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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)

The name of this medicine is Tadoxel. Its common name is docetaxel. Docetaxel is a substance derived from the needles of yew trees. Docetaxel belongs to the group of anti-cancer medicines called toxoids.

 

Tadoxel has been prescribed by your doctor for the treatment of breast cancer, special forms of lung cancer (non-small cell lung cancer), prostate cancer, gastric cancer or head and neck cancer:

-                For the treatment of advanced breast cancer, Tadoxel could be administered either alone or in combination with doxorubicin, or trastuzumab, or capecitabine.

-                For the treatment of early breast cancer with or without lymph node involvement, Tadoxel could be administered in combination with doxorubicin and cyclophosphamide.

-                For the treatment of lung cancer, Tadoxel could be administered either alone or in combination with cisplatin.

-                For the treatment of prostate cancer, Tadoxel is administered in combination with prednisone or prednisolone.

-                For the treatment of metastatic gastric cancer, Tadoxel is administered in combination with cisplatin and 5-fluorouracil.

-                For the treatment of head and neck cancer, Tadoxel is administered in combination with cisplatin and 5-fluorouracil.


-                if you are allergic (hypersensitive) to docetaxel or any of the other ingredients of Tadoxel (listed in section 6).

-                if the number of white blood cells is too low.

-                if you have a severe liver disease.

 

Warnings and precautions

Before each treatment with Tadoxel, you will have blood tests to check that you have enough blood cells and sufficient liver function to receive Tadoxel. In case of white blood cells disturbances, you may experience associated fever or infections.

 

Tell your doctor, pharmacist or nurse immediately if you have abdominal pain or tenderness, diarrhoea, rectal haemorrhage, blood in stool or fever. These symptoms may be the first signs of a serious gastrointestinal toxicity, which could be fatal. Your doctor should address them immediately.

 

Tell your doctor, pharmacist or nurse if you have vision problems. In case of vision problems, in particular blurred vision, you should immediately have your eyes and vision examined.

 

Tell your doctor, pharmacist or nurse if you have experienced an allergic reaction to previous paclitaxel therapy.

 

Tell your doctor, pharmacist or nurse if you have heart problems.

 

If you develop acute or worsening problems with your lungs (fever, shortness of breath or cough), please tell your doctor, pharmacist or nurse immediately. Your doctor may stop your treatment immediately.

 

You will be asked to take premedication consisting of an oral corticosteroid such as dexamethasone, one day prior to Tadoxel administration and to continue for one or two days after it in order to minimise certain undesirable effects which may occur after the infusion of Tadoxel in particular allergic reactions and fluid retention (swelling of the hands, feet, legs or weight gain).

 

During treatment, you may be given other medicines to maintain the number of your blood cells.

 

Severe skin problems such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel:

-                SJS/TEN symptoms may include blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet) with or without a rash. You may also have flu-like symptoms at the same time, such as fever, chills or aching muscles.

-                AGEP symptoms may include a red, scaly widespread rash with bumps under the swollen skin (including your skin folds, trunk, and upper extremities) and blisters accompanied by fever.

If you develop severe skin reactions or any of the reactions listed above, immediately contact your doctor or healthcare professional.

 

Tadoxel contains alcohol. Discuss with your doctor if you suffer from alcohol dependency, epilepsy or liver impairment. See also section “Tadoxel contains ethanol (alcohol)” below.

 

Special care will be taken with Tadoxel if you have severe fluid retention in your heart, lungs or stomach. Your doctor will check for this.

 

Other medicines and Tadoxel

It is not advisable to use any medical treatment without telling your doctor as there may be interactions between Tadoxel and other medicines. Caution should be exercised when taking Tadoxel in combination with medicines such as ciclosporin, ketoconazole and erythromycin since there is a potential for significant interactions. An increase in side effects can occur if Tadoxel is used in combination with medicines such as ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole (known as strong CYP3A4 inhibitors). Please tell your doctor or pharmacist if you are taking or have recently taken any other medicine, including medicines obtained without a prescription. This is because Tadoxel or the other medicine may not work as well as expected and you may be more likely to get a side effect.

 

The amount of alcohol in this medicinal product may alter the effects of other medicines.

 

Pregnancy, breast-feeding and fertility

Ask your doctor for advice before being given any medicine.

 

Tadoxel must NOT be administered if you are pregnant unless clearly indicated by your doctor.

 

You must not become pregnant during treatment with this medicine and must use an effective method of contraception during therapy, because Tadoxel may be harmful for the unborn baby. If pregnancy occurs during your treatment, you must immediately inform your doctor.

 

You must not breast-feed while you are treated with Tadoxel.

 

If you are a man being treated with Tadoxel you are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment because docetaxel may alter male fertility.

 

Driving and using machines

The amount of alcohol in this medicinal product may impair your ability to drive or use machines. You may experience side effects of this medicine that may impair your ability to drive, use tools or operate machines (see section 4 Possible side effects). If this happens, do not drive or use any tools or machines before discussing with your doctor, nurse or pharmacist.

 

Tadoxel contains ethanol (alcohol)

 

20 mg/2 ml vial

This medicinal product contains 23 vol % ethanol anhydrous (alcohol), i.e. 363 mg per vial, equivalent to 9 ml beer or 4 ml wine.

 

80 mg/8 ml vial

This medicinal product contains 23 vol % ethanol anhydrous (alcohol), i.e. 1452 mg per vial, equivalent to 37 ml beer or 15 ml wine.

 

160 mg/16 ml vial

This medicinal product contains 23 vol % ethanol anhydrous (alcohol), i.e. 2904 mg per vial, equivalent to 74 ml beer or 31 ml wine.

 

Harmful for those suffering from alcoholism.

 

To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

 

The amount of alcohol in this medicinal product may have effects on the central nervous system (the part of the nervous system that includes the brain and spinal cord).


Tadoxel will be administered to you by a healthcare professional.

 

Usual dose

The dose will depend on your weight and your general condition. Your doctor will calculate your body surface area in metres squared (m2) and will determine the dose you should receive.

 

Method and route of administration

Tadoxel will be given by infusion into one of your veins (intravenous use). The infusion will last approximately one hour during which you will be in the hospital.

 

Frequency of administration

You should usually receive your infusion once every 3 weeks.

 

Your doctor may change the dose and frequency of dosing depending on your blood tests, your general condition and your response to Tadoxel. In particular, please inform your doctor in case of diarrhoea, sores in the mouth, feeling of numbness or pins and needles, fever and give her/him the results of your blood tests. Such information will allow her/him to decide whether a dose reduction is needed. If you have any further questions on the use of this medicine, ask your doctor, or pharmacist.

 

If you are given more Tadoxel than you should

As this medicine is given in a hospital, it is unlikely that you will be given too little or too much, however tell your doctor if you have any concerns.


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

Your doctor will discuss these with you and will explain the potential risks and benefits of your treatment.

The most commonly reported adverse reactions of Tadoxel alone are: decrease in the number of red blood cells or white blood cells, alopecia (hair loss), nausea, vomiting, sores in the mouth, diarrhoea and tiredness.

The severity of adverse events of Tadoxel may be increased when Tadoxel is given in combination with other chemotherapeutic agents. 

 

During the infusion at the hospital the following allergic reactions may occur (may affect more than 1 in 10 people):

·       flushing, skin reactions, itching

·       chest tightness; difficulty in breathing

·       fever or chills

·       back pain

·       low blood pressure

More severe reactions may occur.

If you had an allergic reaction to paclitaxel, you may also experience an allergic reaction to docetaxel, which may be more severe.

The hospital staff will monitor your condition closely during treatment. Tell them immediately if you notice any of these effects.

Between infusions of Tadoxel the following may occur, and the frequency may vary with the combinations of medicines that are received:

 

Very common: may affect more than 1 in 10 people

·             infections, decrease in the number of red (anaemia) or white blood cells (which are important in fighting infection) and platelets

·             fever: if this happens you must tell your doctor immediately

·             allergic reactions as described above

·             loss of appetite (anorexia)

·             insomnia (inability to sleep)

·             feeling of numbness or pins and needles or pain in the joints or muscles

·             chest pain

·             headache

·             alteration in sense of taste

·             inflammation of the eye or increased tearing of the eyes

·             swelling caused by faulty lymphatic drainage

·             shortness of breath

·             nasal drainage; inflammation of the throat and nose; cough

·             bleeding from the nose

·             sores in the mouth

·             stomach upsets including nausea, vomiting and diarrhoea, constipation

·             abdominal pain

·             indigestion

·             hair loss: in most cases normal hair growth should return; in some cases (frequency not known) permanent hair loss has been observed

·             redness and swelling of the palms of your hands or soles of your feet which may cause your skin to peel (this may also occur on the arms, face or body)

·             change in the colour of your nails, which may detach

·             muscle aches and pains; back pain or bone pain

·             change or absence of menstrual period

·             swelling of the hands, feet, legs

·             tiredness or flu-like symptoms

·             weight gain or loss

·             infection of the upper respiratory tract

Common: may affect up to 1 in 10 people

·             oral candidiasis (fungal infection in the mouth)

·             dehydration

·             dizziness

·             hearing impaired

·             decrease in blood pressure; irregular or rapid heart beat

·             heart failure

·             oesophagitis

·             dry mouth

·             difficulty or painful swallowing

·             haemorrhage

·             raised liver enzymes (hence the need for regular blood tests)

·             rises in blood sugar levels (diabetes)

·             decrease of the potassium, calcium and/or phosphate in your blood

 

Uncommon: may affect up to 1 in 100 people

·             fainting

·             at the injection site, skin reactions, phlebitis (inflammation of the vein) or swelling

·             blood clots

·             acute myeloid leukaemia and myelodysplastic syndrome (types of blood cancer) may occur in patients who are treated with docetaxel together with certain other anticancer treatments

 

Rare: may affect up to 1 in 1,000 people

·             inflammation of the colon, small intestine, which could be fatal (frequency not known); intestinal perforation

·             inflammation and /or fluid on the lungs which may cause you to cough, with or without frothy phlegm; severe cases of lung fibrosis that are sometimes fatal have occurred

·             intestinal blockage causing abdominal pain

·             skin redness at the site of previous radiation therapy

 

Very rare: may affect up to 1 in 10,000 people

·             temporary visual disturbances, e.g. flashes, flashing lights, reduced vision

·             inflammation of the liver

·             skin redness and/or blisters or thickened hard skin

 

Not known: frequency cannot be estimated from the available data

·             problems with your kidneys/decreased kidney function (your doctor will check this)

·             interstitial lung disease (inflammation of the lungs causing coughing and difficulty breathing; inflammation of the lungs can also develop when docetaxel therapy is used with radiotherapy)

·             pneumonia (infection of the lungs)

·             pulmonary fibrosis (scarring and thickening in the lungs with shortness of breath)

·             blurred vision due to swelling of the retina within the eye (cystoid macular oedema)

·             decrease of the sodium and/or magnesium in your blood (electrolyte balance disorders)

·             ventricular arrhythmia or ventricular tachycardia (manifested as irregular and/or rapid heartbeat, severe shortness of breath, dizziness, and/or fainting); some of these symptoms can be serious; if this happens, you must tell your doctor immediately

·             Injection site reactions at the site of a previous reaction.

·             non-Hodgkin lymphoma (a cancer affecting the immune system) and other cancers may occur in patients who are treated with docetaxel together with certain other anticancer treatments

·             Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) (blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet) with or without a rash. You may also have flu-like symptoms at the same time, such as fever, chills or aching muscles.)

·             Acute Generalized Exanthematous Pustulosis (AGEP) (red, scaly widespread rash with bumps under the swollen skin (including your skin folds, trunk, and upper extremities) and blisters accompanied by fever)

 

If any of the side effects gets serious, or if you notice any side effects not mentioned in this leaflet, please inform your doctor.

 


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 label (EXP). The expiry date refers to the last day of that month.

Store below 25ºC.

Store in the original package in order to protect from light.

Use the vial immediately after its opening. If not used immediately, in-use storage times and conditions are the responsibility of the user.

After dilution in 0.9% sodium chloride or 5% glucose, chemical and physical in-use stability has been demonstrated for 4 hours when stored below 25ºC.

From a microbiological point of view, the infusion preparation should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2ºC to 8ºC unless dilution has taken place in controlled and validated aseptic conditions.

Docetaxel infusion solution is supersaturated, therefore may crystallise over time. If crystals appear, the solution must no longer be used and shall be discarded.

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

 


-      The active substance is docetaxel. Each ml of concentrate for solution for infusion contains 10 mg of docetaxel.

-       The other ingredients are citric acid, ethanol anhydrous and Polysorbate 80.


Tadoxel is a clear colourless to pale yellow solution. The medicine comes in glass containers called vials. One ml of solution contains docetaxel 10 mg. One 2 ml vial contains 20 mg docetaxel, one 8 ml vial contains 80 mg docetaxel and one 16 ml vial contains 160 mg docetaxel. The vials may be wrapped in a protective plastic to reduce the risk of spillage if the vials break - these are referred to as ONCO-TAIN®. The vials are available in single packs. Not all pack sizes may be marketed.

  MS Pharma Saudi,

  Riyadh, Kingdome Saudi Arabia.

  info-ksa@mspharma.com

 

Manufacturer by:

 Jiangsu Hengrui Medicine Co,.Ltd- China for MS Pharma-Saudi.


Aug,2020 SPM190386
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

اسم هذا العقار هو تادوكسيل. والاسم الشائع هو دوسيتاكسيل. دوسيتاكسيل هي مادة مشتقة من أوراق شجر الطقسوس. وينتمي عقار دوسيتاكسيل لمجموعة الادوية المضادة للسرطان التي تسمى توكسويد.

ويصف الطبيب عقار تادوكسيل لعلاج سرطان الثدي، والأنواع الأخرى من السرطان (سرطان الرئة ذي الخلايا غير الصغيرة) وسرطان البروستاتا وسرطان المعدة أو سرطان الرأس والعنق.

-          لغرض علاج سرطان الثدي المتقدم، يمكن تناول عقار تادوكسيل إما منفرداً أو بالتزامن مع عقار دوكسوروبيسين أو تراستوزوماب أو كابسيتابين.

-          لغرض علاج حالات سرطان الثدي المبكر مع او بدون تأثير على العقد الليمفاوية ويمكن تناول تادوكسيل مع دُوكسُورُوبِيسِين وسيكلوفوسفاميد.

-          ولعلاج سرطان الرئة، يمكن تناول عقار تادوكسيل إما منفرداً أو مع سيسبلاتين.

-          لعلاج سرطان البروستاتا، يمكن تناول عقار تادوكسيل مع عقار بريدنيزون أو بريدنيزولون.

-          ولعلاج سرطان نقائل المعدة، يمكن تناول عقار تادوكسيل مع سيسبلاتين و5- فلورويوراسيل.

-          لعلاج سرطان الرأس والعنق. يتم تناول عقار تادوكسيل مع فلورويوراسيل.

-          إذا كنت تعاني من الحساسية (الحساسية المفرطة) ضد عقار دوسيتاكسيل أو أي مكونات أخرى بعقار تادوكسيل (المذكورة في الفقرة 6).

-          إذا كان عدد كرات الدم البيضاء قليلة جداً.

-          إذا كان لديك مرض كبدي حاد.

 

التحذيرات والإحتياطات

قبل كل علاج بعقار تادوكسيل، عليك اجراء اختبارات الدم للتأكد من كفاية كرات الدم وكفاءة وظائف الكبد لتناول تادوكسيل. وفي حالة وجود اضطرابات بكرات الدم البيضاء، فإنك قد تعاني من الحمى المصاحبة او العدوى.

أخبر طبيبك أو الصيدلي أو الممرض فوراً إذا شعرت بآلام في المعدة أو آلام أو إسهال أو نزيف بالمستقيم أو دم في البراز أو ارتفاع درجة الحرارة. وقد تكون هذه الأعراض أول علامات السمية الخطيرة بالجهاز الهضمي، والتي يمكن أن تؤدي إلى الوفاة. يجب على طبيبك معالجتها فوراً.

أخبر طبيبك أو الصيدلي أو الممرض إذا كان لديك مشاكل بالرؤية. في حالة المشاكل بالرؤية، وخاصة عدم وضوح الرؤية، عليك فوراً فحص عينك والرؤية.

أخبر طبيبك أو الصيدلي أو الممرض إذا واجهت تفاعل ردة فعل تحسسية لعلاج سابق بعقار باكليتاكسيل.

أخبر طبيبك أو الصيدلي أو الممرض إذا كنت تعاني من مشاكل بالقلب.

إذا كنت تعاني من تطور حاد أو مشاكل متفاقمة برئتيك (حمى أو ضيق في التنفس أو كحة)، يرجى اخبار طبيبك أو الصيدلي أو الممرض فوراً. سيوقف طبيبك عن علاجك فوراً.

سيُطلب منك أخذ التخدير الذي يتكون من الكورتيكوستيرويدات عن طريق الفم مثل ديكساميثازون، قبل يوم واحد من تناول عقار تادوكسيل ليستمر ليوم أو يومين بعد ذلك من أجل تقليل بعض الأثار الضارة التي قد تحدث بعد الحقن الوريدي لعقار تادوكسيل وخاصة تفاعلات الحساسية واحتباس السوائل (تورم اليدين أو القدمين أو الأرجل أو زيادة الوزن).

أثناء العلاج، يمكن إعطاؤك أدوية أخرى للإبقاء على كرات الدم في جسمك.

يتم الإبلاغ عن مشاكل الجلد الحادة مثل مُتَلاَزِمَةُ ستيفنز-جونسون وانحلال البشرة السمي والبثور الطفيلي المتعمم الحاد مع تعاطي عقار الدوسيتاكسل:

-          قد تتضمن أعراض مُتَلاَزِمَةُ ستيفنز-جونسون وانحلال البشرة السمي على تقرح أو تقشير أو نزيف في أي جزء من جلدك (بما في ذلك شفتيك أو عيونك أو أو الفم أو الأنف أو الأعضاء التناسلية أو اليدين أو القدمين) مع أو بدون حكة. وقد تصاب بأعراض مشابهة للأنفلونزا في نفس الوقت مثل ارتفاع درجة الحرارة أو القشعريرة أو آلام العضلات.

-          وقد يتضمن البثور الطفيلي المتعمم الحاد على احمرار وطفح جلدي وتقشر منتشر مع تحاديب تحت تورم البشرة (وتشمل تجاعيد البشرة وجزع الجسم والأطراف العلوية) وتصاحب البثور حمى.

-          إذا تطورت تفاعلات البشرة الحادة أو أي تفاعلات مذكورة أعلاه، يرجى التواصل فوراً مع طبيبك أو متخصص الرعاية الصحية الخاص بك.

-          يحتوي عقار تادوكسيل على الكحول. لذا تحدث إلى طبيبك إذا كنت تعاني من الاعتماد على الكحول أو الصرع أو قصور حاد في وظائف الكبد. أنظر أيضاً الفقرة "احتواء عقار تادوكسيل على الإيثانول (الكحول) أدناه.

-          يتطلب أخذ العناية الخاصة مع عقار تادوكسيل إذا كنت تعاني من احتباس سوائل في القلب أو الرئة أو المعدة. سيفحص طبيبك ذلك.

أدوية أخرى مع تادوكسيل

لا يمكن استخدام العلاج الدوائي بدون اخبار طبيبك حيث أنه من المحتمل وجود تفاعلات بين عقار تادوكسيل وأدوية أخرى. وينبغي توخي الحذر عند تعاطي تادوكسيل مع أدوية أخرى مثل سيكلوسبورين والكيتوكونازول والاريثروميسين لأنه من المحتمل حدوث تفاعلات كبيرة. ويمكن حدوث تأثيرات جانبية إذا أستخدم تادوكسيل مع أدوية مثل الكيتوكونازول وإيتراكونازول وكلاريثروميسين وإندينافير ونيفازودون ونلفينافير وريتونافير وساكوينافير وتيليثروميسين وفوريكونازول (المعروفة بمثبطات سيتوكروم 3اي4 القوية). يرجى إخبار طبيبك أو الصيدلي إذا كنت تتناول أو تناولت مؤخراً أي أدوية أخرى، بما في ذلك الأدوية التي حصلت عليها بدون وصفة الطبيب. وذلك لأن عقار تادوكسيل أو الادوية الأخرى لن تعمل بالشكل المتوقع ويمكن ان يحدث لك تأثيرات جانبية.

قد تغير كمية الكحول في منتج الدواء من تأثيرات الادوية الأخرى.

الحمل والرضاعة والخصوبة

اسال طبيبك للاستشارة قبل إعطاؤك أي ادوية

يجب عدم تناول تادوكسيل إذا كنتي حامل ما لم يحدد الطبيب خلاف ذلك بوضوح.

يجب عدم خضوعك للحمل أثناء العلاج بهذا الدواء ويجب استخدام الطريقة الفعالة لمنع الحمل أثناء العلاج، لأن عقار تادوكسيل قد يضر بالجنين. وإذا حدث حمل أثناء فترة العلاج يجب إخبار الطبيب فوراً.

يجب عليكِ عدم الإرضاع خلال مدة علاجك بعقار تادوكسيل.

وإذا كانت ذكر وتتعاطى عقار تادوكسيل ينصح بعدم التفكير بالإنجاب خلال مدة تصل إلى 6 أشهر بعد العلاج وعليك طلب الاستشارة لحفظ الحيوانات المنوية قبل العلاج لأن عقار دوسيتاكسيل يمكن أن يغير خصوبة الذكور.

القيادة واستخدام الماكينات

قد تؤثر كمية الكحول في هذا الدواء على قدرتك على القيادة أو استخدام الماكينات. وقد تواجه أثار جانبية بهذا الدواء تؤثر بشكل سلبي على قدرتك على القيادة أو استخدام الأدوات او تشغيل الماكينات (أنظر الفقرة 4 الأثار الجانبية المحتملة). وإذا حدث ذلك، لا تقود السيارات أو تستخدم الأدوات أو الماكينات قبل التحدث مع طبيبك أو الممرض أو الصيدلي الخاص بك.

يحتوي عقار تادوكسيل على الإيثانول (الكحول)

عبوة بمقدار 20 ملغم / 1 مل

هذا الدواء يحتوي على 23 % حجم من الإيثانول اللامائي (الكحول)، أي 363 ملغم لكل عبوة.

بما يساوي 9 ملم بيرة أو 4 ملم من النبيذ.

عبوة بمقدار 80 ملغم / 8 مل

هذا الدواء يحتوي على 23 % ملغم من الإيثانول اللامائي (الكحول)، أي 1452 ملغم لكل عبوة، بما يساوي 37 مل بيرة أو 15 مل من النبيذ.

عبوة بمقدار 160 ملغم / 16 مل

هذا الدواء يحتوي على 23 % حجم من الإيثانول اللامائي (الكحول)، أي 2904 مل لكل عبوة، بما يساوي 74 ملم أو 31 مل من النبيذ.

مضر لمن يعانون من إدمان الكحول.

ينبغي مراعاة الحوامل والمرأة المرضعة والأطفال والفئات المعرضة لمخاطر كبيرة مثل مرضى امراض الكبد أو الصرع.

ويمكن ان تؤثر كمية الكحول في هذا الدواء على الجهاز العصبي المركزي (الجزء من الجهاز العصبي الذي يحتوي على المخ والحبل الشوكي).

https://localhost:44358/Dashboard

يتم إعطاؤك عقار تادوكسيل بواسطة متخصص الرعاية الصحية.

 

الجرعة الاعتيادية

ستعتمد الجرعة على وزنك وحالتك العامة. وسيحسب طبيبك مساحة سطح الجسم بالمتر المربع وسيحدد الجرعة التي عليك تناولها.

طريقة التعاطي

سيتم إعطاء عقار تادوكسيل عن طريق الحقن في أحد الأوردة (عن طريق الحقن الوريدي). ويستمر الحقن لمدة ساعة واحدة تقريباً ستكون خلالها في المستشفى.

تكرار الجرعة

عليك أخذ الحقنة مرة واحدة كل 3 أسابيع.

يمكن لطبيبك تغيير الجرعة وتكرار الجرعة حسب تحاليل الدم والحالة العامة لجسمك واستجابتك لعقار تادوكسيل. وعلى وجه الخصوص، يرجى اخبار طبيبك في حالة الإسهال ووجود تقرحات في الفم والشعور بالتنميل أو الوخز والحقن وارتفاع درجة الحرارة وعليك اعطاؤه نتائج تحاليل الدم الخاصة بك. وستسمح له هذه المعلومات بتحديد ما إذا كان هناك حاجة لتخفيض الجرعة أم لا. وإذا كان لديك أي استفسارات إضافية حول استخدام هذا العقار، أسأل طبيبك أو الصيدلي الخاص بك.

إذا تم إعطاؤك جرعة كبيرة من عقار تادوكسيل أكثر من المقرر

بما انه يتم إعطاء العقار في المستشفى، من غير المرجح ان يتم إعطاؤك جرعة أكبر أو أقل، وبصرف النظر عن ذلك، عليك إخبار طبيبك إذا تعرضت لأي متاعب.

 

مثل كل الادوية، يمكن أن يسبب هذا العقار آثار جانبية، على الرغم من انها لا تصيب الجميع.

سيناقش طبيبك ذلك معكم وسيشرح المخاطر المحتملة ومزايا علاجكم.

من التفاعلات المعاكسة والأكثر شيوعًا الناجمة عن تناول عقار تادوكسيل هي: الانخفاض في عدد كرات الدم الحمراء أو كرات الدم البيضاء والصلع والغثيان والقيئ والتقرحات في الفم والإسهال والإعياء.

ويمكن أن تزداد حدة الأحداث العكسية لعقار تادوكسيل عندما يتم تناول عقار تادوكسيل مع عوامل العلاج الكيميائي.

وأثناء الحقن الوريدي في المستشفى، قد تحدث تفاعلات الحساسية التالية (قد تؤثر على نسبة تزيد على 1 لكل 10 أشخاص):

·        احمرار وتفاعلات الجلد والتنميل.

·        ضيق الصدر وصعوبة في التنفس.

·        ارتفاع درجة الحرارة أو البرودة

·        آلام الظهر

·        انخفاض ضغط الدم

يمكن ان تحدث تفاعلات أكثر حدة

إذا أصبت بتفاعلات حساسية ضد باكليتاكسيل، قد تواجه أيضاً تفاعل حساسية ضد دوسيتاكسل، التي قد تكون أكثر حدة.

سيراقب موظفي المستشفى حالتك بدقة أثناء العلاج. أخبرهم فوراً إذا لاحظت أي من هذه التأثيرات.

قد يحدث ما يلي في الفترات بين الحقن، ويمكن تغيير معدل تكرار الجرعة في حالة إضافة الأدوية التي حصل عليها:

شائعة جداً: قد تصيب نسبة تزيد على 1 من بين كل 10 أشخاص

·        إصابات، انخفاض في عدد كرات الدم الحمراء أو البيضاء (التي تعتبر مهمة في مقاومة العدوى) والصفائح الدموية.

·        ارتفاع درجة الحرارة: إذا حدث ذلك يجب إخبار الطبيب فوراً.

·        تفاعلات الحساسية على النحو الموضح أعلاه.

·        فقدان الشهية (فقدان الشهية).

·        الأرق (عدم القدرة على النوم).

·        الشعور بالتنميل أو وخز أو الام في المفاصل أو العضلات.

·        آلام الصدر

·        الصداع

·        تغيير في حاسة التذوق

·        التهاب العين أو زيادة تدمع العين.

·        التورم الناجم عن اضطراب التصريف الليمفاوي

·        ضيق التنفس

·        تصريف الانف: التهاب الحلق والأنف، كحة

·        نزيف من الأنف

·        تقرحات في الفم

·        تقلبات في المعدة تشمل الغثيان والتقيؤ والإسهال والإمساك.

·        مغص في البطن

·        عسر الهضم

·        تساقط الشعر: في معظم الحالات العادية سيعود نمو الشعر، وفي بعض الحالات (معدل تكرارها غير معروف) يلاحظ استمرار تساقط الشعر.

·        احمرار وتورم راحة اليدين أو باطن القدم التي قد تسبب تقشر البشرة (قد يحدث ذلك للأذرع أو الوجه أو الجسم).

·        التغيير في لون الأظافر التي قد تنفصل.

·        آلام في العضلات والام في الظهر وآلام العظام

·        تغيير أو تأخر الدورة الشهرية

·        تورم اليدين والقدم والساقين

·        الإعياء أو الأعراض المشابهة للأنفلونزا

·        زيادة أو فقدان الوزن

·        التهابات الجهاز التنفسي العلوي.

شائعة: قد تصيب نسبة تصل إلى 1 من بين كل 10 أشخاص

·        المبيضات الفموية (التهابات فطرية بالفم)

·        الجفاف

·        الدوخة

·        ضعف السمع

·        انخفاض ضغط الدم وعدم انتظام أو سرعة ضربات القلب.

·        السكتة القلبية

·        التهابات المريء

·        جفاف الفم

·        صعوبة أو الام في البلع

·        نزيف

·        ارتفاع أنزيمات الكبد (لذا يجب اجراء تحاليل دم بشكل دوري)

·        ارتفاع مستويات السكر في الدم (داء السكري)

·        انخفاض البوتاسيوم والكالسيوم و / أو الفوسفات في الدم.

غير شائعة: قد تصيب نسبة تصل إلى 1 من بين كل 100 شخص

·        الإغماء

·        تفاعلات الجلد في موضع الحقن أو الالتهاب الوريدي او تجلط الدم

·        جلطات الدم

·        ابيضاض الدم النخاعي الحاد ومتلازمة خلل النسيج النخاعي (من أنواع سرطان الدم) قد تحدث لدى المرضى الذين يتعاطوا عقار دوسيتاكسيل جنباً إلى جنب مع علاجات أخرى مضادة للسرطان.

 

نادراً: قد تصيب نسبة تصل إلى شخص واحد لكل 1000 شخص

·        التهاب القولون والأمعاء الدقيقة والتي قد تؤدي إلى الوفاة (النسبة غير معلومة)، وانثقاب الأمعاء

·        التهاب و / أو وجود سوائل على الرئتين التي قد تسبب كحة، مع او بدون بلغم مزبد والحالات الحادة لتليف الكبد التي قد تسبب الوفاة في بعض الأحيان.

·        إنسداد الأمعاء الذي يسبب آلام في المعدة

·        احمرار البشرة في موضع علاج إشعاعي سابق.

نادرة جداً: قد تصيب نسبة تصل إلى من واحد إلى 10,000 شخص

·        اضطرابات بصرية مؤقتة أي زغللة بالعين وزغللة الإضاءات وانخفاض الرؤية

·        التهاب بالكبد

·        احمرار البشرة و / او البثور أو تورم البشرة.

غير معروفة: لا يمكن تقدير تكرارها من البيانات المتاحة

·        اضطرابات بكليتيك / انخفاض بوظائف الكلى (سيفحص طبيبك ذلك).

·        المرض الرئوي الخلالي (التهابات بالرئتين تسبب كحة وصعوبة في التنفس، ويمكن ان تتطور أيضاً التهابات الرئتين عن العلاج بعقار دوسيتاكسيل مع العلاج الإشعاعي).

·        نزلة صدرية (التهابات الرئتين).

·        التليف الرؤي (تندب وسماكة في الرئتين مع قصور في التنفس)

·        عدم وضوح الرؤية بسبب تورم شبكية العين (وذمة البقعة الصفراء كيساني).

·        انخفاض الصوديوم و / أو المغنيسيوم في دمك (اضطرابات التوازن الكهربائي).

·        عدم انتظام ضربات القلب البطيني أو عدم انتظام دقات القلب البطيني (تبدوا أنها غير منتظمة و / أو سرعة ضربات القلب وضيق حاد في التنفس والدوخة و / أو الإغماء)، ويمكن أن تكون بعض هذه الأعراض خطيرة، وإذا حدث ذلك، عليك التحدث إلى الطبيب فوراً.

·        تفاعلات بموضع الحقن في مكان التفاعل السابق.

·        اللمفومة اللاهودجكينية (سرطان يصيب الجهاز المناعي) وسرطانات أخرى قد تحدث لدى المرضى الذين يتعاطوا عقار دوسيتاكسيل جنباً إلى جنب مع بعض العلاجات المقاومة للسرطان الأخرى.

·        متلازمة ستيفنز-جونسون  وانحلال البشرة السمي (التقرح أو التقشير أو نزيف في أي جزء من الجلد (منها شفتيك او العينين أو الفم أو الانف أو الأعضاء التناسلية أو اليدين أو القدمين) مع أو بدون طفح جلدي. وقد تصاب أيضاً بأعراض تشبه الانفلونزا في نفس الوقت، مثل ارتفاع درجة الحرارة أو البرد أو آلام العضلات.)

·        البثور الطفيلي المتعمم الحاد (احمرار وطفح جلدي متوسع مع رضوض تحت الجلد المتورم (بما في ذلك تجاعيد البشرة والجزع والأطراف العلوية) البثور المصاحب لارتفاع درجة الحرارة).

في حالة ارتفاع خطورة من هذه الأعراض الجانبية أو إذا لاحظت أي أثار جانبية غير مذكورة في هذه النشرة، يرجى إخبار الطبيب.

يحفظ هذا الدواء بعيد عن أشعة الشمس وبعيدا عن متناول الأطفال.

عدم استخدام هذا الدواء بعد تاريخ انتهاء الصلاحية المذكور في العلبة أو الملصق، يشير تاريخ انتهاء الصلاحية إلى اليوم الأخير من ذلك الشهر.

يتم التخزين في درجة حرارة أقل من 25 درجة مئوية.

يحفظ الدواء في العبوة الأصلية لحمايته من أشعة الشمس.

استخدام زجاجة فوراً بعد الفتح. وإذا لم يتم استخدامه فوراً، ويتحمل المستخدم المسؤولية عن مرات وظروف التخزين أثناء الاستخدام.

ثبت الاستقرار الكيميائي والفيزيائي أثناء الاستخدام لمدة 4 ساعات عند التخزين في درجة حرارة أقل من 25 درجة مئوية بعد التخفيف بنسبة 0.9% من كلوريد الصوديوم أو 5% من الجلوكوز.

من الناحية الميكروبيولوجية، يجب استخدام مستحضر الحقن فوراً. وإذا لم يستخدم فوراً، يتحمل المستخدم المسؤولية عن مرات التخزين أثناء الاستخدام والظروف قبل الاستخدام ولا تظل أكثر من 24 ساعة في درجة حرارة 2 درجة مئوية حتى 8 درجة مئوية ما لم يحدث تخفيف في الظروف تامة التعقيم الخاضعة للرقابة والمتحقق منها.

ويعتبر محلول حقن دوسيتاكسيل فائق التشبع لذلك قد يتبلور مع مرور الوقت. وإذا ظهرت البلورات، يجب عد استخدام المحلول ويجب التخلص من.

لا تلقي أي ادوية في مياه الصرف الصحي، اسأل الصيدلي عن كيفية التخلص من الأدوية الغير مستخدمة. ستساعد هذه التدابير على حماية البيئة.

-          المادة الفعالة هي دوسيتاكسيل. يحتوي كل مل من تركيز المحلول الخاص بالحقن على 20 ملغم من مادة دوسيتاكسيل.

-          المكونات الأخرى هي حمض الستريك والإيثانول اللامائي وبوليسوربات 80.

عقار تادوكسيل محلول ليس له لون ويميل إلى الأصفر الفاتح. العقار بداخل عبوات من الزجاج تسمى قوارير. يحتوي كل واحد مل من المحلول على 10 ملغم من عقار دوسيتاكسيل. وتحتوي القارورة سعة 2 مل على 20 ملغم من عقار دوسيتاكسيل، وتحتوي العبوة الواحدة 8 مل على 80 ملغم من عقار دوسيتاكسيل والقارورة بمقدار 16 مل تحتوي على 160 ملغم من عقار دوسيتاكسيل. ويمكن أن تكون القوارير ملفوفة في بلاستيك حماية لتقليل خطر الإنسكاب إذا انكسرت القوارير – وتسمى ONCO-TAIN. وتتوافر القوارير في عبوات فردية. وقد لا يتم تسويق جميع أحجام العبوات.

 

إم إس فارما السعودية

الرياض ، المملكة العربية السعودية .

    info-ksa@mspharma.com

 

صنعت بواسطة  

شركة جيانغسو هينجروي الطبية، المحدودة- الصين لصالح إم إس فارما – المملكة العربية السعودية .

أغسطس،2020 SPM190386
 Read this leaflet carefully before you start using this product as it contains important information for you

Tadoxel ® 10 mg/ml Concentrate for Solution for Infusion

1 ml concentrate for solution for infusion contains 10 mg docetaxel. 20 mg/2 ml vial One vial of 2 ml contains 20 mg docetaxel. 80 mg/8 ml vial One vial of 8 ml contains 80 mg docetaxel. For the full list of excipients, see section 6.1.

Concentrate for solution for infusion. The concentrate is a clear colourless to pale yellow solution.

Breast cancer

Tadoxel ® in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with:

• operable node-positive breast cancer

• operable node-negative breast cancer

For patients with operable node-negative breast cancer, adjuvant treatment should be restricted to patients eligible to receive chemotherapy according to internationally established criteria for primary therapy of early breast cancer (see section 5.1).

Tadoxel ® in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition.

Tadoxel ® monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent.

Tadoxel ® in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2 and who previously have not received chemotherapy for metastatic disease.

Tadoxel ® in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.

Non-small cell lung cancer

Tadoxel ® is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.

Tadoxel ® in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not previously received chemotherapy for this condition.

Prostate cancer

Tadoxel ® in combination with prednisone or prednisolone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

Tadoxel ® in combination with androgen-deprivation therapy (ADT), with or without prednisone or prednisolone, is indicated for the treatment of patients with metastatic hormone-sensitive prostate cancer.

Gastric adenocarcinoma

Tadoxel ® in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for metastatic disease.

Head and neck cancer

Tadoxel ® in combination with cisplatin and 5-fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck.


Tadoxel ® is for intravenous use only.

The use of docetaxel should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy (see section 6.6).

Posology

For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can be used (see section 4.4).

For metastatic castration-resistant prostate cancer, given the concurrent use of prednisone or prednisolone the recommended premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.4).

For metastatic hormone-sensitive prostate cancer, irrespective of the concurrent use of prednisone or prednisolone, the recommended premedication regimen is oral dexamethasone 8 mg 12 hours, 3 hours, and 1 hour before docetaxel infusion (see section 4.4).

Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities.

Docetaxel is administered as a 1-hour infusion every three weeks.

Breast cancer

In the adjuvant treatment of operable node-positive and node-negative breast cancer, the recommended dose of docetaxel is 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles (TAC regimen) (see also Dose adjustments during treatment).

For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose of docetaxel is 100 mg/m2 in monotherapy. In first-line treatment, docetaxel 75 mg/m2 is given in combination therapy with doxorubicin (50 mg/m2).

In combination with trastuzumab the recommended dose of docetaxel is 100 mg/m2 every three weeks, with trastuzumab administered weekly. In the pivotal study the initial docetaxel infusion was started the day following the first dose of trastuzumab. The subsequent docetaxel doses were administered immediately after completion of the trastuzumab infusion, if the preceding dose of trastuzumab was well tolerated. For trastuzumab dose and administration, see trastuzumab summary of product characteristics.

In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m2 every three weeks, combined with capecitabine at 1250 mg/m2 twice daily (within 30 minutes after a meal) for 2 weeks followed by a 1-week rest period. For capecitabine dose calculation according to body surface area, see capecitabine summary of product characteristics.

Non-small cell lung cancer

In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen is docetaxel 75 mg/m2 immediately followed by cisplatin 75 mg/m2 over 30-60 minutes. For treatment after failure of prior platinum-based chemotherapy, the recommended dose is 75 mg/m2 as a single agent.

Prostate cancer

Metastatic castration-resistant prostate cancer

The recommended dose of docetaxel is 75 mg/m2. Prednisone or prednisolone 5 mg orally twice daily is administered continuously (see section 5.1).

Metastatic hormone-sensitive prostate cancer

The recommended dose of docetaxel is 75 mg/m2 every 3 weeks for 6 cycles. Prednisone or prednisolone 5 mg orally twice daily may be administered continuously.

Gastric adenocarcinoma

The recommended dose of docetaxel is 75 mg/m2 as a 1-hour infusion, followed by cisplatin 75 mg/m2, as a 1- to 3-hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg/m2 per day given as a 24-hour continuous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration. Prophylactic G-CSF should be used to mitigate the risk of haematological toxicities (see also Dose adjustments during treatment).

Head and neck cancer

Patients must receive premedication with antiemetics and appropriate hydration (prior to and after cisplatin administration). Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities. All patients on the docetaxel-containing arm of the TAX 323 and TAX 324 studies, received prophylactic antibiotics.

• Induction chemotherapy followed by radiotherapy (TAX 323)

For the induction treatment of inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m2 as a 1-hour infusion followed by cisplatin 75 mg/m2 over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.

• Induction chemotherapy followed by chemoradiotherapy (TAX 324)

For the induction treatment of patients with locally advanced (technically unresectable, low probability of surgical cure, and aiming at organ preservation) squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m2 as a 1-hour intravenous infusion on day 1, followed by cisplatin 100 mg/madministered as a 30-minute to 3-hour infusion, followed by 5-fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.

For cisplatin and 5-fluorouracil dose modifications, see the corresponding summary of product characteristics.

Dose adjustments during treatment

General

Docetaxel should be administered when the neutrophil count is ≥1,500 cells/mm3.

In patients who experienced either febrile neutropenia, neutrophil count <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy, the dose of docetaxel should be reduced from 100 mg/m2 to 75 mg/m2 and/or from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.

Adjuvant therapy for breast cancer

Primary G-CSF prophylaxis should be considered in patients who receive docetaxel, doxorubicin and cyclophosphamide (TAC) adjuvant therapy for breast cancer. Patients who experience febrile neutropenia and/or neutropenic infection should have their docetaxel dose reduced to 60 mg/m2 in all subsequent cycles (see sections 4.4 and 4.8). Patients who experience Grade 3 or 4 stomatitis should have their dose decreased to 60 mg/m2.

In combination with cisplatin

For patients who are dosed initially at docetaxel 75 mg/m2 in combination with cisplatin and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, or in patients who experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the docetaxel dose in subsequent cycles should be reduced to 65 mg/m2. For cisplatin dose adjustments, see the corresponding summary of product characteristics.

In combination with capecitabine

• For capecitabine dose modifications, see capecitabine summary of product characteristics.

• For patients developing the first appearance of Grade 2 toxicity, which persists at the time of the next docetaxel/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume at 100% of the original dose.

• For patients developing the second appearance of Grade 2 toxicity, or the first appearance of Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0-1 and then resume treatment with docetaxel 55 mg/m2.

• For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the docetaxel dose.

For trastuzumab dose modifications, see trastuzumab summary of product characteristics.

In combination with cisplatin and 5-fluorouracil

If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the docetaxel dose should be reduced from 75 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m2. In case of Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m2. Patients should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist (see section 4.4).

Recommended dose modifications for toxicities in patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (5-FU):

Toxicity

Dose adjustment

Diarrhoea grade 3

First episode: reduce 5-FU dose by 20%.

Second episode: then reduce docetaxel dose by 20%.

Diarrhoea grade 4

First episode: reduce docetaxel and 5-FU doses by 20%.

Second episode: discontinue treatment.

Stomatitis/mucositis grade 3

First episode: reduce 5-FU dose by 20%.

Second episode: stop 5-FU only, at all subsequent cycles.

Third episode: reduce docetaxel dose by 20%.

Stomatitis/mucositis grade 4

First episode: stop 5-FU only, at all subsequent cycles.

Second episode: reduce docetaxel dose by 20%.

For cisplatin and 5-fluorouracil dose adjustments, see the corresponding summary of product characteristics.

In the pivotal SCCHN studies patients who experienced complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to provide prophylactic coverage (e.g. day 6-15) in all subsequent cycles.

Special populations

Patients with hepatic impairment

Based on pharmacokinetic data with docetaxel at 100 mg/m2 as single agent, patients who have both elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of docetaxel is 75 mg/m2 (see sections 4.4 and 5.2). For those patients with serum bilirubin >ULN and/or ALT and AST >3.5 times the ULN associated with alkaline phosphatase >6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST >1.5 times ULN associated with alkaline phosphatase >2.5 times ULN, and bilirubin >1 times ULN; for these patients, no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.

Paediatric population

The safety and efficacy of Tadoxel ® in nasopharyngeal carcinoma in children aged 1 month to less than 18 years have not yet been established.

There is no relevant use of Tadoxel ® in the paediatric population in the indications breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not including type II and III less differentiated nasopharyngeal carcinoma.

Older people

Based on a population pharmacokinetic analysis, there are no special instructions for use in older people.

In combination with capecitabine, for patients 60 years of age or more, a starting dose reduction of capecitabine to 75% is

recommended (see capecitabine summary of product characteristics).

Method of administration

For instructions on preparation and administration of the product, see section 6.6.


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Docetaxel must not be used in patients with baseline neutrophil count of <1,500 cells/mm3. Docetaxel must not be used in patients with severe liver impairment since there is no data available (see sections 4.2 and 4.4). Contraindications for other medicinal products also apply when combined with docetaxel.

 

For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. For prostate cancer, the premedication is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.2).

Haematology

Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a median of 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring of complete blood counts should be conducted on all patients receiving docetaxel. Patients should be retreated with docetaxel when neutrophils recover to a level of ≥1,500 cells/mm3 (see section 4.2).

In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic measures are recommended (see section 4.2).

In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infection occurred at lower rates when patients received prophylactic G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF should be closely monitored (see sections 4.2 and 4.8).

In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received primary G-CSF prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receive adjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should be closely monitored (see sections 4.2 and 4.8).

Gastrointestinal reactions

Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Although majority of cases occurred during the first or second cycle of docetaxel containing regimen, enterocolitis could develop at any time, and could lead to death as early as on the first day of onset. Patients should be closely monitored for early manifestations of serious gastrointestinal toxicity (see sections 4.2, 4.4 Haematology, and 4.8).

Hypersensitivity reactions

Patients should be observed closely for hypersensitivity reactions especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with docetaxel. Patients who have previously experienced a hypersensitivity reaction to paclitaxel may be at risk to develop hypersensitivity reaction to docetaxel, including more severe hypersensitivity reaction. These patients should be closely monitored during initiation of docetaxel therapy.

Cutaneous reactions

Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema followed by desquamation has been observed. Severe symptoms such as eruptions followed by desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see section 4.2).

Severe Cutaneous Adverse Reactions (SCARs) such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and closely monitored. If signs and symptoms suggestive of these reactions appear discontinuation of docetaxel should be considered.

Fluid retention

Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored closely.

Respiratory disorders

Acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure have been reported and may be associated with fatal outcome. Cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptly investigated, and appropriately treated. Interruption of docetaxel therapy is recommended until diagnosis is available. Early use of supportive care measures may help improve the condition. The benefit of resuming docetaxel treatment must be carefully evaluated.

Patients with liver impairment

In patients treated with docetaxel at 100 mg/m2 as single agent who have serum transaminase levels (ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel in those patients with elevated liver function test (LFTs) is 75 mg/m2 and LFTs should be measured at baseline and before each cycle (see section 4.2).

For patients with serum bilirubin levels >ULN and/or ALT and AST >3.5 times the ULN concurrent with serum alkaline phosphatase levels >6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST >1.5 times ULN associated with alkaline phosphatase >2.5 times ULN and bilirubin >1 times ULN; for these patients, no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.

Patients with renal impairment

There are no data available in patients with severely impaired renal function treated with docetaxel.

Tadoxel ® 10 mg/ml solution for infusion contains Macrogol 300 which may increase the risk of nephrotoxicity in patients with renal impairment.

Nervous system

The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2).

Cardiac toxicity

Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab, particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may be moderate to severe and has been associated with death (see section 4.8).

When patients are candidates for treatment with docetaxel in combination with trastuzumab, they should undergo baseline cardiac assessment. Cardiac function should be further monitored during treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. For more details see summary of product characteristics of trastuzumab.

Ventricular arrhythmia including ventricular tachycardia (sometimes fatal) has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide (see section 4.8).

Baseline cardiac assessment is recommended.

Eye disorders

Cystoid macular oedema (CMO) has been reported in patients treated with docetaxel. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO is diagnosed, docetaxel treatment should be discontinued and appropriate treatment initiated (see section 4.8).

Second primary malignancies

Second primary malignancies have been reported when docetaxel was given in combination with anticancer treatments known to be associated with second primary malignancies. Second primary malignancies (including acute myeloid leukaemia, myelodysplastic syndrome and non-Hodgkin lymphoma) may occur several months or years after docetaxel-containing therapy. Patients should be monitored for second primary malignancies (see section 4.8).

Others

Contraceptive measures must be taken by both men and women during treatment and for men at least 6 months after cessation of therapy (see section 4.6).

The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be avoided (see section 4.5).

Additional cautions for use in adjuvant treatment of breast cancer

Complicated neutropenia

For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or infection), G-CSF and dose reduction should be considered (see section 4.2).

Gastrointestinal reactions

Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly.

Congestive heart failure (CHF)

Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow-up period. In patients treated with the TAC regimen for node positive breast cancer, the risk of CHF has been shown to be higher during the first year after treatment (see sections 4.8 and 5.1).

Patients with 4+ nodes

As the benefit observed in patient with 4+ nodes was not statistically significant on disease-free survival (DFS) and overall survival (OS), the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis (see section 5.1).

Elderly

Cautions for use in adjuvant treatment of breast cancer

There are limited data available in patients >70 years of age on docetaxel use in combination with doxorubicin and cyclophosphamide.

Cautions for use in castration-resistant prostate cancer

Of the 333 patients treated with docetaxel every three weeks in a prostate cancer study (TAX 327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every three weeks, the incidence of related nail changes occurred at a rate ≥10% higher in patients who were 65 years of age or greater compared to younger patients. The incidence of related fever, diarrhoea, anorexia and peripheral oedema occurred at rates ≥10% higher in patients who were 75 years of age or greater versus less than 65 years.

Cautions for use in hormone-sensitive prostate cancer

Of the 545 patients treated with docetaxel every 3 weeks in a hormone-sensitive prostate cancer study (STAMPEDE), 296 patients were 65 years of age or older, and 48 patients were 75 years of age or older. More patients aged ≥65 years in the docetaxel arm reported hypersensitivity reaction, neutropenia, anaemia, fluid retention, dyspnoea, and nail changes when compared to the patients aged less than 65 years. None of these increases in frequency reached 10% difference with the control arm. In patients who were 75 years of age or older, when compared to younger patients, neutropenia, anaemia, diarrhoea, dyspnoea and upper respiratory tract infection were reported with a greater incidence (at least 10% higher).

Cautions for use in gastric adenocarcinoma cancer

Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II part) patients treated with docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer study, 74 were 65 years of age or older and 4 patients were 75 years of age or older. The incidence of serious adverse events was higher in older people compared to younger patients. The incidence of the following adverse events (all grades): lethargy, stomatitis, neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients.

Older people treated with TCF should be closely monitored.

Excipients

20mg/2 ml vial

This medicinal product contains 23 vol % ethanol anhydrous (alcohol), i.e. 363 mg per vial, equivalent to 9 ml beer, 4 ml wine.

80 mg/8 ml vial

This medicinal product contains 23 vol % ethanol anhydrous (alcohol), i.e. 1452 mg per vial, equivalent to 37 ml beer, 15 ml wine.

160 mg/16 ml vial

This medicinal product contains 23 vol % ethanol anhydrous (alcohol), i.e. 2904 mg per vial, equivalent to 74 ml beer, 31 ml wine.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

Consideration should be given to possible effects on the central nervous system.

 


The amount of alcohol in this medicinal product may alter the effects of other medicinal products.

In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the enzyme competitively) cytochrome P450-3A such as ciclosporin, ketoconazole and erythromycin. As a result, caution should be exercised when treating patients with these medicinal products as concomitant therapy since there is a potential for a significant interaction.

In case of combination with CYP3A4 inhibitors, the occurrence of docetaxel adverse reactions may increase, as a result of reduced metabolism. If the concomitant use of a strong CYP3A4 inhibitor (e.g. ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) cannot be avoided, a close clinical surveillance is warranted and a dose-adjustment of docetaxel may be suitable during the treatment with the strong CYP3A4 inhibitor (see section 4.4). In a pharmacokinetic study with 7 patients, the co-administration of docetaxel with the strong CYP3A4 inhibitor ketoconazole leads to a significant decrease in docetaxel clearance by 49%.

Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.

Docetaxel is highly protein bound (>95%). Although the possible in vivo interaction of docetaxel with concomitantly administered medicinal product has not been investigated formally, in vitro interactions with tightly protein-bound agents such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel. Docetaxel did not influence the binding of digitoxin.

The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their co-administration. Limited data from a single uncontrolled study were suggestive of an interaction between docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was about 50% higher than values previously reported for carboplatin monotherapy.


Pregnancy

There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats (see section 5.3). As with other cytotoxic medicinal products, docetaxel may cause foetal harm when administered to pregnant women. Therefore, docetaxel must not be used during pregnancy unless clearly indicated.

Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.

Breast-feeding

Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, breast feeding must be discontinued for the duration of docetaxel therapy.

Contraception in males and females

An effective method of contraception should be used during treatment.

Fertility

In non-clinical studies, docetaxel has genotoxic effects and may alter male fertility (see section 5.3). Therefore, men being treated with docetaxel are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment.


No studies on the effects on the ability to drive and use machines have been performed. The amount of alcohol in this medicinal product and the side effects of the product may impair the ability to drive or use machines (see sections 4.4 and 4.8). Therefore, patients should be warned of the potential impact of the amount of alcohol and the side effects of this medicinal product on the ability to drive or use machines, and be advised not to drive or use machines if they experience these side effects during treatment.

 


Summary of the safety profile for all indications

The adverse reactions considered to be possibly or probably related to the administration of docetaxel have been obtained in:

• 1312 and 121 patients who received 100 mg/m2 and 75 mg/m2 of docetaxel as a single agent respectively.

• 258 patients who received docetaxel in combination with doxorubicin.

• 406 patients who received docetaxel in combination with cisplatin.

• 92 patients treated with docetaxel in combination with trastuzumab.

• 255 patients who received docetaxel in combination with capecitabine.

• 332 patients (TAX 327) who received docetaxel in combination with prednisone or prednisolone (clinically important treatment-related adverse events are presented).

• 1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received docetaxel in combination with doxorubicin and cyclophosphamide (clinically important treatment-related adverse events are presented).

• 300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and 79 patients in the phase II part) who received docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment-related adverse events are presented).

• 174 and 251 head and neck cancer patients who received docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment-related adverse events are presented).

• 545 patients (STAMPEDE study) who received docetaxel in combination with prednisone or prednisolone and ADT.

These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3; grade 3-4 = G3/4; grade 4 = G4), the COSTART and the MedDRA terms. Frequencies are defined as: 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 available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most commonly reported adverse reactions of docetaxel alone are: neutropenia (which was reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe neutropenia (<500 cells/mm3) was 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea and asthenia. The severity of adverse events of docetaxel may be increased when docetaxel is given in combination with other chemotherapeutic agents.

For combination with trastuzumab, adverse events (all grades) reported in ≥10% are displayed. There was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the trastuzumab combination arm compared to docetaxel monotherapy.

For combination with capecitabine, the most frequent treatment-related undesirable effects (≥5%) reported in a phase III study in breast cancer patients failing anthracycline treatment are presented (see capecitabine summary of product characteristics).

For combination with ADT and with prednisone or prednisolone (STAMPEDE study), adverse events occurring over the 6 cycles of treatment with docetaxel and having at least 2% higher incidence in the docetaxel treatment arm by comparison to the control arm, are presented, using the CTCAE grading scale.

The following adverse reactions are frequently observed with docetaxel:

Immune system disorders

Hypersensitivity reactions have generally occurred within a few minutes following the start of the infusion of docetaxel and were usually mild to moderate. The most frequently reported symptoms were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and fever or chills. Severe reactions were characterised by hypotension and/or bronchospasm or generalised rash/erythema (see section 4.4).

Nervous system disorders

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paraesthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders

Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion. Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.

General disorders and administration site conditions

Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein.

Fluid retention includes events such as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).

Tabulated list of adverse reactions in breast cancer for docetaxel 100 mg/m2 single agent

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Infections and infestations

Infections (G3/4: 5.7%; including sepsis and pneumonia, fatal in 1.7%)

Infection associated with G4 neutropenia (G3/4: 4.6%)

 

Blood and lymphatic system disorders

Neutropenia (G4: 76.4%); Anaemia (G3/4: 8.9%); Febrile neutropenia

Thrombocytopenia (G4: 0.2%)

 

Immune system disorders

Hypersensitivity (G3/4: 5.3%)

  

Metabolism and nutrition disorders

Anorexia

  

Nervous system disorders

Peripheral sensory neuropathy (G3: 4.1%); Peripheral motor neuropathy (G3/4: 4%); Dysgeusia (severe: 0.07%)

  

Cardiac disorders

 

Arrhythmia (G3/4: 0.7%)

Cardiac failure

Vascular disorders

 

Hypotension; Hypertension; Haemorrhage

 

Respiratory, thoracic and mediastinal disorders

Dyspnoea (severe: 2.7%)

  

Gastrointestinal disorders

Stomatitis (G3/4: 5.3%); Diarrhoea (G3/4: 4%); Nausea (G3/4: 4%); Vomiting (G3/4: 3%)

Constipation (severe: 0.2%); Abdominal pain (severe: 1%); Gastrointestinal haemorrhage (severe: 0.3%)

Oesophagitis (severe: 0.4%)

Skin and subcutaneous tissue disorders

Alopecia; Skin reaction (G3/4: 5.9%); Nail disorders (severe: 2.6%)

  

Musculoskeletal and connective tissue disorders

Myalgia (severe: 1.4%)

Arthralgia

 

General disorders and administration site conditions

Fluid retention (severe: 6.5%); Asthenia (severe: 11.2%); Pain

Infusion site reaction; Non-cardiac chest pain (severe: 0.4%)

 

Investigations

 

G3/4 Blood bilirubin increased (<5%); G3/4 Blood alkaline phosphatase increased (<4%); G3/4 AST increased (<3%); G3/4 ALT increased (<2%)

 

Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m2 single agent

Blood and lymphatic system disorders

Rare: bleeding episodes associated with grade 3/4 thrombocytopenia

Not known: Leucopenia

Nervous system disorders

Reversibility data are available among 35.3% of patients who developed neurotoxicity following docetaxel treatment at 100 mg/m2 as single agent. The events were spontaneously reversible within 3 months.

Skin and subcutaneous tissue disorders

Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions were reversible within 21 days.

General disorders and administration site conditions

The median cumulative dose to treatment discontinuation was more than 1,000 mg/mand the median time to fluid retention reversibility was 16.4 weeks (range 0 to 42 weeks). The onset of moderate and severe retention is delayed (median cumulative dose: 818.9 mg/m2) in patients with premedication compared with patients without premedication (median cumulative dose: 489.7 mg/m2); however, it has been reported in some patients during the early courses of therapy.

Tabulated list of adverse reactions in non-small cell lung cancer for docetaxel 75 mg/m2 single agent

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Infections and infestations

Infections (G3/4: 5%)

 

Blood and lymphatic system disorders

Neutropenia (G4: 54.2%); Anaemia (G3/4: 10.8%); Thrombocytopenia (G4: 1.7%)

Febrile neutropenia

Immune system disorders

 

Hypersensitivity (not severe)

Metabolism and nutrition disorders

Anorexia

 

Nervous system disorders

Peripheral sensory neuropathy (G3/4: 0.8%)

Peripheral motor neuropathy (G3/4: 2.5%)

Cardiac disorders

 

Arrhythmia (no severe)

Vascular disorders

 

Hypotension

Gastrointestinal disorders

Nausea (G3/4: 3.3%); Stomatitis (G3/4: 1.7%); Vomiting (G3/4: 0.8%); Diarrhoea (G3/4: 1.7%)

Constipation

Skin and subcutaneous tissue disorders

Alopecia; Skin reaction (G3/4: 0.8%)

Nail disorders (severe: 0.8%)

Musculoskeletal and connective tissue disorders

 

Myalgia

General disorders and administration site conditions

Asthenia (severe: 12.4%); Fluid retention (severe: 0.8%); Pain

 

Investigations

 

G3/4 Blood bilirubin increased (<2%)

Tabulated list of adverse reactions in breast cancer for docetaxel 75 mg/m2 in combination with doxorubicin

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Infections and infestations

Infection (G3/4: 7.8%)

  

Blood and lymphatic system disorders

Neutropenia (G4: 91.7%); Anaemia (G3/4: 9.4%); Febrile neutropenia

Thrombocytopenia (G4: 0.8%)

  

Immune system disorders

 

Hypersensitivity (G3/4: 1.2%)

 

Metabolism and nutrition disorders

 

Anorexia

 

Nervous system disorders

Peripheral sensory neuropathy (G3: 0.4%)

Peripheral motor neuropathy (G3/4: 0.4%)

 

Cardiac disorders

 

Cardiac failure; Arrhythmia (no severe)

 

Vascular disorders

  

Hypotension

Gastrointestinal disorders

Nausea (G3/4: 5%); Stomatitis (G3/4: 7.8%); Diarrhoea (G3/4: 6.2%); Vomiting (G3/4: 5%); Constipation

  

Skin and subcutaneous tissue disorders

Alopecia; Nail disorders (severe: 0.4%); Skin reaction (no severe)

  

Musculoskeletal and connective tissue disorders

 

Myalgia

 

General disorders and administration site conditions

Asthenia (severe: 8.1%); Fluid retention (severe: 1.2%); Pain

Infusion site reaction

 

Investigations

 

G3/4 Blood bilirubin increased (<2.5%); G3/4 Blood alkaline phosphatase increased (<2.5%)

G3/4 AST increased (<1%); G3/4 ALT increased (<1%)

Tabulated list of adverse reactions in non-small cell lung cancer for docetaxel 75 mg/m2 in combination with cisplatin

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Infections and infestations

Infection (G3/4: 5.7%)

  

Blood and lymphatic system disorders

Neutropenia (G4: 51.5%); Anaemia (G3/4: 6.9%); Thrombocytopenia (G4: 0.5%)

Febrile neutropenia

 

Immune system disorders

Hypersensitivity (G3/4: 2.5%)

  

Metabolism and nutrition disorders

Anorexia

  

Nervous system disorders

Peripheral sensory neuropathy (G3: 3.7%); Peripheral motor neuropathy (G3/4: 2%)

  

Cardiac disorders

 

Arrhythmia (G3/4: 0.7%)

Cardiac failure

Vascular disorders

 

Hypotension (G3/4: 0.7%)

 

Gastrointestinal disorders

Nausea (G3/4: 9.6%); Vomiting (G3/4: 7.6%); Diarrhoea (G3/4: 6.4%); Stomatitis (G3/4: 2%)

Constipation

 

Skin and subcutaneous tissue disorders

Alopecia; Nail disorders (severe: 0.7%); Skin reaction (G3/4: 0.2%)

  

Musculoskeletal and connective tissue disorders

Myalgia (severe: 0.5%)

  

General disorders and administration site conditions

Asthenia (severe: 9.9%); Fluid retention (severe: 0.7%); Fever (G3/4: 1.2%)

Infusion site reaction; Pain

 

Investigations

 

G3/4 Blood bilirubin increased (2.1%); G3/4 ALT increased (1.3%)

G3/4 AST increased (0.5%); G3/4 Blood alkaline phosphatase increased (0.3%)

Tabulated list of adverse reactions in breast cancer for docetaxel 100 mg/m2 in combination with trastuzumab

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Blood and lymphatic system disorders

Neutropenia (G3/4: 32%); Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis

 

Metabolism and nutrition disorders

Anorexia

 

Psychiatric disorders

Insomnia

 

Nervous system disorders

Paraesthesia; Headache; Dysgeusia; Hypoaesthesia

 

Eye disorders

Lacrimation increased; Conjunctivitis

 

Cardiac disorders

 

Cardiac failure

Vascular disorders

Lymphoedema

 

Respiratory, thoracic and mediastinal disorders

Epistaxis; Pharyngolaryngeal pain; Nasopharyngitis; Dyspnoea; Cough; Rhinorrhoea

 

Gastrointestinal disorders

Nausea; Diarrhoea; Vomiting; Constipation; Stomatitis; Dyspepsia; Abdominal pain

 

Skin and subcutaneous tissue disorders

Alopecia; Erythema; Rash; Nail disorders

 

Musculoskeletal and connective tissue disorders

Myalgia; Arthralgia; Pain in extremity; Bone pain; Back pain

 

General disorders and administration site conditions

Asthenia; Oedema peripheral; Pyrexia; Fatigue; Mucosal inflammation; Pain; Influenza like illness; Chest pain; Chills

Lethargy

Investigations

Weight increased

 

Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m2 in combination with trastuzumab

Cardiac disorders

Symptomatic cardiac failure was reported in 2.2% of the patients who received docetaxel plus trastuzumab compared to 0% of patients given docetaxel alone. In the docetaxel plus trastuzumab arm, 64% had received a prior anthracycline as adjuvant therapy compared with 55% in the docetaxel arm alone.

Blood and lymphatic system disorders

Very common: Haematological toxicity was increased in patients receiving trastuzumab and docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC criteria). Note that this is likely to be an underestimate since docetaxel alone at a dose of 100 mg/m2 is known to result in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel alone).

Tabulated list of adverse reactions in breast cancer for docetaxel 75 mg/m2 in combination with capecitabine

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Infections and infestations

 

Oral candidiasis (G3/4: <1%)

Blood and lymphatic system disorders

Neutropenia (G3/4: 63%); Anaemia (G3/4: 10%)

Thrombocytopenia (G3/4: 3%)

Metabolism and nutrition disorders

Anorexia (G3/4: 1%); Decreased appetite

Dehydration (G3/4: 2%)

Nervous system disorders

Dysgeusia (G3/4: <1%); Paraesthesia (G3/4: <1%)

Dizziness; Headache (G3/4: <1%); Neuropathy peripheral

Eye disorders

Lacrimation increased

 

Respiratory, thoracic and mediastinal disorders

Pharyngolaryngeal pain (G3/4: 2%)

Dyspnoea (G3/4: 1%); Cough (G3/4: <1%); Epistaxis (G3/4: <1%)

Gastrointestinal disorders

Stomatitis (G3/4: 18%); Diarrhoea (G3/4: 14%); Nausea (G3/4: 6%); Vomiting (G3/4: 4%); Constipation (G3/4: 1%); Abdominal pain (G3/4: 2%); Dyspepsia

Abdominal pain upper; Dry mouth

Skin and subcutaneous tissue disorders

Hand-foot syndrome (G3/4: 24%); Alopecia (G3/4: 6%); Nail disorders (G3/4: 2%)

Dermatitis; Rash erythematous (G3/4: <1%) ; Nail discolouration; Onycholysis (G3/4: 1%)

Musculoskeletal and connective tissue disorders

Myalgia (G3/4: 2%) Arthralgia (G3/4: 1%)

Pain in extremity (G3/4: <1%); Back pain (G3/4: 1%)

General disorders and administration site conditions

Asthenia (G3/4: 3%); Pyrexia (G3/4: 1%); Fatigue/weakness (G3/4: 5%); Oedema peripheral (G3/4: 1%)

Lethargy; Pain

Investigations

 

Weight decreased; G3/4 Blood bilirubin increased (9%)

Tabulated list of adverse reactions in metastatic castration-resistant prostate cancer for docetaxel 75 mg/m2 in combination with prednisone or prednisolone

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Infections and infestations

Infection (G3/4: 3.3%)

 

Blood and lymphatic system disorders

Neutropenia (G3/4: 32%); Anaemia (G3/4: 4.9%)

Thrombocytopenia (G3/4: 0.6%); Febrile neutropenia

Immune system disorders

 

Hypersensitivity (G3/4: 0.6%)

Metabolism and nutrition disorders

Anorexia (G3/4: 0.6%)

 

Nervous system disorders

Peripheral sensory neuropathy (G3/4: 1.2%); Dysgeusia (G3/4: 0%)

Peripheral motor neuropathy (G3/4: 0%)

Eye disorders

 

Lacrimation increased (G3/4: 0.6%)

Cardiac disorders

 

Cardiac left ventricular function decrease (G3/4: 0.3%)

Respiratory, thoracic and mediastinal disorders

 

Epistaxis (G3/4: 0%); Dyspnoea (G3/4: 0.6%); Cough (G3/4: 0%)

Gastrointestinal disorders

Nausea (G3/4: 2.4%); Diarrhoea (G3/4: 1.2%); Stomatitis/Pharyngitis (G3/4: 0.9%); Vomiting (G3/4: 1.2%)

 

Skin and subcutaneous tissue disorders

Alopecia; Nail disorders (no severe)

Exfoliative rash (G3/4: 0.3%)

Musculoskeletal and connective tissue disorders

 

Arthralgia (G3/4: 0.3%); Myalgia (G3/4: 0.3%)

General disorders and administration site conditions

Fatigue (G3/4: 3.9%); Fluid retention (severe: 0.6%)

 

Tabulated list of adverse reactions in high-risk locally advanced or metastatic hormone-sensitive prostate cancer for docetaxel 75 mg/m² in combination with prednisone or prednisolone and ADT (STAMPEDE study)

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Blood and lymphatic system disorders

Neutropenia (G3-4: 12 %)

Anaemia

Febrile neutropenia (G3-4: 15%)

 

Immune system disorders

 

Hypersensitivity (G3-4: 1%)

Endocrine disorders

 

Diabetes (G3-4: 1%)

Metabolism and nutrition disorders

 

Anorexia

Psychiatric disorders

Insomnia (G3: 1%)

 

Nervous system disorders

Peripheral sensory neuropathy (≥G3: 2%)a

Headache

Dizziness

Eye disorders

 

Blurred vision

Cardiac disorders

 

Hypotension (G3: 0%)

Respiratory, thoracic and mediastinal disorders

Dyspnoea (G3: 1%)

Coughing (G3: 0%)

Upper respiratory tract infection (G3: 1%)

Pharyngitis (G3: 0%)

Gastrointestinal disorders

Diarrhoea (G3: 3%)

Stomatitis (G3: 0%)

Constipation (G3: 0%)

Nausea (G3: 1%)

Dyspepsia

Abdominal pain (G3: 0%)

Flatulence

Vomiting (G3: 1%)

Skin and subcutaneous tissue disorders

Alopecia (G3: 3%)a

Nail changes (G3: 1%)

Rash

Musculoskeletal and connective tissue disorders

Myalgia

 

General disorders and administration site conditions

Lethargy (G3-4: 2%)

Flu-like symptoms (G3: 0%)

Asthenia (G3: 0%)

Fluid retention

Fever (G3: 1%)

Oral candidiasis

Hypocalcaemia (G3: 0%)

Hypophosphataemia (G3-4: 1%)

Hypokalaemia (G3: 0%)

aFrom the GETUG AFU15 study

Tabulated list of adverse reactions for adjuvant therapy with docetaxel 75 mg/m2 in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer-pooled data

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Infections and infestations

Infection (G3/4: 2.4%); Neutropenic infection (G3/4: 2.6%)

  

Blood and lymphatic system disorders

Anaemia (G3/4: 3%)

Neutropenia (G3/4: 59.2%)

Thrombocytopenia (G3/4: 1.6%)

Febrile neutropenia (G3/4: NA)

  

Immune system disorders

 

Hypersensitivity (G3/4: 0.6%)

 

Metabolism and nutrition disorders

Anorexia (G3/4: 1.5%)

  

Nervous system disorders

Dysgeusia (G3/4: 0.6%); Peripheral sensory neuropathy (G3/4: <0.1%)

Peripheral motor neuropathy (G3/4: 0%);

Syncope (G3/4: 0%); Neurotoxicity (G3/4: 0%); Somnolence (G3/4: 0%)

Eye disorders

Conjunctivitis (G3/4: <0.1%)

Lacrimation increased (G3/4: <0.1%)

 

Cardiac disorders

 

Arrhythmia (G3/4: 0.2%)

 

Vascular disorders

Hot flush (G3/4: 0.5%)

Hypotension (G3/4: 0%); Phlebitis (G3/4: 0%)

Lymphoedema (G3/4: 0%)

Respiratory, thoracic and mediastinal disorders

 

Cough (G3/4: 0%)

 

Gastrointestinal disorders

Nausea (G3/4: 5.0%); Stomatitis (G3/4: 6.0%); Vomiting (G3/4: 4.2%); Diarrhoea (G3/4: 3.4%); Constipation (G3/4: 0.5%)

Abdominal pain (G3/4: 0.4%)

 

Skin and subcutaneous tissue disorders

Alopecia (persisting: <3%); Skin disorder (G3/4: 0.6%); Nail disorders (G3/4: 0.4%)

  

Musculoskeletal and connective tissue disorders

Myalgia (G3/4: 0.7%); Arthralgia (G3/4: 0.2%)

  

Reproductive system and breast disorders

Amenorrhoea (G3/4: NA)

  

General disorders and administration site conditions

Asthenia (G3/4: 10.0%); Pyrexia (G3/4: NA); Oedema peripheral (G3/4: 0.2%)

  

Investigations

 

Weight increased (G3/4: 0%); Weight decreased (G3/4: 0.2%)

 

Description of selected adverse reactions for adjuvant therapy with docetaxel 75 mg/m2 in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer

Nervous system disorders

In study TAX316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2%) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.

In GEICAM 9805 study, peripheral sensory neuropathy that started during the treatment period persisted into the follow-up period in 10 patients (1.9%) in TAC arm and 4 patients (0.8%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), peripheral sensory neuropathy was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Cardiac disorders

In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm experienced congestive heart failure. All except one patient in each arm were diagnosed with CHF more than 30 days after the treatment period. Two patients in the TAC arm and 4 patients in the FAC arm died because of cardiac failure.

In GEICAM 9805 study, 3 patients (0.6%) in TAC arm and 3 patients (0.6%) in FAC arm developed congestive heart failure during the follow-up period. At the end of the follow-up period (actual median follow-up time of 10 years and 5 months), no patients had CHF in TAC arm and 1 patient in TAC arm died because of dilated cardiomyopathy, and CHF was observed to be ongoing in 1 patient (0.2%) in FAC arm.

Skin and subcutaneous tissue disorders

In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%). At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study, alopecia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 49 patients (9.2%) in TAC arm and 35 patients (6.7%) in FAC arm. Alopecia related to study drug started or worsened during the follow-up period in 42 patients (7.9%) in TAC arm and 30 patients (5.8%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), alopecia was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Reproductive system and breast disorders

In TAX316, amenorrhoea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

In GEICAM 9805 study, amenorrhoea that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 18 patients (3.4%) in TAC arm and 5 patients (1.0%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), amenorrhoea was observed to be ongoing in 7 patients (1.3%) in TAC arm, and in 4 patients (0.8%) in FAC arm.

General disorders and administration site conditions

In study TAX316, peripheral oedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral oedema was ongoing in 19 TAC patients (2.6%) and 4 FAC patients (0.5%).

In study TAX316, lymphoedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphoedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).

In study TAX316, asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In study GEICAM 9805, peripheral oedema that started during the treatment period persisted into the follow-up period in 4 patients (0.8%) in TAC arm and in 2 patients (0.4%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), no patients (0%) in TAC arm had peripheral oedema and it was observed to be ongoing in 1 patient (0.2%) in FAC arm. Lymphoedema that started during the treatment period persisted into the follow-up period in 5 patients (0.9%) in TAC arm and 2 patients (0.4%) in FAC arm. At the end of the follow-up period, lymphoedema was observed to be ongoing in 4 patients (0.8%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Asthenia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 12 patients (2.3%) in TAC arm and 4 patients (0.8%) in FAC arm. At the end of the follow-up period, asthenia was observed to be ongoing in 2 patients (0.4%) in TAC arm, and in 2 patients (0.4%) in FAC arm.

Acute leukaemia/myelodysplastic syndrome

After 10 years of follow-up in study TAX316, acute leukaemia was reported in 3 of 744 TAC patients (0.4%) and in 1 of 736 FAC patients (0.1%). One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome was reported in 2 of 744 TAC patients (0.3%) and in 1 of 736 FAC patients (0.1%).

After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred in 1 of 532 (0.2%) patients in TAC arm. No cases were reported in patients in FAC arm. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.

Neutropenic complications

Table below shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis after it was made mandatory in the TAC arm – GEICAM study.

Neutropenic complications in patients receiving TAC with or without primary G-CSF prophylaxis (GEICAM 9805)

 

Without primary G-CSF prophylaxis

(n = 111)

n (%)

With primary G-CSF prophylaxis

(n = 421)

n (%)

Neutropenia (Grade 4)

104 (93.7)

135 (32.1)

Febrile neutropenia

28 (25.2)

23 (5.5)

Neutropenic infection

14 (12.6)

21 (5.0)

Neutropenic infection (Grade 3-4)

2 (1.8)

5 (1.2)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for docetaxel 75 mg/m2 in combination with cisplatin and 5-fluorouracil

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Infections and infestations

Neutropenic infection; Infection (G3/4: 11.7%)

 

Blood and lymphatic system disorders

Anaemia (G3/4: 20.9%);

Neutropenia (G3/4: 83.2%);

Thrombocytopenia (G3/4: 8.8%);

Febrile neutropenia

 

Immune system disorders

Hypersensitivity (G3/4: 1.7%)

 

Metabolism and nutrition disorders

Anorexia (G3/4: 11.7%)

 

Nervous system disorders

Peripheral sensory neuropathy (G3/4: 8.7%)

Dizziness (G3/4: 2.3%); Peripheral motor neuropathy (G3/4: 1.3%)

Eye disorders

 

Lacrimation increased (G3/4: 0%)

Ear and labyrinth disorders

 

Hearing impaired (G3/4: 0%)

Cardiac disorders

 

Arrhythmia (G3/4: 1.0%)

Gastrointestinal disorders

Diarrhoea (G3/4: 19.7%);

Nausea (G3/4: 16%);

Stomatitis (G3/4: 23.7%);

Vomiting (G3/4: 14.3%)

Constipation (G3/4: 1.0%);

Gastrointestinal pain (G3/4: 1.0%);

Oesophagitis/dysphagia/odynophagia (G3/4: 0.7%)

Skin and subcutaneous tissue disorders

Alopecia (G3/4: 4.0%)

Rash pruritus (G3/4: 0.7%);

Nail disorders (G3/4: 0.7%);

Skin exfoliation (G3/4: 0%)

General disorders and administration site conditions

Lethargy (G3/4: 19.0%);

Fever (G3/4: 2.3%);

Fluid retention (severe/life-threatening: 1%)

 

Description of selected adverse reactions in gastric adenocarcinoma cancer for docetaxel 75 mg/m2 in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders

Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively, regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of patients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without prophylactic G-CSF (see section 4.2).

Tabulated list of adverse reactions in head and neck cancer for docetaxel 75 mg/min combination with cisplatin and 5-fluorouracil

Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Infections and infestations

Infection (G3/4: 6.3%); Neutropenic infection

  

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

 

Cancer pain (G3/4: 0.6%)

 

Blood and lymphatic system disorders

Neutropenia (G3/4: 76.3%); Anaemia (G3/4: 9.2%); Thrombocytopenia (G3/4: 5.2%)

Febrile neutropenia

 

Immune system disorders

 

Hypersensitivity (not severe)

 

Metabolism and nutrition disorders

Anorexia (G3/4: 0.6%)

  

Nervous system disorders

Dysgeusia/Parosmia; Peripheral sensory neuropathy (G3/4: 0.6%)

Dizziness

 

Eye disorders

 

Lacrimation increased; Conjunctivitis

 

Ear and labyrinth disorders

 

Hearing impaired

 

Cardiac disorders

 

Myocardial ischaemia (G3/4: 1.7%)

Arrhythmia (G3/4: 0.6%)

Vascular disorders

 

Venous disorder (G3/4: 0.6%)

 

Gastrointestinal disorders

Nausea (G3/4: 0.6%); Stomatitis (G3/4: 4.0%); Diarrhoea (G3/4: 2.9%); Vomiting (G3/4: 0.6%)

Constipation; Oesophagitis/dysphagia/ odynophagia (G3/4: 0.6%); Abdominal pain; Dyspepsia; Gastrointestinal haemorrhage (G3/4: 0.6%)

 

Skin and subcutaneous tissue disorders

Alopecia (G3/4: 10.9%)

Rash pruritic; Dry skin; Skin exfoliative (G3/4: 0.6%)

 

Musculoskeletal and connective tissue disorders

 

Myalgia (G3/4: 0.6%)

 

General disorders and administration site conditions

Lethargy (G3/4: 3.4%); Pyrexia (G3/4: 0.6%); Fluid retention; Oedema

  

Investigations

 

Weight increased

 

Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA system organ classes

Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Infections and infestations

Infection (G3/4: 3.6%)

Neutropenic infection

 

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

 

Cancer pain (G3/4: 1.2%)

 

Blood and lymphatic system disorders

Neutropenia (G3/4: 83.5%); Anaemia (G3/4: 12.4%); Thrombocytopenia (G3/4: 4.0%); Febrile neutropenia

  

Immune system disorders

  

Hypersensitivity

Metabolism and nutrition disorders

Anorexia (G3/4: 12.0%)

  

Nervous system disorders

Dysgeusia/Parosmia (G3/4: 0.4%); Peripheral sensory neuropathy (G3/4: 1.2%)

Dizziness (G3/4: 2.0%); Peripheral motor neuropathy (G3/4: 0.4%)

 

Eye disorders

 

Lacrimation increased

Conjunctivitis

Ear and labyrinth disorders

Hearing impaired (G3/4: 1.2%)

  

Cardiac disorders

 

Arrhythmia (G3/4: 2.0%)

Ischaemia myocardial

Vascular disorders

  

Venous disorder

Gastrointestinal disorders

Nausea (G3/4: 13.9%); Stomatitis (G3/4: 20.7%); Vomiting (G3/4: 8.4%); Diarrhoea (G3/4: 6.8%); Oesophagitis/dysphagia/odynophagia (G3/4: 12.0%); Constipation (G3/4: 0.4%)

Dyspepsia (G3/4: 0.8%); Gastrointestinal pain (G3/4: 1.2%); Gastrointestinal haemorrhage (G3/4:0.4%)

 

Skin and subcutaneous tissue disorders

Alopecia (G3/4: 4.0%); Rash pruritic

Dry skin; Desquamation

 

Musculoskeletal and connective tissue disorders

 

Myalgia (G3/4: 0.4%)

 

General disorders and administration site conditions

Lethargy (G3/4: 4.0%); Pyrexia (G3/4: 3.6%); Fluid retention (G3/4: 1.2%); Oedema (G3/4: 1.2%)

  

Investigations

Weight decreased

 

Weight increased

Post-marketing experience

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Second primary malignancies (frequency not known), including non-Hodgkin lymphoma have been reported in association with docetaxel when used in combination with other anticancer treatments known to be associated with second primary malignancies. Acute myeloid leukaemia and myelodysplastic syndrome have been reported (frequency uncommon) in pivotal clinical studies in breast cancer with TAC regimen.

Blood and lymphatic system disorders

Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminated intravascular coagulation (DIC), often in association with sepsis or multi-organ failure, has been reported.

Immune system disorders

Some cases of anaphylactic shock, sometimes fatal, have been reported.

Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

Nervous system disorders

Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel administration. These reactions sometimes appear during the infusion of the medicinal product.

Eye disorders

Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during infusion of the medicinal product and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been rarely reported. Cases of cystoid macular oedema (CMO) have been reported in patients treated with docetaxel.

Ear and labyrinth disorders

Rare cases of ototoxicity, hearing impaired and/or hearing loss have been reported.

Cardiac disorders

Rare cases of myocardial infarction have been reported.

Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/ or cyclophosphamide.

Vascular disorders

Venous thromboembolic events have rarely been reported.

Respiratory, thoracic and mediastinal disorders

Acute respiratory distress syndrome and cases of interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure, sometimes fatal, have rarely been reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Gastrointestinal disorders

Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, have been reported with a potential fatal outcome (frequency not known).

Rare occurrences of dehydration have been reported as a consequence of gastrointestinal events, including enterocolitis and gastrointestinal perforation.

Rare cases of ileus and intestinal obstruction have been reported.

Hepatobiliary disorders

Very rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.

Skin and subcutaneous tissue disorders

Cases of cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme, and severe cutaneous adverse reactions such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel. Scleroderma-like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of permanent alopecia (frequency not known) have been reported.

Renal and urinary disorders

Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no risk factors for acute renal failure such as concomitant nephrotoxic medicinal products and gastrointestinal disorders.

General disorders and administration site conditions

Radiation recall phenomena have rarely been reported.

Injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) has been observed at the site of previous extravasation (frequency not known).

Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration and pulmonary oedema have rarely been reported.

Metabolism and nutrition disorders

Cases of electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia. Hypokalaemia, hypomagnesaemia, and hypocalcaemia were observed, usually in association with gastrointestinal disorders and in particular with diarrhoea.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at:www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store.

There were a few reports of overdose. There is no known antidote for docetaxel overdose. In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In cases of overdose, exacerbation of adverse events may be expected. The primary anticipated complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

 

To report any side effect(s):

  • Saudi Arabia:

National Pharmacovigilance & Drug Safety Centre (NPC):

  • SFDA Call Center: 19999
  • E-mail: npc.drug@sfda.gov.sa
  • Website: https://ade.sfda.gov.sa

 

 

 


 

There were a few reports of overdose. There is no known antidote for docetaxel overdose. In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In cases of overdose, exacerbation of adverse events may be expected. The primary anticipated complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

 


Pharmacotherapeutic group: Taxanes, ATC Code: L01CD 02

Mechanism of action

Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The binding of docetaxel to microtubules does not alter the number of protofilaments.

Docetaxel has been shown in vitro to disrupt the microtubular network in cells which is essential for vital mitotic and interphase cellular functions.

Pharmacodynamic effects

Docetaxel was found to be cytotoxic in vitro against various murine and human tumour cell lines and against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular concentrations with a long cell residence time. In addition, docetaxel was found to be active on some but not all cell lines overexpressing the p-glycoprotein which is encoded by the multidrug resistance gene. In vivo, docetaxel is schedule independent and has a broad spectrum of experimental anti-tumour activity against advanced murine and human grafted tumours.

Clinical efficacy and safety

Breast cancer

Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy

Patients with operable node-positive breast cancer (TAX 316): Data from a multi-centre open-label randomised study support the use of docetaxel for the adjuvant treatment of patients with operable node-positive breast cancer and KPS ≥80%, between 18 and 70 years of age. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomised to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2 (FAC arm). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other medicinal products were given as intravenous bolus on day one. G-CSF was administered as secondary prophylaxis to patients who experienced complicated neutropenia (febrile neutropenia, prolonged neutropenia, or infection). Patients on the TAC arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent. In both arms, after the last cycle of chemotherapy, patients with positive oestrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC. Two interim analyses and one final analysis were performed. The first interim analysis was planned 3 years after the date when half of study enrolment was done. The second interim analysis was done after 400 DFS events had been recorded overall, which led to a median follow-up of 55 months. The final analysis was performed when all patients had reached their 10-year follow-up visit (unless they had a DFS event or were lost to follow-up before). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint.

A final analysis was performed with an actual median follow-up of 96 months. Significantly longer disease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of relapses at 10 years was reduced in patients receiving TAC compared to those who received FAC (39% versus 45%, respectively) i.e. an absolute risk reduction by 6% (p = 0.0043). Overall survival at 10 years was also significantly increased with TAC compared to FAC (76% versus 69%, respectively) i.e. an absolute reduction of the risk of death by 7% (p = 0.002). As the benefit observed in patients with 4+ nodes was not statistically significant on DFS and OS, the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis.

Overall, the study results demonstrate a positive benefit risk ratio for TAC compared to FAC.

TAC-treated patient subsets according to prospectively defined major prognostic factors were analysed:

  

Disease free survival

Overall survival

Patient subset

Number of patients

Hazard ratio*

95% CI

p=

Hazard ratio*

95% CI

p=

No of positive nodes

       

Overall

745

0.80

0.68-0.93

0.0043

0.74

0.61-0.90

0.0020

1-3

467

0.72

0.58-0.91

0.0047

0.62

0.46-0.82

0.0008

4+

278

0.87

0.70-1.09

0.2290

0.87

0.67-1.12

0.2746

*a hazard ratio of less than 1 indicates that TAC is associated with a longer disease-free survival and overall survival compared to FAC

Patients with operable node-negative breast cancer eligible to receive chemotherapy (GEICAM 9805): Data from a multi-centre open-label randomised trial support the use of docetaxel for the adjuvant treatment of patients with operable node-negative breast cancer eligible to receive chemotherapy.

1060 patients were randomised to receive either docetaxel 75 mg/madministered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m(539 patients in TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2 (521 patients in FAC arm), as adjuvant treatment of operable node-negative breast cancer patients with high risk of relapse according to 1998 St. Gallen criteria (tumour size >2 cm and/or negative ER and PR and/or high histological/nuclear grade (grade 2 to 3) and /or age <35 years). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other medicinal products were given intravenously on day 1 every three weeks. Primary prophylactic G-CSF was made mandatory in TAC arm after 230 patients were randomised. The incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis (see section 4.8). In both arms, after the last cycle of chemotherapy, patients with ER+ and/or PgR+ tumours received tamoxifen 20 mg once a day for up to 5 years. Adjuvant radiation therapy was administered according to guidelines in place at participating institutions and was given to 57.3% of patients who received TAC and 51.2% of patients who received FAC.

One primary analysis and one updated analysis were performed. The primary analysis was done when all patients had a follow-up of greater than 5 years (median follow-up time of 77 months). The updated analysis was performed when all patients had reached their 10-year (median follow-up time of 10 years and 5 months) follow-up visit (unless they had a DFS event or were lost to follow-up previously). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint.

At the median follow-up time of 77 months, significantly longer disease-free survival for the TAC arm compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in the risk of relapse compared to those treated with FAC (hazard ratio = 0.68, 95% CI (0.49-0.93), p = 0.01). At the median follow-up time of 10 years and 5 months, TAC-treated patients had a 16.5% reduction in the risk of relapse compared to those treated with FAC (hazard ratio = 0.84, 95% CI (0.65-1.08), p = 0.1646). DFS data were not statistically significant but were still associated with a positive trend in favour of TAC.

At the median follow-up time of 77 months, overall survival (OS) was longer in the TAC arm with TAC-treated patients having a 24% reduction in the risk of death compared to FAC (hazard ratio = 0.76, 95% CI (0.46-1.26), p = 0.29). However, the distribution of OS was not significantly different between the 2 groups.

At the median follow-up time of 10 years and 5 months, TAC-treated patients had a 9% reduction in the risk of death compared to FAC-treated patients (hazard ratio = 0.91, 95% CI (0.63-1.32)).

The survival rate was 93.7% in the TAC arm and 91.4% in the FAC arm, at the 8-year follow-up time point, and 91.3% in the TAC arm and 89% in the FAC arm, at the 10-year follow-up time point.

The positive benefit risk ratio for TAC compared to FAC remained unchanged.

TAC-treated patient subsets according to prospectively defined major prognostic factors were analysed in the primary analysis (at the median follow-up time of 77 months) (see table below):

Subset analyses-adjuvant therapy in patients with node-negative breast cancer study (intent-to-treat analysis)

Patient subset

Number of patients

in TAC group

Disease Free Survival

Hazard ratio*

95% CI

Overall

539

0.68

0.49-0.93

Age category 1

<50 years

≥50 years

260

279

0.67

0.67

0.43-1.05

0.43-1.05

Age category 2

<35 years

≥35 years

42

497

0.31

0.73

0.11-0.89

0.52-1.01

Hormonal receptor status

Negative

Positive

195

344

0.7

0.62

0.45-1.1

0.4-0.97

Tumour size

≤ 2 cm

>2 cm

285

254

0.69

0.68

0.43-1.1

0.45-1.04

Histological grade

Grade1 (includes grade not assessed)

Grade 2

Grade 3

64

216

259

0.79

0.77

0.59

0.24-2.6

0.46-1.3

0.39-0.9

Menopausal status

Pre-Menopausal

Post-Menopausal

285

254

0.64

0.72

0.40-1

0.47-1.12

*a hazard ratio (TAC/FAC) of less than 1 indicates that TAC is associated with a longer disease-free survival compared to FAC

Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St. Gallen chemotherapy criteria – (ITT population) were performed and presented here below:

Subgroups

TAC

(n = 539)

FAC

(n = 521)

Hazard ratio

(TAC/FAC)

(95% CI)

p-value

Meeting relative indication for chemotherapya

    

No

18/214

(8.4%)

26/227

(11.5%)

0.796 (0.434 - 1.459)

0.4593

Yes

48/325

(14.8%)

69/294

(23.5%)

0.606 (0.42 - 0.877)

0.0072

TAC = docetaxel, doxorubicin and cyclophosphamide

FAC = 5-fluorouracil, doxorubicin and cyclophosphamide

CI = confidence interval; ER = oestrogen receptor

PR = progesterone receptor

aER/PR-negative or Grade 3 or tumour size >5 cm

The estimated hazard ratio was using Cox proportional hazard model with treatment group as the factor.

Docetaxel as single agent

Two randomised phase III comparative studies, involving a total of 326 alkylating or 392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at the recommended dose and regimen of 100 mg/m2 every 3 weeks.

In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m2 every 3 weeks). Without affecting overall survival time (docetaxel 15 months vs. doxorubicin 14 months, p = 0.38) or time to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks, p = 0.54), docetaxel increased response rate (52% vs. 37%, p = 0.01) and shortened time to response (12 weeks vs. 23 weeks, p = 0.007). Three docetaxel patients (2%) discontinued the treatment due to fluid retention, whereas 15 doxorubicin patients (9%) discontinued due to cardiac toxicity (three cases of fatal congestive heart failure).

In anthracycline-failure patients, docetaxel was compared to the combination of mitomycin C and vinblastine (12 mg/m2 every 6 weeks and 6 mg/m2 every 3 weeks). Docetaxel increased response rate (33% vs. 12%, p<0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p = 0.0004) and prolonged overall survival (11 months vs. 9 months, p = 0.01).

During these two phase III studies, the safety profile of docetaxel was consistent with the safety profile observed in phase II studies (see section 4.8).

An open-label, multi-centre, randomised phase III study was conducted to compare docetaxel monotherapy and paclitaxel in the treatment of advanced breast cancer in patients whose previous therapy should have included an anthracycline. A total of 449 patients were randomised to receive either docetaxel monotherapy 100 mg/m2 as a 1-hour infusion or paclitaxel 175 mg/m2 as a 3 hour infusion. Both regimens were administered every 3 weeks.

Without affecting the primary endpoint, overall response rate (32% vs. 25%, p = 0.10), docetaxel prolonged median time to progression (24.6 weeks vs. 15.6 weeks; p<0.01) and median survival (15.3 months vs. 12.7 months; p = 0.03).

More grade 3/4 adverse events were observed for docetaxel monotherapy (55.4%) compared to paclitaxel (23.0%).

Docetaxel in combination with doxorubicin

One large randomised phase III study, involving 429 previously untreated patients with metastatic disease, has been performed with doxorubicin (50 mg/m2) in combination with docetaxel (75 mg/m2) (AT arm) versus doxorubicin (60 mg/m2) in combination with cyclophosphamide (600 mg/m2) (AC arm). Both regimens were administered on day 1 every 3 weeks.

• Time to progression (TTP) was significantly longer in the AT arm versus AC arm, p = 0.0138. The median TTP was 37.3 weeks (95% CI: 33.4-42.1) in AT arm and 31.9 weeks (95% CI: 27.4-36.0) in AC arm.

• Overall response rate (ORR) was significantly higher in the AT arm versus AC arm, p = 0.009. The ORR was 59.3% (95% CI: 52.8-65.9) in AT arm versus 46.5% (95% CI: 39.8-53.2) in AC arm.

In this study, AT arm showed a higher incidence of severe neutropenia (90% versus 68.6%), febrile neutropenia (33.3% versus 10%), infection (8% versus 2.4%), diarrhoea (7.5% versus 1.4%), asthenia (8.5% versus 2.4%), and pain (2.8% versus 0%) than AC arm. On the other hand, AC arm showed a higher incidence of severe anaemia (15.8% versus 8.5%) than AT arm, and, in addition, a higher incidence of severe cardiac toxicity: congestive heart failure (3.8% versus 2.8%), absolute LVEF decrease ≥20% (13.1% versus 6.1%), absolute LVEF decrease ≥30% (6.2% versus 1.1%). Toxic deaths occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC arm (1 due to septic shock and 3 due to congestive heart failure).

In both arms, quality of life measured by the EORTC questionnaire was comparable and stable during treatment and follow-up.

Docetaxel in combination with trastuzumab

Docetaxel in combination with trastuzumab was studied for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2, and who previously had not received chemotherapy for metastatic disease. One hundred eighty six patients were randomised to receive docetaxel (100 mg/m2) with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they had received prior adjuvant anthracyclines. The main test method used to determine HER2 positivity in this pivotal study was immunohistochemistry (IHC). A minority of patients were tested using fluorescence in-situ hybridisation (FISH). In this study, 87% of patients had disease that was IHC 3+, and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results are summarised in the following table:

Parameter

Docetaxel plus trastuzumab1

n = 92

Docetaxel1

n = 94

Response rate

(95% CI)

61%

(50-71)

34%

(25-45)

Median duration of response (months)

(95% CI)

11.4

(9.2-15.0)

5.1

(4.4-6.2)

Median TTP (months)

(95% CI)

10.6

(7.6-12.9)

5.7

(5.0-6.5)

Median survival (months)

(95% CI)

30.52

(26.8-ne)

22.12

(17.6-28.9)

TTP = time to progression; “ne” indicates that it could not be estimated or it was not yet reached.

1Full analysis set (intent-to-treat)

Estimated median survival

Docetaxel in combination with capecitabine

Data from one multi-centre, randomised, controlled phase III clinical study support the use of docetaxel in combination with capecitabine for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this study, 255 patients were randomised to treatment with docetaxel (75 mg/m2 as a 1-hour intravenous infusion every 3 weeks) and capecitabine (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). 256 patients were randomised to treatment with docetaxel alone (100 mg/m2 as a 1-hour intravenous infusion every 3 weeks). Survival was superior in the docetaxel + capecitabine combination arm (p = 0.0126). Median survival was 442 days (docetaxel + capecitabine) vs. 352 days (docetaxel alone). The overall objective response rates in the all-randomised population (investigator assessment) were 41.6% (docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive disease was superior in the docetaxel + capecitabine combination arm (p<0.0001). The median time to progression was 186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).

Non-small cell lung cancer

Patients previously treated with chemotherapy with or without radiotherapy

In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks) and overall survival were significantly longer for docetaxel at 75 mg/m2 compared to Best Supportive Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).

There was less use of morphinic analgesic (p<0.01), non-morphinic analgesics (p<0.01), other disease-related medications (p = 0.06) and radiotherapy (p<0.01) in patients treated with docetaxel at 75 mg/m2 compared to those with BSC.

The overall response rate was 6.8% in the evaluable patients, and the median duration of response was 26.1 weeks.

Docetaxel in combination with platinum agents in chemotherapy-naïve patients

In a phase III study, 1218 patients with unresectable stage IIIB or IV NSCLC, with KPS of 70% or greater, and who did not receive previous chemotherapy for this condition, were randomised to either docetaxel (T) 75 mg/mas a 1-hour infusion immediately followed by cisplatin (Cis) 75 mg/mover 30-60 minutes every 3 weeks (TCis), docetaxel 75 mg/m2 as a 1-hour infusion in combination with carboplatin (AUC 6 mg/ml•min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/m2 administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered on day 1 of cycles repeated every 4 weeks (VCis).

Survival data, median time to progression and response rates for two arms of the study are illustrated in the following table:

 

TCis

n = 408

VCis

n = 404

Statistical analysis

Overall survival

(Primary end-point)

   

Median survival (months)

11.3

10.1

Hazard ratio: 1.122

[97.2% CI: 0.937; 1.342]*

1-year survival (%)

46

41

Treatment difference: 5.4%

[95% CI: -1.1; 12.0]

2-year survival (%)

21

14

Treatment difference: 6.2%

[95% CI: 0.2; 12.3]

Median time to progression (weeks)

22.0

23.0

Hazard ratio: 1.032

[95% CI: 0.876; 1.216]

Overall response rate (%)

31.6

24.5

Treatment difference: 7.1%

[95% CI: 0.7; 13.5]

*Corrected for multiple comparisons and adjusted for stratification factors (stage of disease and region of treatment), based on evaluable patient population.

Secondary end-points included change of pain, global rating of quality of life by EuroQoL-5D, Lung Cancer Symptom Scale, and changes in Karnofsky performance status. Results on these end-points were supportive of the primary end-points results.

For docetaxel/carboplatin combination, neither equivalent nor non-inferior efficacy could be proven compared to the reference treatment combination VCis.

Prostate cancer

Metastatic castration-resistant prostate cancer

The safety and efficacy of docetaxel in combination with prednisone or prednisolone in patients with metastatic castration resistant prostate cancer were evaluated in a randomised multi-centre phase III study (TAX 327). A total of 1006 patients with KPS ≥60 were randomised to the following treatment groups:

• Docetaxel 75 mg/m2 every 3 weeks for 10 cycles.

• Docetaxel 30 mg/m2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles.

• Mitoxantrone 12 mg/m2 every 3 weeks for 10 cycles.

All 3 regimens were administered in combination with prednisone or prednisolone 5 mg twice daily, continuously.

Patients who received docetaxel every three weeks demonstrated significantly longer overall survival compared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weekly arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for the docetaxel arms versus the control arm are summarized in the following table:

Endpoint

Docetaxel every 3 weeks

Docetaxel every week

Mitoxantrone every 3 weeks

Number of patients

Median survival (months)

95% CI

Hazard ratio

95% CI

p-value *

335

18.9

(17.0-21.2)

0.761

(0.619-0.936)

0.0094

334

17.4

(15.7-19.0)

0.912

(0.747-1.113)

0.3624

337

16.5

(14.4-18.6)

--

--

--

Number of patients

PSA** response rate (%)

95% CI

p-value*

291

45.4

(39.5-51.3)

0.0005

282

47.9

(41.9-53.9)

<0.0001

300

31.7

(26.4-37.3)

--

Number of patients

Pain response rate (%)

95% CI

p-value*

153

34.6

(27.1-42.7)

0.0107

154

31.2

(24.0-39.1)

0.0798

157

21.7

(15.5-28.9)

--

Number of patients

Tumour response rate (%)

95% CI

p-value*

141

12.1

(7.2-18.6)

0.1112

134

8.2

(4.2-14.2)

0.5853

137

6.6

(3.0-12.1)

--

†Stratified log-rank test

*Threshold for statistical significance = 0.0175

**PSA: Prostate-Specific Antigen

Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every 3 weeks, it is possible that certain patients may benefit from docetaxel every week.

No statistical differences were observed between treatment groups for Global Quality of Life.

Metastatic hormone-sensitive prostate cancer

STAMPEDE study: The safety and efficacy of docetaxel administered concomitantly with standard of care (ADT) in patients with high-risk locally advanced or metastatic hormone-sensitive prostate cancer were evaluated in a randomised multi-centre, multi-arm multi-stage (MAMS) study with a seamless phase II/III design (STAMPEDE – MRC PR08). A total of 1776 male patients were allocated to the treatment arms of interest:

• Standard of care + docetaxel 75 mg/m², administered every 3 weeks for 6 cycles.

• Standard of care alone.

Docetaxel regimen was administered in combination with prednisone or prednisolone 5 mg twice daily continuously.

Among the 1776 randomised patients 1086 (61%) had metastatic disease, 362 were randomised to docetaxel in combination with standard of care, 724 received standard of care alone.

In these metastatic prostate cancer patients, the median overall survival was significantly longer in docetaxel treatment groups than in the standard of care alone group, with a median overall survival 19 months longer with the addition of docetaxel to standard of care (HR = 0.76, 95% CI = 0.62-0.92, p=0.005).

Efficacy results in metastatic prostate cancer patients for docetaxel arm versus control arm are summarized in the following table:

Efficacy of docetaxel in combination with prednisone or prednisolone and standard of care in the treatment of patients with metastatic hormone-sensitive prostate cancer (STAMPEDE)

Endpoint

Docetaxel + standard of care

Standard of care alone

Number of metastatic prostate cancer patients

Median overall survival (months)

95% CI

362

62

51-73

724

43

40-48

Adjusted hazard ratio

95% CI

p-valuea

0.76

(0.62-0.92)

0.005

Failure-Free survivalb

Median (months)

95% CI

20.4

16.8-25.2

12

9.6-12

Adjusted hazard ratio

95% CI

p-valuea

0.66

(0.57-0.76)

< 0.001

ap-value calculated from the likelihood ratio test and adjusted for all stratification factors (except center and planned hormone therapy) and stratified by trial period.

bFailure-free survival: time from randomization to first evidence of at least one of: biochemical failure (defined as a rise in PSA of 50% above the within-24-week nadir and above 4 ng/mL and confirmed by retest or treatment); progression either locally, in lymph nodes, or in distant metastases; skeletal-related event; or death from prostate cancer.

CHAARTED study: The safety and efficacy of docetaxel administered at the beginning of androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer were evaluated in a randomised Phase III multi-centre study (CHAARTED). A total of 790 male patients were allocated to the 2 treatment groups:

• ADT + docetaxel 75 mg/m² given at the beginning of ADT, administered every 3 weeks for 6 cycles.

• ADT alone.

The median overall survival was significantly longer in docetaxel treatment group than in the ADT alone group, with a median overall survival 13.6 months longer with the addition of docetaxel to ADT (hazard ratio (HR) = 0.61, 95% confidence interval (CI) = 0.47-0.80, p=0.0003).

Efficacy results or the docetaxel arm versus the control arm are summarized in the following table:

Efficacy of docetaxel and ADT in the treatment of patients with metastatic hormone-sensitive prostate cancer (CHAARTED)

Endpoint

Docetaxel + ADT

ADT alone

Number of patients

Median overall survival (months)

All patients

95% CI

Adjusted hazard ratio

397

57.6

49.1-72.8

0.61

393

44.0

34.4-49.1

--

95% CI

(0.47-0.80)

--

p-valuea

0.0003

--

Progression Free Survival

Median (months)

95% CI

Adjusted hazard ratio

95% CI

p-value*

19.8

16.7-22.8

0.60

0.51-0.72

P<0.0001

11.6

10.8-14.3

--

--

--

PSA response** at 6 months – N(%)

p-valuea*

127 (32.0)

<0.0001

77 (19.6)

--

PSA response** at 12 months – N(%)

p-valuea*

110 (27.7)

<0.0001

66 (16.8)

--

Time to castration-resistant prostate cancerb

Median (months)

95% CI

Adjusted hazard ratio

20.2

(17.2-23.6)

0.61

11.7

(10.8-14.7)

--

95% CI

(0.51-0.72)

--

p-valuea*

<0.0001

--

Time to clinical progressionc

Median (months)

33.0

19.8

95% CI

(27.3-41.2)

(17.9-22.8)

Adjusted hazard ratio

0.61

--

95% CI

(0.50-0.75)

--

p-valuea*

<0.0001

--

aTime to event variables: Stratified log-rank test.

Response rate variables: Fisher's Exact test.

*p-value for descriptive purpose.

**PSA response: Prostate-Specific Antigen response: PSA level <0.2 ng/mL measured for two consecutive measurements at least 4 weeks apart.

bTime to castration-resistant prostate cancer = time from randomization to PSA progression or clinical progression (i.e. increasing symptomatic bone metastases, progression per Response Evaluation Criteria in Solid Tumours (RECIST) criteria, or clinical deterioration due to cancer per the Investigator's opinion), whichever occurred first.

cThe time to clinical progression = the time from randomization until clinical progression (i.e. increased symptoms of bone metastases; progression according to RECIST; or clinical deterioration due to cancer according to the investigator's opinion).

Gastric adenocarcinoma

A multi-centre, open-label, randomised study was conducted to evaluate the safety and efficacy of docetaxel for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for metastatic disease. A total of 445 patients with KPS >70 were treated with either docetaxel (T) (75 mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and 5-fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The median number of cycles administered per patient was 6 (with a range of 1-16) for the TCF arm compared to 4 (with a range of 1-12) for the CF arm. Time to progression (TTP) was the primary endpoint. The risk reduction of progression was 32.1% and was associated with a significantly longer TTP (p = 0.0004) in favour of the TCF arm. Overall survival was also significantly longer (p = 0.0201) in favour of the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results are summarized in the following table:

Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma

Endpoint

TCF

n = 221

CF

n = 224

Median TTP (months)

(95% CI)

Hazard ratio

(95% CI)

*p-value

5.6

(4.86-5.91)

3.7

(3.45-4.47)

1.473

(1.189-1.825)

0.0004

Median survival (months)

(95% CI)

2-year estimate (%)

Hazard ratio

(95% CI)

*p-value

9.2

8.6

(8.38-10.58)

(7.16-9.46)

18.4

8.8

1.293

(1.041-1.606)

0.0201

Overall response rate (CR+PR) (%)

p-value

36.7

25.4

0.0106

Progressive disease as best overall response (%)

16.7

25.9

*Unstratified log-rank test

Subgroup analyses across age, gender and race consistently favoured the TCF arm compared to the CF arm.

A survival update analysis conducted with a median follow-up time of 41.6 months no longer showed a statistically significant difference although always in favour of the TCF regimen and showed that the benefit of TCF over CF is clearly observed between 18 and 30 months of follow-up.

Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favour of the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global health status on the QLQ-C30 questionnaire (p = 0.0121) and a longer time to definitive worsening of Karnofsky performance status (p = 0.0088) compared to patients treated with CF.

Head and neck cancer

Induction chemotherapy followed by radiotherapy (TAX 323)

The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a phase III, multi-centre, open-label, randomised study (TAX 323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomised to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 followed by 5-fluorouracil (F) 750 mg/m2 per day as a continuous infusion for 5 days. This regimen was administered every three weeks for 4 cycles in case at least a minor response (≥25% reduction in bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 followed by 5-fluorouracil (F) 1000 mg/m2 per day for 5 days. This regimen was administered every three weeks for 4 cycles in case at least a minor response (≥25% reduction in bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (PF/RT). Locoregional therapy with radiation was delivered either with a conventional fraction (1.8 Gy-2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy), or accelerated/hyperfractionated regimens of radiation therapy (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for accelerated regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed following chemotherapy, before or after radiotherapy. Patients on the TPF arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent. The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p = 0.0042 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow-up time of 33.7 months. Median overall survival was also significantly longer in favour of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.5 months respectively) with a 28% risk reduction of mortality, p = 0.0128. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with inoperable locally advanced SCCHN (intent-to-treat analysis)

Endpoint

Docetaxel +

Cis + 5-FU

n = 177

Cis + 5-FU

n = 181

Median progression free survival (months)

(95% CI)

11.4

(10.1-14.0)

8.3

(7.4-9.1)

Adjusted hazard ratio

(95% CI)

*p-value

0.70

(0.55-0.89)

0.0042

Median survival (months)

(95% CI)

18.6

(15.7-24.0)

14.5

(11.6-18.7)

Hazard ratio

(95% CI)

**p-value

0.72

(0.56-0.93)

0.0128

Best overall response to chemotherapy (%)

(95% CI)

67.8

(60.4-74.6)

53.6

(46.0-61.0)

***p-value

0.006

Best overall response to study treatment [chemotherapy +/- radiotherapy] (%)

(95% CI)

72.3

(65.1-78.8)

58.6

(51.0-65.8)

***p-value

0.006

Median duration of response to chemotherapy ± radiotherapy (months)

(95% CI)

n = 128

15.7

(13.4-24.6)

n = 106

11.7

(10.2-17.4)

Hazard ratio

(95% CI)

**p-value

0.72

(0.52-0.99)

0.0457

A hazard ratio of less than 1 favours docetaxel + cisplatin + 5-FU

*Cox model (adjustment for Primary tumour site, T and N clinical stages and PSWHO)

**Log-rank test

***Chi-square test

Quality of life parameters

Patients treated with TPF experienced significantly less deterioration of their Global health score compared to those treated with PF (p = 0.01, using the EORTC QLQ-C30 scale).

Clinical benefit parameters

The performance status scale, for head and neck (PSS-HN) subscales designed to measure understandability of speech, ability to eat in public, and normalcy of diet, was significantly in favour of TPF as compared to PF.

Median time to first deterioration of WHO performance status was significantly longer in the TPF arm compared to PF. Pain intensity score improved during treatment in both groups indicating adequate pain management.

Induction chemotherapy followed by chemoradiotherapy (TAX 324)

The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a randomised, multi-centre open-label, phase III study (TAX 324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomised to one of two arms. The study population comprised patients with technically unresectable disease, patients with low probability of surgical cure and patients aiming at organ preservation. The efficacy and safety evaluation solely addressed survival endpoints and the success of organ preservation was not formally addressed. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m2 administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of 5-fluorouracil (F) 1000 mg/m2/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to receive chemoradiotherapy (CRT) as per protocol (TPF/CRT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of 5-fluorouracil (F) 1000 mg/m2/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to receive CRT as per protocol (PF/CRT).

Patients in both treatment arms were to receive 7 weeks of CRT following induction chemotherapy with a minimum interval of 3 weeks and no later than 8 weeks after start of the last cycle (day 22 to day 56 of last cycle). During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks, for a total dose of 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time following completion of CRT. All patients on the docetaxel-containing arm of the study received prophylactic antibiotics. The primary efficacy endpoint in this study, overall survival (OS) was significantly longer (log-rank test, p = 0.0058) with the docetaxel-containing regimen compared to PF (median OS: 70.6 versus 30.1 months respectively), with a 30% risk reduction in mortality compared to PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54-0.90) with an overall median follow-up time of 41.9 months. The secondary endpoint, PFS, demonstrated a 29% risk reduction of progression or death and a 22 month improvement in median PFS (35.5 months for TPF and 13.1 for PF). This was also statistically significant with an HR of 0.71; 95% CI 0.56-0.90; log-rank test p = 0.004. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with locally advanced SCCHN (Intent-to-Treat Analysis)

Endpoint

Docetaxel + Cis + 5-FU

Cis + 5-FU

n = 255

n = 246

Median overall survival (months)

70.6

30.1

(95% CI)

(49.0-NA)

(20.9-51.5)

Hazard ratio:

(95% CI)

*p-value

0.70

(0.54-0.90)

0.0058

Median PFS (months)

35.5

13.1

(95% CI)

(19.3-NA)

(10.6 - 20.2)

Hazard ratio:

(95% CI)

**p-value

0.71

(0.56 - 0.90)

0.004

Best overall response (CR + PR) to chemotherapy (%)

(95% CI)

71.8

(65.8-77.2)

64.2

(57.9-70.2)

***p-value

0.070

Best overall response (CR + PR) to study treatment [chemotherapy +/- chemoradiotherapy] (%)

(95%CI)

76.5

(70.8-81.5)

71.5

(65.5-77.1)

***p-value

0.209

A hazard ratio of less than 1 favours docetaxel + cisplatin + fluorouracil

*un-adjusted log-rank test

**un-adjusted log-rank test, not adjusted for multiple comparisons

***Chi square test, not adjusted for multiple comparisons

NA-not applicable

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with docetaxel in all subsets of the paediatric population in breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not including type II and III less differentiated nasopharyngeal carcinoma (see section 4.2 for information on paediatric use).

 


 

Absorption

The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20-115 mg/m2 in phase I studies. The kinetic profile of docetaxel is dose independent and consistent with a three-compartment pharmacokinetic model with half-lives for the α, β, and γ phases of 4 min, 36 min and 11.1 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment.

Distribution

Following the administration of a 100 mg/m2 dose given as a 1-hour infusion a mean peak plasma level of 3.7 μg/ml was obtained with a corresponding AUC of 4.6 h.μg/ml. Mean values for total body clearance and steady-state volume of distribution were 21 l/h/m2 and 113 l, respectively. Inter individual variation in total body clearance was approximately 50%. Docetaxel is more than 95% bound to plasma proteins.

Elimination

A study of 14C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated in both the urine and faeces following cytochrome P450-mediated oxidative metabolism of the tert-butyl ester group, within seven days, the urinary and faecal excretion accounted for about 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in faeces is excreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolites and very low amounts of unchanged medicinal product.

Special populations

Age and gender

A population pharmacokinetic analysis has been performed with docetaxel in 577 patients. Pharmacokinetic parameters estimated by the model were very close to those estimated from phase I studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient.

Hepatic impairment

In a small number of patients (n = 23) with clinical chemistry data suggestive of mild to moderate liver function impairment (ALT, AST ≥1.5 times the ULN associated with alkaline phosphatase ≥2.5 times the ULN), total clearance was lowered by 27% on average (see section 4.2).

Fluid retention

Docetaxel clearance was not modified in patients with mild to moderate fluid retention and there are no data available in patients with severe fluid retention.

Combination therapy

Doxorubicin

When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their co-administration.

Capecitabine

Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC) and no effect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5'-DFUR.

Cisplatin

Clearance of docetaxel in combination therapy with cisplatin was similar to that observed following monotherapy. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion is similar to that observed with cisplatin alone.

Cisplatin and 5-fluorouracil

The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid tumours had no influence on the pharmacokinetics of each individual medicinal product.

Prednisone and dexamethasone

The effect of prednisone on the pharmacokinetics of docetaxel administered with standard dexamethasone premedication has been studied in 42 patients.

Prednisone

No effect of prednisone on the pharmacokinetics of docetaxel was observed.


The carcinogenic potential of docetaxel has not been studied.

Docetaxel has been shown to be mutagenic in the in vitro micronucleus and chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in the mouse. However, it did not induce mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent with the pharmacological activity of docetaxel.

Undesirable effects on the testis observed in rodent toxicity studies suggest that docetaxel may impair male fertility.


 

 

Material Name

Function

Amount (mg)/one vial(20mg/1mL)*

Amount (mg)/one vial(80mg/4mL)*

Docetaxel trihydrate

Active ingredient

21.34mg (Equivalent to 20mg of Docetaxel)

85.35mg (Equivalent to 80mg of Docetaxel)

Polysorbate 80

Vehicle

540mg

2160mg

Dehydrated alcohol

Solvent

395mg

1580mg

Anhydrous citric acid**

pH adjuster

q.s.

q.s.

Nitrogen ***

Processing aid

q.s.

q.s.

 

 

 

 *Amount per unit doesn’t include the overfill.

**Anhydrous citric acid is used to adjust the pH of the drug product.

***Nitrogen is used for vacuum breaking during vacuum concentration process.

 

 


This medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.6.

 


Unopened vial 24 months After opening of the vial Each vial is for single use and should be used immediately after opening. If not used immediately, in-use storage times and conditions are the responsibility of the user. Once added to the infusion bag From a microbiological point of view, reconstitution/dilution must take place in controlled and aseptic conditions and the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. Once added as recommended into the infusion bag, the docetaxel infusion solution, if stored below 25°C, is stable for 6 hours. It should be used within 6 hours (including the one hour infusion intravenous administration). In addition, physical and chemical in-use stability of the infusion solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when stored between 2 to 8°C. Docetaxel infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.

Store below 25°C.

Keep the vial in the outer carton in order to protect from light.

For storage conditions of the diluted medicinal product, see section 6.3.

 


20 mg per mL Single-Dose Vial 1 vial per carton

80 mg per 4 mL Single-Dose Vial 1 vial per carton

Tadoxel ®, USP 20 mg per 1 mL : 20 mg docetaxel in 1 mL in 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol. The vial is in a blister pack in one carton.

Tadoxel ®, USP 80 mg per 4 mL : 80 mg docetaxel in 4 mL in 50/50 (v/v) ratio polysorbate 80/dehydrated alcohol.


Tadoxel ® is an antineoplastic agent and, as with other potentially toxic agents, caution should be exercised during handling and preparing solutions of Tadoxel ®.

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

Guidelines for the safe handling and disposal of antineoplastic agents

Preparation

Local guidelines on safe preparation and handling should be consulted.

Cytotoxic agents should only be prepared and handled by personnel trained in the safe handling of such preparations. Pregnant personnel should not handle cytotoxic agents.

All personnel involved with handling cytotoxic agents should be adequately protected with appropriate personal protective equipment, including protective disposable gloves, eye shield, mask and long-sleeved gown. Preparation and manipulation of solutions should be performed in a designated handling area.

Contamination

In the event of skin contact, thoroughly wash the affected area with soap and water, taking care not to abrade the skin. A bland cream may be used to treat transient stinging of the skin. In the event of contact with the eyes, irrigate with copious amounts of water or sodium chloride 0.9%. Seek medical evaluation.

In the event of spillage, trained personnel wearing appropriate personal protective equipment should remove the maximum amount of material by use of a cytotoxic drug spill kit or designated absorbent materials. The area should be rinsed with copious amounts of water. All contaminated cleaning materials should be disposed of as described below.

Disposal

All contaminated waste materials (including sharps, containers, absorbent materials, unused solutions, etc.) should be placed in a designated sealed and labelled impervious waste disposal bag or rigid waste container, and incinerated in accordance with local procedures for destruction of hazardous waste.

Instructions for preparation

Refer to section 6.3 Shelf life.

Inspect visually prior to use. Only clear solutions without visible particles should be used. Must be diluted before use.

Contact of Tadoxel ® with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimise patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, Tadoxel ®  should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Inject the required volume into a 250 ml infusion bag or bottle containing either:

• Sodium Chloride 9 mg/ml (0.9%)

• Glucose 50 mg/ml (5%)

If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/ml docetaxel is not exceeded.

Compatibility: It is not recommended to mix docetaxel with other drugs.

Administration: For instructions on administration see Section 4.2.

Allow the required number of boxes of Docetaxel concentrate for solution for infusion to stand below 25°C for 5 minutes before use.

More than one vial of Docetaxel concentrate for solution for infusion may be necessary to obtain the required dose for the patient. Aseptically withdraw the required amount of Docetaxel concentrate for solution for infusion using a calibrated syringe.

In Docetaxel 20 mg /ml vial the concentration of docetaxel is 20 mg/ml.

The required volume of Docetaxel concentrate for solution for infusion must be injected into a 250 ml infusion bag or bottle containing either glucose solution 50 mg/ml (5%) or sodium chloride 9 mg/ml (0.9%) solution for infusion.

If a dose greater than 190 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/ml docetaxel is not exceeded.

Mix the infusion bag or bottle manually using a rocking motion.

The infusion bag solution should be used within 8 hours below 25°C including the one hour infusion to the patient.

As with all parenteral products, Docetaxel infusion solution should be visually inspected prior to use, solutions containing a precipitate should be discarded.

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

 


c. Marketing authorization holder: MS Pharma Saudi, Riyadh, Kingdome Saudi Arabia. medical-ksa@mspharma.com

Feb,2021
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