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Read all of this leaflet carefully before you start using this medicine because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What Ogivri is and what it is used for
2. What you need to know before you are given Ogivri
3. How Ogivri is given
4. Possible side effects
5. How to store Ogivri
6. Contents of the pack and other information
1. What Ogivri is and what it is used for
Ogivri contains the active substance trastuzumab, which is a monoclonal antibody. Monoclonal antibodies attach to specific proteins or antigens. Trastuzumab is designed to bind selectively to an antigen called human epidermal growth factor receptor 2 (HER2). HER2 is found in large amounts on the surface of some cancer cells where it stimulates their growth. When Ogivri binds to HER2 it stops the growth of such cells and causes them to die.
Your doctor may prescribe Ogivri for the treatment of breast and gastric cancer when:
· You have early breast cancer, with high levels of a protein called HER2.
· You have metastatic breast cancer (breast cancer that has spread beyond the original tumour) with high levels of HER2. Ogivri may be prescribed in combination with the chemotherapy medicine paclitaxel or docetaxel as first treatment for metastatic breast cancer or it may be prescribed alone if other treatments have proved unsuccessful. It is also used in combination with medicines called aromatase inhibitors with patients with high levels of HER2 and hormone receptor-positive metastatic breast cancer (cancer that is sensitive to the presence of female sex hormones).
· You have metastatic gastric cancer with high levels of HER2, when it is in combination with the other cancer medicines capecitabine or 5-fluorouracil and cisplatin.
2. What you need to know before you are given Ogivri
Do not use Ogivri:
· if you are allergic to trastuzumab, murine (mouse) proteins, or any of the other ingredients of this medicine (listed in section 6).
· if you have severe breathing problems at rest due to your cancer or if you need oxygen treatment.
Warnings and precautions
Your doctor will closely supervise your therapy.
Heart checks
Treatment with Ogivri alone or with a taxane may affect the heart, especially if you have ever used an anthracycline (taxanes and anthracyclines are two other kinds of medicine used to treat cancer).
The effects may be moderate to severe and could cause death. Therefore, your heart function will be checked before, during (every three months) and after (up to two to five years) treatment with Ogivri. If you develop any signs of heart failure (inadequate pumping of blood by the heart), your heart function may be checked more frequently (every six to eight weeks), you may receive treatment for heart failure or you may have to stop Ogivri treatment.
Talk to your doctor, pharmacist or nurse before you are given Ogivri if:
• you have had heart failure, coronary artery disease, heart valve disease (heart murmurs), high blood pressure, taken any high blood pressure medicine or are currently taking any high blood pressure medicine.
• you have ever had or are currently using a medicine called doxorubicin or epirubicin (medicines used to treat cancer). These medicines (or any other anthracyclines) can damage heart muscle and increase the risk of heart problems with Ogivri.
• you suffer from breathlessness, especially if you are currently using a taxane. Ogivri can cause breathing difficulties, especially when it is first given. This could be more serious if you are already breathless. Very rarely, patients with severe breathing difficulties before treatment have died when they were given Ogivri.
• you have ever had any other treatment for cancer.
If you receive Ogivri with any other medicine to treat cancer, such as paclitaxel, docetaxel, an aromatase inhibitor, capecitabine, 5-fluorouracil, or cisplatin you should also read the patient information leaflets for these products.
Children and adolescents
Ogivri is not recommended for anyone under the age of 18 years.
Other medicines and Ogivri
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
It may take up to 7 months for Ogivri to be removed from the body. Therefore, you should tell your doctor, pharmacist or nurse that you have had Ogivri if you start any new medicine in the 7 months after stopping treatment.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor, pharmacist or nurse for advice before taking this medicine.
Pregnancy
You should use effective contraception during treatment with Ogivri and for at least 7 months after treatment has ended.
· Your doctor will advise you of the risks and benefits of taking Ogivri during pregnancy. In rare cases, a reduction in the amount of (amniotic) fluid that surrounds the developing baby within the womb has been observed in pregnant women receiving trastuzumab. This condition may be harmful to your baby in the womb and has been associated with the lungs not developing fully resulting in foetal death.
Breast-feeding
Do not breast-feed your baby during Ogivri therapy and for 7 months after the last dose of Ogivri as this medicine may pass to your baby through your breast milk. Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Ogivri may affect your ability to drive a car or operate machines. If during treatment you experience symptoms, such as chills or fever, you should not drive or use machines until these symptoms disappear.
Ogivri contains sorbitol (E420)
Ogivri 420 mg powder for concentrate for solution for infusion.
This medicine contains 322.6 mg sorbitol in each vial.
Sorbitol is a source of fructose. If you have hereditary fructose intolerance (HFI), a rare genetic disorder, you must not receive this medicine. Patients with HFI cannot break down fructose, which may cause serious side effects.
You must tell your doctor before receiving this medicine if you have HFI or if you can no longer take sweet foods or drinks because you feel sick, vomit or get unpleasant effects such as bloating, stomach cramps or diarrhoea.
3. How Ogivri is given
Before starting the treatment your doctor will determine the amount of HER2 in your tumour. Only patients with a large amount of HER2 will be treated with Ogivri. Ogivri should only be given by a doctor or nurse. Your doctor will prescribe a dose and treatment regimen that is right for you. The dose of Ogivri depends on your body weight.
The first dose of your treatment is given over 90 minutes and you will be observed by a health professional while it is being given in case you have any side effects. If the first dose is well tolerated the next doses may be given over 30 minutes (see section 2 under “Warnings and precautions”). The number of infusions you receive will depend on how you respond to the treatment. Your doctor will discuss this with you.
Ogivri is given as an infusion into a vein (intravenous infusion, drip), this intravenous formulation is not for subcutaneous use and should be given as an intravenous infusion only.
For early breast cancer, metastatic breast cancer and metastatic gastric cancer, Ogivri is given every 3 weeks. Ogivri may also be given once a week for metastatic breast cancer.
In order to prevent medication errors it is important to check the vial labels to ensure that the medicine being prepared and given is Ogivri (trastuzumab) and not trastuzumab emtansine.
If you stop using Ogivri
Do not stop using this medicine without talking to your doctor first. All doses should be taken at the right time every week or every three weeks (depending on your dosing schedule). This helps your medicine work as well as it can.
It may take up to 7 months for Ogivri to be removed from your body. Therefore, your doctor may decide to continue to check your heart functions, even after you finish treatment.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some of these side effects may be serious and may lead to hospitalisation.
During an Ogivri infusion, chills, fever and other flu like symptoms may occur. These are very common (may affect more than 1 in 10 people).
Other infusion-related symptoms are: feeling sick (nausea), vomiting, pain, increased muscle tension and shaking, headache, dizziness, breathing difficulties, wheezing, high or low blood pressure, heart rhythm disturbances (palpitations, heart fluttering or irregular heart beat), swelling of the face and lips, rash and feeling tired.
Some of these symptoms can be serious and some patients have died (see section 2 under “Warnings and precautions”).
These effects mainly occur with the first intravenous infusion (“drip” into your vein) and during the first few hours after the start of the infusion. They are usually temporary. You will be observed by a health care professional during the infusion and for at least six hours after the start of the first infusion and for two hours after the start of other infusions. If you develop a reaction, they will slow down or stop the infusion and may give you treatment to counteract the side effects. The infusion may be continued after the symptoms improve.
Occasionally, symptoms start later than six hours after the infusion begins. If this happens to you, contact your doctor immediately. Sometimes, symptoms may improve and then get worse later.
Serious side effects
Other side effects can occur at any time during treatment with Ogivri, not just related to an infusion. Tell a doctor or nurse straight away, if you notice any of the following side effects:
· Heart problems can sometimes occur during treatment and occasionally after treatment has stopped and can be serious. They include weakening of the heart muscle possibly leading to heart failure, inflammation of the lining around the heart and heart rhythm disturbances. This can lead to symptoms such as breathlessness (including breathlessness at night), cough, fluid retention (swelling) in the legs or arms, palpitations (heart fluttering or irregular heart beat) (see 2. Heart checks).
Your doctor will monitor your heart regularly during and after treatment but you should tell your doctor immediately if you notice any of the above symptoms.
· Tumour lysis syndrome (a group of metabolic complications occurring after cancer treatment characterised by high blood levels of potassium and phosphate, and low blood levels of calcium). Symptoms may include kidney problems (weakness, shortness of breath, fatigue and confusion), heart problems (fluttering of the heart or a faster or slower heartbeat), seizures, vomiting or diarrhoea and tingling in the mouth, hands or feet.
If you experience any of the above symptoms when your treatment with Ogivri has finished, you should see your doctor and tell them that you have previously been treated with Ogivri.
Very common side effects: may affect more than 1 in 10 people
· infections
· diarrhoea
· constipation
· heartburn (dyspepsia)
· fatigue
· skin rashes
· chest pain
· abdominal (stomach) pain
· joint pain
· low counts of red blood cells and white blood cells (which help fight infection) sometimes with fever
· muscle pain
· conjunctivitis (discharge with itching of the eyes and crusty eyelids)
· watery eyes
· nose bleeds
· runny nose
· hair loss
· tremor
· hot flush
· dizziness
· nail disorders
· weight loss
· loss of appetite
· inability to sleep (insomnia)
· altered taste
· low platelet count
· bruising
· numbness or tingling of the fingers and toes
· redness, swelling or sores in your mouth and/or throat
· pain, swelling, redness or tingling of hands and/or feet
· breathlessness
· headache
· cough
· vomiting
· nausea (feeling sick)
Common side effects: may affect up to 1 in 10 people
· allergic reactions
· dry mouth and skin
· throat infections
· dry eyes
· bladder and skin infections
· sweating
· shingles
· feeling weak and unwell
· inflammation of the breast
· anxiety
· inflammation of the liver
· depression
· kidney disorders
· abnormal thinking
· increased muscle tone or tension (hypertonia)
· asthma
· infection of lungs
· pain in the arms and/or legs
· lung disorders
· itchy rash
· back pain
· sleepiness (somnolence)
· neck pain
· haemorrhoids (swelling of blood vessels around the back passage)
· bone pain
· itchiness
· acne
· leg cramps
Uncommon side effects: may affect up to 1 in 100 people
· deafness
· bumpy rash
· blood infection
Rare side effects: may affect up to 1 in 1000 people
· muscle weakness
· jaundice (yellowing of the skin and the whites of the eyes)
· inflammation or scarring of the lungs
Side effects of not known frequency: frequency cannot be estimated from the available data
· abnormal or impaired blood clotting
· anaphylactic reactions (serious sudden allergic reaction with symptoms such as rash, itchy skin, difficulty breathing or feeling dizzy or faint)
· high potassium levels
· swelling of the brain
· swelling or bleeding at the back of the eyes
· shock (a dangerous decrease of blood pressure causing symptoms like rapid, shallow breathing, cold, clammy skin, a rapid, weak pulse, dizziness, weakness and fainting)
· swelling of the lining of the heart
· slow heart rate
· abnormal heart rhythm
· respiratory distress
· respiratory failure
· acute accumulation of fluid in the lungs
· acute narrowing of the airways
· abnormally low oxygen levels in the blood
· difficulty in breathing when lying flat
· liver damage/failure
· swelling of the face, lips and throat
· kidney failure
· abnormally low levels of fluid around baby in womb
· failure of lungs to develop in the womb
· abnormal kidney development in the womb
Some of the side effects you experience may be due to your underlying breast cancer. If you receive
Ogivri in combination with chemotherapy, some of them may also be due to the chemotherapy.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. To report adverse events and/or product complaints, find below the details:
Saudi Arabia:
The National Pharmacovigilance Centre (NPC):
Fax: +966-11-205-7662
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa/Mylan
Other Countries:
Please contact the relevant competent authority.
Mylan
• Website: www.viatris.in
• E-mail: pharmacovigilance.india@viatris.in or contactmppl@viatris.com
5. How to store Ogivri
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 outer carton and on the vial label after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C – 8°C).
Infusion solutions should be used immediately after dilution. Do not use Ogivri if you notice any particulate matter or discoloration prior to administration.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What Ogivri contains
- The active substance is trastuzumab. Each vial contains; 420 mg trastuzumab that has to be
dissolved in 20 mL of
- The resulting solution contains approximately 21 mg/mL trastuzumab.
- The other ingredient(s) are L-histidine hydrochloride, L-histidine, sorbitol (E420 (see section 2
“Ogivri contains sorbitol”)), macrogol 3350, hydrochloric acid and sodium hydroxide (for pH
adjustment).
Marketing Authorization Holder
Mylan GmBH
Thurgauerstrasse 40, Zurich,
Zurich CH-8050, Switzerland
Manufacturer:
M/s. Biocon Biologics India Limited
Block No. B1, B2, Q13 of Q1 and W20 , Special Economic Zone
Plot Nos. 2, 3, 4 & 5, Phase-IV
Bommasandra-Jigani Link Road
Bommasandra Post
Bengaluru - 560 099, India
The following information is intended for healthcare professionals only
Always keep this medicine in the closed original pack at a temperature of 2ºC – 8 ºC in a refrigerator. A vial of Ogivri reconstituted with water for injections (not supplied) is stable for 10 days at 2ºC – 8ºC after reconstitution and must not be frozen.
Ogivri should be carefully handled during reconstitution. Causing excessive foaming during reconstitution or shaking the reconstituted Ogivri may result in problems with the amount of Ogivri that can be withdrawn from the vial.
Ogivri 420 mg powder for concentrate for solution for infusion
Appropriate aseptic technique should be used. Each 420 mg vial of Ogivri is reconstituted with 20 mL of sterile water for injections (not supplied). Use of other reconstitution solvents should be avoided. This yields a 21 mL solution for single-dose use, containing approximately
21 mg/mL trastuzumab. A volume overage of 4.8 % ensures that the labelled dose of 420 mg can be withdrawn from each vial.
Ogivri vial |
| Volume of sterile water for injections |
| Final concentration |
420 mg vial | + | 20 mL | = | 21 mg/mL |
Instructions for reconstitution
1) Using a sterile syringe, slowly inject the appropriate volume (as noted above) of water for injections in the vial containing the lyophilised Ogivri, directing the stream into the lyophilised cake.
2) Swirl vial gently to aid reconstitution. DO NOT SHAKE!
Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The reconstituted Ogivri results in a colourless to pale yellow transparent solution and should be essentially free of visible particulates.
Determine the volume of the solution required:
• based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose of 2 mg trastuzumab/kg body weight:
Volume (mL) = Body weight (kg) x dose (4 mg/kg for loading or 2 mg/kg for maintenance)
21 (mg/mL, concentration of reconstituted solution)
• based on a loading dose of 8 mg trastuzumab/kg body weight, or a subsequent 3-weekly dose of 6 mg trastuzumab/kg body weight:
Volume (mL) = Body weight (kg) x dose (8 mg/kg for loading or 6 mg/kg for maintenance)
21 (mg/mL, concentration of reconstituted solution)
The appropriate amount of solution should be withdrawn from the vial and added to a polyvinylchloride, polyethylene or polypropylene infusion bag containing 250 mL of sodium chloride 9 mg/mL (0.9%) solution for injection. Do not use with glucose-containing solutions.
The bag should be gently inverted to mix the solution in order to avoid foaming. Parenteral solutions should be inspected visually for particulates and discoloration prior to administration. Once the infusion is prepared it should be administered immediately. If diluted aseptically, it may be stored for up to 90 days at 2°C – 8°C and 24 hours at temperatures not exceeding 30°C.
يُرجى ﻘﺭﺍءﺓ ﻫﺫﻩ ﺍﻟﻧﺷﺭﺓ ﺟﻳدًا ﻗﺑﻝ البدء في استخدام ﻫﺫﺍ ﺍﻟﺩﻭﺍء، ﺣﻳﺙ ﺃﻧﻬﺎ ﺗﺣﺗﻭﻯ ﻋﻠﻰ ﻣﻌﻠﻭﻣﺎﺕ مهمة لك.
- احتفظ بهذه النَّشرة؛ فقد تحتاج إلى قراءتها مرة أخرى.
- إذا كانت لديك أية أسئلة إضافية، فاستشر الطبيب المعالج لك أو الصيدلي الخاص بك أو الممرض(ة) المتابع (ة) لحالتك.
- إذا عانيت من أية آثار جانبية، فتحدث إلى الطبيب المعالج لك أو الصيدلي الخاص بك أو ﺍﻟﻣﻣﺭﺽ (ة) المتابع(ة) لحالتك. يشمل ذلك أية آثار جانبية محتملة غير مُدرجة في هذه النشرة. انظر القسم رقم 4.
محتويات هذه النَّشرة:
1. ما هو دواء أوجيفري؟ ﻭﻣﺎ ﻫﻲ ﺩﻭﺍﻋﻲ ﺍﺳﺗﻌﻣﺎﻟﻪ؟
2. ﻣﺎ ﺍﻟﺫﻱ ﻳﺟﺏ ﻋﻠﻳﻙ ﻣﻌﺭﻓﺗﻪ ﻗﺑﻝ أن يتم إعطائك دواء أوجيفري؟
3. كيف يتم إعطائك دواء أوجيفري.
4. الآثار الجانبية المُحتمَلة.
5. كيفية حفظ دواء أوجيفري.
6. محتويات العبوة ومعلومات أخرى
1. ما هو دواء أوجيفري؟ وما هي دواعي استعماله؟
يحتوي دواء أوجيفري على المادة الفعالة تراستوزوماب وهي أجسام مضادة أحادية النسيلة. ترتبط الأجسام المضادة وحيدة النسيلة ببروتينات أو مستضدات مُحددة. يٌستخدم تراستوزوماب للارتباط بمستضد انتقائيًا (اختياريًا) يُعرف باسم مستقبل عامل نمو البشرة 2(HER2). حيث تم اكتشاف وجود أعداد كبيرة من مستقبلات عامل نمو البشرة 2 على سطح بعض الخلايا السرطانية التي تحفز نموها. عندما يرتبط دواء أوجيفري بمستقبلات عامل نمو البشرة 2، فإنه يعمل على وقف نمو هذه الخلايا مما يؤدي إلى تلفها.
قد يصف الطبيب المعالج لك دواء أوجيفري لعلاج سرطان الثدي وسرطان المعدة في الحالات التالية:
· إذا كنت تعانين من سرطان الثدي في مرحلة مبكرة، مع ارتفاع مستويات البروتينات المعروفة باسم مستقبلات عامل نمو البشرة 2.
· إذا كنتِ تعانين من سرطان الثدي النقيلي (سرطان الثدي الناجم عن انتشار الورم الأصلي) مع ارتفاع معدلات مستقبلات عامل نمو البشرة2. قد يتم وصف دواء أوجيفري بالتزامن مع العلاج الكيميائي باستخدام باكليتاكسيل أو دوسيتاكسيل كعلاج أولي لسرطان الثدي النقيلي أو يمكن استخدامه بمفرده إذا ثبت عدم فعالية العلاجات الأخرى. يُستخدم أيضًا بالتزامن مع أدوية تُعرف باسم مثبطات الأروماتيز في المرضى الذين يعانون من ارتفاع معدلات مستقبلات عامل نمو البشرة 2 وسرطان الثدي النقيلي الإيجابي لمستقبلات الهرمونات الأنثوية (أحد السرطانات المرتبطة بالهرمونات الجنسية الأنثوية).
· إذا كنت تعاني من سرطان المعدة النقيلي مع ارتفاع معدلات مستقبلات عامل نمو البشرة 2، عندما يتم استخدام دواء أوجيفري بالتزامن مع الأدوية الأخرى المضادة للسرطان مثل: كابيسيتابين أو 5 فلورويوراسيل وسيسبلاتين.
2. ﻣﺎ ﺍﻟﺫﻱ ﻳﺟﺏ ﻋﻠﻳﻙ ﻣﻌﺭﻓﺗﻪ ﻗﺑﻝ أن يتم إعطائك دواء أوجيفري؟
يحظر عليك استخدام دواء أوجيفري في الحالات التَّالية:
· إذا كنت تعاني من حساسية تجاه المادة الفعّالة تراستوزوماب أو البروتينات الفَأْرِيَةّ (الفئران) أو تجاه أيٍّ مكون من المكونات الأخرى الداخلة في تركيب هذا الدَّواء (المٌدرجة في القسم رقم 6).
· • إذا كنت تعاني من اضطرابات شديدة أثناء التَّنفس في وضع الراحة ناجمة عن إصابتك بالسرطان أو إذا كنت تحتاج إلى العلاج بالأكسجين.
تحذيرات واحتياطات
سيتابع الطبيب الخاص بك علاج حالتك بعناية عن قرب.
فحوصات القلب
قد يؤثر العلاج باستخدام دواء أوجيفري بمفرده أو بالتزامن مع تاكسان على القلب، خاصة إذا كنت قد استخدمت دواء أنثراسيكلين مسبقًا (حيث يُعد كلًا من تاكسان وأنثراسيكلين نوعين أخرين يتم استخدامهما كأدوية لعلاج السرطان).
يتراوح معدل الآثار الناجمة عن استخدام دواء أوجيفري على القلب من متوسطة إلى خطيرة وقد تكون مسببة للوفاة. ولذلك، سيتم فحص وظائف القلب لديك قبل العلاج وأثناء استخدامه، حيث سيتم فحص القلب بشكل دوري (كل ثلاثة أشهر)، ويستمر متابعة الفحص بعد إيقاف العلاج باستخدام دواء أوجيفري (خلال مدة تتراوح من سنتين إلى خمس سنوات). إذا ظهرت عليك أي أعراض تدل على الإصابة بفشل القلب (عدم ضخ القلب لكمية كفاية من الدم)، فقد يتم فحص وظائف القلب بصورة متكررة (كل ستة إلى ثمانية أسابيع)، وقد تتلقى علاجًا لفشل القلب أو قد تضطر إلى إيقاف العلاج باستخدام دواء أوجيفري.
تحدث إلى الطبيب المعالج لك أو الصيدلي الخاص بك أو الممرض(ة) المتابع (ة) لحالتك قبل استخدام دواء أوجيفري في الحالات التالية:
• إذا كنت قد عانيت من فشل القلب أو مرض الشريان التاجي أو أمراض صمامات القلب (النفخات القلبية) أو ارتفاع ضغط الدم أو إذا كنت تستخدم أي دواء مضاد لارتفاع ضغط الدم أو تتناول حاليًا أي دواء لارتفاع ضغط الدم؛
• إذا تناولت مسبقًا أو إذا كنت تٌستخدم حاليًا دواء يُعرف بدوكسوروبيسين أو إيبيروبوسين (أدوية تستخدم لعلاج السرطان). يمكن لهذه الأدوية (أو أي أدوية أخرى من فئة أنثراسيكلين) أن تدمر عضلة القلب وتزيد من خطر الإصابة بأمراض القلب أثناء استخدام أوجيفري.
• إذا كنت تعاني من ضيق في التنفس، خاصة إذا كنت تستخدم تاكسان في الفترة الحالية. حيث يمكن يؤدي استخدام دواء أوجيفري إلى صعوبات في التنفس، خاصة عندما يتم إعطاؤه لأول مرة. قد يُعد ذلك أكثر خطرًا إذا كنت تعاني بالفعل من ضيق التنفس. يعد من النادر جدًا أن يتعرض المرضى إلى الوفاة نتيجة لاستخدام دواء أوجيفري إذا كانوا يعانون بالفعل من مشاكل خطيرة بالجهاز التنفسي قبل استخدامه.
• إذا استخدمت مسبقًا أية أدوية أخرى لعلاج السرطان.
كما ينبغي عليك أيضًا، إذا كنت تتلقي العلاج باستخدام دواء أوجيفري بالتزامن مع أية ادوية أخري لعلاج السرطان مثل باكليتاكسيل أو مثبط الأروماتيز أو كابيسيتابين أو 5 فلورويوراسيل أو سيسبلاتين، يُرجى قراءة نشرات العبوة المُرفقة مع هذه الأدوية.
الاستخدام في المرضى من الأطفال والمراهقين
لا يُوصى باستخدام دواء أوجيفري في المرضى الذين تقل أعمارهم عن 18 عامًا.
استخدام دواء أوجيفري مع الأدوية الأخرى
يُرجى إبلاغ الطبيب المعالج لك أو الصيدلي الخاص بك أو الممرض(ة) المتابع(ة) لحالتك إذا كنت تتناول أو تناولت مؤخرًا أو قد تتناول أية أدوية أخرى.
قد يستغرق التخلص من دواء أوجيفري من الجسم لمدة تصل إلى سبعة أشهر. ولذلك ينبغي إبلاغ الطبيب المعالج لك أو الصيدلي الخاص بك أو الممرض(ة) المتابع (ة) لحالتك بأنك كنت تستخدم دواء أوجيفري عند البدء في استخدام أي دواء آخر جديد في غضون سبعة أشهر عقب انتهاء مرحلة العلاج.
الحمل والرضاعة الطبيعية
إذا كنتِ حاملًا أو تمارسين الرضاعة الطبيعية أو تعتقدين أنكِ قد تكونين حاملاً أو تخططين للحمل، فاستشيري الطبيب المعالج لكِ أو الصيدلي الخاص بكِ أو الممرض (ة) المتابع (ة) لحالتك للحصول على النصيحة قبل استخدام هذا الدَّواء.
الحمل
· يجب عليكِ استخدام وسائل فعّالة لمنع الحمل أثناء العلاج باستخدام دواء أوجيفري ولمدة سبعة أشهر على الأقل عقب انتهاء فترة العلاج.
· سيقوم الطبيب المعالج لكِ بتقديم النصائح المتعلقة بمخاطر وفوائد استخدام دواء أوجيفري أثناء فترة الحمل. تم ملاحظة انخفاض كمية السائل (الأمنيوسي) المحيط بالجنين، في حالات نادرة جداً، أثناء نمو وتطور الجنين داخل رحم السيدات الحوامل اللاتي يستخدمن دواء تراستوزوماب. قد تضر هذه الحالة بالجنين داخل الرحم، حيث ارتبط استخدام دواء تراستوزوماب بنقص نمو وتطور الرئتين بشكل كامل مما يؤدي إلى وفاة الجنين.
الرضاعة الطبيعية
يحظر عليكِ ممارسة الرضاعة الطبيعية أثناء تلقي العلاج باستخدام دواء أوجيفري ولمدة تصل إلى سبعة أشهر عقب تلقي أخر جرعة من دواء أوجيفري، حيث وُجد أن هذا الدواء قد ينتقل إلى الطفل عن طريق لبن الأم. استشيري الطبيب المعالج لك أو الصيدلي الخاص بك للحصول على النصيحة قبل تناول أي دواء.
قيادة السيارات واستخدام الآلات:
قد يؤثر دواء أوجيفري على القدرة على قيادة السيارات أو تشغيل الآلات. يحظر قيادة السيارات أو استخدام الآلات إذا عانيت من أي أعراض أثناء العلاج، مثل قشعريرة أو حمى، حتى تزول هذه الأعراض.
يحتوي دواء أوجيفري على سوربيتول (إي 420).
أوجيفري 420 مجم مسحوق لإعداد محلول مركز للحقن بالتنقيط داخل الوريد.
يحتوي هذا الدَّواء على 322.6 مجم من سوربيتول في كل زجاجة.
يعد السوربيتول أحد مصادر الفركتوز. يحظر عليك استخدام هذا الدواء، إذا كنت تعاني من عَدَمُ التَّحَمُّلِ الوِراثِيُّ للفَرَكْتوز(HFI)، وهو اضطراب وراثي نادر. فيحظر عليك استخدام هذا الدواء. لا يتمكن المرضى الذين يعانون من عَدَمُ التَّحَمُّلِ الوِراثِيُّ للفَرَكْتوز(HFI) من تكسير الفركتوز مما قد يسبب آثارًا جانية خطيرة.
يتعين عليك إخبار الطبيب المعالج لك قبل استخدام هذا الدواء، إذا كنت تعاني من عَدَمُ التَّحَمُّلِ الوِراثِيُّ للفَرَكْتوز(HFI) أو إذا لم تعد تتحمل تناول الأطعمة أو المشروبات التي تحتوي على كثير من السكريات لأنك قد تشعر بغثيان أو قيء أو تعاني من آثار جانبية غير مرغوبة مثل انتفاخ أو تقلصات المعدة أو إسهال.
. كيفية استخدام دواء أوجيفري
سيقرر الطبيب المعالج لك عدد مستقبلات عامل نمو البشرة 2(HER2) في الورم قبل البدء في العلاج. يجب إعطائك دواء أوجيفري فقط تحت إشراف الطبيب المعالج لك أو الممرض(ة) المتابع (ة) لحالتك فقط للمرضى الذين يعانون من ارتفاع عدد مستقبلات عامل نمو البشرة 2(HER2). سيصف الطبيب المعالج لك الجرعة ونظام العلاج المناسبين لك. تعتمد جرعة دواء أوجيفري على وزن الجسم.
يتم إعطاء الجرعة الأولى من دواء أوجيفري خلال90 دقيقة، حيث يتم متابعة المرضى من قِبَل أخصائي الرعاية الصحية أثناء فترة إعطاء العلاج لملاحظة حدوث أية آثار جانبية. إذا كانت استجابتك للجرعة الأولى جيدة، فيمكن إعطاء الجرعات التالية خلال 30 دقيقة (انظر القسم رقم 2 تحت عنوان "تحذيرات واحتياطات"). يعتمد عدد جرعات الحقن بالتنقيط داخل الوريد التي تتلقاها على مدى استجابتك للعلاج. سيتناقش معك الطبيب المعالج لك حول هذا الامر.
يتم استخدام دواء أوجيفري في شكل حُقن عن طريق التنقيط داخل الوريد (التنقيط، التسريب داخل الوريد)، وهذه التركيبة الوريدية غير معدة للحَقن تحت الجلد، وإنما هي مُعدة فقط للاستخدام عن طريق الحقن بالتنقيط داخل الوريد.
يتم إعطاء دواء أوجيفري للمرضى المصابين بسرطان الثدي في مراحله المبكرة، وبالتحديد سرطان الثدي النقيلي وسرطان المعدة النقيلي كل ثلاثة أسابيع. كما يمكن إعطاء دواء أوجيفري أيضًا مرة واحدة أسبوعيًا لمرضى سرطان الثدي النقيلي.
يُرجى التحقق الملصق المثبت على الزجاجة، لمنع الأخطاء الطبية وللتأكد من أن الدواء الذي تم إعداده وتحضيره هو دواء أوجيفري (تراستوزوماب) وليس تراستوزوماب إمتانسين.
إذا توقفت عن استخدام دواء أوجيفري
يحظر إيقاف هذا الدواء دون استشارة الطبيب المعالج لك أولًا. ينبغي تلقي جميع الجرعات في الوقت المحدد لها كل أسبوع أو كل ثلاثة أسابيع (وفقًا لجدول الجرعات الخاص بك). حيث يساعد ذلك في الحصول على أقصي فعالية للدواء.
قد يستغرق التخلص من دواء أوجيفري من الجسم لمدة تصل إلى سبعة أشهر. ولذلك قد يقرر الطبيب المعالج لك الاستمرار في متابعة فحوصات وظائف القلب، حتى بعد انتهاء فترة العلاج.
إذا كانت لديك أية أسئلة إضافية حول استخدام هذا الدَّواء، فاستشر الطبيب المعالج لك أو الصيدلي الخاص بك أو الممرض(ة) المتابع(ة) لحالتك.
. الآثار الجانبية المحتملة
قد يُسبب هذا الدَّواء، مثله مثل كافة الأدوية، آثارًا جانبية على الرَّغم من عدم حدوثها لجميع المرضى.
قد تكون بعض هذه الآثار الجانبية خطيرة ويتطلب عناية طبية في المستشفى.
قد تعاني من بعض الأعراض مثل قشعريرة وحمى وأعراض تشبه أعراض الأنفلونزا أثناء العلاج باستخدام دواء أوجيفري عن طريق الحقن بالتنقيط داخل الوريد. وهذه آثار جانبية شائعة جدًّا (قد تُؤثر على أكثر من مريض واحد من بين كل 10 مرضى).
تشمل الأعراض الأخرى المرتبطة بالحقن عن طريق التنقيط داخل الوريد: شعور بإعياء(غثيان)، قيء، ألم، زيادة تشنج العضلات، ارتعاش، صداع، دوخة، صعوبات بالتنفس، أزيز بالصدر، ارتفاع أو انخفاض ضغط الدم، اضطرابات نظم القلب (خفقان، سرعة ضربات القلب أو عدم انتظامها)، تورم الوجه والشفتين، طفح جلدي وشعور بالتعب.
قد تكون بعض هذه الأعراض خطيرة وقد تُؤدي إلى الوفاة في بعض المرضى (انظر القسم رقم 2 تحت عنوان "تحذيرات واحتياطات").
تحدث هذه الآثار الجانبية بشكل رئيسي عند إعطاء الجرعة التنقيط الوريدي الأولى (الحقن "بالتنقيط" داخل الوريد) وخلال الساعات القليلة الأولى بعد بدء التنقيط داخل الوريد. عادة ما تكون هذه الأعراض مؤقتة. سيتم متابعتك من قبل أخصائي الرعاية الصحية أثناء الحقن بالتنقيط داخل الوريد لمدة 6 ساعات على الأقل بعد تلقي جرعة التنقيط الوريدي الأولى ولمدة ساعتين عقب جرعات التنقيط الوريدي الأخرى. إذا عانيت من تفاعلات حساسية، قد يقلل الطبيب المعالج لك الجرعة أو يطلب منك إيقاف العلاج عن طريق الحقن بالتنقيط داخل الوريد للتغلب على الأثار الجانبية. يمكن استكمال التنقيط الوريدي بعد تحسن الأعراض.
تبدأ الأعراض أحيانًا بعد انقضاء أكثر من 6 ساعات من بدء الحقن بالتنقيط داخل الوريد. إذا عانيت من ذلك، فاتصل بالطبيب المعالج لك فورًا. وفي بعض الأحيان قد تتحسن الأعراض ثم تزداد سوءً بعد ذلك.
الأثار الجانبية الخطيرة:
قد تحدث آثار جانبية أخرى في أي وقت أثناء العلاج باستخدام أوجيفري، وتكون غير متعلقة بالحقن بالتنقيط داخل الوريد فقط. أبلغ الطبيب المعالج أو الممرض(ة) المتابع لحالتك فورًا، إذا لاحظت أيًّا من الآثار الجانبية التالية:
· قد تحدث أحياناً مشاكل بالقلب أثناء العلاج أو عقب إيقافه من وقت لأخر، ويمكن أن تكون خطيرة. وتشتمل الآثار الجانبية الخطيرة على ضعف عضلة القلب مما قد يؤدي إلى قصور القلب والتهاب الغشاء المحيط بالقلب واضطرابات نظم القلب. يمكن أن يؤدي ذلك إلى الإصابة بأعراض مثل ضيق التنفس (بما في ذلك ضيق التنفس أثناء الليل) وسعال واحتباس السوائل (تورم) في الساقين أو الذراعين وخفقان القلب (خفقان القلب أو عدم انتظام ضربات القلب) (انظر القسم رقم 2 تحت عنوان "فحوصات القلب").
سيتابع الطبيب المعالج لك وظائف القلب بانتظام أثناء العلاج وبعده، ولكن يجب عليك إخبار الطبيب المعالج لك فورًا إذا لاحظت أيًا من الأعراض المذكورة أعلاه.
· متلازمة انحلال الورم (هي عبارة عن مجموعة من المضاعفات الأيضية التي تحدث بعد علاج السرطان والتي تتميز بارتفاع مستويات البوتاسيوم والفوسفات في الدم وانخفاض مستويات الكالسيوم في الدم). قد تشمل الأعراض على اضطرابات بالكلى (ضعف وضيق في التنفس وتعب وارتباك) ومشاكل بالقلب (خفقان القلب وتسارع أو تباطؤ معدل ضربات القلب) ونوبات تشنجية أو قيء أو إسهال وتنميل في الفم أو اليدين أو القدمين.
ينبغي عليك زيارة الطبيب المعالج لك وإخباره أنه قد تم علاجك مسبقًا بدواء أوجيفري، إذا عانيت من أي من الأعراض المذكورة أعلاه عقب إيقاف العلاج باستخدام أوجيفري.
آثار جانبية شائعة جدًا: (قد تُؤثر على أكثر من مريض واحد من بين كل 10 مرضى)
· حالات عدوى.
· إسهال
· إمساك
· حموضة (عُسْرُ الهَضْم)
· إرهاق
· طفح جلدي
· ألم بالصدر
· - ألم بالبطن (ألم بالمعدة)
· ألم المفاصل
· انخفاض عدد خلايا الدَّم الحمراء والبيضاء (خلايا الدَّم التي تُساعد على مكافحة العدوى)، أحياناً مصحوبة بحمى،
· ألم بالعضلات.
· التهاب الملتحمة (إفرازات مصحوبة بحكة في العينين وتقشر الجفون)
· زيادة إفراز الدموع من العينين
· نزيف بالأنف
· سيلان الأنف
· تساقط الشعر
· ارتعاش
· هبَّات ساخنة (ومضة ساخنة)
· دوخة
· اضطرابات الأظافر
· فقدان في الوزن
· فقدان الشهية
· عدم القدرة على النوم (أرق)
· اضطرابات بحاسة التذوق
· نقص عدد الصفائح الدموية
· ظهور كدمات
· تنميل أو وخز في أصابع اليدين والقدمين.
· احمرار أو تورم أو تقرحات بالفم و/ أو الحلق
· ألم أو تورم أو احمرار أو وخز باليدين و/أو القدمين
· ضيق في التَّنفس
· صداع
· سعال
· قيء
· غثيان (شعور بإعياء).
آثار جانبية الشائعة (قد تُؤثر على ما يصل إلى مريض واحد من بين كل 10 مرضى)
· تفاعلات الحساسية
· جفاف الفم والجلد
· عدوى الحلق
· جفاف العينين
· عدوى المثانة والجلد
· زيادة إفراز العرق
· الهربس النطاقي (قوباء منطقية)
· شعور بضعف أو إجهاد
· التهاب الثدي
· قلق.
· التهاب الكبد
· اكتئاب
· اضطرابات الكلى
· تفكير غير طبيعي
· زيادة التوتر العضلي أو القلق (التوتر التشنجي)
· ربو
· حالات عدوى بالرئتين
· ألم في الذراعين و/أو القدمين
· اضطرابات بالرئة
· طفح جلدي مصحوب بحكة
· ألم بالظهر
· نعاس (زيادة النوم)
· ألم بالرقبة
· الإصابة بالبواسير (تورم الأوعية الدموية حول المستقيم)
· ألم بالعظام
· حكة
· بثور حبوب الشباب
· تقلُّص عضلات الساق
آثار جانبية غير شائعة (قد تُؤثر على ما يصل إلى مريض واحد من بين كل 100 مريض)
· صمم
· طفح جلدي مصحوب بنتوءات
· حالات عدوى بالدم
آثار جانبية نادرة (قد تُؤثر على ما يصل إلى مريض واحد من بين كل 1000 مريض)
· ضعف العضلات
· يرقان (اصفرار الجلد وبياض العينين)
· التهاب أو تندب الرئة.
آثار جانبية غير معروف مُعدَّل تكرارها (لا يمكن تقدير مُعدَّل التكرار من واقع البيانات المُتاحة):
· ضعف تخثر الدم أو تجلطه بمعدل غير طبيعي،
· تفاعُلات تَأَقِيّة (وهي عبارة عن رد فعل تحسسي مفاجئ خطير مصحوبًا بأعراض مثل: طفح جلدي أو حكة أو صعوبة في التنفس أو شعور بدوار أو إغماء)
· ارتفاع نسبة مستوى البوتاسيوم،
· تورم الدماغ،
· تورم أو نزيف في مؤخرة العين،
· صدمة (انخفاض خطير في ضغط الدم يسبب أعراضًا مثل: سرعة وبطء التنفس ونزلة برد ورطوبة الجلد (تعرق) وسرعة وضعف نظم القلب ودوخة ووهن وإغماء).
· التهاب الغشاء المبطن للقلب،
· بطء معدل ضربات القلب،
· إيقاع القلب غير طبيعي،
· ضيق التَّنفس،
· فشل بالجهاز التَّنفسي،
· تراكم حاد للسوائل في الرئتين
· ضيق حاد في الشعب الهوائية،
· نقص مستويات الأكسجين في الدم (بشكل غير طبيعي)،
· صعوبة التنفس أثناء الاستلقاء على الظهر،
· تلف / فشل الكبد،
· تورُّم الوجه والشفتين والحَلْق،
· فشل كلوي،
· انخفاض مستوي السوائل حول الجنين في الرحم بشكل غير طبيعي،
· فشل تطور ونمو رئتي الجنين في الرحم،
· تطور ونمو غير طبيعي لكلى الجنين في الرحم،
يمكن أن تحدث بعض الأثار الجانبية بشكل أساسي نتيجة لسرطان الثدي. إذا كنت تستخدم دواء أوجيفري بالتزامن مع علاج كيميائي آخر، فقد تكون بعض الآثار الجانبية ناجمة عن تلقي العلاج الكيميائي.
الإبلاغ عن الآثار الجانبية
إذا تعرضت للإصابة بأي من هذه الآثار الجانبية، فاستشر الطبيب المعالج لك أو الصيدلي الخاص بك أو الممرض(ة) المتابع(ة) لحالتك. ويشمل ذلك أية آثار جانبية غير مُدرجة في هذه النشرة. كما يمكنك الإبلاغ عن الآثار السلبية و/ أو شكاوى تخص المنتج، انظر التفاصيل أدناه:
المُركز الوطني للتيقظ والسلامة الدوائية (NPC)
فاكس رقم: 7662-205-11-966+
مركز اتصالات الھیئة العامة للغذاء والدواء السعودیة 19999 :
البريد الالكتروني:npc.drug@sfda.gov.sa
الموقع الإلكتروني: https://ade.sfda.gov.sa
دول أخرى:
یرجى الاتصال بالسلطة المختصة ذات الصلة.
شركة ميلان
الموقع الإلكتروني: www.viatris.in
البريد الالكتروني: pharmacovigilance.india@viatris.in أو
contactmppl@viatris.com
5.كيفية حفظ دواء أوجيفري
يُحفظ هذا الدواء بعيدًا عن رؤية ومتناول الأطفال.
يحظر استخدام هذا الدَّواء بعد انتهاء تاريخ الصلاحية المدون على العبوة الكرتونية الخارجية وملصق الزجاجة بعد كلمة EXP"". يُشير تاريخ انتهاء الصَّلاحية إلى اليوم الأخير من ذلك الشهر.
يُحفظ الدواء في الثلاجة (عند درجة حرارة تتراوح من 2° إلى 8 ° درجة مئوية).
يجب استخدام محلول التنقيط داخل الوريد فورًا عقب تخفيفه. لا تستخدم دواء أوجفيري إذا لاحظت وجود أي جزيئات أو تغيير في لون المحلول قبل الاستخدام.
لا تتخلص من الأدوية عن طريق إلقائها في مياه الصرف أو مع المخلفات المنزلية. استشر الصيدلي الخاص بك عن كيفية التَّخلص من الأدوية التي لم تَعُد تستخدمها. ستُساعد هذه الإجراءات على حماية البيئة.
. محتويات العبوة ومعلومات أخرى.
محتويات دواء أوجيفري
- المادة الفعالة هي تراستوزوماب. تحتوي كل زجاجة على 420 مجم من تراستوزوماب تذاب في 20 مل من الماء المعد للحقن.
- بحيث يحتوي المحلول الناتج على 21 مجم / مل تقريبًا من تراستوزوماب.
- المكونات الأخرى هي: إل-هيستيدين هيدروكلوريد، إل- هيستيدين، سوربيتول (إي 420) (انظر قسم رقم 2 "يحتوي أوجيفري على سوربيتول")، ماكروجول 3350، حمض الهيدروكلوريك وهيدروكسيد الصوديوم (لتعديل درجة الحموضة).
ما هو شكل دواء أوجيفري وماهي محتويات العبوة:
أوجيفري هو مسحوق لإعداد محلول مركز للحقن بالتنقيط داخل الوريد، معبأ في عبوة زجاجية مغلقة بسدادة مطاطية تحتوي على 420 مجم من تراستوزوماب. مسحوق أبيض مائل إلى الأصفر الباهت. تحتوي كل عبوة كرتونية على زجاجة واحدة من المسحوق.
الشركة مالكة حق التَّسويق
شركة ميلان جي ام بي إتش
40 شارع تورجاور، زيوريخ،
زيوريخ CH-8050، سويسرا
الشركة المصنعة:
بیوكون بیولوجیكز المحدودة الھند
بلوك رقم:1 Q13, B2, B من W20 & Q
المنطقة الاقتصادیة الخاصة
القطعة رقم 2و3 و4و 5 المرحلة الرابعة
طریق رابط بوماساندرا - جیجاني
بوماساندرا بوست
بنغالورو - 560099
الھند
المعلومات التالية مخصَّصة لأخصائي الرعاية الصحية فقط
احفظ الدواء دائمًا في العبوة الأصلیة المغلقة في الثلاجة عند درجة حرارة تتراوح بین 2 إلى 8 درجة مئویة. تظل زجاجة أوجیفري التي تم تحضیرھا باستخدام ماء
معد للحقن (غیر متوفر مع الدواء) محتفظة باستقرارھا الكیمیائي لمدة 10 أیام عند درجة حرارة تتراوح من 2 إلى 8 درجة مئویة بعد تحضیرھا، ویجب عدم
تجمیدھا.
یجب التعامل مع أوجیفري بعنایة أثناء تحضیره. قد یشیر تكون رغوة كثیفة أثناء تحضیر دواء أوجیفري أو تحریكھ المحلول الذي تم تحضیره إلى وجود مشاكل في
كمیة أوجیفري التي یمكن سحبھا من الزجاجة.
أوجفيري 420 مجم مسحوق لإعداد محلول مركز للحقن بالتنقيط داخل الوريد
يجب استخدام طرق التعقيم المناسبة. يتم تحضير كل زجاجة 420 مجم من أوجيفري مع 20 مل من الماء المعقم المعد للحَقْنِ (غير متوفر مع العبوة). ينبغي تجنب استخدام مذيبات التحضير الأخرى. ينتج عن ذلك محلول 21 مل للاستخدام كجرعة واحدة، أي يحتوي على ما يقارب 21 مجم / مل من تراستوزوماب. عندما تزيد الكمية بنسبة 4.8 ٪، يمكن سحب الجرعة الموصوفة التي تبلغ 420 مجم من كل زجاجة.
زجاجة أوجفيري |
| كمية الماء المُعَقِّم المعد للحَقْنِ |
| التركيز النهائي |
زجاجة 420 مجم | + | 20 مل | = | 21 مجم/ مل |
تعليمات تحضير محلول دواء أوجيفري
1) يجب استخدام حقنة معقمة، مع سحب الكمية الملائمة ببطء (كما هو موضح أعلاه) من الماء المعد للحقن في الزجاجة التي تحتوي على أوجيفري المجفف بالتجميد، وتوجيه التدفق نحو الكتلة المجففة بالتجميد.
قم بتحريك (التقليب في شكل دوامة) الزجاجة بلطف للمساعدة في تحضير الدواء (الذوبان). لا تقم برجّها.
قد تتكون رغوة طفيفة عند تحضير الدواء. لا تحرك الزجاجة لمدة 5 دقائق تقريبًا. ينتج عن دواء أوجيفري الذي تم تحضيره محلول شفاف يتراوح لونه من عديم اللون إلى أصفر باهت، ويجب أن يكون خاليًا من الشوائب بشكل أساسي.
قم بتحديد كمية المحلول المطلوبة:
• بناءً على جرعة التحميل (جرعة بدء عالية) 4 مجم من تراستوزوماب لكل كجم من وزن الجسم، أو جرعة أسبوعية لاحقة 2 مجم من تراستوزوماب لكل كجم من وزن الجسم:
الحجم (مللي لتر) = وزن الجسم (كجم) x الجرعة (4 مجم/كجم جرعة التحميل أو 2 مجم للمداومة).
21 (مجم/مل، هو تركيز المحلول الذي تم تحضيره)
• بناءً على جرعة التحميل 8 مجم من تراستوزوماب لكل كجم من وزن الجسم، أو جرعة لاحقة كل ثلاثة أسابيع 6 مجم من تراستوزوماب لكل كجم من وزن الجسم:
الحجم (مللي لتر) = وزن الجسم (كجم) x الجرعة (8 مجم/كجم جرعة التحميل أو 6 مجم للمداومة).
21 (مجم/مل، هو تركيز المحلول الذي تم تحضيره)
يجب سحب الكمية المناسبة من المحلول من الزجاجة وإضافتها إلى كيس التنقيط داخل الوريد المصنوع من مادة بولي فينيل كلوريد أو بولي إيثيلين أو بولي بروبيلين الذي يحتوي على 250 مل من محلول كلوريد الصوديوم 9 مجم / مل (0.9٪) للحقن. لا تستخدم الدواء مع المحاليل التي تحتوي على الجلوكوز. يجب قلب الكيس برفق عند خلط المحلول لتجنب الرغوة. يجب فحص المحلول الوريدي بالعين المجردة للتحقق من عدم وجود شوائب أو تغير في اللون قبل الاستخدام. يجب استخدام حقن التنقيط داخل الوريد فور تحضيرها. إذا تم تخفيف المحلول بطريقة معقمة، فيمكن حفظه لمدة لمدة تصل إلى 90 یومًا من ° 2 إلى ° 8 درجة مئویة و لمدة 24 ساعة في
درجة حرارة لا تتجاوز ° 30 درجة مئویة.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Breast cancer
Metastatic breast cancer
Ogivri is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer
(MBC):
- as monotherapy for the treatment of those patients who have received at least two chemotherapy
regimens for their metastatic disease. Prior chemotherapy must have included at least an
anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor
positive patients must also have failed hormonal therapy, unless patients are unsuitable for these
treatments
- in combination with paclitaxel for the treatment of those patients who have not received
chemotherapy for their metastatic disease and for whom an anthracycline is not suitable
- in combination with docetaxel for the treatment of those patients who have not received
chemotherapy for their metastatic disease
- in combination with an aromatase inhibitor for the treatment of postmenopausal patients with
hormone-receptor positive MBC, not previously treated with trastuzumab.
Early breast cancer
Ogivri is indicated for the treatment of adult patients with HER2 positive early breast cancer (EBC):
- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see
section 5.1)
- following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with
paclitaxel or docetaxel
- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
- in combination with neoadjuvant chemotherapy followed by adjuvant Ogivri therapy, for locally
advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 4.4 and
5.1).
Ogivri should only be used in patients with metastatic or EBC whose tumours have either HER2
overexpression or HER2 gene amplification as determined by an accurate and validated assay (see
sections 4.4 and 5.1).
Metastatic gastric cancer
Ogivri in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of
adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal
junction who have not received prior anti-cancer treatment for their metastatic disease.
Ogivri should only be used in patients with metastatic gastric cancer (MGC) whose tumours have
HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC 3+
result. Accurate and validated assay methods should be used (see sections 4.4 and 5.1).
4.2 Posology and method of administration
HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Trastuzumab
treatment should only be initiated by a physician experienced in the administration of cytotoxic
chemotherapy (see section 4.4), and should be administered by a healthcare professional only.
Ogivri intravenous formulation is not intended for subcutaneous administration and should be
administered via an intravenous infusion only.
If an alternate route of administration is required, other trastuzumab products offering such an option
should be used.
In order to prevent medication errors it is important to check the vial labels to ensure that the
medicinal product being prepared and administered is trastuzumab and not trastuzumab emtansine.
Posology
Metastatic breast cancer
Three-weekly schedule
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose
at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
Weekly schedule
The recommended initial loading dose of trastuzumab is 4 mg/kg body weight. The recommended
weekly maintenance dose of trastuzumab is 2 mg/kg body weight, beginning one week after the
loading dose.
Administration in combination with paclitaxel or docetaxel
In the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day following the
first dose of trastuzumab (for dose, see the Summary of Product Characteristics (SmPC) for paclitaxel
or docetaxel) and immediately after the subsequent doses of trastuzumab if the preceding dose of
trastuzumab was well tolerated.
Administration in combination with an aromatase inhibitor
In the pivotal trial (BO16216) trastuzumab and anastrozole were administered from day 1. There were
no restrictions on the relative timing of trastuzumab and anastrozole at administration (for dose, see
the SmPC for anastrozole or other aromatase inhibitors).
Early breast cancer
Three-weekly and weekly schedule
As a three-weekly regimen the recommended initial loading dose of trastuzumab is 8 mg/kg body
weight. The recommended maintenance dose of trastuzumab at three-weekly intervals is 6 mg/kg body
weight, beginning three weeks after the loading dose.
As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/kg every week) concomitantly
with paclitaxel following chemotherapy with doxorubicin and cyclophosphamide.
See section 5.1 for chemotherapy combination dosing.
Metastatic gastric cancer
Three-weekly schedule
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose
at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
Breast cancer and gastric cancer
Duration of treatment
Patients with MBC or MGC should be treated with trastuzumab until progression of disease.
Patients with EBC should be treated with trastuzumab for 1 year or until disease recurrence, whichever
occurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).
Dose reduction
No reductions in the dose of trastuzumab were made during clinical trials. Patients may continue
therapy during periods of reversible, chemotherapy-induced myelosuppression but they should be
monitored carefully for complications of neutropenia during this time. Refer to the SmPC for
paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.
If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 points from baseline AND to below
50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately
3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure
(CHF) has developed, discontinuation of trastuzumab should be strongly considered, unless the
benefits for the individual patient are deemed to outweigh the risks. All such patients should be
referred for assessment by a cardiologist and followed up.
Missed doses
If the patient has missed a dose of trastuzumab by one week or less, then the usual maintenance dose
(weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administered as soon as
possible. Do not wait until the next planned cycle. Subsequent maintenance doses should be
administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.
If the patient has missed a dose of trastuzumab by more than one week, a re-loading dose of
trastuzumab should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; threeweekly regimen: 8 mg/kg) as soon as possible. Subsequent trastuzumab maintenance doses (weekly
regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should be administered 7 days or 21
days later according to the weekly or three-weekly schedules respectively.
Special populations
Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not
been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown
to affect trastuzumab disposition.
Paediatric population
There is no relevant use of trastuzumab in the paediatric population.
Method of administration
Trastuzumab loading dose should be administered as a 90-minute intravenous infusion. Do not
administer as an intravenous push or bolus. Trastuzumab intravenous infusion should be administered
by a healthcare provider prepared to manage anaphylaxis and an emergency kit should be available.
Patients should be observed for at least six hours after the start of the first infusion and for two hours
after the start of the subsequent infusions for symptoms like fever and chills or other infusion-related
symptoms (see sections 4.4 and 4.8). Interruption or slowing the rate of the infusion may help control
such symptoms. The infusion may be resumed when symptoms abate.
If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute
infusion.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
4.4 Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number
of the administered product should be clearly recorded.
HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of
the testing procedures (see section 5.1).
Currently no data from clinical trials are available on re-treatment of patients with previous exposure
to trastuzumab in the adjuvant setting.
Cardiac dysfunction
General considerations
Patients treated with trastuzumab are at increased risk for developing CHF (New York Heart
Association [NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been
observed in patients receiving trastuzumab therapy alone or in combination with paclitaxel or
docetaxel, particularly following anthracycline (doxorubicin or epirubicin) containing chemotherapy.
These may be moderate to severe and have been associated with death (see section 4.8). In addition,
caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension,
documented coronary artery disease, CHF, LVEF of < 55%, older age.
All candidates for treatment with trastuzumab, but especially those with prior anthracycline and
cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and
physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition
(MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop
cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months
during treatment and every 6 months following discontinuation of treatment until 24 months from the
last administration of trastuzumab. A careful risk-benefit assessment should be made before deciding
to treat with trastuzumab.
Trastuzumab may persist in the circulation for up to 7 months after stopping Ogivri treatment based on
population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive
anthracyclines after stopping trastuzumab may possibly be at increased risk of cardiac dysfunction. If
possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping
trastuzumab. If anthracyclines are used, the patient’s cardiac function should be monitored carefully.
Formal cardiological assessment should be considered in patients in whom there are cardiovascular
concerns following baseline screening. In all patients cardiac function should be monitored during
treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac
dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent
monitoring (e.g. every 6 - 8 weeks). If patients have a continued decrease in left ventricular function,
but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of
trastuzumab therapy has been seen.
The safety of continuation or resumption of trastuzumab in patients who experience cardiac
dysfunction has not been prospectively studied. If LVEF percentage drops ≥ 10 points from baseline
AND to below 50%, treatment should be suspended and a repeat LVEF assessment performed within
approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF has
developed, discontinuation of trastuzumab should be strongly considered, unless the benefits for the
individual patient are deemed to outweigh the risks. All such patients should be referred for
assessment by a cardiologist and followed up.
If symptomatic cardiac failure develops during trastuzumab therapy, it should be treated with standard
medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction
in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting
enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of
patients with cardiac symptoms and evidence of a clinical benefit of trastuzumab treatment continued
on therapy without additional clinical cardiac events.
Metastatic breast cancer
Trastuzumab and anthracyclines should not be given concurrently in combination in the MBC setting.
Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction
with trastuzumab treatment, although the risk is lower than with concurrent use of trastuzumab and
anthracyclines.
Early breast cancer
For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3
months during treatment and every 6 months following discontinuation of treatment until 24 months
from the last administration of trastuzumab. In patients who receive anthracycline-containing
chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last
administration of trastuzumab, or longer if a continuous decrease of LVEF is observed.
Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment,
history of or existing CHF (NYHA Class II –IV), LVEF of < 55%, other cardiomyopathy, cardiac
arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly
controlled hypertension (hypertension controlled by standard medical treatment eligible), and
hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC
pivotal trials with trastuzumab and therefore treatment cannot be recommended in such patients.
Adjuvant treatment
Trastuzumab and anthracyclines should not be given concurrently in combination in the adjuvant
treatment setting.
In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events
was observed when trastuzumab was administered after anthracycline-containing chemotherapy
compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was
more marked when trastuzumab was administered concurrently with taxanes than when administered
sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred
within the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of
5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic
cardiac or LVEF events was observed in patients who were administered trastuzumab concurrently
with a taxane following anthracycline therapy up to 2.37 % compared to approximately 1 % in the two
comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin
and trastuzumab).
Risk factors for a cardiac event identified in four large adjuvant studies included advanced age
(> 50 years), low LVEF (< 55 %) at baseline, prior to or following the initiation of paclitaxel
treatment, decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive
medicinal products.
In patients receiving trastuzumab after completion of adjuvant chemotherapy, the risk of cardiac
dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of
trastuzumab and a body mass index (BMI) > 25 kg/m2.
Neoadjuvant-adjuvant treatment
In patients with EBC eligible for neoadjuvant-adjuvant treatment, trastuzumab should be used
concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose
anthracycline regimens i.e. maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin
360 mg/m2.
If patients have been treated concurrently with a full course of low-dose anthracyclines and
trastuzumab in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after
surgery. In other situations, the decision on the need for additional cytotoxic chemotherapy is
determined based on individual factors.
Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is
currently limited to the trial MO16432.
In the pivotal trial MO16432, trastuzumab was administered concurrently with neoadjuvant
chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2).
The incidence of symptomatic cardiac dysfunction was 1.7 % in the trastuzumab arm.
Clinical experience is limited in patients above 65 years of age.
Infusion-related reactions (IRRs) and hypersensitivity
Serious IRRs to trastuzumab infusion including dyspnoea, hypotension, wheezing, hypertension,
bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory
distress, urticaria and angioedema have been reported (see section 4.8). Pre-medication may be used to
reduce risk of occurrence of these events. The majority of these events occur during or within 2.5
hours of the start of the first infusion. Should an infusion reaction occur the infusion should be
discontinued or the rate of infusion slowed and the patient should be monitored until resolution of all
observed symptoms (see section 4.2). These symptoms can be treated with an analgesic/antipyretic
such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. The majority of
patients experienced resolution of symptoms and subsequently received further infusions of
trastuzumab. Serious reactions have been treated successfully with supportive therapy such as oxygen,
beta agonists, and corticosteroids. In rare cases, these reactions are associated with a clinical course
culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of
advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction.
Therefore, these patients should not be treated with trastuzumab (see section 4.3).
Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical
deterioration have also been reported. Fatalities have occurred within hours and up to one week
following infusion. On very rare occasions, patients have experienced the onset of infusion symptoms
and pulmonary symptoms more than six hours after the start of the trastuzumab infusion. Patients
should be warned of the possibility of such a late onset and should be instructed to contact their
physician if these symptoms occur.
Pulmonary events
Severe pulmonary events have been reported with the use of trastuzumab in the post-marketing setting
(see section 4.8). These events have occasionally been fatal. In addition, cases of interstitial lung
disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis,
pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been
reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy
with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine,
vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or
with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced
malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients
should not be treated with trastuzumab (see section 4.3). Caution should be exercised for pneumonitis,
especially in patients being treated concomitantly with taxanes.
Sorbitol content
Ogivri 420 mg contains 322.6 mg sorbitol in each vial.
Patients with hereditary fructose intolerance (HFI) must not be given this medicine unless strictly
necessary.
A detailed history with regards to HFI symptoms has to be taken of each patient prior to being given
this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed. Clinically significant interactions between trastuzumab
and the concomitant medicinal products used in clinical trials have not been observed.
Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents
Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC
suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxylpaclitaxel,
POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or
4 mg/kg intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous,
respectively).
However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13
dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this
metabolite were unclear.
Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg intravenous loading dose and
2 mg/kg intravenous weekly) and docetaxel (60 mg/m2 intravenous) in Japanese women with HER2-
positive MBC, suggested that concomitant administration of trastuzumab had no effect on the single
dose pharmacokinetics of docetaxel. Study JP19959 was a sub study of BO18255 (ToGA) performed
in male and female Japanese patients with advanced gastric cancer (AGC) to study the
pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. The results of
this sub study suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was
not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab.
However, capecitabine itself showed higher concentrations and a longer half-life when combined with
trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by
concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.
Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advanced
inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.
Effect of antineoplastic agents on trastuzumab pharmacokinetics
By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy
(4 mg/kg loading/2 mg/kg q1w intravenous) and observed serum concentrations in Japanese women
with HER2- positive MBC (study JP16003) no evidence of a PK effect of concurrent administration of
docetaxel on the pharmacokinetics of trastuzumab was found.
Comparison of PK results from two phase II studies (BO15935 and M77004) and one phase III study
(H0648g) in which patients were treated concomitantly with trastuzumab and paclitaxel and two phase
II studies in which trastuzumab was administered as monotherapy (W016229 and MO16982), in
women with HER2-positive MBC indicates that individual and mean trastuzumab trough serum
concentrations varied within and across studies but there was no clear effect of the concomitant
administration of paclitaxel on the pharmacokinetics of trastuzumab. Comparison of trastuzumab PK
data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with
trastuzumab, paclitaxel and doxorubicin to trastuzumab PK data in studies where trastuzumab was
administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide
or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the
pharmacokinetics of trastuzumab.
Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the
PK of trastuzumab.
The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of
trastuzumab.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should be advised to use effective contraception during treatment
with trastuzumab and for 7 months after treatment has concluded (see section 5.2).
Pregnancy
Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the
weekly human maintenance dose of 2 mg/kg trastuzumab intravenous formulation and have revealed
no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the
early (days 20–50 of gestation) and late (days 120–150 of gestation) foetal development period was
observed. It is not known whether trastuzumab can affect reproductive capacity. As animal
reproduction studies are not always predictive of human response, trastuzumab should be avoided
during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus.
In the post-marketing setting, cases of foetal renal growth and/or function impairment in association
with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been
reported in pregnant women receiving trastuzumab. Women who become pregnant should be advised
of the possibility of harm to the foetus. If a pregnant woman is treated with trastuzumab, or if a patient
becomes pregnant while receiving trastuzumab or within 7 months following the last dose of
trastuzumab, close monitoring by a multidisciplinary team is desirable.
Breast-feeding
A study conducted in lactating Cynomolgus monkeys at doses 25 times that of the weekly human
maintenance dose of 2 mg/kg trastuzumab intravenous formulation demonstrated that trastuzumab is
secreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated
with any adverse effects on their growth or development from birth to 1 month of age. It is not known
whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the
potential for harm to the infant is unknown, women should not breast-feed during trastuzumab therapy
and for 7 months after the last dose.
Fertility
There is no fertility data available.
4.7 Effects on ability to drive and use machines
Ogivri may have a minor influence on the ability to drive and use machines (see section 4.8). Patients
experiencing infusion-related symptoms (see section 4.4) should be advised not to drive and use
machines until symptoms abate.
4.8 Undesirable effects
Summary of the safety profile
Amongst the most serious and/or common adverse reactions reported in trastuzumab usage
(intravenous and subcutaneous formulations) to date are cardiac dysfunction, infusion-related
reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions.
Tabulated list of adverse reactions
In this section, the following categories of frequency have been used: very common (≥ 1/10), common
(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare
(< 1/10,000), not known (cannot be estimated from the available data). Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness.
Presented in Table 1 are adverse reactions that have been reported in association with the use of
intravenous trastuzumab alone or in combination with chemotherapy in pivotal clinical trials and in the
post-marketing setting.
All the terms included are based on the highest percentage seen in pivotal clinical trials. In addition,
terms reported in the post marketing setting are included in Table 1.
Table 1 Undesirable effects reported with intravenous trastuzumab monotherapy or in combination
with chemotherapy in pivotal clinical trials (N = 8386) and in post-marketing
System organ class
Neoplasms benign, malignant and unspecified
(incl. cysts and polyps)
Blood and lymphatic system disorders
Immune system disorders
Metabolism and nutrition disorders
Psychiatric disorders
Nervous system disorders
Eye disorders
Ear and labyrinth disorders
Cardiac disorders
System organ class
Vascular disorders
Respiratory, thoracic and mediastinal disorders
Gastrointestinal disorders
Hepatobiliary disorders
Skin and subcutaneous tissue disorders
System organ class
Musculoskeletal and connective tissue disorders
Renal and urinary disorders
Pregnancy, puerperium and perinatal conditions
Reproductive system and breast disorders
General disorders and administration site conditions
Injury, poisoning and procedural complications
System organ class | Adverse reaction | Frequency |
Infections and infestations | Infection | Very common |
Nasopharyngitis | Very common | |
Neutropenic sepsis | Common | |
Cystitis | Common | |
Herpes zoster | Common | |
Influenza | Common | |
Sinusitis | Common | |
Skin infection | Common | |
Rhinitis | Common | |
Upper respiratory tract infection | Common | |
Urinary tract infection | Common | |
Erysipelas | Common | |
Cellulitis | Common | |
Pharyngitis | Common | |
Adverse reaction | Frequency | |
Sepsis | Uncommon | |
Malignant neoplasm progression | Not known | |
Neoplasm progression | Not known | |
Febrile neutropenia | Very common | |
Anaemia | Very common | |
Neutropenia | Very common | |
White blood cell count decreased/leukopenia | Very common | |
Thrombocytopenia | Very common | |
Hypoprothrombinaemia | Not known | |
Immune thrombocytopenia | Not known | |
Hypersensitivity | Common | |
+Anaphylactic reaction | Not known | |
+Anaphylactic shock | Not known | |
Weight decreased/Weight loss | Very common | |
Anorexia | Very common | |
Tumour lysis syndrome | Not known | |
Hyperkalaemia | Not known | |
Insomnia | Very common | |
Anxiety | Common | |
Depression | Common | |
Thinking abnormal | Common | |
1Tremor | Very common | |
Dizziness | Very common | |
Headache | Very common | |
Paraesthesia | Very common | |
Dysgeusia | Very common | |
Peripheral neuropathy | Common | |
Hypertonia | Common | |
Somnolence | Common | |
Ataxia | Common | |
Paresis | Rare | |
Brain oedema | Not known | |
Conjunctivitis | Very common | |
Lacrimation increased | Very common | |
Dry eye | Common | |
Papilloedema | Not known | |
Retinal haemorrhage | Not known | |
Deafness | Uncommon | |
1 Blood pressure decreased | Very common | |
1 Blood pressure increased | Very common | |
1 Heart beat irregular | Very common | |
1Palpitation | Very common | |
1Cardiac flutter | Very common | |
Ejection fraction decreased* | Very common | |
+Cardiac failure (congestive) | Common | |
+1Supraventricular tachyarrhythmia | Common | |
Cardiomyopathy | Common | |
Pericardial effusion | Uncommon | |
Cardiogenic shock | Not known | |
Adverse reaction | Frequency | |
Pericarditis | Not known | |
Bradycardia | Not known | |
Gallop rhythm present | Not known | |
Hot flush | Very common | |
+1 Hypotension | Common | |
Vasodilatation | Common | |
+1Wheezing | Very common | |
+Dyspnoea | Very common | |
Cough | Very common | |
Epistaxis | Very common | |
Rhinorrhoea | Very common | |
+Pneumonia | Common | |
Asthma | Common | |
Lung disorder | Common | |
+Pleural effusion | Common | |
Pneumonitis | Rare | |
+Pulmonary fibrosis | Not known | |
+Respiratory distress | Not known | |
+Respiratory failure | Not known | |
+Lung infiltration | Not known | |
+Acute pulmonary oedema | Not known | |
+Acute respiratory distress syndrome | Not known | |
+Bronchospasm | Not known | |
+Hypoxia | Not known | |
+Oxygen saturation decreased | Not known | |
Laryngeal oedema | Not known | |
Orthopnoea | Not known | |
Pulmonary oedema | Not known | |
Interstitial lung disease | Not known | |
Diarrhoea | Very common | |
Vomiting | Very common | |
Nausea | Very common | |
1 Lip swelling | Very common | |
Abdominal pain | Very common | |
Dyspepsia | Very common | |
Constipation | Very common | |
Stomatitis | Very common | |
Haemorrhoids | Common | |
Dry mouth | Common | |
Hepatocellular injury | Common | |
Hepatitis | Common | |
Liver tenderness | Common | |
Jaundice | Rare | |
Hepatic failure | Not known | |
Erythema | Very common | |
Rash | Very common | |
1 Swelling face | Very common | |
Alopecia | Very common | |
Nail disorder | Very common | |
Palmar-plantar erythrodysaesthesia syndrome | Very common | |
Adverse reaction | Frequency | |
Acne | Common | |
Dry skin | Common | |
Ecchymosis | Common | |
Hyperhydrosis | Common | |
Maculopapular rash | Common | |
Pruritus | Common | |
Onychoclasis | Common | |
Dermatitis | Common | |
Urticaria | Uncommon | |
Angioedema | Not known | |
Arthralgia | Very common | |
1Muscle tightness | Very common | |
Myalgia | Very common | |
Arthritis | Common | |
Back pain | Common | |
Bone pain | Common | |
Muscle spasms | Common | |
Neck Pain | Common | |
Pain in extremity | Common | |
Renal disorder | Common | |
Glomerulonephritis membranous | Not known | |
Glomerulonephropathy | Not known | |
Renal failure | Not known | |
Oligohydramnios | Not known | |
Renal hypoplasia | Not known | |
Pulmonary hypoplasia | Not known | |
Breast inflammation/mastitis | Common | |
Asthenia | Very common | |
Chest pain | Very common | |
Chills | Very common | |
Fatigue | Very common | |
Influenza-like symptoms | Very common | |
Infusion related reaction | Very common | |
Pain | Very common | |
Pyrexia | Very common | |
Mucosal inflammation | Very common | |
Peripheral oedema | Very common | |
Malaise | Common | |
Oedema | Common | |
Contusion | Common |
+ Denotes adverse reactions that have been reported in association with a fatal outcome.
1 Denotes adverse reactions that are reported largely in association with Infusion-related reactions. Specific
percentages for these are not available.
* Observed with combination therapy following anthracyclines and combined with taxanes
Description of selected adverse reactions
Cardiac dysfunction
Congestive heart failure (NYHA Class II – IV) is a common adverse reaction associated with the use
of trastuzumab and has been associated with a fatal outcome (see section 4.4). Signs and symptoms of
cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or
reduced ventricular ejection fraction, have been observed in patients treated with trastuzumab (see
section 4.4).
In 3 pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy, the
incidence of grade 3/4 cardiac dysfunction (specifically symptomatic Congestive Heart Failure) was
similar in patients who were administered chemotherapy alone (i.e. did not receive trastuzumab) and
in patients who were administered trastuzumab sequentially after a taxane (0.3-0.4 %). The rate was
highest in patients who were administered trastuzumab concurrently with a taxane (2.0 %). In the
neoadjuvant setting, the experience of concurrent administration of trastuzumab and low dose
anthracycline regimen is limited (see section 4.4).
When trastuzumab was administered after completion of adjuvant chemotherapy NYHA Class III - IV
heart failure was observed in 0.6 % of patients in the one-year arm after a median follow-up of 12
months. In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA
Class III & IV) in the trastuzumab 1 year treatment arm was 0.8 %, and the rate of mild symptomatic
and asymptomatic left ventricular dysfunction was 4.6 %.
Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥ 50 %
after the event) was evident for 71.4 % of trastuzumab-treated patients. Reversibility of mild
symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5 % of patients.
Approximately 17 % of cardiac dysfunction related events occurred after completion of trastuzumab.
In the pivotal metastatic trials of intravenous trastuzumab, the incidence of cardiac dysfunction varied
between 9 % and 12 % when it was combined with paclitaxel compared with 1 % – 4 % for paclitaxel
alone. For monotherapy, the rate was 6 % – 9 %. The highest rate of cardiac dysfunction was seen in
patients receiving trastuzumab concurrently with anthracycline/cyclophosphamide (27 %), and was
significantly higher than for anthracycline/cyclophosphamide alone (7 % – 10 %). In a subsequent trial
with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2 % in
patients receiving trastuzumab and docetaxel, compared with 0 % in patients receiving docetaxel
alone. Most of the patients (79 %) who developed cardiac dysfunction in these trials experienced an
improvement after receiving standard treatment for CHF.
Infusion reactions, allergic-like reactions and hypersensitivity
It is estimated that approximately 40 % of patients who are treated with trastuzumab will experience
some form of infusion-related reaction. However, the majority of infusion-related reactions are mild to
moderate in intensity (NCI-CTC grading system) and tend to occur earlier in treatment, i.e. during
infusions one, two and three and lessen in frequency in subsequent infusions. Reactions include chills,
fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation,
respiratory distress, rash, nausea, vomiting and headache (see section 4.4). The rate of infusion-related
reactions of all grades varied between studies depending on the indication, the data collection
methodology, and whether trastuzumab was given concurrently with chemotherapy or as
monotherapy.
Severe anaphylactic reactions requiring immediate additional intervention can occur usually during
either the first or second infusion of trastuzumab (see section 4.4) and have been associated with a
fatal outcome.
Anaphylactoid reactions have been observed in isolated cases.
Haematotoxicity
Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred very
commonly. The frequency of occurrence of hypoprothrombinemia is not known. The risk of
neutropenia may be slightly increased when trastuzumab is administered with docetaxel following
anthracycline therapy.
Pulmonary events
Severe pulmonary adverse reactions occur in association with the use of trastuzumab and have been
associated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acute
respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute
pulmonary oedema and respiratory insufficiency (see section 4.4).
Details of risk minimisation measures that are consistent with the EU Risk Management Plan are
presented in (section 4.4) Warnings and Precautions.
Immunogenicity
In the neoadjuvant-adjuvant EBC study (BO22227), at a median follow-up exceeding 70 months,
10.1 % (30/296) of patients treated with trastuzumab intravenous developed antibodies against
trastuzumab.
Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in
the trastuzumab intravenous arm.
The clinical relevance of these antibodies is not known. The presence of anti-trastuzumab antibodies
had no impact on pharmacokinetics, efficacy (determined by pathological Complete Response [pCR]
and event free survival [EFS]) and safety determined by occurrence of administration related reactions
(ARRs) of trastuzumab intravenous.
There are no immunogenicity data available for trastuzumab in gastric cancer.
Switching treatment between trastuzumab intravenous and trastuzumab subcutaneous formulation and
vice versa.
Study MO22982 investigated switching between the trastuzumab intravenous and trastuzumab
subcutaneous formulation with a primary objective to evaluate patient preference for either
intravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one using
subcutaneous formulation in vial and one using subcutaneous formulation in administration system)
were investigated using a 2-arm, cross-over design with 488 patients being randomized to one of two
different three-weekly Trastuzumab treatment sequences (intravenous [Cycles 1-4]→ subcutaneous
[Cycles 5-8], or subcutaneous [Cycles 1-4]→ intravenous [Cycles 5-8]). Patients were either naïve to
trastuzumab intravenous treatment (20.3 %) or pre-exposed to trastuzumab intravenous (79.7 %). For
the sequence intravenous → subcutaneous (subcutaneous vial and subcutaneous formulation in
administration system cohorts combined), adverse event rates (all grades) were described preswitching
(Cycles 1-4) and post-switching (Cycles 5-8) as 53.8 % vs. 56.4 %, respectively; for the
sequence subcutaneous → intravenous (subcutaneous vial and subcutaneous formulation in
administration system cohorts combined), adverse event rates (all grades) were described pre- and
post-switching as 65.4 % vs. 48.7 %, respectively.
Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatment
discontinuations due to adverse events were low (< 5 %) and similar to post-switching rates (Cycles 5-
8). No grade 4 or grade 5 adverse events were reported.
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
Saudi Arabia:
The National Pharmacovigilance Centre (NPC):
Fax: +966-11-205-7662
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa
Other GCC States:
Please contact the relevant competent authority.
4.9 Overdose
There is no experience with overdose in human clinical trials. Single doses of trastuzumab alone
greater than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of
10 mg/kg q3w following a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic
gastric cancer patients. Doses up to this level were well tolerated.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03
Ogivri is a biosimilar medicinal product. Detailed information is available on the website of the
European Medicines Agency http://www.ema.europa.eu.
Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal
growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20 %-30 % of primary
breast cancers. Studies of HER2-positivity rates in gastric cancer (GC) using immunohistochemistry
(IHC) and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) have
shown that there is a broad variation of HER2-positivity ranging from 6.8 % to 34.0 % for IHC and
7.1 % to 42.6 % for FISH. Studies indicate that breast cancer patients whose tumours overexpress
HER2 have a shortened disease-free survival compared to patients whose tumours do not overexpress
HER2. The extracellular domain of the receptor (ECD, p105) can be shed into the blood stream and
measured in serum samples.
Mechanism of action
Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of
HER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2
signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism
of HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit
the proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent
mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated
ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared
with cancer cells that do not overexpress HER2.
Detection of HER2 overexpression or HER2 gene amplification
Detection of HER2 overexpression or HER2 gene amplification in breast cancer
Trastuzumab should only be used in patients whose tumours have HER2 overexpression or HER2
gene amplification as determined by an accurate and validated assay. HER2 overexpression should be
detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see
section 4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation
(FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for
Ogivri treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a
positive FISH or CISH result.
To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory,
which can ensure validation of the testing procedures.
The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:
Table 2 Recommended scoring system to evaluate the IHC staining patterns in breast cancer
Score | Staining pattern | HER2 overexpression assessment |
0 | No staining is observed or membrane staining is observed in < 10 % of the tumour cells | Negative |
1+ | A faint/barely perceptible membrane staining is detected in > 10 % of the tumour cells. The cells are only stained in part of their membrane. | Negative |
2+ | A weak to moderate complete membrane staining is detected in > 10 % of the tumour cells. | Equivocal |
3+ | Strong complete membrane staining is detected in > 10 % of the tumour cells. | Positive |
In general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to
the chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the
HER2 gene per tumour cell if no chromosome 17 control is used.
In general, CISH is considered positive if there are more than 5 copies of the HER2 gene per nucleus
in greater than 50 % of tumour cells.
For full instructions on assay performance and interpretation please refer to the package inserts of
validated FISH and CISH assays. Official recommendations on HER2 testing may also apply.
For any other method that may be used for the assessment of HER2 protein or gene expression, the
analyses should only be performed by laboratories that provide adequate state-of-the-art performance
of validated methods. Such methods must clearly be precise and accurate enough to demonstrate
overexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) and
strong (congruent with 3+) overexpression of HER2.
Detection of HER2 over expression or HER2 gene amplification in gastric cancer
Only an accurate and validated assay should be used to detect HER2 over expression or HER2 gene
amplification. IHC is recommended as the first testing modality and in cases where HER2 gene
amplification status is also required, either a silver-enhanced in situ hybridization (SISH) or a FISH
technique must be applied. SISH technology is however, recommended to allow for the parallel
evaluation of tumour histology and morphology. To ensure validation of testing procedures and the
generation of accurate and reproducible results, HER2 testing must be performed in a laboratory
staffed by trained personnel. Full instructions on assay performance and results interpretation should
be taken from the product information leaflet provided with the HER2 testing assays used.
In the ToGA (BO18255) trial, patients whose tumours were either IHC3+ or FISH positive were
defined as HER2 positive and thus included in the trial. Based on the clinical trial results, the
beneficial effects were limited to patients with the highest level of HER2 protein overexpression,
defined by a 3+ score by IHC, or a 2+ score by IHC and a positive FISH result.
In a method comparison study (study D008548) a high degree of concordance (>95 %) was observed
for SISH and FISH techniques for the detection of HER2 gene amplification in gastric cancer patients.
HER2 over expression should be detected using an immunohistochemistry (IHC)-based assessment of
fixed tumour blocks; HER2 gene amplification should be detected using in situ hybridisation using
either SISH or FISH on fixed tumour blocks.
The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3:
Table 3 Recommended scoring system to evaluate the IHC staining patterns in gastric cancer
Score | Surgical specimen - staining pattern | Biopsy specimen – staining pattern | HER2 overexpression assessment |
0 | No reactivity or membranous reactivity in < 10 % of tumour cells | No reactivity or membranous reactivity in any tumour cell |
Negative |
1+ | Faint ⁄ barely perceptible membranous reactivity in ≥ 10 % of tumour cells; cells are reactive only in part of their membrane | Tumour cell cluster with a faint ⁄ barely perceptible membranous reactivity irrespective of percentage of tumour cells stained |
Negative |
2+ | Weak to moderate complete, basolateral or lateral membranous reactivity in ≥ 10 % of tumour cells | Tumour cell cluster with a weak to moderate complete, basolateral or lateral membranous reactivity irrespective of percentage of tumour cells stained |
Equivocal |
3+ | Strong complete, basolateral or lateral membranous reactivity in ≥ 10 % of tumour cells | Tumour cell cluster with a strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumour cells stained |
Positive |
In general, SISH or FISH is considered positive if the ratio of the HER2 gene copy number per tumour
cell to the chromosome 17 copy number is greater than or equal to 2.
Clinical efficacy and safety
Metastatic breast cancer
Trastuzumab has been used in clinical trials as monotherapy for patients with MBC who have tumours
that overexpress HER2 and who have failed one or more chemotherapy regimens for their metastatic
disease (trastuzumab alone).
Trastuzumab has also been used in combination with paclitaxel or docetaxel for the treatment of
patients who have not received chemotherapy for their metastatic disease. Patients who had previously
received anthracycline-based adjuvant chemotherapy were treated with paclitaxel (175 mg/m2 infused
over 3 hours) with or without trastuzumab. In the pivotal trial of docetaxel (100 mg/m2 infused over
1 hour) with or without trastuzumab, 60 % of the patients had received prior anthracycline-based
adjuvant chemotherapy. Patients were treated with trastuzumab until progression of disease.
The efficacy of trastuzumab in combination with paclitaxel in patients who did not receive prior
adjuvant anthracyclines has not been studied. However, trastuzumab plus docetaxel was efficacious in
patients whether or not they had received prior adjuvant anthracyclines.
The test method for HER2 overexpression used to determine eligibility of patients in the pivotal
trastuzumab monotherapy and trastuzumab plus paclitaxel clinical trials employed
immunohistochemical staining for HER2 of fixed material from breast tumours using the murine
monoclonal antibodies CB11 and 4D5. These tissues were fixed in formalin or Bouin’s fixative. This
investigative clinical trial assay performed in a central laboratory utilised a 0 to 3+ scale. Patients
classified as staining 2+ or 3+ were included, while those staining 0 or 1+ were excluded. Greater
than 70 % of patients enrolled exhibited 3+ overexpression. The data suggest that beneficial effects
were greater among those patients with higher levels of overexpression of HER2 (3+).
The main test method used to determine HER2 positivity in the pivotal trial of docetaxel, with or
without trastuzumab, was immunohistochemistry. A minority of patients was tested using fluorescence
in-situ hybridisation (FISH). In this trial, 87 % of patients entered had disease that was IHC3+, and
95 % of patients entered had disease that was IHC3+ and/or FISH-positive.
Weekly dosing in metastatic breast cancer
The efficacy results from the monotherapy and combination therapy studies are summarised in
Table 4:
Table 4 Efficacy results from the monotherapy and combination therapy studies
Parameter | Monotherapy | Combination Therapy | |||
| Trastuzumab1 N = 172 | Trastuzumab plus paclitaxel2 N = 68 | Paclitaxel2 N = 77 | Trastuzumab plus docetaxel3 N = 92 | Docetaxel3 N = 94 |
Response rate (95 %CI) | 18 % (13 - 25) | 49 % (36 - 61) | 17 % (9 - 27) | 61 % (50-71) | 34 % (25-45) |
Median duration of response (months) (95 %CI) | 9.1 (5.6-10.3) | 8.3 (7.3-8.8) | 4.6 (3.7-7.4) | 11.7 (9.3 – 15.0) | 5.7 (4.6-7.6) |
Median TTP (months) (95 %CI) | 3.2 (2.6-3.5) | 7.1 (6.2-12.0) | 3.0 (2.0-4.4) | 11.7 (9.2-13.5) | 6.1 (5.4-7.2) |
Median Survival (months) (95 %CI) | 16.4 (12.3-ne) | 24.8 (18.6-33.7) | 17.9 (11.2-23.8) | 31.2 (27.3-40.8) | 22.74 (19.1-30.8) |
TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached.
1. Study H0649g: IHC3+ patient subset
2. Study H0648g: IHC3+ patient subset
3. Study M77001: Full analysis set (intent-to-treat), 24 months results
Combination treatment with Trastuzumab and anastrozole
Trastuzumab has been studied in combination with anastrozole for first line treatment of MBC in
HER2 overexpressing, hormone-receptor (i.e. estrogen-receptor (ER) and/or progesterone-receptor
(PR)) positive postmenopausal patients. Progression free survival was doubled in the trastuzumab plus
anastrozole arm compared to anastrozole (4.8 months versus 2.4 months). For the other parameters the
improvements seen for the combination were for overall response (16.5 % versus 6.7 %); clinical
benefit rate (42.7 % versus 27.9 %); time to progression (4.8 months versus 2.4 months). For time to
response and duration of response no difference could be recorded between the arms. The median
overall survival was extended by 4.6 months for patients in the combination arm. The difference was
not statistically significant, however more than half of the patients in the anastrozole alone arm
crossed over to a trastuzumab containing regimen after progression of disease.
Three -weekly dosing in metastatic breast cancer
The efficacy results from the non-comparative monotherapy and combination therapy studies are
summarised in Table 5:
Table 5 Efficacy results from the non-comparative monotherapy and combination therapy studies
Parameter | Monotherapy | Combination Therapy | ||
| Trastuzumab1 N = 105 | Trastuzumab2 N = 72 | Trastuzumab plus paclitaxel3 N = 32 | Trastuzumab plus docetaxel4 N = 110 |
Response rate (95 %CI) | 24 % (15 - 35) | 27 % (14 - 43) | 59 % (41-76) | 73 % (63-81) |
Median duration of response (months) (range) | 10.1 (2.8-35.6) | 7.9 (2.1-18.8) | 10.5 (1.8-21) | 13.4 (2.1-55.1) |
Median TTP (months) (95 %CI) | 3.4 (2.8-4.1) | 7.7 (4.2-8.3) | 12.2 (6.2-ne) | 13.6 (11-16) |
Median Survival (months) (95 %CI) | ne | ne | ne | 47.3 (32-ne) |
TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached.
1. Study WO16229: loading dose 8 mg/kg, followed by 6 mg/kg 3 weekly schedule
2. Study MO16982: loading dose 6 mg/kg weekly x 3; followed by 6 mg/kg 3-weekly schedule
3. Study BO15935
4. Study MO16419
Sites of progression
The frequency of progression in the liver was significantly reduced in patients treated with the
combination of trastuzumab and paclitaxel, compared to paclitaxel alone (21.8 % versus 45.7 %;
p = 0.004). More patients treated with trastuzumab and paclitaxel progressed in the central nervous
system than those treated with paclitaxel alone (12.6 % versus 6.5 %; p = 0.377).
Early breast cancer (adjuvant setting)
EBC is defined as non-metastatic primary invasive carcinoma of the breast.
In the adjuvant treatment setting, trastuzumab was investigated in 4 large multicentre, randomised,
trials.
- Study BO16348 was designed to compare one and two years of three-weekly trastuzumab
treatment versus observation in patients with HER2 positive EBC following surgery, established
chemotherapy and radiotherapy (if applicable). In addition, comparison of two years of
trastuzumab treatment versus one year of trastuzumab treatment was performed. Patients
assigned to receive trastuzumab were given an initial loading dose of 8 mg/kg, followed by
6 mg/kg every three weeks for either one or two years.
- The NSABP B-31 and NCCTG N9831 studies that comprise the joint analysis were designed to
investigate the clinical utility of combining trastuzumab treatment with paclitaxel following AC
chemotherapy; additionally, the NCCTG N9831 study also investigated adding trastuzumab
sequentially to AC→P chemotherapy in patients with HER2 positive EBC following surgery.
- The BCIRG 006 study was designed to investigate combining trastuzumab treatment with
docetaxel either following AC chemotherapy or in combination with docetaxel and carboplatin
in patients with HER2 positive EBC following surgery.
EBC in the HERA trial was limited to operable, primary, invasive adenocarcinoma of the breast, with
axillary nodes positive or axillary nodes negative if tumours at least 1 cm in diameter.
In the joint analysis of the NSABP B-31 and NCCTG N9831 studies, EBC was limited to women with
operable breast cancer at high risk, defined as HER2-positive and axillary lymph node positive or
HER2 positive and lymph node negative with high risk features (tumour size > 1 cm and ER negative
or tumour size > 2 cm, regardless of hormonal status).
In the BCIRG 006 study HER2 positive, EBC was defined as either lymph node positive or high risk
node negative patients with no (pN0) lymph node involvement, and at least 1 of the following factors:
tumour size greater than 2 cm, estrogen receptor and progesterone receptor negative, histological
and/or nuclear grade 2-3, or age < 35 years).
The efficacy results from the BO16348 trial following 12 months* and 8 years** median follow-up
are summarized in Table 6:
Table 6 Efficacy results from study BO16348
| Median follow-up 12 months* | Median follow-up 8 years** | ||
Parameter | Observation N = 1693 | Trastuzumab 1 Year N = 1693 | Observation N = 1697*** | Trastuzumab 1 Year N = 1702*** |
Disease-free survival - No. patients with event - No. patients without event P-value versus Observation Hazard Ratio versus Observation |
219 (12.9 %) 127 (7.5 %) 1474 (87.1 %) 1566 (92.5 %) < 0.0001 0.54 |
570 (33.6 %) 471 (27.7 %) 1127 (66.4 %) 1231 (72.3 %) < 0.0001 0.76 | ||
Recurrence-free survival - No. patients with event - No. patients without event P-value versus Observation Hazard Ratio versus Observation |
208 (12.3 %) 113 (6.7 %) 1485 (87.7 %) 1580 (93.3 %) < 0.0001 0.51 |
506 (29.8 %) 399 (23.4 %) 1191 (70.2 %) 1303 (76.6 %) < 0.0001 0.73 | ||
Distant disease-free survival - No. patients with event - No. patients without event P-value versus Observation Hazard Ratio versus Observation |
184 (10.9 %) 99 (5.8 %) 1508 (89.1 %) 1594 (94.6 %) < 0.0001 0.50 |
488 (28.8 %) 399 (23.4 %) 1209 (71.2 %) 1303 (76.6 %) < 0.0001 0.76 | ||
Overall survival (death) - No. patients with event - No. patients without event P-value versus Observation Hazard Ratio versus Observation |
40 (2.4 %) 31 (1.8 %) 1653 (97.6 %) 1662 (98.2 %) 0.24 0.75 |
350 (20.6 %) 278 (16.3 %) 1347 (79.4 %) 1424 (83.7 %) 0.0005 0.76 | ||
*Co-primary endpoint of DFS of 1 year versus observation met the pre-defined statistical boundary
**Final analysis (including crossover of 52 % of patients from the observation arm to trastuzumab)
*** There is a discrepancy in the overall sample size due to a small number of patients who were randomised
after the cut-off date for the 12-month median follow-up analysis
The efficacy results from the interim efficacy analysis crossed the protocol pre-specified statistical
boundary for the comparison of 1-year of trastuzumab versus observation. After a median follow-up of
12 months, the hazard ratio (HR) for disease free survival (DFS) was 0.54 (95 % CI 0.44, 0.67) which
translates into an absolute benefit, in terms of a 2-year disease-free survival rate, of 7.6 percentage
points (85.8 % versus 78.2 %) in favour of the trastuzumab arm.
A final analysis was performed after a median follow-up of 8 years, which showed that 1 year
trastuzumab treatment is associated with a 24 % risk reduction compared to observation only
(HR = 0.76, 95 % CI 0.67, 0.86). This translates into an absolute benefit in terms of an 8 year disease
free survival rate of 6.4 percentage points in favour of 1 year trastuzumab treatment.
In this final analysis, extending trastuzumab treatment for a duration of two years did not show
additional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 years
versus 1 yea r= 0.99 (95 % CI: 0.87, 1.13), p-value = 0.90 and OS HR = 0.98 (0.83, 1.15); pvalue
= 0.78]. The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm
(8.1 % versus 4.6 % in the 1-year treatment arm). More patients experienced at least one grade 3 or 4
adverse event in the 2-year treatment arm (20.4 %) compared with the 1-year treatment arm (16.3 %).
In the NSABP B-31 and NCCTG N9831 studies trastuzumab was administered in combination with
paclitaxel, following AC chemotherapy.
Doxorubicin and cyclophosphamide were administered concurrently as follows:
- intravenous push doxorubicin, at 60 mg/ m2, given every 3 weeks for 4 cycles.
- intravenous cyclophosphamide, at 600 mg/ m2 over 30 minutes, given every 3 weeks for 4
cycles
Paclitaxel, in combination with trastuzumab, was administered as follows:
- intravenous paclitaxel – 80 mg/ m2 as a continuous intravenous infusion, given every week for
12 weeks.
or
- intravenous paclitaxel – 175 mg/ m2 as a continuous intravenous infusion, given every 3 weeks
for 4 cycles (day 1 of each cycle).
The efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831 trials at the time
of the definitive analysis of DFS* are summarized in Table 7. The median duration of follow up was
1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm.
Table 7 Summary of efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831
trials at the time of the definitive DFS analysis*
Parameter | AC→P (n = 1679) | AC→PH (n = 1672) | Hazard Ratio vs AC→P (95% CI) p-value |
| |||
Disease-free survival | 261 (15.5) | 133 (8.0) | 0.48 (0.39, 0.59) |
No. patients with event (%) |
|
| p < 0.0001 |
|
|
|
|
Distant Recurrence | 193 (11.5) | 96 (5.7) | 0.47 (0.37, 0.60) |
No. patients with event |
|
| p < 0.0001 |
|
|
|
|
Death (OS event): | 92 (5.5) | 62 (3.7) | 0.67 (0.48, 0.92) |
No. patients with event |
|
| p = 0.014** |
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab
* At median duration of follow up of 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the
AC→PH arm
** p value for OS did not cross the pre-specified statistical boundary for comparison of AC→PH vs. AC→P
For the primary endpoint, DFS, the addition of trastuzumab to paclitaxel chemotherapy resulted in a
52 % decrease in the risk of disease recurrence. The hazard ratio translates into an absolute benefit, in
terms of 3-year disease-free survival rate estimates of 11.8 percentage points (87.2 % versus 75.4 %)
in favour of the AC→PH (trastuzumab) arm.
At the time of a safety update after a median of 3.5-3.8 years follow up, an analysis of DFS reconfirms
the magnitude of the benefit shown in the definitive analysis of DFS. Despite the cross-over to
trastuzumab in the control arm, the addition of trastuzumab to paclitaxel chemotherapy resulted in a
52 % decrease in the risk of disease recurrence. The addition of trastuzumab to paclitaxel
chemotherapy also resulted in a 37 % decrease in the risk of death.
The pre-planned final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG
N9831 was performed when 707 deaths had occurred (median follow-up 8.3 years in the AC→P H
group). Treatment with AC→PH resulted in a statistically significant improvement in OS compared
with AC→P (stratified HR = 0.64; 95% CI [0.55, 0.74]; log-rank p-value < 0.0001). At 8 years, the
survival rate was estimated to be 86.9 % in the AC→PH arm and 79.4 % in the AC→P arm, an
absolute benefit of 7.4 % (95 % CI 4.9 %, 10.0 %).
The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are
summarized in Table 8 below:
Table 8 Final overall survival analysis from the joint analysis of trials NSABP B-31 and NCCTG
N9831
Parameter | AC→P (N = 2032) | AC→PH (N = 2031) | p-value versus AC→P | Hazard Ratio versus AC→P (95 % CI) |
Death (OS event): |
|
|
|
|
No. patients with event (%) | 418 (20.6 %) | 289 (14.2 %) | < 0.0001 | 0.64 (0.55, 0.74) |
|
|
|
|
|
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab
DFS analysis was also performed at the final analysis of OS from the joint analysis of studies NSABP
B-31 and NCCTG N9831. The updated DFS analysis results (stratified HR = 0.61; 95% CI [0.54,
0.69]) showed a similar DFS benefit compared to the definitive primary DFS analysis, despite 24.8 %
patients in the AC→P arm who crossed over to receive trastuzumab. At 8 years, the disease-free
survival rate was estimated to be 77.2 % (95 % CI: 75.4, 79.1) in the AC→PH arm, an absolute benefit
of 11.8% compared with the AC→P arm.
In the BCIRG 006 study trastuzumab was administered either in combination with docetaxel,
following AC chemotherapy (AC→DH) or in combination with docetaxel and carboplatin (DCarbH).
Docetaxel was administered as follows:
- intravenous docetaxel – 100 mg/m2 as an intravenous infusion over 1 hour, given every 3 weeks
for 4 cycles (day 2 of first docetaxel cycle, then day 1 of each subsequent cycle).
or
- intravenous docetaxel – 75 mg/m2 as an intravenous infusion over 1 hour, given every 3 weeks
for 6 cycles (day 2 of cycle 1, then day 1 of each subsequent cycle).
which was followed by:
- carboplatin – at target AUC = 6 mg/mL/min administered by intravenous infusion over 30-
60 minutes repeated every 3 weeks for a total of six cycles.
Trastuzumab was administered weekly with chemotherapy and 3 weekly thereafter for a total of 52
weeks.
25
The efficacy results from the BCIRG 006 are summarized in Tables 9 and 10. The median duration of
follow up was 2.9 years in the AC→D arm and 3.0 years in each of the AC→DH and DCarbH arms.
Table 9 Overview of efficacy analyses BCIRG 006 AC→D versus AC→DH
Parameter | AC→D (n = 1073) | AC→DH (n = 1074) | Hazard Ratio vs AC→D (95 % CI) p-value |
Disease-free survival No. patients with event | 195 | 134 | 0.61 (0.49, 0.77) p < 0.0001 |
Distant recurrence No. patients with event | 144 | 95 | 0.59 (0.46, 0.77) p < 0.0001 |
Death (OS event) No. patients with event | 80 | 49 | 0.58 (0.40, 0.83) p = 0.0024 |
AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; AC→DH = doxorubicin plus cyclophosphamide, followed by docetaxel plus trastuzumab; CI = confidence interval
Table 10 Overview of efficacy analyses BCIRG 006 AC→D versus DCarbH
Parameter | AC→D (n = 1073) | DCarbH (n = 1074) | Hazard Ratio vs AC→D (95 % CI) p-value |
Disease-free survival No. patients with event | 195 | 145 | 0.67 (0.54, 0.83) p = 0.0003 |
Distant recurrence No. patients with event | 144 | 103 | 0.65 (0.50, 0.84) p = 0.0008 |
Death (OS event) No. patients with event | 80 | 56 | 0.66 (0.47, 0.93) p = 0.0182 |
AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; DCarbH = docetaxel, carboplatin and trastuzumab; CI = confidence interval
In the BCIRG 006 study for the primary endpoint, DFS, the hazard ratio translates into an absolute
benefit, in terms of 3-year disease-free survival rate estimates of 5.8 percentage points (86.7 % versus
80.9 %) in favour of the AC→DH (trastuzumab) arm and 4.6 percentage points (85.5 % versus
80.9 %) in favour of the DCarbH (trastuzumab) arm compared to AC→D.
In study BCIRG 006, 213/1075 patients in the DCarbH (TCH) arm, 221/1074 patients in the AC→DH
(AC→TH) arm, and 217/1073 in the AC→D (AC→T) arm had a Karnofsky performance status ≤ 90
(either 80 or 90). No disease-free survival (DFS) benefit was noticed in this subgroup of patients
(hazard ratio = 1.16, 95 % CI [0.73, 1.83] for DCarbH (TCH) versus AC→D (AC→T); hazard ratio
0.97, 95 % CI [0.60, 1.55] for AC→DH (AC→TH) versus AC→D).
In addition, a post-hoc exploratory analysis was performed on the data sets from the joint analysis (JA)
NSABP B-31/NCCTG N9831* and BCIRG006 clinical studies combining DFS events and
symptomatic cardiac events and summarised in Table 11:
Table 11 Post-Hoc exploratory analysis results from the joint analysis NSABP B-31/NCCTG N9831 and BCIRG006 clinical studies combining DFS events and symptomatic cardiac events
| AC→PH (vs. AC→P) (NSABP B-31 and NCCTG N9831)* | AC→DH (vs. AC→D) (BCIRG 006) | DCarbH (vs. AC→D) (BCIRG 006) |
Primary efficacy analysis DFS Hazard ratios (95 % CI) p-value |
0.48 (0.39, 0.59) p < 0.0001 |
0.61 (0.49, 0.77) p < 0.0001 |
0.67 (0.54, 0.83) p = 0.0003 |
Long term follow-up efficacy analysis** DFS Hazard ratios (95 % CI) p-value |
0.61 (0.54, 0.69) p < 0.0001 |
0.72 (0.61, 0.85) p < 0.0001 |
0.77 (0.65, 0.90) p = 0.0011 |
Post-hoc exploratory analysis with DFS and symptomatic cardiac events Long term follow-up** Hazard ratios (95 % CI) |
0.67 (0.60, 0.75) |
0.77 (0.66, 0.90) |
0.77 (0.66, 0.90) |
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel; Carb: carboplatin; H: trastuzumab CI = confidence interval
* At the time of the definitive analysis of DFS. Median duration of follow up was 1.8 years in the
AC→P arm and 2.0 years in the AC→PH arm
** Median duration of long term follow-up for the Joint Analysis clinical studies was 8.3 years (range:
0.1 to 12.1) for the AC→PH arm and 7.9 years (range: 0.0 to 12.2) for the AC→P arm; Median duration of long term follow-up for the BCIRG 006 study was 10.3 years in both the AC→D arm (range: 0.0 to 12.6) arm and the DCarbH arm (range: 0.0 to 13.1), and was 10.4 years (range: 0.0 to 12.7) in the AC→DH arm
Early breast cancer (neoadjuvant-adjuvant setting)
So far, no results are available which compare the efficacy of trastuzumab administered with
chemotherapy in the adjuvant setting with that obtained in the neo-adjuvant/adjuvant setting.
In the neoadjuvant-adjuvant treatment setting, study MO16432, a multicentre randomised trial, was
designed to investigate the clinical efficacy of concurrent administration of trastuzumab with
neoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant
trastuzumab, up to a total treatment duration of 1 year. The study recruited patients with newly
diagnosed locally advanced (Stage III) or inflammatory EBC. Patients with HER2+ tumours were
randomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant
trastuzumab, or neoadjuvant chemotherapy alone.
In study MO16432, trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance every 3
weeks) was administered concurrently with 10 cycles of neoadjuvant chemotherapy as follows:
- Doxorubicin 60 mg/m2 and paclitaxel 150 mg/m2, administered 3-weekly for 3 cycles,
which was followed by
- Paclitaxel 175 mg/m2 administered 3-weekly for 4 cycles,
which was followed by
- CMF on day 1 and 8 every 4 weeks for 3 cycles
which was followed after surgery by
- additional cycles of adjuvant trastuzumab (to complete 1 year of treatment)
The efficacy results from Study MO16432 are summarized in Table 12. The median duration of
follow-up in the trastuzumab arm was 3.8 years.
Table 12 Efficacy results from MO16432
* defined as absence of any invasive cancer both in the breast and axillary nodes
An absolute benefit of 13 percentage points in favour of the trastuzumab arm was estimated in terms
of 3-year event-free survival rate (65 % versus 52 %).
Metastatic gastric cancer
Trastuzumab has been investigated in one randomised, open-label phase III trial ToGA (BO18255) in
combination with chemotherapy versus chemotherapy alone.
Chemotherapy was administered as follows:
- capecitabine – 1000 mg/m2 orally twice daily for 14 days every 3 weeks for 6 cycles (evening of
day 1 to morning of day 15 of each cycle)
or
- intravenous 5-fluorouracil - 800 mg/m2/day as a continuous intravenous infusion over 5 days,
given every 3 weeks for 6 cycles (days 1 to 5 of each cycle)
Either of which was administered with:
- cisplatin – 80 mg/m2 every 3 weeks for 6 cycles on day 1 of each cycle.
The efficacy results from study BO18225 are summarised in Table 13:
Table 13 Efficacy results from BO18225
Parameter | FP N = 290 | FP +H N = 294 | HR (95 % CI) | p-value |
Overall Survival, Median months | 11.1 | 13.8 | 0.74 (0.60-0.91) | 0.0046 |
Progression-Free Survival, Median months | 5.5 | 6.7 | 0.71 (0.59-0.85) | 0.0002 |
Time to Disease Progression, Median months | 5.6 | 7.1 | 0.70 (0.58-0.85) | 0.0003 |
Overall Response Rate, % | 34.5 % | 47.3 % | 1.70a (1.22, 2.38) | 0.0017 |
Duration of Response, Median months | 4.8 | 6.9 | 0.54 (0.40-0.73) | < 0.0001 |
FP + H: Fluoropyrimidine/cisplatin + Trastuzumab FP: Fluoropyrimidine/cisplatin
a Odds ratio
Patients were recruited to the trial who were previously untreated for HER2-positive inoperable locally
advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal
junction not amenable to curative therapy. The primary endpoint was overall survival which was
defined as the time from the date of randomisation to the date of death from any cause. At the time of
the analysis a total of 349 randomised patients had died: 182 patients (62.8 %) in the control arm and
167 patients (56.8 %) in the treatment arm. The majority of the deaths were due to events related to the
underlying cancer.
Post-hoc subgroup analyses indicate that positive treatment effects are limited to targeting tumours
with higher levels of HER2 protein (IHC 2+/FISH+ or IHC 3+). The median overall survival for the
high HER2 expressing group was 11.8 months versus 16 months, HR 0.65 (95 % CI 0.51-0.83) and
the median progression free survival was 5.5 months versus 7.6 months, HR 0.64 (95 % CI 0.51-0.79)
for FP versus FP + H, respectively. For overall survival, the HR was 0.75 (95 % CI 0.51-1.11) in the
IHC 2+/FISH+ group and the HR was 0.58 (95 % CI 0.41-0.81) in the IHC 3+/FISH+ group.
In an exploratory subgroup analysis performed in the TOGA (BO18255) trial there was no apparent
benefit on overall survival with the addition of trastuzumab in patients with ECOG PS 2 at baseline
[HR 0.96 (95 % CI 0.51-1.79)], non-measurable [HR 1.78 (95 % CI 0.87-3.66)] and locally advanced
disease [HR 1.20 (95 % CI 0.29-4.97)].
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with the
reference medicinal product containing trastuzumab in all subsets of the paediatric population for
breast and gastric cancer (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis
using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or
other tumour types, and healthy volunteers, in 18 Phase I, II and III trials receiving trastuzumab IV. A
two-compartment model with parallel linear and non-linear elimination from the central compartment
described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance
increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can
be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval (see Table 16).
MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central compartment
volume (Vc)) and population-predicted steady-state exposures (Cmin, Cmax and AUC). Linear clearance
was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC. The non-linear elimination
parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 mcg/mL for the
Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The central compartment
volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC. In the final
population PK model, in addition to primary tumour type, body-weight, serum aspartate
aminotransferase and albumin were identified as a statistically significant covariates affecting the
exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab
exposure suggests that these covariates are unlikely to have a clinically meaningful effect on
trastuzumab concentrations.
The population predicted PK exposure values (median with 5th - 95th Percentiles) and PK parameter
values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treated
with the approved q1w and q3w dosing regimens are shown in Table 14 (cycle 1), Table 15 (steadystate),
and Table 16 (PK parameters).
Table 14 Population predicted cycle 1 PK exposure values (median with 5th - 95th percentiles)
fortrastuzumab intravenous dosing regimens in MBC, EBC and AGC patients
Regimen | Primary tumour type | N | Cmin (mcg/mL) | Cmax (mcg/mL) | AUC0-21days (mcg.day/mL) |
8 mg/kg + 6 mg/kg q3w |
MBC |
805 |
28.7 (2.9 - 46.3) |
182 (134 - 280) |
1376 (728 - 1998) |
EBC |
390 | 30.9 (18.7 - 45.5) | 176 (127 - 227) | 1390 (1039 - 1895) | |
AGC |
274 | 23.1 (6.1 - 50.3) | 132 (84.2 – 225) | 1109 (588 – 1938) | |
4 mg/kg + 2 mg/kg qw |
MBC |
805 | 37.4 (8.7 - 58.9) | 76.5 (49.4 - 114) | 1073 (597 – 1584) |
EBC |
390 | 38.9 (25.3 - 58.8) | 76.0 (54.7 - 104) | 1074 (783 - 1502) |
Table 15 Population predicted steady state PK exposure values (median with 5th - 95th percentiles)for trastuzumab intravenous dosing regimens in MBC, EBC and AGC patients
Regimen |
Primary tumour type |
N |
Cmin,ss* (mcg/mL) |
Cmax,ss** (mcg/mL) | AUCss, 0-21days (mcg.day/mL) | Time to steady- state*** (week) |
|
|
| 44.2 | 179 | 1736 |
|
8 mg/kg + | MBC | 805 | (1.8 - 85.4) | (123 - 266) | (618 - 2756) | 12 |
6 mg/kg q3w |
| |||||
|
| 53.8 | 184 | 1927 |
| |
| EBC | 390 | (28.7 - 85.8) | (134 - 247) | (1332 -2771) | 15 |
|
|
| 32.9 | 131 | 1338 |
|
| AGC | 274 | (6.1 – 88.9) | (72.5 -251) | (557 - 2875) | 9 |
|
|
| 63.1 | 107 | 1710 |
|
4 mg/kg + | MBC | 805 | (11.7 - 107) | (54.2 - 164) | (581 - 2715) | 12 |
2 mg/kg qw |
|
|
|
|
|
|
|
| 72.6 | 115 | 1893 |
| |
| EBC | 390 | (46 - 109) | (82.6 - 160) | (1309 -2734) | 14 |
*Cmin,ss – Cmin at steady state
**Cmax,ss = Cmax at steady state
*** time to 90% of steady-state
Table 16 Population predicted PK parameter values at steady state for trastuzumab intravenous dosing regimens in MBC, EBC and AGC patients
Regimen |
Primary tumour type |
N | Total CL range from Cmax,ss to Cmin,ss (L/day) |
t1/2 range from Cmax,ss to Cmin,ss (day) |
8 mg/kg + 6 mg/kg q3w | MBC | 805 | 0.183 - 0.302 | 15.1 - 23.3 |
EBC | 390 | 0.158 - 0.253 | 17.5 – 26.6 | |
AGC | 274 | 0.189 - 0.337 | 12.6 - 20.6
| |
4 mg/kg + 2 mg/kg qw | MBC | 805 | 0.213 - 0.259 | 17.2 - 20.4 |
EBC | 390 | 0.184 - 0.221 | 19.7 - 23.2 |
Trastuzumab washout
Trastuzumab washout period was assessed following q1w or q3w intravenous administration using the population PK model. The results of these simulations indicate that at least 95 % of patients will reach concentrations that are < 1 mcg/mL (approximately 3 % of the population predicted Cmin,ss, or about
97 % washout) by 7 months.
Circulating shed HER2-ECD
The exploratory analyses of covariates with information in only a subset of patients suggested that patients with greater shed HER2-ECD level had faster nonlinear clearance (lower Km) (P < 0.001). There was a correlation between shed antigen and SGOT/AST levels; part of the impact of shed antigen on clearance may have been explained by SGOT/AST levels.
Baseline levels of the shed HER2-ECD observed in MGC patients were comparable to those in MBC
and EBC patients and no apparent impact on trastuzumab clearance was observed.
5.3 Preclinical safety data
There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, or
reproductive toxicity in teratology, female fertility or late gestational toxicity/placental transfer
studies. Trastuzumab is not genotoxic.
No long-term animal studies have been performed to establish the carcinogenic potential of
trastuzumab, or to determine its effects on fertility in males.
6.1 List of excipients
L-histidine hydrochloride
L-histidine
Sorbitol (E420)
Macrogol 3350
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
6.2 Incompatibilities
This medicinal product must not be mixed or diluted with other medicinal products except those
mentioned in section 6.6.
Glucose solutions must not be used for dilution since these cause aggregation of the protein.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
For storage conditions after reconstitution of the medicinal product, see sections 6.3 and 6.6.
6.5 Nature and contents of container
Ogivri 420 mg powder for concentrate for solution for infusion
50 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film containing
420 mg of trastuzumab.
Each carton contains one vial.
6.6 Special precautions for disposal and other handling
Ogivri should be carefully handled during reconstitution. Causing excessive foaming during
reconstitution or shaking the reconstituted solution may result in problems with the amount of Ogivri
that can be withdrawn from the vial.
The reconstituted solution should not be frozen.
Ogivri 420 mg powder for concentrate for solution for infusion
Each 420 mg vial of Ogivri is reconstituted with 20 mL of sterile water for injections (not supplied).
Use of other reconstitution solvents should be avoided. This yields a 21 mL solution for single-dose
use, containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. A volume
overage of 4.8 % ensures that the labelled dose of 420 mg can be withdrawn from each vial.
Ogivri vial |
| Volume of sterile water for injections |
| Final concentration |
420 mg vial | + | 20 mL | = | 21 mg/mL |
Instructions for reconstitution
- Using a sterile syringe, slowly inject the appropriate volume (as noted above) of sterile water for injections in the vial containing the lyophilised Ogivri, directing the stream into the lyophilised cake.
- Swirl the vial gently to aid reconstitution. DO NOT SHAKE!
Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The reconstituted Ogivri results in a colourless to pale yellow transparent solution and should be essentially free of visible particulates.
Determine the volume of the solution required:
- based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose of 2 mg trastuzumab/kg body weight:
Volume (mL) = Body weight (kg) x dose (4 mg/kg for loading or 2 mg/kg for maintenance)
21 (mg/mL, concentration of reconstituted solution)
- based on a loading dose of 8 mg trastuzumab/kg body weight, or a subsequent 3-weekly dose of 6 mg trastuzumab/kg body weight:
Volume (mL) = Body weight (kg) x dose (8 mg/kg for loading or 6 mg/kg for maintenance)
21 (mg/mL, concentration of reconstituted solution)
The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag containing 250 mL of sodium chloride 9 mg/mL (0.9 %) solution for injection. Do not use with
glucose-containing solutions (see section 6.2). The bag should be gently inverted to mix the solution in order to avoid foaming. Once the infusion is prepared it should be administered immediately. If diluted aseptically, it may be stored for up to 90 days at 2°C – 8°C and 24 hours at temperatures not exceeding 30°C
Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration.
Ogivri is for single-use only, as the product contains no preservatives.
No incompatibilities between Ogivri and polyvinylchloride, polyethylene or polypropylene bags have been observed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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