.0%), nausea (12.4%), liver function test abnormalities of elevation of AST (7.5%), elevation of ALT (7.0%) and elevation of GGT (4.8%), headache (8.6%), diarrhoea (7.0%) and musculoskeletal pain (5.9%). The most common Grade 3 or 4 adverse reaction (≥ 2%) was asthenia (2.7%). Serious adverse reactions were pneumonia (1.1%), cellulitis, infectious colitis, staphylococcal bacteraemia, diarrhoea, nausea, vomiting, microangiopathic haemolytic anaemia, multiple organ dysfunction syndrome and cGVHD (0.5% each).
The most common adverse reactions leading to discontinuation were nausea (2.4%) and headache (2.4%). Adverse reactions leading to dose interruption occurred in 9.6% of patients and were mainly investigations (3.6%), including ALT increased, GGT increased and blood creatine phosphokinase increased (1.2% each), and infections (2.4%).
Tabulated list of adverse reactions
Table 2 presents the frequency category for adverse reactions reported in the open-label clinical trials (studies KD025-208 and KD025-213) with belumosudil. A total of 186 adult patients with chronic GVHD were treated with belumosudil 200 mg once daily (N=83), 200 mg twice daily (N=82), or 400 mg once daily (N=21) (see section 5.1). The median duration of treatment of the 83 patients with 200 mg once daily belumosudil was 9.2 months (range 0.5 to 44.7 months) and in the 186 patients across the three dosing cohorts was 9.89 months (range 0.39 to 44.71 months).
The frequency of adverse reactions are defined as follows:
Very common: (≥1/10)
Common: (≥1/100 to <1/10)
Uncommon: (≥1/1000 to <1/100)
Rare: (≥1/10,000 to <1/1000)
Very rare: (<1/10,000)
Not known: (cannot be estimated from the available data)
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 2: Adverse reactions (≥2%) in patients with chronic GVHD who received belumosudilDescription of selected adverse reactions
Hepatobiliary disorders
Elevations of liver enzymes were reported in patients treated with belumosudil in clinical trials. In two randomised, open label, multi-centre clinical trials in patients with cGVHD (studies KD025-208 and KD025-213), any grade laboratory abnormalities of increased AST, increased ALT and increased GGT occurred in 7.5%, 7.0% and 4.8%, respectively, of patients receiving belumosudil. Grade ≥ 3 laboratory abnormalities of increased AST, increased ALT and increased GGT occurred in 1.6%, 1.1% and 1.1%, respectively, of patients receiving belumosudil. Events resolved with few drug discontinuations, drug interruptions or dose reductions. The events generally occurred early during belumosudil treatment with the incidence decreasing thereafter. For recommended dosage modifications following elevations of liver enzymes see section 4.2. For recommended monitoring of liver enzymes see section 4.4.
Blood and lymphatic disorders
In the randomised, open label, multi-centre clinical trials in patients with cGVHD (studies KD025-208 and KD025-213), any grade anaemia and leukopenia occurred in 3.2% and 4.8%, respectively, of patients receiving belumosudil. Grade ≥ 3 events of anaemia and leukopenia occurred in 0.5% and 1.6%, respectively, of patients receiving belumosudil. Grade 3 cytopenias were often associated with relapse of the underlying malignancy.
Reporting of suspected adverse reactions
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.
To report any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
• SFDA call center : 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: https://ade.sfda.gov.sa/
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com
No cases of overdose have been reported.
There is no specific experience in the management of belumosudil overdose in patients. There is no known antidote for overdoses with belumosudil. Single doses up to 1000 mg have been given with acceptable tolerability in healthy volunteers. Appropriate supportive treatment should be given.
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA48.
Mechanism of action
Belumosudil is a potent and selective Rho-associated, coiled-coil containing protein kinase-2 (ROCK2) inhibitor that mediates signalling in immune cellular function and fibrotic pathways. In vivo, belumosudil has demonstrated activity in a variety of clinically relevant animal models of disease including chronic GVHD.
Pharmacodynamic effects
Cardiac Electrophysiology
At a dose of 5 times the recommended dose, belumosudil does not prolong the QT interval to any clinically relevant extent.
Clinical efficacy and safety
Two open-label Phase 2 studies (studies KD025-208 and KD025-213) were conducted in patients with chronic GVHD.
Study KD025-213
Study KD025-213 (N=131) was a randomized, open-label, multicentre study of belumosudil for treatment of patients with chronic GVHD. Patients were eligible for the study if they had received 2 to 5 prior lines of systemic therapy and required additional therapy. Patients received a stable dose of corticosteroids for two weeks prior to entry to the study. Patients were randomised 1:1 to receive belumosudil dosed orally at 200 mg once daily or 200 mg twice daily. Randomization was stratified according to prior cGVHD treatment with ibrutinib (yes/no) and severe cGVHD (yes/no).
Where patients were on a stable dose/schedule of standard of care therapies for chronic GVHD, concomitant use of these was permitted, including local and topical treatments and ECP. Transient increases in corticosteroid dosing (that did not exceed 1 mg/kg/day prednisone equivalent) were permitted for the treatment of cGVHD flare, but the dose must have been reduced back to the pre-randomization dose within 6 weeks. If the dose remained elevated for more than 6 weeks, this was considered a belumosudil treatment failure. More than 2 episodes of cGVHD flare that required increased corticosteroid therapy in the first 6 months of belumosudil treatment was also considered a belumosudil treatment failure. Initiation of one or more new systemic therapies for chronic GVHD indicated a new line of therapy and was classified as a treatment failure.
Of patients enrolled in the study, the median age was 55 years (range 21 to 77 years), 57% of patients were male and 85% were white. The majority (67%) of patients had severe cGVHD disease and 73% of patients were refractory to their last systemic therapy prior to enrolling in the study. The most common underlying malignancies leading to transplantation were acute myeloid leukaemia, acute lymphocytic leukaemia and myelodysplastic syndromes. The organs involved at baseline were skin (83%), joints/fascia (76%), eyes (74%), lung (36%), mouth (54%), oesophagus (24%), upper GI (17%), lower GI (10%) and liver (10%), and 51% of patients had 4 or more organs involved. The most common prior systemic therapy was corticosteroids (98%), followed by calcineurin inhibitors (tacrolimus 62% and sirolimus 47%), ECP (48%), ibrutinib (34%) and ruxolitinib (29%). The median prior lines of therapy was 3 (range 2-6).
The primary efficacy endpoint was the overall response rate (ORR), defined as the proportion of subjects who achieved a complete response or a partial response according to the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in chronic GVHD. Responses were assessed by investigators. Secondary endpoints included duration of response, changes in symptom burden/bother using the Lee Symptom Scale Score (LSS) and time to next treatment.
Study KD025-213 met its primary objective. For the 200 mg once daily dose, the ORR (data cut-off: 19-Aug-2020) was 74% (62-84%); 6% of patients achieved a CR and 68% of patients achieved a PR. Responses, including complete responses, were achieved across all organs involved (skin, eyes, joints/fascia, mouth, lung, oesophagus, upper GI, lower GI and liver). Duration of response (defined as the time from first ORR response to progression of disease in any organ measured in comparison to nadir, new systemic therapy, or death whichever comes first) was 8 weeks (95% CI 4-64 weeks).
Results for Study KD025-213 at the 200 mg once daily belumosudil dose are presented in Table 3.
Table 3: Best overall response rate and other efficacy results in Study KD025-213For the 200 mg twice daily dose, the ORR was 77.3% (95% CI 65.3%, 86.7%) and the DOR (defined as the time from first ORR response to progression of disease in any organ measured in comparison to nadir, new systemic therapy, or death whichever comes first) was 8 weeks (95% CI 2-81 weeks).
Study KD025-208
Study KD025-208 (N=54) was a dose-escalation, open-label, multicentre study of belumosudil for treatment of patients with chronic GVHD who had received 1 to 3 prior lines of systemic therapy and required additional therapy. Belumosudil was administered orally at 200 mg once daily (N=17), 200 mg twice daily (N=16), or 400 mg once daily (N=21).
Where patients were on a stable dose/schedule of standard of care therapies for chronic GVHD, concomitant use of these was permitted, including corticosteroids and calcineurin inhibitors. Initiation of one or more new systemic therapies for chronic GVHD indicated a new line of therapy and was classified as a treatment failure.
Of patients enrolled in the study, the median age was 52 years (range 20 to 75 years), 63% of patients were male and 87% were white. The majority (78%) of patients had severe cGVHD disease and 73% of patients were refractory to their last systemic therapy prior to enrolling in the study. The most common underlying malignancies leading to transplantation were acute myeloid leukaemia, acute lymphocytic leukaemia and myelodysplastic syndromes. The organs involved at baseline were eyes (78%), skin (74%), mouth (65%), joints/fascia (63%), lung (32%), upper GI (15%), oesophagus (11%), lower GI (7%), and liver (4%), and 50% of patients had 4 or more organs involved. The most common prior systemic therapy was corticosteroids (100%), followed by calcineurin inhibitors (tacrolimus 48% and sirolimus 44%), rituximab (30%), and ECP (28%). The median number of prior lines of therapy was 2.5 (range 1-4).
The primary efficacy endpoint was the overall response rate (ORR), defined as the proportion of subjects who achieved a complete response or a partial response according to the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in chronic GVHD. Responses were assessed by investigators. Secondary endpoints included duration of response, failure free survival and time to next treatment.
Study KD025-208 met its primary objective. For the 200 mg once daily dose, the ORR was 64.7% (95% CI 38.3%, 85.8%). Responses (partial response) were achieved across all organs involved, there were no complete responses reported. Duration of response (defined as the time from first ORR response to progression of disease in any organ measured in comparison to nadir, new systemic therapy, or death whichever comes first) was 19 weeks (95% CI 7-128 weeks).
Safety and efficacy in older patients
Of the 186 patients with chronic GVHD in clinical studies of belumosudil, 25.8% were 65 years and older. No overall differences in safety or effectiveness of belumosudil were observed between these patients and younger patients.
Paediatric population
The Medicines and Healthcare Products Regulatory Agency has deferred the obligation to submit the results of studies with Rezurock.
Absorption
Median Tmax of belumosudil across studies was approximately 3 hours. Following a single oral dose of belumosudil 200 mg, mean absorption (% coefficient of variation) was 64% (17%).
Effect of Food
In healthy subjects, the administration of a single 200 mg dose of belumosudil with a high-fat and high-calorie meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) increased belumosudil Cmax to 2.2 times that following fasted administration and AUC to 2 times that following fasted administration. Median Tmax was delayed 0.5 hours.
The mean steady-state AUC (% coefficient of variation) observed in patients with chronic GVHD receiving 200 mg once daily administered with food was 22700 (48%) h•ng/mL; mean steady-state Cmax was 2390 (44%) ng/mL. With once daily administration, steady-state concentrations of belumosudil were achieved with an accumulation ratio of 1.4.
Distribution
Pharmacokinetics were described by a two compartmental model with a distribution half-life of 1.8 h. Belumosudil volume of distribution of the central compartment (% coefficient of variation, CV) was 29.7 L (143%). In in vitro preparations, binding to human serum albumin was 99.9% and binding to human α1-acid glycoprotein was 98.6%.
Biotransformation
Based on in vitro assessment, CYP3A4 was the predominant CYP isoform responsible for the metabolism of belumosudil, although CYP2C8, CYP2D6 and UGT1A9 contributed to a lesser extent.
Elimination
Population PK modelling results in chronic GVHD patients showed that belumosudil elimination half-life (% coefficient of variation, CV) was 19.0 h (39%). Belumosudil clearance (% coefficient of variation, CV) was 9.83 L/h (46%).
The Human Mass Balance study results indicated that faecal excretion is the major route of excretion (85% of the dose). Of the dose recovered in faeces, 30% was parent belumosudil. Less than 5% of the dose was recovered in urine.
Linearity/non-linearity of dose
Exposure to belumosudil (Cmax and AUC) appears to be slightly greater than dose proportional over the 20 to 500 mg once daily dose range, but less than dose-proportional for doses above 500 mg in healthy subjects. In chronic GVHD subjects, the exposure increase between 200 and 400 mg is approximately proportional.
Special populations
No clinically relevant differences in belumosudil pharmacokinetics were observed with regard to age, race, sex, weight or renal impairment (mild or moderate; severe renal impairment has not been studied).
Hepatic impairment
In a single-dose hepatic impairment study, the exposure in subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment had exposure ≤1.5 times the exposure observed in normal subjects. Cmax was not changed significantly by mild and moderate hepatic impairment. In subjects with severe hepatic impairment (Child-Pugh C), the AUC of belumosudil increased 4.21-fold while there was no apparent effect on its Cmax (1.32-fold increase), relative to subjects with normal liver function.
Carcinogenicity studies have not been conducted with belumosudil.
Belumosudil was not mutagenic in an in vitro bacterial mutagenicity (Ames) assay. Belumosudil was not clastogenic in either an in vitro chromosome aberration assay in mammalian (CHO) cells or an in vivo mouse bone marrow micronucleus assay.
In a female rat fertility study, belumosudil was administered to female rats 14 days prior to mating and up to gestation day 7. Belumosudil had no effect on fertility or reproductive function of female rats at doses of 50, 150 or 275 mg/kg/day. However, in female rats at a dose of 275 mg/kg/day resulted in maternal toxicity and increased post-implantation loss/resorptions and decrease in the number of viable foetuses. The exposure (AUC) at the dose of 275 mg/kg/day is approximately 9.4 times the clinical exposure (AUC) at the maximum recommended dose of 200 mg daily.
In a male rat fertility study, belumosudil was administered to male rats 70 days prior to and throughout mating to non-treated female rats. Belumosudil had no effects on fertility or reproductive function in male rats at doses of 50 and 150 mg/kg/day. However, a dose of 275 mg/kg/day resulted in generalized toxicity, reduced male fertility, abnormal sperm findings (reduced motility, reduced concentration and increased percentage of abnormal sperm), and testes/epididymis organ changes. The exposure (AUC) at the dose of 275 mg/kg/day is approximately 8.6 times the clinical exposure at the maximum recommended dose of 200 mg daily.
Adverse changes in male and female reproductive organs also occurred in general toxicology studies; findings included spermatozoa degeneration at a belumosudil dose of 35 mg/kg/day in dogs and decreased follicular development in ovaries at 275 mg/kg/day in rats. Changes were partially or fully reversed during the recovery period. The exposure (AUC) at the doses of 35 mg/kg/day in dogs, and 275 mg/kg/day in rats is 0.5 times and 8-9 times, respectively, the clinical exposure at the recommended dose of 200 mg daily.
In pregnant rats, oral administration of belumosudil during the period of organogenesis resulted in maternal toxicity (reduced body weight gain and low food consumption) at doses ≥ 50 mg/kg/day. Foetal effects included decreased foetal weight at ≥ 150 mg/kg/day (approximately 3.9 times the human exposure at the recommended dose based on AUC).
In pregnant rabbits, oral administration of belumosudil during the peroid of organogenesis resulted in maternal toxicity (body weight loss, reduced body weight gain, low food consumption and mortality) at doses ≥ 125 mg/kg/day. Foetal effects included abortions, increased post-implantation loss, decreased percentage of live foetuses, decreased foetal body weight, and skeletal/external malformations in foetuses at doses ≥ 50 mg/kg/day (approximately 0.07 times the human exposure at the recommended dose based on AUC).
Tablet core
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