Active ingredients: Bevacizumab
Avastin 25 mg / ml concentrate for solution for infusion
Why is Avastin used? What is it for?
Avastin contains the active substance bevacizumab, a humanised monoclonal antibody (in general, antibodies are a type of protein that is normally produced by the immune system to help the body defend itself against infection and cancer).
Bevacizumab selectively binds to a protein called 'human vascular endothelial growth factor' (VEGF), which is present on the lining of the body's blood and lymphatic vessels. The VEGF protein determines the growth of blood vessels within the tumor; these blood vessels supply the tumor with nutrients and oxygen. Once bevacizumab binds to VEGF, tumor growth is prevented by blocking the development of blood vessels that supply nutrients. and oxygen to the tumor Avastin is a medicine used to treat adult patients with advanced cancer of the large intestine, ie colon or rectum. Avastin will be given in combination with a chemotherapy treatment containing a fluoropyrimidine-based medicine.
Avastin is also used to treat adult patients with metastatic breast cancer. In patients with this type of cancer, Avastin will be given with a paclitaxel or capecitabine-based chemotherapy regimen.
Avastin is also used to treat adult patients with advanced non-small cell lung cancer. Avastin will be given together with a platinum-based chemotherapy regimen.
Avastin is also used to treat adult patients with advanced kidney cancer. In patients with this type of cancer, Avastin will be given with another type of medicine called interferon.
Avastin is also used to treat adult patients with epithelial ovarian cancer, fallopian tube cancer or advanced primary peritoneal cancer. In patients with this type of cancer, Avastin will be given in combination with carboplatin and paclitaxel.
Avastin will be given in combination with carboplatin and gemcitabine when used in adult patients with epithelial ovarian cancer, fallopian tube cancer or advanced primary peritoneal cancer whose disease has re-manifested at least 6 months after the last time they were treated with a chemotherapy regimen containing a platinum-based agent.
Avastin will be given in combination with paclitaxel, topotecan or pegylated liposomal doxorubicin when used in adult patients with epithelial ovarian cancer, fallopian tube cancer or advanced primary peritoneal cancer whose disease has re-emerged less than 6 months after the last. once they have been treated with a chemotherapy regimen containing a platinum-based agent.
Avastin is also used to treat adult patients with persistent, recurrent or metastatic cervical cancer. Avastin will be given in combination with paclitaxel and cisplatin or alternatively paclitaxel and topotecan in patients who cannot be treated with platinum.
Contraindications When Avastin should not be used
Do not use Avastin:
- if you are allergic (hypersensitive) to bevacizumab or any of the other ingredients of this medicine
- if you are allergic (hypersensitive) to products derived from Chinese Hamster Ovary (CHO) cells or to other human or humanised recombinant antibodies.
- if you are pregnant.
Precautions for use What you need to know before taking Avastin
Talk to your doctor, pharmacist or nurse before using Avastin
- It is possible that Avastin may increase the risk of developing perforations in the intestinal wall. If you have conditions that cause inflammation in the abdomen (eg diverticulitis, stomach ulcers, chemotherapy associated colitis), discuss this with your doctor.
- Avastin can increase the risk of developing an abnormal connection or passage between two organs or vessels. The presence of persistent, recurrent, or metastatic cervical cancer can lead to an increased risk of developing connections between the vagina and any section of the gastrointestinal tract.
- This medicine may increase the risk of bleeding or increase the risk of problems with wound healing after surgery. If you are going to have an operation, if you have had major surgery in the last 28 days or if you have a surgical wound that has not yet healed; you should not take this medicine.
- Avastin can increase your risk of developing severe infections of the skin or deeper layers under the skin, especially if you have perforations in the intestinal wall or have problems with wound healing.
- Avastin may increase the incidence of high blood pressure. If you have high blood pressure that is not well controlled with blood pressure medications, please discuss this with your doctor. It is important to make sure that your blood pressure is under control before starting treatment with Avastin.
- This medicine increases the risk of having protein in your urine, especially if you already have high blood pressure.
- The risk of developing blood clots in the arteries (a type of blood vessel) may be increased if you are over the age of 65, have diabetes and have had previous blood clots in the arteries. Talk to your doctor because blood clots can lead to heart attacks and strokes.
- Avastin can also increase the risk of developing blood clots in the veins (a type of blood vessel).
- This medicine can cause bleeding, especially tumor-related bleeding. Consult your doctor if you or other family members tend to have blood clotting problems or if you are taking blood thinning medicines for any reason.
- It is possible that Avastin can cause bleeding in and around the brain. Consult your doctor if you have metastatic disease involving the brain.
- It is possible that Avastin may increase the risk of bleeding in the lungs, including blood in the cough or saliva. Discuss with your doctor if you have noticed these events in the past.
- Avastin may increase the risk of developing "heart failure. It is important for your doctor to know if you have previously received anthracyclines (eg doxorubicin, a special type of chemotherapy used to treat some cancers) or chest radiotherapy," or if you have heart disease.
- This medicine can cause infections and a reduction in the number of neutrophils (a type of blood cell important for protection against bacteria).
- It is possible that Avastin may cause hypersensitivity and / or infusion reactions (reactions related to the injection of the medicine). Tell your doctor, pharmacist or nurse if you have already had any problems after the injections, such as dizziness / fainting, lack of breathing, swelling or rash.
- A rare neurological side effect called posterior reversible encephalopathy syndrome has been associated with treatment with Avastin. If you have headache, disturbed vision, confusion or seizures with or without increased blood pressure, please contact your doctor.
Talk to your doctor even if the above has only happened in the past.
Before starting treatment with Avastin or during treatment with Avastin:
- if you have had or have pain in the mouth, teeth and / or jaw, or swelling or inflammation in the mouth, or numbness or heaviness in the jaw, or loosing a tooth, report it immediately to your doctor and dentist ;
- if you are due to undergo invasive dental treatment or dental surgery, please tell your dentist that you are being treated with Avastin, particularly if you have received or are receiving a "bisphosphonate injection. Your doctor or dentist may suggest that you have a dental check-up before going to start treatment with Avastin.
Interactions Which drugs or foods may change the effect of Avastin
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
Combination of Avastin with another medicine called sunitinib malate (prescribed for kidney and gastrointestinal cancer) can cause severe side effects. Talk to your doctor to make sure you don't combine these medications.
Tell your doctor if you are using platinum- or taxane-based therapies for metastatic lung or breast cancer. These therapies in combination with Avastin may increase the risk of severe side effects.
Tell your doctor if you have recently received or are currently receiving radiation therapy.
Warnings It is important to know that:
Children and adolescents
Avastin therapy is not recommended in children and adolescents below 18 years of age as neither safety nor benefits have been established in this patient population.
Do not give Avastin to children aged 3 to 18 with malignant tumors of the brain and spinal cord that grow rapidly and develop through brain tissue following treatment failure (relapse or high-grade progressive glioma) as two studies limited have shown ineffectiveness in these types of tumors.
Pregnancy, breastfeeding and fertility
If you are pregnant you should not use Avastin. Avastin can harm the unborn baby as it can stop the formation of new blood vessels. Your doctor will advise you to use adequate contraception measures during Avastin therapy and for at least 6 months after taking the last dose of Avastin.
If you are pregnant, if you suspect that you are pregnant while taking this medicine or are planning to become pregnant in the immediate future, please speak to your doctor immediately.
You should not breast-feed your baby while taking Avastin and for at least 6 months after taking the last dose of Avastin, as Avastin may interfere with your baby's growth and development.
Avastin can reduce female fertility. Consult your doctor for more information.
Ask your doctor, pharmacist or nurse for advice before taking any medicine.
Driving and using machines
Avastin has not been shown to reduce the ability to drive or use any tools or machines. However, somnolence and syncope have been reported with the use of Avastin. If you experience symptoms affecting your vision or concentration, or your ability to react, do not drive or operate machinery until symptoms disappear.
Dose, Method and Time of Administration How to use Avastin: Posology
Dosage and frequency of administration
The dose of Avastin you need depends on your body weight and the type of cancer being treated. The recommended dose is 5 mg, 7.5 mg, 10 mg or 15 mg per kilogram of body weight. Your doctor will prescribe Avastin at the appropriate dose for you. Treatment with Avastin will be given to you once every 2 to 3 weeks. The number of infusions you will receive will depend on your response to treatment; however, you must continue treatment until Avastin can no longer stop your tumor from growing. Your doctor will neither speak to you.
Method and route of administration
Avastin is a concentrate for solution for infusion. Depending on the dose that is prescribed to you, part of the contents of the Avastin vial or the entire vial will be diluted with sodium chloride solution before use. Your doctor or nurse will give you this diluted solution of Avastin as an intravenous infusion (a drip into a vein). The first infusion will be given over 90 minutes. If this is well tolerated, the second infusion can be given over 60 minutes. Subsequent infusions could be given to you over 30 minutes.
Administration of Avastin should be temporarily interrupted
- if you have severe high blood pressure problems, which require treatment with medicines to control your blood pressure,
- if you have wound healing problems after surgery,
- if you are going to have a "surgery."
Administration of Avastin must be permanently discontinued if any of the following problems occur
- severe high blood pressure that cannot be controlled with suitable medicines, or sudden and severe increase in blood pressure,
- presence of protein in the urine associated with edema (swelling of the body),
- perforation of the intestinal wall,
- an abnormal connection or passage between the trachea and esophagus, internal organs and skin, the vagina and any section of the gastrointestinal tract, or between other tissues that are not normally connected (fistula), and which are judged by the doctor to be severe,
- severe infections of the skin or the deeper layers under the skin,
- blood clots in the arteries,
- blood clots in the lung blood vessels,
- severe bleeding of any kind.
Overdose What to do if you have taken too much Avastin
If too much Avastin is given
- You may experience severe headache. In this case, contact your doctor, pharmacist or nurse immediately.
If you forget to take a dose of Avastin
- Your doctor will decide when is best for you to take your next dose of Avastin. Discuss this with your doctor.
If you stop taking Avastin
Stopping treatment with Avastin may stop the tumor growth restraint action. Do not stop taking Avastin until you have talked to your doctor.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Avastin
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
The side effects listed below have been observed in patients treated with Avastin combined with chemotherapy. This does not mean that these side effects were necessarily caused by Avastin.
Allergic reactions
If you have an allergic reaction, tell your doctor or a member of the medical staff straight away. The signs could include: difficulty breathing or chest pain. There may also be redness of the skin or flushing or rash, chills and shaking, feeling sick (nausea) or vomiting.
If you experience any of the side effects described below, get help immediately.
Severe side effects, which can be very common (affect more than 1 in 10 patients), include:
- high blood pressure,
- feeling of numbness or tingling in the hands or feet,
- reduction in the number of blood cells, including white blood cells, which act against infections (this may be accompanied by fever), and in cells that contribute to blood clotting,
- feeling of weakness and lack of energy,
- tiredness,
- diarrhea, nausea, vomiting and abdominal pain.
Severe side effects, which may be common (affects 1 to 10 users in 100), include:
- intestinal perforation,
- bleeding, including bleeding into the lungs in patients with non-small cell lung cancer,
- arteries blocked by a blood clot,
- veins blocked by a blood clot,
- pulmonary blood vessels blocked by a blood clot,
- leg veins blocked by a blood clot,
- heart failure,
- wound healing problems after surgery,
- redness, peeling, soreness, pain or blistering of the fingers or feet,
- reduction in the number of red blood cells,
- lack of energy,
- stomach and intestinal disorders,
- muscle and joint pain, muscle weakness,
- dry mouth associated with thirst and / or decreased or dark urine,
- inflammation of the oral mucosa, intestines, lungs and airways, reproductive and urinary tract,
- ulcers in the mouth and esophagus which can cause pain and difficulty in swallowing,
- pain, including headache, back pain and pain around the pelvis and anus,
- localized abscesses,
- infection, and especially infection in the blood or bladder,
- reduced blood supply to the brain or stroke,
- drowsiness,
- nosebleeds,
- increased heart rate (pulse),
- intestinal blockage,
- abnormal urine tests (presence of protein in the urine),
- shortness of breath or reduced oxygen levels in the blood,
- infections of the skin or deeper layers of the skin,
- fistulas: abnormal tubular connection between internal organs and skin or other tissues that are not normally connected to each other, including connections between the vagina and the gastrointestinal tract in patients with cervical cancer.
Severe side effects of not known frequency (frequency cannot be estimated from the available data) include:
- severe infections of the skin or deeper layers under the skin, especially if you have had perforations in the intestinal wall or problems with wound healing,
- allergic reactions (signs may include difficulty in breathing, redness of the face, rash, low or high blood pressure, low oxygen in the blood, chest pain or nausea / vomiting),
- an adverse effect on women's ability to have children (see the next paragraphs in the list of side effects for further recommendations),
- a condition of the brain with symptoms such as seizures (fits), headache, confusion and changes in vision (posterior reversible encephalopathy syndrome (PRES)),
- symptoms that suggest changes in normal brain function (headache, visual disturbances, confusion or seizures) and high blood pressure,
- obstruction of a small blood vessel (s) in the kidney,
- an "abnormal high blood pressure in the vessels of the lungs which makes the right side of the heart work harder than normal,
- perforation of the cartilage wall that separates the nostrils,
- perforation of the stomach or intestines,
- an open wound or perforation in the lining of the stomach or small intestine (signs may include abdominal pain, bloating, black tarry stools, blood in stools or blood in vomit),
- bleeding from the lower part of the large intestine,
- gum injury, with exposure of a non-healing jaw bone, which may be associated with pain and inflammation of the surrounding tissue (see the following paragraphs in the list of undesirable effects for further recommendations),
- gallbladder perforation (symptoms and signs may include abdominal pain, fever and nausea / vomiting).
If you experience any of the side effects described below, get help as soon as possible
Very common side effects (affects more than 1 in 10 patients), which were not severe, include:
- constipation,
- loss of appetite,
- fever,
- eye problems (including increased tearing),
- speech changes,
- altered sense of taste,
- a runny nose,
- dry skin, peeling and inflammation of the skin, change in skin color,
- loss of body weight.
Common side effects (affects 1 to 10 users in 100), which were not severe, include:
- voice changes and hoarseness.
Patients over the age of 65 have an increased risk of having the following side effects:
- blood clots in the arteries, which can lead to stroke or heart attack
- reduction in the number of white blood cells and cells that contribute to blood clotting,
- diarrhea,
- sense of malaise,
- headache,
- feeling of fatigue,
- high blood pressure.
Avastin can also cause changes in the results of the laboratory tests prescribed by your doctor. These include: a reduction in the number of white blood cells, especially neutrophils (a type of white blood cell that helps protect against infection) in the blood, the presence of protein in the urine, a decrease in potassium, sodium or phosphorus (a mineral) in the blood, increased blood sugar, increased alkaline phosphatase (an enzyme) in the blood, decreased hemoglobin (found in red blood cells and carries oxygen), which can be severe.
Pain in the mouth, teeth and / or jaw, swelling or blistering in the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. These may be signs and symptoms of bone damage in the jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience any of these.
Premenopausal women (women who have a menstrual cycle) may notice irregular menstrual cycles, absence of menstruation and could have negative consequences on fertility. If you are considering having children, you should discuss this with your doctor before starting treatment.
Avastin was developed and manufactured for the treatment of cancer by intravenous injection.
It was not developed or manufactured for administration by injection into the eye.
Therefore, the use of this route of administration is not authorized. When Avastin is injected directly into the eye (use not approved), the following side effects may occur:
- infection or inflammation of the eyeball,
- redness of the eye, the appearance of particles or floating points in the field of vision ("flying flies"), pain in the eye,
- flashes of light and "flying flies" that progress to the loss of part of the visual field,
- increased pressure in the eye,
- eye bleeding.
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. You can also report side effects directly via the national reporting system listed in Appendix V.
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
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 vial label after the abbreviation EXP. The expiry date refers to the last day of the month.
Store in a refrigerator (2 ° C-8 ° C).
Do not freeze
Keep the vial in the outer carton to protect the medicine from light.
Infusion solutions should be used immediately after being diluted. Do not use Avastin if you notice any particulate matter or color changes before administration.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Contents of the pack and other information
What Avastin contains
- The active ingredient is bevacizumab.
Each mL of concentrate contains 25 mg of bevacizumab, corresponding to 1.4-16.5 mg / mL when diluted as recommended.
Each 4 ml vial contains 100 mg of bevacizumab, corresponding to 1.4 mg / ml when diluted as recommended.
Each 16 ml vial contains 400 mg of bevacizumab, corresponding to 16.5 mg / ml when diluted as recommended.
- The other ingredients are trehalose dihydrate, sodium phosphate, polysorbate 20 and water for injections.
What Avastin looks like and contents of the pack
Avastin is a concentrate for solution for infusion. The concentrate is a clear, colorless to light brown liquid in a glass vial closed with a rubber stopper. Each vial contains 100 mg of bevacizumab in 4 ml of solution or 400 mg of bevacizumab in 16 ml of solution. Each Avastin pack contains one vial.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
AVASTIN 25 MG / ML CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of concentrate contains 25 mg of bevacizumab *.
Each 4 ml vial contains 100 mg of bevacizumab.
Each 16 ml vial contains 400 mg of bevacizumab.
For dilution and other handling recommendations, see section 6.6.
* Bevacizumab is a humanized monoclonal antibody produced by recombinant DNA technique in Chinese Hamster Ovary cells.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear to slightly opalescent and colorless to light brown liquid.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for the treatment of adult patients with metastatic cancer of the colon and rectum.
Bevacizumab in combination with paclitaxel is indicated for the first-line treatment of adult patients with metastatic breast cancer. For further information on human epidermal growth factor receptor 2 (HER2) status please refer to section 5.1.
Bevacizumab in combination with capecitabine is indicated for the first-line treatment of adult patients with metastatic breast cancer for whom therapy with other chemotherapy regimens, including taxane or anthracyclines, is not considered appropriate. Patients who have received adjuvant taxane or anthracycline treatment within the previous 12 months should not receive treatment with Avastin in combination with capecitabine. For more information regarding HER2 status, please refer to section 5.1.
Bevacizumab, as an adjunct to platinum-based chemotherapy, is indicated for the first-line treatment of adult patients with unresectable, advanced, metastatic or recurrent non-small cell lung cancer with predominantly non-squamous cell histology.
Bevacizumab in combination with interferon alfa-2a is indicated for the first-line treatment of adult patients with advanced and / or metastatic renal cell carcinoma.
Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the first-line treatment of epithelial ovarian cancer, fallopian tube cancer or advanced primary peritoneal cancer (stage III B, III C and IV, according to the International Federation of Gynecology and Obstetrics (FIGO)) in adult patients.
Bevacizumab, in combination with carboplatin and gemcitabine is indicated for the treatment of adult patients with first relapse of epithelial ovarian cancer, fallopian tube cancer or platinum-sensitive primary peritoneal cancer who have not received prior therapy with bevacizumab or other factor inhibitors. vascular endothelial growth factor (VEGF) or other agents targeting the VEGF receptor.
Bevacizumab in combination with paclitaxel, topotecan or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with relapsed epithelial ovarian cancer, fallopian tube cancer or platinum-resistant primary peritoneal cancer who have received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or other VEGF receptor targeting agents (see section 5.1).
Bevacizumab, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in women who cannot be treated with platinum, is indicated for the treatment of adult patients with persistent, recurrent or metastatic cervical cancer ( see section 5.1).
04.2 Posology and method of administration
Avastin must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.
Dosage
Metastatic cancer of the colon and rectum (mCRC)
The recommended dose of Avastin, administered by intravenous infusion, is 5 mg / kg or 10 mg / kg body weight once every 2 weeksor 7.5 mg / kg or 15 mg / kg body weight once every 3 weeks.
It is recommended to continue treatment until disease progression or until unacceptable toxicity appears.
Metastatic breast cancer (mBC)
The recommended dose of Avastin is 10 mg / kg body weight given once every 2 weeks or 15 mg / kg body weight given once every 3 weeks as an intravenous infusion.
It is recommended to continue treatment until disease progression or until unacceptable toxicity appears.
Non-small cell lung cancer (NSCLC)
Avastin is given as an adjunct to platinum-based chemotherapy for up to 6 treatment cycles, followed by Avastin alone until disease progression.
The recommended dose of Avastin is 7.5 mg / kg or 15 mg / kg body weight, given once every 3 weeks as an intravenous infusion.
Clinical benefit has been demonstrated in NSCLC patients at both 7.5 mg / kg and 15 mg / kg doses (see section 5.1).
It is recommended to continue treatment until disease progression or until unacceptable toxicity appears.
Advanced and / or metastatic renal cell carcinoma (mRCC)
The recommended dose of Avastin is 10 mg / kg body weight to be administered once every 2 weeks by intravenous infusion.
It is recommended to continue treatment until disease progression or until unacceptable toxicity appears.
Epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer
Frontline treatment: Avastin is given as an adjunct to carboplatin and paclitaxel for up to 6 treatment cycles, followed by administration of Avastin alone to be continued until disease progression or for up to 15 months or until unacceptable toxicity occurs, whichever occurs. first.
The recommended dose of Avastin is 15 mg / kg body weight, to be administered once every 3 weeks by intravenous infusion.
Treatment of platinum-sensitive disease recurrence: Avastin is given in combination with carboplatin and gemcitabine for 6 cycles up to a maximum of 10 cycles followed by Avastin alone to be continued until disease progression. The recommended dose of Avastin is 15 mg / kg body weight, to be administered once every 3 weeks by intravenous infusion.
Treatment of relapse of platinum-resistant disease : Avastin is given in combination with one of the following agents: paclitaxel, topotecan (given every week) or pegylated liposomal doxorubicin. The recommended dose of Avastin is 10 mg / kg body weight, to be administered once every 2 weeks by intravenous infusion. If Avastin is given in combination with topotecan (given on days 1-5, every 3 weeks), the recommended dose of Avastin is 15 mg / kg body weight, given every 3 weeks as an intravenous infusion. It is recommended that treatment be continued until disease progression or development of unacceptable toxicity (see section 5.1, study MO22224).
Carcinoma of the cervix
Avastin is given in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin or paclitaxel and topotecan.
The recommended dose of Avastin is 15 mg / kg body weight, to be administered once every 3 weeks by intravenous infusion.
It is recommended that treatment be continued until progression of the underlying disease or the appearance of unacceptable toxicity (see section 5.1).
Particular patient populations
Elderly patients: No dose adjustment of Avastin is required in elderly patients.
Patients with renal insufficiency: the safety and efficacy in patients with renal insufficiency have not been studied (see section 5.2).
Patients with hepatic insufficiency: the safety and efficacy in patients with hepatic insufficiency have not been studied (see section 5.2).
Pediatric population
The safety and efficacy of bevacizumab in children and adolescents have not been established. There is no relevant use of bevacizumab in the pediatric population within the authorized indications. Currently available data are described in sections 5.1, 5.2 and 5.3. but no recommendation on posology can be made.
Avastin should not be used in children aged 3 to 18 years with relapse or progression of high-grade glioma due to efficacy concerns (see section 5.1 for the results of studies in pediatric patients).
Dose reduction associated with adverse reactions is not recommended. If indicated, therapy should be permanently discontinued or temporarily suspended as described in section 4.4.
Method of administration
The starting dose should be administered as a 90 minute intravenous infusion. If the first infusion is well tolerated, the second can be given over 60 minutes. If the 60 minute infusion is well tolerated, all subsequent infusions can be given over 30 minutes.
It must not be administered by rapid intravenous infusion or intravenous bolus.
Precautions to be taken before handling or administering the medicinal product
For instructions on dilution of the medicinal product before administration, see section 6.6. Avastin infusions should not be administered or mixed with glucose solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other human or humanised recombinant antibodies.
• Pregnancy (see section 4.6).
04.4 Special warnings and appropriate precautions for use
To improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient's medical record.
Gastrointestinal (GI) perforations and fistulas (see section 4.8)
Patients may be at increased risk of developing gastrointestinal perforation and gallbladder perforation during treatment with Avastin. In patients with metastatic carcinoma of the colon or rectum, an intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforation, therefore, caution should be exercised in treating these patients. Previous radiotherapy is a risk factor for gastrointestinal perforation in patients treated with Avastin for persistent, recurrent or metastatic cervical cancer and all patients with GI perforations have previously undergone irradiation. In patients who develop gastrointestinal perforation, therapy must be permanently discontinued.
Vagino-gastrointestinal fistulas in study GOG-0240
Patients treated with Avastin for persistent, recurrent or metastatic cervical cancer may be at increased risk of developing fistulas between the vagina and any section of the gastrointestinal tract (vagino-gastrointestinal fistulas). Previous radiotherapy is one of the major risk factors for the development of vagino-gastrointestinal fistulas and all patients with vagino-gastrointestinal fistulas have previously undergone irradiation. Recurrence of carcinoma in previously irradiated areas is an important additional risk factor for the development of vagino-gastrointestinal fistulas.
Non-GI fistulas (see section 4.8)
Patients may be at increased risk of developing fistulas while being treated with Avastin.
In patients who develop a tracheoesophageal (TE) fistula or any Grade 4 fistula [according to the US National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3)], Avastin therapy should be discontinued. definitely. Limited information is available on the continued use of Avastin in patients with other fistulas. In cases of internal fistulas that do not develop in the gastrointestinal tract, discontinuation of Avastin should be considered.
Complications in the healing process (see section 4.8)
Avastin can negatively affect the healing process. Serious complications, including anastomotic complications, have been reported in the healing process with fatal outcome. Therapy should not be started for at least 28 days after major surgery or until the surgical wound is completely healed. In patients who experience complications in the healing process during treatment, therapy must be suspended until the scar has completely healed. Therapy must be suspended in case of elective surgery.
Cases of necrotizing fasciitis, some fatal, have been reported rarely in patients treated with Avastin. This condition is typically caused by wound healing complications, gastrointestinal perforations, or fistula formation. In patients who develop necrotizing fasciitis, Avastin treatment should be discontinued, and appropriate therapy instituted promptly.
Hypertension (see section 4.8)
A higher incidence of hypertension has been observed in patients treated with Avastin. Clinical safety data indicate that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertension should be adequately controlled before initiating treatment with Avastin. There are no data on the effect of Avastin in patients who have uncontrolled hypertension at the time of initiation of therapy. Blood pressure monitoring is generally recommended during therapy.
In most cases, hypertension was adequately controlled with standard antihypertensive treatment appropriate to the individual situation of the affected patient. The use of diuretics for the treatment of hypertension is not recommended in patients on cisplatin-based chemotherapy regimen. Avastin should be permanently discontinued if clinically significant hypertension cannot be adequately controlled with antihypertensive therapy or if the patient experiences hypertensive crisis or hypertensive encephalopathy.
Posterior reversible encephalopathy syndrome (PRES) (see section 4.8)
There have been rare reports of patients treated with Avastin who have experienced signs and symptoms related to PRES, a rare neurological disorder which may present with, among others, the following signs and symptoms: seizures, headache, altered mental status , vision disturbance or cortical blindness, whether or not associated with hypertension. Diagnosis of PRES requires confirmation by brain radiology, preferably magnetic resonance imaging (MRI). In patients experiencing PRES, treatment of specific symptoms including control of hypertension and discontinuation of Avastin is recommended. The safety associated with resuming Avastin therapy in patients who have previously experienced PRES is unknown.
Proteinuria (see section 4.8)
Patients with a history of hypertension may have an increased risk of developing proteinuria when treated with Avastin. Some data indicate that proteinuria of all grades (according to the US National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE v.3]) may be dose related. Before starting the therapy and during the same it is recommended to carry out a monitoring of the proteinuria by means of urinalysis with test strips. In patients who develop Grade 4 proteinuria (nephrotic syndrome) (NCI-CTCAE v.3), therapy should be permanently discontinued.
Arterial thromboembolism (see section 4.8)
In clinical trials, the incidence of arterial thromboembolic reactions, including cases of cerebral stroke (CVA), transient ischemic attacks (TIA) and myocardial infarction (MI), was higher in patients treated with Avastin plus chemotherapy than in patients undergoing chemotherapy. to chemotherapy alone.
Patients treated with chemotherapy together with Avastin, with a history of arterial thromboembolism, diabetes or over 65 years of age have an increased risk of developing arterial thromboembolic reactions during therapy. Some caution should be exercised when treating these patients with Avastin.
In patients experiencing arterial thromboembolic reactions, therapy should be permanently discontinued.
Venous thromboembolism (see section 4.8)
Patients treated with Avastin may be at risk for venous thromboembolic events, including pulmonary embolism.
Patients treated with Avastin in combination with paclitaxel and cisplatin for persistent, recurrent or metastatic cervical cancer may be at increased risk for venous thromboembolic events.
Avastin treatment should be discontinued in patients with life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism (NCI-CTCAE v.3). Patients with Grade ≤ 3 thromboembolic reactions should be closely monitored (NCI-CTCAE v.3).
Hemorrhage
Patients treated with Avastin have an increased risk of bleeding, especially associated with cancer. Avastin therapy should be permanently discontinued in patients who experience Grade 3 or 4 haemorrhage during Avastin therapy (NCI-CTCAE v.3) (see section 4.8).
Patients with untreated central nervous system (CNS) metastases were routinely excluded from clinical trials with Avastin based on radiological examinations or signs and symptoms. Consequently, the risk of CNS haemorrhage in this patient category has not been prospectively assessed in randomized clinical trials (see section 4.8). Patients should be monitored for signs and symptoms of CNS bleeding and treatment with Avastin should be stopped in case of intracranial bleeding.
There are no data on the safety profile of Avastin in patients with congenital haemorrhagic diathesis, acquired coagulopathy or in patients treated with full-dose anticoagulants for thromboembolism prior to initiation of Avastin therapy, as these patients were excluded from clinical trials. therefore caution should be observed before initiating therapy in these patients. However, patients who develop venous thrombosis during therapy do not appear to have an increased risk of Grade 3 or greater haemorrhage when treated concomitantly with full-dose warfarin and Avastin (NCI-CTCAE v.3).
Pulmonary haemorrhage / hemoptysis
Patients with non-small cell lung cancer treated with Avastin may be at risk of severe, and in some cases fatal, pulmonary bleeding / haemoptysis. Patients with recent onset pulmonary haemorrhage / haemoptysis (> 2.5 ml of bright red blood) should not be treated with Avastin.
Congestive heart failure (ICC) (see section 4.8)
Reactions consistent with a diagnosis of CHF have been reported in clinical studies. Symptoms encountered ranged from asymptomatic reduction in left ventricular ejection fraction to symptomatic CHF requiring treatment or hospitalization. Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary heart disease or CHF with Avastin.
Most patients who experienced CHF had metastatic breast cancer and had previously received anthracyclines treatment, left chest wall radiation therapy, or had other risk factors for CHF.
In patients from study AVF3694g, who received anthracycline treatment and who had not received anthracyclines previously, no increase in the incidence of CHF of all Grades was observed in the bevacizumab + anthracycline group compared to anthracyclines alone. Onset of Grade 3 or higher CHF was sometimes more frequent in patients treated with bevacizumab plus chemotherapy than in patients receiving chemotherapy alone. This observation is consistent with the results observed in patients from other metastatic breast cancer studies who had not received concomitant anthracyclines treatment (NCI-CTCAE v.3) (see section 4.8).
Neutropenia and infections (see section 4.8)
In patients treated with myelotoxic chemotherapy regimens together with Avastin, higher rates of severe neutropenia, febrile neutropenia or infection with or without severe neutropenia (including some with fatal outcome) have been observed compared to chemotherapy alone. This has mainly been observed in association with platinum- or taxane-based therapies in the treatment of NSCLC, mBC and in combination with paclitaxel and topotecan in persistent, recurrent or metastatic cervical cancer.
Hypersensitivity reactions / infusion reactions (see section 4.8)
Patients may be at risk of developing infusion / hypersensitivity reactions. Close observation of the patient during and after administration of bevacizumab is recommended as expected for any humanized monoclonal antibody infusion. If a reaction occurs, the infusion must be stopped and appropriate medical therapy administered. Systematic premedication is not justified.
Osteonecrosis of the jaw (ONM) (see section 4.8)
Cases of ONM have been reported in cancer patients treated with Avastin, most of whom had previously or concurrently received intravenous bisphosphonate therapy, for which ONM is a known risk.
Caution should be exercised when administering Avastin and intravenous bisphosphonates simultaneously or sequentially.
Invasive dental procedures have also been identified as a risk factor. Dental evaluation and appropriate dental prevention should be considered prior to treatment with Avastin. If possible, invasive dental procedures should be avoided in patients who have previously received or are on intravenous bisphosphonate treatment.
Intravitreal use
Avastin is not formulated for intravitreal use
Eye disorders
Serious ocular adverse reactions both individually and in patient groups have been reported following the unapproved intravitreal use of Avastin, consisting of vials approved for intravenous administration in cancer patients. These reactions include infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis , vitreitis, retinal detachment, tear of the retinal pigment epithelium, increased intraocular pressure, intraocular haemorrhages such as intravitreal haemorrhages or retinal haemorrhages and conjunctival haemorrhages. Some of these reactions have led to varying degrees of vision loss, including permanent blindness.
Systemic effects following intravitreal use
A reduction in circulating VEGF concentration has been demonstrated following intravitreal anti-VEGF therapy. Systemic adverse reactions such as non-ocular haemorrhages and arterial thromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors.
Ovarian failure / fertility
Avastin may impair female fertility (see sections 4.6 and 4.8). Therefore, therapeutic strategies to preserve fertility should be discussed with patients of childbearing potential before initiating treatment with Avastin.
04.5 Interactions with other medicinal products and other forms of interaction
Effect of antineoplastic agents on bevacizumab pharmacokinetics
Based on the results obtained from a population pharmacokinetic analysis, no clinically relevant pharmacokinetic interactions of concomitant chemotherapy were observed on the pharmacokinetics of Avastin. There were no statistically significant or clinically relevant differences in the clearance of Avastin in patients who received Avastin. monotherapy versus patients who received Avastin in combination with interferon alfa-2a or other chemotherapies (IFL, 5-FU / LV, carboplatin / paclitaxel, capecitabine, doxorubicin or cisplatin / gemcitabine).
Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents
Results from a drug interaction study did not demonstrate any significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN38.
The results of a study in patients with metastatic colorectal cancer did not show any significant effect of bevacizumab on the pharmacokinetics of capecitabine and its metabolites and on the pharmacokinetics of oxaliplatin, as determined by the free and total platinum assay.
The results of a study in patients with renal cell carcinoma did not demonstrate any significant effect of bevacizumab on the pharmacokinetics of interferon alfa-2a.
The potential effect of bevacizumab on the pharmacokinetics of cisplatin and gemcitabine was studied in patients with non-squamous NSCLC. The results of the study showed that bevacizumab has no significant effect on the pharmacokinetics of cisplatin. Given the high interpatient and sample variability. limited, the results of this study do not allow definitive conclusions to be drawn on the impact of bevacizumab on gemcitabine pharmacokinetics.
Combination of bevacizumab and diseased sunitinib
In two clinical studies in metastatic renal cell carcinoma, microangiopathic haemolytic anemia (MAHA) was reported in 7 of 19 patients treated with the combination of bevacizumab (10 mg / kg every two weeks) and sunitinib malate (50 mg / day).
MAHA is a haemolytic disease that can present with red blood cell fragmentation, anemia and thrombocytopenia. In addition, hypertension (including hypertensive crises), elevated creatinine, and neurological symptoms have been observed in some of these patients. All of these manifestations were reversible on discontinuation of bevacizumab and diseased sunitinib (see Hypertension, Proteinuria and PRES in paragraph 4.4).
Association with platinum-based or taxane-based therapies (see sections 4.4 and 4.8)
Greater rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some with fatal outcome) have been observed mainly in patients treated with platinum- or taxane-based therapies in the treatment of NSCLC and mBC.
Radiotherapy
The safety and efficacy of concomitant administration of radiotherapy and Avastin have not been established.
EGFR monoclonal antibodies, in combination with bevacizumab-containing chemotherapy regimens
No interaction studies have been performed. EGFR monoclonal antibodies should not be administered for the treatment of mCRC in combination with bevacizumab-containing chemotherapy regimens. The results of the randomized phase III trials, PACCE and CAIRO-2, in patients with mCRC suggest that the use of monoclonal antibodies to EGFR panitumumab and cetuximab, respectively, in combination with bevacizumab together with chemotherapy, is associated with a reduction in survival. free of progression (PFS) and / or overall survival (OS), and higher toxicity than bevacizumab together with chemotherapy alone.
04.6 Pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should use effective contraception during (and up to 6 months after) treatment.
Pregnancy
There are no clinical study data from the use of bevacizumab in pregnant women. Animal studies have shown reproductive toxicity, including malformations (see section 5.3). IgG is known to cross the placenta, and Avastin is expected to inhibit fetal angiogenesis and therefore is thought to cause severe congenital abnormalities when administered during pregnancy. Post-marketing cases of fetal abnormalities have been observed in women treated with bevacizumab. as monotherapy or in combination with known embryotoxic chemotherapeutic agents (see section 4.8) Avastin is contraindicated in pregnancy (see section 4.3).
Feeding time
It is unknown whether bevacizumab is excreted in human milk. Because maternal IgG is excreted in milk and bevacizumab can impair the growth and development of the baby (see section 5.3), women should stop breastfeeding during therapy and avoid breastfeeding for at least six months thereafter. taking the last dose of Avastin.
Fertility
Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility (see section 5.3). In a Phase III adjuvant treatment study conducted in patients with colon cancer, a "parallel analysis in premenopausal patients found a" higher incidence of new cases of ovarian failure in the bevacizumab group than in the control group. Most patients recovered ovarian function after discontinuation of bevacizumab treatment. The long-term effects of bevacizumab treatment on fertility are unknown.
04.8 Undesirable effects
Summary of the safety profile
The overall safety profile of Avastin is based on data collected in clinical trials of over 5200 patients with various cancers, mainly treated with Avastin in combination with chemotherapy.
The most serious adverse reactions were the following:
• gastrointestinal perforation (see section 4.4),
• haemorrhage, including pulmonary haemorrhage / haemoptysis, which is more common in patients with non-small cell lung cancer (see section 4.4),
• arterial thromboembolism (see section 4.4).
The most frequently observed adverse reactions in clinical studies in patients treated with Avastin were hypertension, fatigue or asthenia, diarrhea and abdominal pain.
Analysis of clinical safety data indicates that the onset of hypertension and proteinuria associated with Avastin therapy is likely to be dose dependent.
List of adverse reactions in the form of a table
Adverse reactions listed in this section fall into the following frequency categories: Very common (≥ 1/10); common (≥ 1/100 y
Tables 1 and 2 list adverse reactions associated with the use of Avastin in combination with different chemotherapy regimens in multiple indications.
Table 1 presents all adverse reactions ranked by frequency whose causal relationship to Avastin was determined on the basis of:
• comparative incidences identified between treatment arms of clinical trials (with a difference of at least 10% compared to the control arm for NCI-CTCAE Grade 1-5 reactions or a difference of at least 2% compared to the control for Grade 3-5 reactions according to the "NCI-CTCAE),
• post-authorization safety studies,
• spontaneous reporting,
• epidemiological / non-interventional or observational studies,
• or through an assessment of individual cases.
Table 2 indicates the frequency of severe adverse reactions. Severe reactions are defined as adverse events with a difference of at least 2% from the control arm in clinical trials for Grade 3-5 reactions according to the NCI-CTCAE. Table 2 also includes adverse reactions that according to the MA holders are considered clinically significant or severe.
Post-marketing adverse reactions are included in both Table 1 and Table 2, if applicable. Detailed information on these post-marketing reactions is provided in Table 3.
Adverse reactions are placed in the appropriate frequency category from the tables below based on the highest incidence observed in any indication.
Within each frequency category, adverse reactions are presented in order of decreasing severity.
Some of the adverse reactions are reactions commonly seen with chemotherapy; however Avastin can exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorder or alopecia with paclitaxel
Table 1 Adverse reactions ranked by frequency
When events were identified in clinical trials as either any grade or grade 3-5 adverse drug reactions, the highest frequency observed in patients was reported. The data are not adjusted for different duration of treatment.
a For further information refer to Table 3 "Adverse Reactions Reported Post Marketing".
b Terms represent a set of events that describe a medical concept rather than a single condition or preferred terms MedDRA (Medical Dictionary for Regulatory Activities). This group of medical terms may imply the same underlying pathophysiology (eg arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischemic attack and other arterial thromboembolic reactions).
c Based on a substudy involving 295 patients from NSABP C-08.
d For further information refer to the following section "Further information on specific serious adverse reactions".
e Rectovaginal fistulas are the most common of GI fistulas.
Table 2 Severe adverse reactions ranked by frequency
Table 2 indicates the frequency of severe adverse reactions Severe reactions are defined as adverse events with a difference of at least 2% from the control arm in clinical trials for NCI-CTCAE Grade 3-5 reactions. Table 2 also includes adverse reactions considered by the MAH to be clinically significant or severe. These clinically significant adverse reactions have been reported in clinical studies, but Grade 3-5 reactions did not reach the threshold of a difference of at least 2% compared to the control arm. Table 2 also includes clinically significant adverse reactions observed only in the post-marketing setting, therefore the frequency and grade according to NCI-CTCAE are not known. Therefore these clinically significant reactions have been included in table 2 in the column bearing the title "Frequency not known".
a Terms represent a collection of events that describe a medical concept rather than a single condition or preferred terms MedDRA (Medical Dictionary for Regulatory Activities). This group of medical terms may imply the same underlying pathophysiology (eg arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischemic attack and other arterial thromboembolic reactions).
b For further information refer to the following section "Further information on specific serious adverse reactions".
c For further information refer to Table 3 "Adverse Reactions Reported Post Marketing"
d Rectovaginal fistulas are the most common of the GI-vaginal fistulas.
Description of specific serious adverse reactions
Gastrointestinal (GI) perforations and fistulas (see section 4.4)
Avastin therapy has been associated with severe episodes of gastrointestinal perforation.
Gastrointestinal perforations have been reported in clinical studies with an "incidence of less than 1% in patients with metastatic breast cancer or with non-small cell and non-squamous lung cancer, up to 2.0% in patients with metastatic renal cancer or in patients with ovarian cancer patients undergoing first-line treatment and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. In a clinical study of patients with persistent, recurrent or metastatic cervical cancer (study GOG-0240), GI perforations (of any grade) were reported in 3.2% of patients, all of whom had previously undergone pelvic irradiation.
The type and severity with which these events occurred were varied: from the presence of free air detected by direct abdominal radiography, which resolved without any treatment, to intestinal perforation with abdominal abscess and fatal outcome. In some cases, there was underlying abdominal inflammation due to gastric ulcer, tumor necrosis, diverticulitis, or chemotherapy-associated colitis.
About one third of severe cases of gastrointestinal perforation were fatal. This figure represents 0.2% -1% of all patients treated with Avastin.
Gastrointestinal fistulas (of any grade) have been reported in clinical trials with Avastin with a "maximum incidence of 2% in patients with ovarian cancer and metastatic colorectal cancer. Such fistulas, however, were less commonly reported in patients with other cancers. .
Vagino-gastrointestinal fistulas in study GOG-0240
In a study conducted in patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI fistulas was 8.3% in patients treated with Avastin and 0.9% in patients in the control arm. , all previously undergoing pelvic irradiation The frequency of vagino-gastrointestinal fistulas in the Avastin + chemotherapy group was higher in patients with relapse in previously irradiated areas (16.7%) than in patients with relapse in areas not undergoing irradiation. to previous irradiation (3.6%). Corresponding frequencies in the chemotherapy-only control group were 1.1% vs. 0.8% Patients who develop GI-vaginal fistulas may also experience intestinal obstruction and require surgery and ostomy packing.
Non-GI fistulas (see section 4.4)
Avastin therapy has been associated with severe episodes of fistulas, some of which were fatal.
In a clinical study in patients with persistent, recurrent or metastatic cervical cancer (GOG-240), non-gastrointestinal fistulas affecting the female vagina, bladder or genital tract were reported in 1.8% of patients treated with Avastin. and in 1.4% of patients in the control arm.
Uncommon manifestations (≥ 0.1% - biliary) have been observed in the various indications.Fistulas have also been reported in post-marketing experience.
Reactions have been reported at various time points during therapy, ranging from one week to more than 1 year after initiation of Avastin treatment, with most reactions occurring within the first 6 months of therapy.
Healing process (see section 4.4)
Because Avastin therapy may adversely affect the healing process, patients who had undergone major surgery within the previous 28 days were excluded from the phase III studies.
In clinical studies of metastatic cancer of the colon or rectum, there was no evidence of an increased risk of postoperative bleeding or complications in the healing process in patients undergoing major surgery 28 to 60 days prior to initiation of Avastin therapy. An "increased incidence of postoperative bleeding or complications in the healing process occurring within 60 days of major surgery was observed in patients treated with Avastin at the time of surgery. The incidence ranged between 10% (4/40 ) and 20% (3/15).
Serious wound healing complications have been reported, including anastomotic complications, some of which have been fatal.
In metastatic or locally recurrent breast cancer studies, Grade 3-5 healing complications were observed in up to 1.1% of patients treated with Avastin compared with up to 0.9% of patients of the control arms (NCI-CTCAE v.3).
In clinical trials of ovarian cancer, Grade 3-5 wound healing complications were observed in up to 1.2% of patients in the bevacizumab arm vs. 0.1% of the control arm (NCI-CTCAE v.3).
Hypertension (see section 4.4)
A higher incidence of hypertension (all grades) of up to 42.1% was observed in patients treated with Avastin in clinical studies compared with 14% in those treated with control. Grade 3 and 4 hypertension (requiring oral antihypertensive drugs) was observed in 0.4% -17.9% of patients treated with Avastin. Grade 4 hypertension (hypertensive crisis) occurred in 1.0% of patients treated with Avastin and chemotherapy compared to 0.2% of patients treated with the same chemotherapy alone (NCI-CTCAE v.3).
Generally, hypertension has been adequately controlled with oral antihypertensives such as angiotensin converting enzyme inhibitors, diuretics and calcium channel blockers. This event has rarely resulted in discontinuation of Avastin treatment or hospitalization.
Very rare cases of hypertensive encephalopathy have been reported, some of which have been fatal.
The risk of hypertension associated with Avastin therapy was not related to patients' baseline characteristics, underlying disease or concomitant therapies.
Posterior reversible encephalopathy syndrome "." (PRES) (see section 4.4)
In rare cases, signs and symptoms related to PRES, a rare neurological disorder, have been reported during the treatment of patients with Avastin. Manifestations may include seizures, headache, altered mental status, visual disturbances or cortical blindness, with or without associated hypertension. The clinical presentation of PRES is often nonspecific so the diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI).
In patients suspected of PRES, early recognition of specific symptoms and their treatment including control of hypertension (if associated with severe uncontrolled hypertension), in addition to discontinuation of bevacizumab therapy, is recommended. Symptoms usually resolve or improve within days of stopping treatment, although some patients have experienced some neurological sequelae. The safety associated with restarting Avastin therapy in patients who have previously experienced PRES is unknown.
Eight cases of PRES were reported across all clinical trials. Two out of eight cases did not have radiological confirmation by MRI.
Proteinuria (see section 4.4)
In clinical studies, proteinuria was found in between 0.7% and 38% of patients treated with Avastin.
The proteinuria manifested itself with a severity that ranged from a clinically asymptomatic, transient and trace proteinuria to a nephrotic syndrome; in most cases it was Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was reported in up to 8.1% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was observed in 1.4% of treated patients. Proteinuria observed in clinical trials with Avastin was not associated with renal failure and rarely required permanent discontinuation of therapy. It is recommended that proteinuria be checked before initiating Avastin therapy. In many clinical studies, proteinuria levels ≥ 2 g / 24 h led to discontinuation of Avastin until the level fell below 2 g / 24 h.
Hemorrhage (see section 4.4)
In clinical studies for all indications, the overall incidence of NCI-CTCAE v.3 Grade 3-5 bleeding reactions ranged from 0.4% to 6.9% in patients treated with Avastin compared to a maximum 4.5% of patients in the control group with chemotherapy.
In a clinical study in patients with persistent, recurrent or metastatic cervical cancer (study GOG-0240), Grade 3-5 haemorrhagic reactions were reported in up to 8.3% of patients treated with Avastin in combination with paclitaxel. and topotecan versus maximum 4.6% of patients treated with paclitaxel and topotecan.
The haemorrhagic reactions observed in clinical trials were predominantly tumor-associated haemorrhage (see below) and minor mucocutaneous haemorrhage (e.g. epistaxis).
Tumor-associated bleeding (see section 4.4)
Massive or major pulmonary haemorrhage / hemoptysis has been observed mainly in studies in patients with non-small cell lung cancer (NSCLC). Possible risk factors include: squamous cell histology, treatment with antirheumatic / anti-inflammatory drugs, treatment with anticoagulants, previous radiotherapy, Avastin therapy, history of atherosclerosis, central tumor location, and tumor cavitation before or during therapy. The only variables that demonstrated statistically significant correlations with bleeding were Avastin therapy and squamous cell histology. NSCLC patients with confirmed squamous cell or mixed squamous cell histology were excluded from subsequent phase studies. III, while patients with unknown tumor histology were included.
In patients with NSCLC, with the exclusion of those with predominantly squamous cell histology, reactions of all Grades were detected, with a frequency of up to 9% when treated with Avastin and chemotherapy, compared with 5% in patients treated with chemotherapy alone. Grade 3-5 reactions were observed in up to 2.3% of patients treated with Avastin and chemotherapy compared to
Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in patients with colorectal cancer and have been evaluated as tumor associated haemorrhages.
Tumor-associated haemorrhage has also been rarely reported in other types and locations of tumors, including cases of central nervous system (CNS) haemorrhage in patients with CNS metastases (see section 4.4).
The incidence of CNS haemorrhages in patients with non-pretreated CNS metastases receiving bevacizumab has not been prospectively assessed in randomized clinical trials. cancer, 3 of 91 (3.3%) patients with brain metastases had CNS haemorrhages (all Grade 4) when treated with bevacizumab, compared with 1 case (Grade 5) of 96 patients (1%) who were not been exposed to bevacizumab. In two subsequent studies in patients with pretreated brain metastases (involving approximately 800 patients), one case of Grade 2 CNS haemorrhage occurred in 83 patients treated with bevacizumab (1.2%) at the time of analysis. security ad interim (NCI-CTCAE v.3).
In all clinical trials with Avastin, "mucocutaneous bleeding was observed in up to 50% of patients treated with Avastin. Most of these were NCI-CTCAE v.3 Grade 1 nosebleeds. lasting less than 5 minutes and resolved without medical intervention and without the need to vary the Avastin dosing schedule. Clinical safety data suggest that the incidence of minor mucocutaneous bleeding (eg epistaxis) may be dose dependent.
Reactions of minor mucocutaneous haemorrhage at other sites were also recorded less frequently; for example gingival or vaginal bleeding.
Thromboembolism (see section 4.4)
Arterial thromboembolism: An "increased incidence of arterial thromboembolic reactions, including cerebrovascular accidents, myocardial infarction, transient ischemic attacks and other arterial thromboembolic reactions was observed in patients treated with Avastin in all indications.
In clinical trials, the overall incidence of arterial thromboembolic reactions was up to 3.8% in the Avastin-containing arms compared with up to 1.7% in the chemotherapy control arms. Fatal events were reported in 0.8% of patients treated with Avastin compared to 0.5% of patients treated with chemotherapy alone. Cerebrovascular accidents (including transient ischemic attacks) were reported in up to 2.3% of patients treated with Avastin in combination with chemotherapy compared to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was recorded in 1.4% of patients treated with Avastin in combination with chemotherapy compared to 0.7% of patients treated with chemotherapy alone.
In a clinical study evaluating Avastin in combination with 5-fluorouracil / folinic acid, AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment with irinotecan were included. In this study, arterial thromboembolic reactions were observed in 11% (11/100) of patients compared with 5.8% (6/104) in the control group with chemotherapy.
Venous thromboembolism: In clinical trials, the incidence of venous thromboembolic reactions was similar in patients treated with Avastin in combination with chemotherapy compared to those treated with control chemotherapy alone. Venous thromboembolic reactions include deep vein thrombosis, pulmonary embolism and thrombophlebitis.
In clinical trials for all indications, the overall incidence of venous thromboembolic reactions ranged from 2.8% to 17.3% of patients treated with Avastin compared to 3.2% -15.6% in the control arms.
Grade 3-5 venous thromboembolic reactions (NCI-CTCAE v.3) have been reported in up to 7.8% of patients treated with chemotherapy plus bevacizumab compared to up to 4.9% of patients treated with only chemotherapy (in the various indications, with the exception of persistent, recurrent or metastatic cervical cancer).
In a clinical study in patients with persistent, recurrent or metastatic cervical cancer (study GOG-0240), grade 3-5 venous thromboembolic events were reported in up to 15.6% of patients treated with Avastin in combination with paclitaxel. and cisplatin against maximum 7.0% of patients treated with paclitaxel and cisplatin.
Patients who have experienced a venous thromboembolic reaction may be at greater risk of recurrence if they receive Avastin in combination with chemotherapy than chemotherapy alone.
Congestive heart failure (ICC):
In clinical trials with Avastin, congestive heart failure (CHF) occurred in all cancer indications studied to date, but mainly occurred in patients with metastatic breast cancer. In the four phase III studies (AVF2119g, E2100, BO17708 and AVF3694g) in patients with metastatic breast cancer Grade 3 (NCI-CTCAE v.3) or higher has been reported with an "incidence of up to 3.5% of patients treated with Avastin in combination with chemotherapy compared to a maximum of 0 , 9% in the control arms. For patients included in study AVF3694g treated with anthracyclines concomitantly with bevacizumab, the incidence of CHF Grade 3 or higher for the respective bevacizumab and control arms was similar to that seen in other metastatic breast cancer studies: 2.9% in the anthracycline + bevacizumab arm and 0% in the anthracycline + placebo arm. In addition, in study AVF3694g, the observed incidence of any Grade CHF was similar for the anthracycline + Avastin arm (6, 2%) and for the anthracycline + placebo arm (6.0%).
Most patients who developed CHF during mBC clinical trials showed improvement in left ventricular symptoms and / or function after appropriate medical therapy.
In the majority of clinical trials with Avastin, patients with pre-existing NYHA stage II-IV CHF (New York Heart Association) were excluded and therefore no information is available on the risk of CHF in this population.
Previous anthracyclines exposure and / or previous chest wall radiation therapy may represent risk factors for developing CHF.
An increased incidence of CHF was observed in a clinical study in patients with diffuse large B cell lymphoma when treated with bevacizumab in combination with a cumulative dose of doxorubicin greater than 300 mg / m2. This phase III study had the goal to compare rituximab / cyclophosphamide / doxorubicin / vincristine / prednisone (R-CHOP) in combination with bevacizumab with R-CHOP without bevacizumab. While the incidence of CHF was higher in both study arms than previously observed for doxorubin, the percentage was higher in the R-CHOP and bevacizumab arm. These results suggest that careful consideration should be considered. clinical observation with appropriate cardiological evaluation in patients exposed to cumulative doses of doxorubicin greater than 300 mg / m2 when in combination with bevacizumab.
Hypersensitivity reactions / infusion reactions (see section 4.4 and Post-marketing experience under)
More frequent anaphylactic or anaphylactoid-type reactions have been reported in some clinical trials in patients receiving Avastin in combination with chemotherapy than in those receiving chemotherapy alone. The incidence of these reactions in some clinical trials with Avastin is common (up to 5% of patients treated with bevacizumab).
Infections
In a clinical study in patients with persistent, recurrent or metastatic cervical cancer (study GOG-0240), grade 3-5 infections were reported in up to 24% of patients treated with Avastin in combination with paclitaxel and topotecan against the Maximum 13% of patients treated with paclitaxel and topotecan.
Ovarian failure / fertility (see sections 4.4 and 4.6)
In the phase III NSABP C-08 study with Avastin in adjuvant treatment in colon cancer patients, the incidence of new cases of ovarian failure, defined as amenorrhea lasting 3 months or longer, with blood FSH levels ≥ 30 mIU / ml and negative for the serum β-HCG pregnancy test, was analyzed in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% of patients treated with mFOLFOX-6 compared to 39% in the group of patients treated with mFOLFOX-6 + bevacizumab. At the end of treatment with bevacizumab, ovarian function recovered in 86.2% of the patients evaluated. The long-term effects of bevacizumab on fertility are unknown.
Alterations of laboratory parameters
Treatment with Avastin may be associated with decreased neutrophil and white blood cell counts, and the presence of protein in the urine.
In all clinical studies, the following Grade 3 and 4 (NCI-CTCAE v.3) alterations in laboratory parameters occurred in patients treated with Avastin with at least a 2% difference from the corresponding control groups: hyperglycaemia, decreased hemoglobin, hypokalaemia, hyponatremia, decreased white blood cell count, increased international normalized ratio (INR).
Other special populations
Elderly patients
In randomized clinical trials, an age> 65 years has been associated with an increased risk of developing arterial thromboembolic reactions, including cerebrovascular accidents (ACV), transient ischemic attacks (TIA) and myocardial infarction (MI). Other reactions seen with higher frequency in patients aged> 65 years were Grade 3-4 leukopenia and thrombocytopenia (NCI-CTCAE v.3), neutropenia, diarrhea, nausea, headache and fatigue of any Grade compared to treated patients aged ≤ 65 years with Avastin (see sections 4.4 and 4.8 under the heading Thromboembolism).In a clinical study, the incidence of Grade ≥ 3 hypertension was twice as high in patients> 65 years of age compared to the younger age group (
In elderly patients (> 65 years) treated with Avastin, there was no higher incidence of other reactions, including gastrointestinal perforation, complications in the healing process, CHF and haemorrhage compared to patients aged ≤ 65 years treated with Avastin.
Pediatric population
The safety of Avastin in children and adolescents has not been established.
Post-marketing experience
Table 3 Adverse reactions reported post-marketing
* if specified, frequency was derived from clinical trial data
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
The highest dose evaluated in humans (20 mg / kg body weight, intravenously every 2 weeks) has been associated with severe migraine in many patients.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic and immunomodulatory agents, antineoplastic agents, other antineoplastic agents, monoclonal antibodies, ATC code: L01XC07.
Mechanism of action
Bevacizumab, by binding to vascular endothelial cell growth factor (VEGF), a key promoter of vasculogenesis and "angiogenesis, prevents the latter from binding to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2). , on the surface of the endothelial cells. The blocking of the biological activity of VEGF regresses the vascularization of tumors, normalizes the residual tumor vascularization, and inhibits the formation of new vascularization, thus preventing tumor growth.
Pharmacodynamic effects
Administration of bevacizumab or its corresponding mouse antibody in tumor xenograft models in nude mice demonstrated "extensive antitumor activity in human cancers, including those of the colon, breast, pancreas and prostate. The progression of metastatic disease was blocked and reduced microvascular permeability.
Clinical efficacy
Metastatic cancer of the colon or rectum (mCRC)
The safety and efficacy of the recommended dose (5 mg / kg body weight every two weeks) in metastatic carcinoma of the colon or rectum was studied in three randomized, active-controlled clinical trials, in combination with first-line chemotherapy a fluoropyrimidine base Avastin was combined with two chemotherapy regimens:
• Study AVF2107g: Weekly administration of irinotecan / bolus of 5-fluorouracil / folinic acid (IFL) for a total of 4 weeks of each 6-week cycle (Saltz regimen).
• Study AVF0780g: in combination with bolus 5-fluorouracil / folinic acid (5-FU / FA) for a total of 6 weeks of each 8-week cycle (Roswell Park regimen).
• Study AVF2192g: in combination with bolus 5-FU / FA for a total of 6 weeks of each 8-week cycle (Roswell Park regimen) in patients deemed not optimal candidates for first-line irinotecan treatment.
Three additional studies were conducted with bevacizumab in patients with mCRC: first-line (NO16966), second-line in patients who had received no prior treatment with bevacizumab (E3200), and second-line in patients previously treated with first-line bevacizumab who had progressed (ML18147). In these studies, bevacizumab was administered in combination with FOLFOX-4 (5FU / LV / oxaliplatin), XELOX (capecitabine / oxaliplatin), and fluoropyrimidine / irinotecan or fluoropyrimidine / oxaliplatin, according to the following dosing regimens:
• NO16966: Avastin 7.5 mg / kg body weight every 3 weeks in combination with oral capecitabine and intravenous oxaliplatin (XELOX) or Avastin 5 mg / kg every 2 weeks in combination with leucovorin plus bolus 5-fluorouracil, followed by 5 -fluorouracil as an infusion, with intravenous oxaliplatin (FOLFOX-4).
• E3200: Avastin 10 mg / kg body weight every 2 weeks in combination with leucovorin and bolus 5-fluorouracil, followed by infusion of 5-fluorouracil, with intravenous oxaliplatin (FOLFOX-4) in patients not previously treated with bevacizumab.
ML18147: Avastin 5.0 mg / kg body weight every 2 weeks or Avastin 7.5 mg / kg body weight every 3 weeks in combination with fluoropyrimidine / irinotecan or fluoropyrimidine / oxaliplatin in patients with disease progression following treatment with first line with bevacizumab. The use of a regimen containing irinotecan or oxaliplatin was changed depending on the first-line use of oxaliplatin or irinotecan.
AVF2107g
This randomized, phase III, double-blind, active-controlled clinical trial evaluated the combination of Avastin with IFL in the first-line treatment of metastatic cancer of the colon or rectum. Eight hundred and thirteen patients were randomized to receive IFL. + placebo (arm 1) or IFL + Avastin (5 mg / kg every 2 weeks, arm 2). A third group of 110 patients received bolus 5-FU / FA + Avastin (arm 3). Enrollment in arm 3 was discontinued, as expected, once the safety of Avastin in combination with the IFL regimen was established and deemed acceptable. All treatments were continued until disease progression. The overall mean age was 59.4 years; 56.6% of patients had a performance status ECOG of 0, 43% had a level of 1 and 0.4% a level of 2. 15.5% had previously undergone radiotherapy and 28.4% had chemotherapy.
Overall survival was the primary objective for evaluating efficacy in the study. Addition of Avastin to the IFL regimen resulted in statistically significant increases in overall survival, progression-free survival and overall response rate (see table 4). Clinical benefit, as measured by overall survival, was observed in all subgroups. of pre-specified patients, including those defined by age, gender, performance status, location of the primary tumor, number of organs involved and duration of metastatic disease.
The efficacy results of Avastin in combination with IFL chemotherapy are shown in Table 4.
Table 4 Efficacy results from study AVF2107g
to 5 mg / kg every 2 weeks
b Relative to the control arm
Among the 110 patients randomized to Arm 3 (5-FU / FA + Avastin) prior to discontinuation of this arm, the median duration of overall survival was 18.3 months and the median progression-free survival was 8. 8 months.
AVF2192g
This randomized, phase II, double-blind, active-controlled clinical study evaluated the efficacy and safety of Avastin in combination with 5-FU / folinic acid in the first-line treatment of metastatic colorectal cancer in non-patients. considered optimal candidates for irinotecan first-line therapy. One hundred and five patients were randomized to the 5-FU / FA + placebo arm and 104 patients to the 5-FU / FA + Avastin arm (5 mg / kg every 2 weeks). All treatments were continued until disease progression. Addition of Avastin 5 mg / kg every two weeks to 5-FU / FA resulted in higher objective response rates, significantly longer progression-free survival, and tendency to longer survival than 5-FU / FA chemotherapy alone.
AVF0780g
This randomized, phase II, active-controlled, open-label clinical trial evaluated Avastin in combination with 5-FU / FA in the first-line treatment of metastatic colorectal cancer. Median age was 64 years. 19% of patients had previously received chemotherapy and 14% had radiotherapy. Seventy-one patients were randomized to receive either the 5-FU / FA in bolus or the 5-FU / FA combination. + Avastin (5 mg / kg every 2 weeks). A third group of 33 patients received bolus 5-FU / FA + Avastin (10 mg / kg every 2 weeks). Patients were treated until disease progression. endpoint the primary focuses of the study were objective response rate and progression-free survival. Adding Avastin 5 mg / kg every two weeks to 5-FU / FA resulted in higher objective response rates, longer progression-free survival, and a trend towards longer survival compared to 5-FU / FA chemotherapy alone (see Table 5) These efficacy data are in line with the findings in study AVF2107g.
The efficacy data from studies AVF0780g and AVF2192g, which evaluated the use of Avastin in combination with 5-FU / FA chemotherapy, are summarized in Table 5.
04.7 Effects on ability to drive and use machines
Avastin has no or negligible influence on the ability to drive or use machines. However, somnolence and syncope have been reported with the use of Avastin (see table 1 section 4.8). Patients who experience symptoms affecting their vision or concentration, or their ability to react, should be advised not to drive and not to use machines until the symptoms disappear.
Table 5 Efficacy data from studies AVF0780g and AVF2192g
NO16966
This was a phase III, randomized, double-blind (for bevacizumab) study evaluating Avastin 7.5 mg / kg in combination with oral capecitabine and i.v. oxaliplatin. (XELOX), given in 3-week cycles, or Avastin 5 mg / kg in combination with leucovorin and bolus 5-fluorouracil, followed by infusional 5-fluorouracil, with oxaliplatin i.v. (FOLFOX-4) given in 2-week cycles. The study consisted of two phases: an initial part with 2 arms (part I) where patients were randomized to two different treatment groups (XELOX and FOLFOX-4), and a subsequent part with 4 arms 2 x 2 factorial (part II) where patients were randomized to four treatment groups (XELOX + placebo, FOLFOX-4 + placebo, XELOX + Avastin, FOLFOX-4 + Avastin). In Part II, treatment assignment was double-blinded with respect to Avastin administration.
Approximately 350 patients were randomized to each of the 4 study arms in Part II of the study.
Table 6 Treatment regimens in study NO16966 (mCRC)
The primary parameter for evaluating the efficacy of the study was the duration of progression-free survival. In this study there were two different primary objectives: to demonstrate that XELOX was not inferior to FOLFOX-4 and to show that Avastin in combination with FOLFOX- chemotherapy. 4 or XELOX was superior to chemotherapy alone.Both primary goals were achieved:
• Non-inferiority of the XELOX-containing arms compared to the FOLFOX-4 containing arms in the overall comparison was demonstrated in terms of progression-free survival and overall survival in the eligible population treated as per protocol.
• The superiority of the Avastin-containing arms over the chemotherapy-only arms in the overall comparison was demonstrated in terms of progression-free survival in the ITT population (Table 7).
Secondary analyzes of PFS, based on the assessment of the patients' responses under treatment, confirmed the significantly superior clinical benefit for patients treated with Avastin (analyzes shown in Table 7), consistent with the statistically significant benefit observed in the pooled analysis.
Table 7 Key efficacy results for "superiority analysis (ITT population". "Study NO16966)
* Overall survival analysis at clinical cut-off as of January 31, 2007
** Primary analysis at clinical cut-off as of January 31, 2006
a Relative to the control arm
In the FOLFOX-treated subgroup, the median PFS was 8.6 months in placebo-treated patients and 9.4 months in bevacizumab-treated patients, HR = 0.89, 97.5% CI = [0.73; 1.08]; p-value = 0.1871, while the corresponding results in the XELOX-treated subgroup were 7.4 vs. 9.3 months, HR = 0.77, 97.5% CI = [0.63; 0.94]; p-value = 0.0026.
In the FOLFOX subgroup the median overall survival was 20.3 months in placebo-treated patients and 21.2 months in bevacizumab treated patients, HR = 0.94, 97.5% CI = [0.75; 1.16]; p-value = 0.4937, while the corresponding results in the XELOX-treated subgroup were 19.2 vs. 21.4 months, HR = 0.84, 97.5% CI = [0.68; 1.04]; p-value = 0.0698.
ECOG E3200
This was a randomized, open-label, controlled phase III study evaluating Avastin 10 mg / kg in combination with leucovorin and bolus 5-fluorouracil followed by infusional 5-fluorouracil with i.v. oxaliplatin. (FOLFOX-4), administered in 2-week cycles in previously treated patients (second line) with advanced colorectal cancer. In the chemotherapy arms, the FOLFOX-4 regimen was used at the same doses and schedule shown in Table 6 for study NO16966.
The primary efficacy parameter of the study was overall survival defined as the time from randomization to death from any cause. Eight hundred and twenty-nine patients were randomized (292 FOLFOX-4, 293 Avastin + FOLFOX-4, and 244 Avastin). alone.) Addition of Avastin to the FOLFOX-4 regimen statistically significantly prolonged survival. Statistically significant improvements in progression-free survival and objective response rate were also observed (see Table 8).
Table 8 Efficacy results for study E3200
There was no significant difference in overall survival duration between patients who received Avastin monotherapy and patients treated with FOLFOX-4. Progression-free survival and objective response rate were lower in the Avastin monotherapy arm than in the FOLFOX-4 arm.
ML18147
This randomized, controlled, open-label Phase III clinical trial evaluated the use of Avastin 5.0 mg / kg every 2 weeks or 7.5 mg / kg every 3 weeks in combination with fluoropyrimidine-based chemotherapy versus chemotherapy. with fluoropyrimidine monotherapy in patients with mCRC who have progressed after first-line treatment containing bevacizumab.
Patients with histologically confirmed mCRC and disease progression were randomized 1: 1 within 3 months after discontinuation of first-line bevacizumab therapy to receive fluoropyrimidine / oxaliplatin or fluoropyrimidine / irinotecan-based chemotherapy ( chemotherapy changed based on first-line chemotherapy received) with or without bevacizumab. Treatment was continued until disease progression or development of unacceptable toxicity. The study's primary endpoint was overall survival defined as the time since randomization to death from any cause.
820 patients were randomized. The addition of bevacizumab to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of the survival of patients with mCRC who progressed after first-line treatment containing bevacizumab (ITT = 819) (see Table 9).
Table 9 Efficacy results for study ML18147 (ITT population)
a 5.0 mg / kg every 2 weeks or 7.5 mg / kg every 3 weeks
Statistically significant improvements were also observed in progression-free survival. The objective response rate was low in both treatment arms and the difference was not significant.
Study E3200 used a bevacizumab dose of 5 mg / kg / week in patients not previously treated with bevacizumab, while study ML18147 used a bevacizumab dose of 2.5 mg / kg / week in bevacizumab pretreated patients. A comparison between studies in terms of efficacy and safety is limited by the differences between the studies themselves, especially in terms of patient population, previously treated with bevacizumab and chemotherapy regimens. Both bevacizumab doses of 5 mg / kg / week and 2.5 mg / kg / week provided statistically significant OS benefit (HR 0.751 in study E3200; HR 0.81 in study ML18147) and PFS (HR 0.518 in study E3200; HR 0.68 in study ML18147). In terms of safety, there was a higher overall incidence of Grade 3-5 AEs in study E3200 compared to study ML18147.
Metastatic breast cancer (mBC)
Two large phase III studies were conducted in order to evaluate the effect of treatment with Avastin in combination with two different chemotherapy regimens in terms of PFS as a primary endpoint. In both studies, a significant increase in PFS was observed. both from a clinical and statistical point of view.
The PFS results for the individual chemotherapeutic agents included in the indication are summarized below:
• Study E2100 (paclitaxel)
• 5.6 month increase in median PFS, HR 0.421 (p
• Study AVF3694g (capecitabine)
• 2.9-month increase in median PFS, HR 0.69 (p = 0.0002, 95% CI 0.56, 0.84)
Further details relating to each study are provided below.
ECOG E2100
Study E2100 is a multicenter, open-design, randomized, active-controlled clinical trial evaluating Avastin in combination with paclitaxel for metastatic or locally recurrent breast cancer in patients who have not previously received chemotherapy for metastatic disease and locally recurring. Patients were randomized to paclitaxel alone (90 mg / m2 as a 1 hour i.v. infusion once weekly for three weeks out of four) or in combination with Avastin (10 mg / kg as an IV infusion every two weeks). Previous hormone therapy was allowed for the treatment of metastatic disease. Adjuvant taxane therapy was permitted only if completed at least 12 months prior to study inclusion. Among the 722 patients in the study, the majority of patients had HER2-negative disease (90%), with a small number of patients reporting had an unknown (8%) or confirmed positive (2%) HER2 status previously treated with trastuzumab or deemed ineligible for trastuzumab therapy. In addition, 65% of patients had received prior adjuvant taxane-based chemotherapy in 19% of cases and anthracyclines in 49% of cases Patients with central nervous system metastases, including previously treated or resected brain lesions, were excluded.
In study E2100, patients were treated until disease progression. In cases requiring early cessation of chemotherapy, Avastin monotherapy treatment continued until disease progression. Patient characteristics were similar between the two arms of the study. The primary endpoint of the study was progression-free survival (PFS), based on the study investigators' assessment of disease progression. In addition, an independent assessment of the primary endpoint was also conducted. The results of this study are reported in Table 10.
Table 10 Efficacy results from study E2100
* primary analysis
The clinical benefit of Avastin assessed in terms of PFS was observed in all predefined subgroups analyzed (including disease-free interval, number of metastatic sites, prior adjuvant chemotherapy intake, and estrogen receptor status (RE )).
AVF3694g
AVF3694g is a phase III, multicentre, randomized, placebo-controlled study designed to evaluate the efficacy and safety of Avastin in combination with chemotherapy versus chemotherapy plus placebo in the first-line treatment of patients with metastatic or HER2-negative breast cancer. locally recurring.
The chemotherapy regimen was chosen at the investigator's discretion prior to randomization, in a 2: 1 ratio, to receive chemotherapy plus Avastin or chemotherapy plus placebo. Chemotherapy options included capecitabine, taxanes (protein-bound paclitaxel, docetaxel) and anthracycline-containing regimens (doxorubicin / cyclophosphamide, epirubicin / cyclophosphamide, 5-fluorouracil / doxorubicin / cyclophosphamide, 5-fluorouracil / epirubicin / cyclophosphamide) administered every 3 weeks. Avastin or placebo was given at a dose of 15 mg / kg every three weeks.
This study included a blinded treatment phase, an optional open label phase after disease progression, and a follow upto evaluate survival. During the blinded treatment phase, patients received chemotherapy treatment and medication (Avastin or placebo) every 3 weeks until disease progression, treatment-limiting toxicity or death. Upon documented disease progression, patients placed in the optional open-label phase could receive open-label Avastin in combination with a wide variety of approved second-line agents.
Statistical analyzes were conducted independently for the two patient cohorts: 1) patients receiving capecitabine in combination with Avastin or placebo; 2) patients undergoing taxane or anthracycline regimens in combination with Avastin or placebo. L"endpoint primary study was PFS as assessed by the investigator. Furthermore, the "endpoint primary was also evaluated by an Independent Review Committee (IRC).
The results of this study from the final analysis defined in the protocol and conducted in the statistically independent potency cohort of patients treated with capecitabine from study AVF3694g for progression-free survival and response rates are shown in Table 11. Results from an "exploratory overall survival analysis that includes an additional 7 months of follow up (approximately 46% of patients had died) are also indicated. The percentage of patients who received Avastin in the open-label phase was 62.1% in the capecitabine + placebo arm and 49.9% in the capecitabine + Avastin arm.
Table 11 Efficacy results for study AVF3694g: "." Capecitabinaae Avastin / Placebo (Cap + Avastin / Pl)
1000 mg / m2 orally twice daily for 14 days given every 3 weeks
b Stratified analysis including all progression and death events excluding those for which non-protocol treatment (NPT) was initiated prior to documented progression; data from these patients were censored at the last tumor assessment prior to the start of NPT.
A "non-stratified analysis of PFS (investigator-assessed) was conducted without censoring patients for whom non-protocol treatment (NPT) was initiated prior to disease progression. The results of these analyzes were very similar. to the results of the primary analysis of the PFS.
Non-small cell lung cancer (NSCLC)
The safety and efficacy of Avastin as an adjunct to platinum-based chemotherapy in the first-line treatment of patients with non-squamous non-small cell lung cancer (NSCLC) were investigated in studies E4599 and BO17704. Study E4599 demonstrated a overall survival benefit with bevacizumab dose of 15 mg / kg once every 3 weeks. Study BO17704 demonstrated that both bevacizumab doses of 7.5 mg / kg and 15 mg / kg once every 3 weeks increase progression-free survival and response rate.
E4599
Study E4599 was a multicentre, open-label, randomized, active-drug-controlled clinical trial evaluating Avastin as first-line treatment of patients with locally advanced NSCLC (stage IIIb with malignant pleural effusion) metastatic or recurrent with non-histology. predominant squamous cell.
Patients were randomized to treatment with platinum-based chemotherapy (paclitaxel 200 mg / m2 and carboplatin AUC = 6.0, both by IV infusion (PC) on day 1 of each cycle from 3 weeks up to 6 cycles or PC in combination with Avastin at a dose of 15 mg / kg IV infusion on infusion day 1 of each 3-week cycle. Upon completion of 6 cycles of carboplatin-paclitaxel chemotherapy or early discontinuation of chemotherapy, patients in the Avastin + carboplatin arm -paclitaxel continued to receive Avastin as monotherapy every 3 weeks until disease progression 878 patients were randomized into the two arms.
During the study, of the patients who received study treatment, 32.2% (136/422) received 7-12 administrations of Avastin and 21.1% (89/422) received 13 or more administrations of Avastin.
The primary endpoint was duration of survival. Results are presented in Table 12.
Table 12 Efficacy results from study E4599
In an exploratory analysis, the overall survival benefit of Avastin was less relevant in the subgroup of patients who did not have adenocarcinoma histology.
BO17704
Study BO17704 was a randomized, double-blind, phase III study of Avastin in addition to cisplatin and gemcitabine versus placebo, cisplatin and gemcitabine in patients with locally advanced non-squamous NSCLC (stage III b with supraclavicular lymph node metastasis or malignant effusion pleural or pericardial), metastatic or recurrent, who had not received previous chemotherapy. L"endpoint primary was progression-free survival; among the endpoint Secondary studies included overall survival duration.
Patients were randomized to platinum-based chemotherapy, cisplatin 80 mg / m2 intravenous infusion on day 1 and gemcitabine 1250 mg / m2 intravenous infusion on days 1 and 8 of each 3-week cycle up to 6 cycles (CG) with placebo or CG with Avastin at a dose of 7.5 or 15 mg / kg by IV infusion on day 1 of each 3-week cycle. In the Avastin arms, patients could receive Avastin as monotherapy every 3 weeks until disease progression or intolerable toxicity. The results of the study showed that 94% (277/296) of eligible patients continued to receive bevacizumab as a cycle 7 monotherapy. protocol, which may have had an impact on the overall survival analysis.
The efficacy results are presented in Table 13.
Table 13 Efficacy results from study BO17704
patients with measurable disease at baseline
Advanced and / or metastatic renal cell carcinoma (mRCC)
Avastin in combination with interferon alfa-2a for first-line treatment of advanced and / or metastatic renal cell carcinoma (BO17705)
This was a double-blind, randomized Phase III study to evaluate the efficacy and safety of Avastin in combination with interferon (IFN) alpha-2a versus interferon (IFN) alpha-2a alone in first-line treatment. The 649 randomized patients (641 treated) had a Karnofsky Performance Status (KPS) ≥ 70%, no CNS metastases, and "adequate organ function." The patients were nephrectomized for primary renal cell carcinoma. Avastin was administered at a dose of 10 mg / kg every 2 weeks until disease progression.IFN alfa-2a was administered for up to 52 weeks or until disease progression at the recommended starting dose of 9 MIU three times per week, allowing for a dose reduction of up to 3 MIU three times per week in 2 steps. Patients were stratified by country and Motzer criteria and the treatment arms were well balanced for prognostic factors.
The endpoint primary of the study was overall survival, with endpoint secondary including progression-free survival. The addition of Avastin to IFN-alpha-2a significantly increased PFS and the objective response rate. These results were confirmed by an independent radiological review. However, the two-month increase inendpoint primary overall survival was not significant (HR = 0.91). A large proportion of patients (approximately 63% IFN / placebo; 55% Avastin / IFN) received a series of unspecified anticancer therapies, including antineoplastic agents that may have impacted the overall survival assessment, following study exit.
The efficacy results are shown in Table 14.
Table 14 Efficacy results from study BO17705
A "multivariate exploratory analysis according to the Cox regression model using predefined parameters, indicated that the following prognostic factors assessed at baseline were closely correlated with survival, regardless of treatment: gender, white blood cell and platelet counts, decrease in body weight in the 6 months prior to enrollment, number of metastatic sites, sum of major diameters of target lesions, Motzer criteria. Adjustment for these factors resulted in a hazard ratio of 0.78 (95% CI [0.63; 0.96], p = 0.0219), indicating a 22% reduction in the risk of death for patients in the Avastin + IFN alpha-2a arm compared to those in the IFN alpha-2a arm.
Ninety-seven patients in the IFN alpha-2a arm and 131 patients in the Avastin arm reduced the dose of IFN alpha 2a from 9 MIU to 6 or 3 MIU three times per week as specified in the protocol. Dose reduction of IFN alpha-2a does not appear to have impacted the efficacy of the combination of Avastin and IFN alpha-2a in terms of PFS, as evidenced by a subgroup analysis. The 131 patients in the Avastin + IFN arm alpha-2a who reduced and maintained the dose of IFN alpha-2a to 6 or 3 MIU during the study had a 6, 12, and 18-month disease-free survival rate of 73, 52, and 21%, respectively, compared with 61, 43 and 17% in the global population of patients treated with Avastin and IFN alfa-2a.
AVF2938
This was a randomized, double-blind, phase II clinical trial to study Avastin 10 mg / kg in a 2-week schedule versus Avastin at the same dose in combination with erlotinib 150 mg daily in patients with renal cell carcinoma. clear cell metastatic. In this study, a total of 104 patients were randomized to treatment, 53 with Avastin 10 mg / kg every 2 weeks plus placebo and 51 with Avastin 10 mg / kg every 2 weeks plus erlotinib 150 mg daily. The "analysis of"endpoint primary did not differ between the Avastin + placebo arm and the Avastin + erlotinib arm (median PFS 8.5 versus 9.9 months). Seven patients in each arm had an objective response. Addition of erlotinib to bevacizumab did not result in improvement in OS (HR 1.764; p = 0.1789), duration of objective response (6.7 versus 9.1 months), or time to symptom progression ( HR = 1.172; p = 0.5076).
AVF0890
This was a randomized Phase II study to compare the efficacy and safety of bevacizumab versus placebo. A total of 116 patients were randomized to receive bevacizumab at 3 mg / kg every 2 weeks (n = 39 ), 10 mg / kg every 2 weeks (n = 37) or placebo (n = 40) interim showed that there was a significant prolongation of time to disease progression in the 10 mg / kg group compared to the placebo group (hazard ratio 2.55; p
Epithelial ovarian, fallopian tube and primary peritoneal cancer
First-line treatment of ovarian cancer
The safety and efficacy of Avastin in the first-line treatment of patients with epithelial ovarian, fallopian tube or primary peritoneal cancer were evaluated in two phase III clinical trials (GOG-0218 and BO17707) that evaluated the effects of "Addition of Avastin to a carboplatin and paclitaxel regimen versus chemotherapy alone.
GOG-0218
Study GOG-0218 was a Phase III, multicenter, randomized, double-blind, placebo-controlled, three-arm study that evaluated the effect of adding Avastin to an approved chemotherapy regimen (carboplatin and paclitaxel) in patients with epithelial ovarian cancer, fallopian tube cancer or advanced primary peritoneal cancer (FIGO stage IIIB, IIIC and IV).
Patients previously treated for ovarian cancer with bevacizumab or antineoplastic therapy (eg chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormone therapy) or patients who had previously received radiotherapy of the abdomen or abdomen were excluded from the study. pelvis.
A total of 1873 patients were randomized, in equal ratios, into the following three arms:
• CPP arm: Five cycles of placebo (initiated from cycle 2) in combination with carboplatin (AUC 6) and paclitaxel (175 mg / m2) for 6 cycles followed by the administration of placebo only for up to 15 months of therapy
• CPB15 arm: Five cycles of Avastin (15 mg / kg q3w started from 2nd cycle) in combination with carboplatin (AUC 6) and paclitaxel (175 mg / m2) for 6 cycles followed by the administration of placebo only for up to 15 months of therapy
• CPB15 + arm: Five courses of Avastin (15 mg / kg q3w started from 2nd cycle) in combination with carboplatin (AUC 6) and paclitaxel (175 mg / m2) for 6 cycles followed by continuous administration of Avastin monotherapy (15 mg / kg q3w) up to 15 months of therapy.
Most of the patients included in the study were white (87% across the three arms); the median age was 60 years in the CPP and CPB15 arm and 59 years in the CPB15 + arm; 29% of patients in the CPP and CPB15 and 26% in the CPB15 + arm were older than 65 years. Approximately 50% of all patients had a GOG PS of 0 at baseline, approximately 43% a GOG PS of 1, and approximately 7% a GOG PS of 2. Most patients had a diagnosis of EOC (82% in CPP and CPB15, 85% in CPB15 +), PPC (16% in CPP, 15% in CPB15, 13% in CPB15 +) and FTC (1% in CPP, 3% in CPB15, 2% in CPB15 +) . Most of the patients had serous-type adenocarcinoma (85% in CPP and CPB15, 86% in CPB15 +). Approximately 34% of all enrolled patients were in FIGO stage III optimally resected with evaluable residual disease, 40% in FIGO stage III with suboptimal radicalization, and 26% were in FIGO stage IV.
The primary endpoint was investigator-assessed PFS considering disease progression based on radiological images, CA 125 levels, or worsening of symptoms as defined by the protocol. In addition, a prespecified data analysis was conducted by censoring for progression events defined on the basis of CA 125 values, as well as an independent assessment of the PFS as a function of radiological assessments only.
The study met the primary goal of improvement in PFS. Compared to patients treated with chemotherapy alone (carboplatin and paclitaxel) in the first-line treatment, patients who received bevacizumab at a dose of 15 mg / kg q3w in combination to chemotherapy and who continued to receive bevacizumab monotherapy (CPB15 +), demonstrated clinically and statistically significant improvement in PFS.
In patients treated with bevacizumab alone in combination with chemotherapy and who did not continue on bevacizumab monotherapy (CPB15), no clinically significant improvement in PFS was observed.
The results of this study are summarized in Table 15.
Table 15 Efficacy results from study GOG-0218
1 Investigator-assessed PFS analysis based on protocol-specified GOG parameters (patients not censored either for CA 125 defined progression or NPT prior to disease progression) with data cut-off as of February 25, 2010.
2 Compared to the control arm; stratified hazard ratio.
3 One-sided log-rank test, p-value
4 Value of p boundary equal to 0.0116.
5 Patients with evaluable disease at baseline.
6 Final overall survival analysis performed when 46.9% of patients had died.
Prespecified analyzes of the PFS were conducted, all having a cut-off date of 29 September 2009. The results of these analyzes are as follows:
• The investigator-assessed PFS analysis specified in the protocol (not censoring for progression defined by tumor marker CA 125 and NPT values) showed a stratified hazard ratio of 0.71 (95% CI: 0 , 61-0.83; 1-sided log rank test, p-value
• The primary analysis of PFS assessed by the investigators (censoring by second the progression defined by the CA-125 values and for the NPT) showed a stratified hazard ratio of 0.62 (95% CI: 0.52- 0.75, 1-sided log rank test, p-value
• PFS analysis as determined by the independent review committee (censoring for NPT) demonstrated a stratified hazard ratio of 0.62 (95% CI: 0.50-0.77, 1-sided log rank test, p value
PFS analyzes by subgroups related to disease stage and primary surgery are shown in Table 16. These results confirm the robustness of the PFS analysis as shown in Table 15.
Table 16 - Results of PFS1 by stage of disease and surgery resulting from study GOG-0218
1 Investigator-assessed PFS analysis based on protocol-specified GOG parameters (patients not censored either for CA 125 defined progression or NPT prior to disease progression) with data cut-off as of February 25, 2010.
2 With gross residual disease
3 3.7% of all randomized patients were in Stage IIIB disease
4Relative to the control arm
BO17707 (ICON7)
BO17707 is a phase III, two-arm, multicentre, randomized, controlled, open label study aimed at evaluating the effect of adding Avastin to carboplatin and paclitaxel after surgery in patients with epithelial ovarian cancer. Fallopian tube carcinoma or primary peritoneal carcinoma stage I or IIA according to the FIGO classification (Grade 3 or clear cell histological subtype; n = 142), or stage IIB - IV according to the FIGO classification (all Grades and all types histologicals, n = 1386) (NCI-CTCAE v.3).
Patients who had previously been treated with bevacizumab or antineoplastic therapy for ovarian cancer (eg chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormone therapy) or patients who had previously received radiation therapy treatment were excluded from the study. abdomen or pelvis.
A total of 1528 patients were randomized, in equal ratios, into the following two arms:
• CP arm: Carboplatin (AUC 6) and paclitaxel (175 mg / m2) for 6 cycles lasting 3 weeks
• CPB7.5 + arm: Carboplatin (AUC 6) and paclitaxel (175 mg / m2) for 6 cycles every 3 weeks in combination with Avastin (7.5 mg / kg q3w) for up to 12 months (Avastin administration is started from the 2nd cycle of chemotherapy if treatment was started within 4 weeks of surgery or from the 1st cycle if treatment was started more than 4 weeks after surgery).
Most of the patients included in the study were white Caucasian (96%), the median age was 57 years in both treatment arms, 25% of the patients were 65 years or older and approximately 50% of patients had a PS of 1 on the ECOG scale, and 7% of patients in each treatment arm had an ECOG PS of 2. Most patients had a diagnosis of EOC (87.7%) followed by PPC (6.9%) and FTC (3.7%) or a "mixed histology (1.7%). Most patients were FIGO stage III (68 % in both) followed by stage IV according to the FIGO classification (13% and 14%), Stage II according to the FIGO classification (10% and 11%) and Stage I according to the FIGO classification (9% and 7%). most patients in each treatment arm (74% and 71%) had an initial diagnosis of poorly differentiated neoplasm (Grade 3). The incidence of histol subtypes EOC symptoms were similar across treatment arms; 69% of patients in each arm had serous-type adenocarcinoma.
L"endpoint primary was PFS, assessed by the investigator using RECIST.
The study met its primary objective in terms of improvement in PFS. Compared to patients treated with first-line chemotherapy alone (carboplatin and paclitaxel), patients administered bevacizumab at a dose of 7.5 mg / kg q3w in combination with chemotherapy and who continued taking bevacizumab for up to 18 cycles showed statistically significant improvement in PFS.
The results of this study are summarized in Table 17.
Table 17 Efficacy results from study BO17707 (ICON7)
1 In patients with measurable disease at baseline.
2 Investigator-assessed PFS analysis with data cut-off as of November 30, 2010.
3 The final analysis of the overall survival was performed with the data cut-off as of March 31, 2013, when 46.7% of the patients had died.
The primary investigator-assessed PFS analysis with data cut-off dating back to February 28, 2010 showed an unstratified hazard ratio of 0.79 (95% CI: 0.68-0.91, log-rank test at 2-sided, p-value 0.0010) with a median PFS of 16.0 months in the CP arm and 18.3 months in the CPB7.5 + arm.
The PFS analysis by subgroups related to disease stage and primary surgery is shown in table 18. These results confirm the robustness of the PFS analysis as reported in table 17.
Table 18 - PFS1 Outcomes by Disease Stage and Surgery from Study BO17707 (ICON7)
1 Investigator-assessed PFS analysis with data cut-off as of November 30, 2010.
2 With or without gross residual disease
3 5.8% of all patients were stage IIIB disease
4Relative to the control arm
Recurrent ovarian cancer
The safety and efficacy of Avastin in the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer was studied in two phase III studies (AVF4095g and MO22224) with different chemotherapy regimens and patient populations.
• Study AVF4095g evaluated the efficacy and safety of bevacizumab in combination with carboplatin and gemcitabine in patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer.
• Study MO22224 evaluated the efficacy and safety of bevacizumab in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin in patients with relapsed epithelial ovarian, fallopian tube or platinum-resistant primary peritoneal cancer.
AVF4095g
The randomized phase III, double-blind, placebo-controlled study (AVF4095g) evaluated the safety and efficacy of Avastin in the treatment of patients with recurrence of platinum-sensitive disease of epithelial ovarian cancer, fallopian tube cancer or in cancer. peritoneal disease, who had not received prior chemotherapy for relapse or previous treatment with bevacizumab. The study compared the effect of adding Avastin to carboplatin and gemcitabine chemotherapy followed by continued use of Avastin alone until progression of the disease, compared to chemotherapy with carboplatin and gemcitabine alone.
Only patients with ovarian cancer, primary peritoneal cancer, or histologically documented fallopian tube cancer that relapsed at least 6 months after completion of platinum-based chemotherapy and who had neither received relapsed chemotherapy nor previous therapy were included in the study. with bevacizumab or other VEGF inhibitors or other VEGF receptor targeting agents.
A total of 484 patients with measurable disease were randomized 1: 1 to:
• carboplatin (AUC4, day 1) and gemcitabine (1000 mg / m2 on days 1 and 8) and concomitant placebo every 3 weeks for 6 cycles and up to 10 cycles followed by placebo alone (every 3 weeks) until disease progression or unacceptable toxicity.
• carboplatin (AUC4, day 1) and gemcitabine (1000 mg / m2 on days 1 and 8) and concomitant Avastin (15 mg / kg on day 1) every 3 weeks for 6 cycles and up to 10 cycles followed by Avastin (15 mg / kg every 3 weeks) alone until disease progression or unacceptable toxicity.
L"endpoint primary was progression-free survival based on investigator assessment with modified RECIST 1.0. Moreendpoint they included objective response, duration of response, overall survival, and safety. An independent review of the " endpoint primary.
The results of this study are summarized in Table 19.
Table 19 Efficacy results from study AVF4095
PFS analyzes for subgroups defined by time to relapse from the last platinum therapy are summarized in Table 20.
Table 20 Progression-free survival from last platinum therapy to relapse
MO22224
Study MO22224 evaluated the efficacy and safety of bevacizumab in combination with chemotherapy in the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, or platinum-resistant primary peritoneal cancer. The trial design included a phase III study. two-arm, randomized, open label to evaluate bevacizumab treatment in combination with chemotherapy (CT + BV) versus chemotherapy alone (CT).
The study enrolled a total of 361 patients who received chemotherapy alone [paclitaxel, topotecan or pegylated liposomal doxorubicin (PLD)] or chemotherapy in combination with bevacizumab:
• CT arm (chemotherapy only):
• paclitaxel 80 mg / m2 as an i.v. infusion 1 hour on Days 1, 8, 15 and 22 every 4 weeks.
• topotecan 4 mg / m2 as an i.v. 30 minutes on Days 1, 8 and 15 every 4 weeks. Alternatively, a dose of 1.25 mg / m2 can be administered for 30 minutes on Days 1-5 every 3 weeks.
• PLD 40 mg / m2 as an i.v. infusion 1 mg / min on Day 1 only every 4 weeks. After Cycle 1, the medicine can be administered as a 1 hour infusion.
• CT + BV arm (chemotherapy + bevacizumab):
• The chemotherapy of choice was given in combination with bevacizumab 10 mg / kg i.v. every 2 weeks (or bevacizumab 15 mg / kg every 3 weeks when in combination with topotecan 1.25 mg / m2 on Days 1 "." 5 every 3 weeks).
Eligible patients had epithelial ovarian cancer, fallopian tube cancer, or progressive primary peritoneal cancer less than 6 months after prior platinum-based therapy consisting of a minimum of 4 treatment courses.
Patients must have had a life expectancy of ≥12 weeks and must have had no previous radiotherapy to the pelvis or abdomen. Most of the patients had FIGO IIIC or IV stage disease. The majority of patients in both arms had an ECOG Performance Status (PS) of 0 (CT: 56.4% vs CT + BV: 61.2%). The percentage of patients with ECOG PS of 1 or ≥ 2 was 38.7% and 5.0% in the CT arm, and 29.8% and 9.0% in the CT + BV arm. Race information is available for 29.3% of patients and nearly all patients were Caucasian. The mean age of the patients was 61.0 (range: 25-84) years. A total of 16 patients (4.4%) were aged> 75 years. The overall rates of discontinuation due to adverse events were of 8.8% in the CT arm and 43.6% in the CT + BV arm (mainly due to Grade 2-3 adverse events) and the median time to discontinuation in the CT + BV arm was 5.2 months versus 2.4 months in the CT arm. Discontinuation rates due to adverse events in the subgroup of patients> 65 years were 8.8% in the CT arm and 50.0% in the CT + BV arm. . The HR for PFS was 0.47 (95% CI: 0.35, 0.62) and 0.45 (95% CI: 0.31, 0.67) for age subgroups, respectively.
The primary endpoint was progression-free survival, while the secondary endpoints included objective response rate and overall survival. The results are presented in Table 21.
Table 21 Efficacy results from study MO22224
All analyzes presented in this table are stratified analyzes.
* The data cut-off date with which the primary analysis was conducted is November 14, 2011.
** Randomized patients with measurable disease at baseline.
*** The final analysis of the overall survival was conducted once 266 deaths were observed, equal to 73.7% of the enrolled patients.
The study achieved its primary goal of improving PFS. Compared to patients treated with chemotherapy alone (paclitaxel, topotecan or PLD) in the setting of platinum-resistant relapse, patients who received bevacizumab at a dose of 10 mg / kg every 2 weeks (or 15 mg / kg every 3 weeks when used in combination with topotecan 1.25 mg / m2 on Days 1 "." 5 every 3 weeks) in combination with chemotherapy and who continued to receive bevacizumab until disease progression or development of unacceptable toxicity showed improvement statistically significant of PFS. Exploratory analyzes of PFS and OS in the chemotherapy cohort (paclitaxel, topotecan and PLD) are summarized in Table 22.
Table 22: PFS and OS exploratory analysis by chemotherapy cohorts.
Carcinoma of the cervix
GOG-0240
The efficacy and safety of Avastin in combination with chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) in the treatment of patients with persistent, recurrent or metastatic cervical cancer were investigated in the GOG-0240 trial, a phase III study. randomized, four-arm, open-label and multicenter.
A total of 452 patients were randomized to treatment with:
• Paclitaxel 135 mg / m2 i.v. over 24 hours on Day 1 and cisplatin 50 mg / m2 i.v. on Day 2, every 3 weeks (q3w); or
Paclitaxel 175 mg / m2 i.v. over 3 hours on Day 1 and cisplatin 50 mg / m2 i.v. on Day 2 (q3w); or
Paclitaxel 175 mg / m2 i.v. over 3 hours on Day 1 and cisplatin 50 mg / m2 i.v. on Day 1 (q3w)
• Paclitaxel 135 mg / m2 i.v. over 24 hours on Day 1 and cisplatin 50 mg / m2 i.v. on Day 2 + bevacizumab 15 mg / kg i.v. on Day 2 (q3w); or
Paclitaxel 175 mg / m2 i.v. over 3 hours on Day 1 and cisplatin 50 mg / m2 i.v. on Day 2 + bevacizumab 15 mg / kg i.v. on Day 2 (q3w); or
Paclitaxel 175 mg / m2 i.v. over 3 hours on Day 1 and cisplatin 50 mg / m2 i.v. on Day 1 + bevacizumab 15 mg / kg i.v. on Day 1 (q3w)
• Paclitaxel 175 mg / m2 i.v. over 3 hours on Day 1 and topotecan 0.75 mg / m2 i.v. over 30 minutes on Days 1-3 (q3w)
• Paclitaxel 175 mg / m2 i.v. over 3 hours on Day 1 and topotecan 0.75 mg / m2 i.v. over 30 minutes on Days 1-3 + bevacizumab 15 mg / kg i.v. on Day 1 (q3w).
Eligible patients had persistent, recurrent or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix that was not amenable to curative intent by surgery and / or radiotherapy and had not been pretreated with bevacizumab or other VEGF inhibitors or receptor-targeting agents VEGF.
The median age was 46.0 years (range: 20-83) in the chemotherapy-only group and 48.0 years (range: 22-85) in the chemotherapy + Avastin group, with a age over 65 years respectively by 9.3% in the group treated with chemotherapy alone and 7.5% in the group treated with chemotherapy + Avastin.
Most of the 452 randomized patients at baseline were Caucasian (80.0% in the chemotherapy-only group and 75.3% in the chemotherapy + Avastin group), had squamous cell carcinoma (67.1% in the chemotherapy-only group). and 69.6% in the chemotherapy + Avastin group), persistence / relapse of disease (83.6% in the chemotherapy-only group and 82.8% in the chemotherapy + Avastin group), 1-2 metastatic sites ( 72.0% in the chemotherapy-only group and 76.2% in the chemotherapy + Avastin group), lymph node involvement (50.2% in the chemotherapy-only group and 56.4% in the chemotherapy + Avastin group) and platinum-free interval ≥ 6 months (72.5% in the chemotherapy-only group and 64.4% in the chemotherapy + Avastin group).
The primary efficacy endpoint was overall survival. Secondary efficacy endpoints included progression-free survival and objective response rate. Results from primary analysis and follow-up analysis are shown as a function of Avastin treatment. and of the experimental treatment in Table 23 and 24, respectively.
Table 23 Efficacy results from study GOG-0240 with Avastin-based treatment
1 Estimates according to Kaplan-Meier
2 Patients and percentage of patients with partial response (PR) or complete response (CR) confirmed as best overall response; percentage calculated on patients with measurable disease at baseline.
3 95% CI for a binomial sample according to the Pearson-Clopper method
4IC at 95% approximate for the difference between the two rates according to the Hauck-Anderson method
5 Log-rank test (stratified)
6L "primary analysis was performed with a cut-off date of 12 December 2012 and is considered as final analysis.
7 The follow-up analysis was performed with a cut-off date of 7 March 2014.
8 The p-value is shown for descriptive purposes only
Table 24 Overall survival results from study GOG-0240 with investigational treatment
1 The primary analysis was performed with a cut-off date of 12 December 2012 and is considered as the final analysis.
2 Follow-up analysis was performed with a cut-off date of 7 March 2014 All p-values are shown for descriptive purposes only
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with bevacizumab in all subsets of the pediatric population, in breast cancer, in colon and rectal adenocarcinoma, in lung cancer (microcytoma and non-small cell), kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, meroblastic nephroma, renal medullary carcinoma and rhabdoid tumor of the kidney), ovarian cancer (excluding rhabdomyosarcoma and germ cell tumors ), fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumors), peritoneal carcinoma (excluding blastomas and sarcomas) and carcinoma of the cervix and body of the uterus.
No anticancer activity was observed in two studies involving a total of 30 children aged> 3 years with relapsed or progressive high-grade glioma when treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of bevacizumab in newly diagnosed children with high-grade glioma.
In a single-arm study (PBTC-022), 18 children with relapsed or progressive non-pontine high-grade glioma (including 8 with glioblastoma [WHO Grade IV], 9 with anaplastic astrocytoma [Grade III] and 1 with anaplastic oligodendroglioma [Grade III]) were treated with bevacizumab (10 mg / kg) two weeks apart and then with bevacizumab in combination with CPT-11 (125-350 mg / m2) once every two weeks until progression. There were no objective (partial or complete) radiological responses (MacDonald criteria). Toxicity and adverse reactions included arterial hypertension and fatigue as well as CNS ischemia with acute neurological deficit.
In a retrospective series performed at a single institution, 12 children with relapsing or progressive high-grade glioma (3 with WHO Grade IV, 9 with Grade III) were treated consecutively (2005 to 2008) with bevacizumab (10 mg / kg) and irinotecan (125 mg / m2) every 2 weeks. There were 2 partial responses and no complete responses (MacDonald criteria).
05.2 Pharmacokinetic properties
Pharmacokinetic data for bevacizumab collected in ten clinical studies performed in patients with solid malignancies are available. In all clinical studies, bevacizumab was administered as an intravenous infusion. The infusion rate depended on tolerability, with an initial infusion duration of 90 minutes.The pharmacokinetic profile of bevacizumab was linear at doses ranging from 1 to 10 mg / kg.
Distribution
The typical central compartment volume (Vc) value was 2.73 l and 3.28 l for female and male patients respectively, values in the range that has been described for IgG and other monoclonal antibodies. typical peripheral compartment volume value (Vp) was 1.69 l and 2.35 l for female and male patients, respectively, when bevacizumab is administered with antineoplastic agents. After correction for body weight, gender patients male patients had a larger Vc (+ 20%) than female patients.
Biotransformation
Analysis of the metabolism of bevacizumab in rabbits treated with a single iv dose of 125I-bevacizumab revealed a metabolic profile similar to that expected for a native IgG molecule, which does not bind to VEGF. The metabolism and elimination of bevacizumab it is similar to that of endogenous IgG, therefore primarily through proteolytic catabolism in every part of the body, including endothelial cells and is not primarily based on elimination through the kidneys and liver. The binding of IgG to the FcRn receptor determines protection from cellular metabolism and a long terminal half-life.
Elimination
The clearance value averaged 0.188 and 0.220 l / day for female and male patients respectively. After correction for body weight, male patients had a higher clearance of bevacizumab (+ 17%) than female patients. In relation to the bicompartmental model, the elimination half-life is 18 days for a typical female patient and 20 days for a typical male patient.
Low albumin values and a large tumor burden are generally indicators of disease severity. Clearance of bevacizumab was approximately 30% faster in patients with low serum albumin and 7% faster in subjects with large tumor burden when compared to a typical patient with albumin values and average tumor burden.
Pharmacokinetics in particular patient populations
Population pharmacokinetics were analyzed to evaluate the effects of demographic characteristics. The results of this analysis did not reveal a significant difference in the pharmacokinetics of bevacizumab based on age.
Kidney failure
No studies have been performed to investigate the pharmacokinetics of bevacizumab in patients with renal insufficiency as the kidneys are not a critical organ for the metabolism or excretion of bevacizumab.
Hepatic insufficiency
No studies have been performed to investigate the pharmacokinetics of bevacizumab in patients with hepatic insufficiency as the liver is not a critical organ for the metabolism or excretion of bevacizumab.
Pediatric population
The pharmacokinetics of bevacizumab have been studied in a limited number of pediatric patients. The pharmacokinetic data obtained suggest that the volume of distribution and clearance of bevacizumab are comparable to those in adults with solid tumors.
05.3 Preclinical safety data
In studies of up to 26 weeks duration in cynomolgus monkeys, epiphyseal dysplasia was observed in juvenile animals with open growth plates at mean serum concentrations of bevacizumab below the mean therapeutic serum concentrations expected in humans. In rabbits, bevacizumab has the wound healing process was inhibited at doses below the proposed clinical dose, but the effects on the wound healing process were fully reversible.
No studies have been performed to evaluate the mutagenic and carcinogenic potential of bevacizumab.
No specific animal studies have been performed to evaluate the effect on fertility. However, an adverse effect on female fertility can be expected, as studies carried out on animals on the toxicity associated with the administration of multiple doses have shown an "inhibition of the maturation of ovarian follicles and a reduction / absence of corpora lutea, with the consequent reduction in the weight of the ovaries and uterus, as well as the number of menstrual cycles.
Bevacizumab was embryotoxic and teratogenic in the rabbit. Effects observed included decreased maternal and fetal weight, increased number of fetal resorptions, and increased incidence of specific severe malformations and fetal skeletal malformations. Fatal outcomes affecting the fetus were observed at all dosages tested; the lowest dose administered resulted in mean serum concentrations approximately 3 times higher than those found in humans following administration of 5 mg / kg every 2 weeks. Information on fetal malformations observed post-marketing is provided in section 4.6. Fertility , pregnancy and lactation and 4.8 Undesirable effects.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Trehalose dihydrate
Sodium phosphate
Polysorbate 20
Water for injections
06.2 Incompatibility
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
When bevacizumab is diluted with glucose solutions (5%), a concentration dependent degradation profile is observed.
06.3 Period of validity
Vial (closed)
2 years.
Diluted medicine
Chemical and physical in-use stability has been demonstrated for 48 hours at 2 ° C to 30 ° C in sodium chloride 9 mg / ml (0.9%) solution for injection. microbiological, the product must be used immediately. If the use is not immediate, the user is to be held responsible for the storage times and conditions, which normally should not exceed 24 hours at a temperature between 2 ° C and 8 ° C, unless dilution has taken place under controlled and validated aseptic conditions.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C-8 ° C).
Do not freeze.
Keep the vial in the outer carton in order to protect it from light.
For storage conditions after dilution of the medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
4 ml of solution in a vial (Type I glass) with a stopper (butyl rubber) containing 100 mg of bevacizumab.
16 ml of solution in a vial (Type I glass), with a stopper (butyl rubber) containing 400 mg of bevacizumab.
Pack of 1 vial.
06.6 Instructions for use and handling
Avastin must be prepared by a healthcare professional using aseptic technique to ensure the sterility of the final solution prepared.
The required amount of bevacizumab should be withdrawn and diluted to the appropriate administration volume with sodium chloride 9 mg / ml (0.9%) solution for injection. The concentration of the final bevacizumab solution should be maintained within the range of 1.4 mg / mL to 16.5 mg / mL. In most cases the required amount of Avastin can be diluted with 0.9% sodium chloride solution for injection to a total volume of 100 mL.
Medicinal products intended for parenteral administration should be subjected to a visual examination before being administered to rule out the presence of particulates and signs of color change.
No incompatibilities have been observed between Avastin and polyvinyl chloride or polyolefin infusion bags or sets.
Avastin is for single use only, as the product contains no preservatives. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/04/300/001 - 100 mg / 4 ml vial
036680015
EU / 1/04/300/002 - 400 mg / 16 ml vial
036680027
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 12 January 2005
Date of last renewal: January 14, 2015
10.0 DATE OF REVISION OF THE TEXT
March 2015
