Avastin 400mg/16ml

Active Ingredient: Avastin 400mg/16ml (humanised anti-VEGF monoclonal antibody).

Avastin 400mg/16ml is supplied in 100 mg and 400 mg preservative-free, single-use vials containing 4 mL or 16 mL of Avastin 400mg/16ml (25 mg/mL).

Each Avastin 400mg/16ml 100 mg vial contains 100 mg of Avastin 400mg/16ml.

Avastin 400mg/16ml is not formulated for intravitreal use.

Excipients/Inactive Ingredients: α, α-trehalose dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous disodium phosphate, polysorbate 20 and sterile water for injections.

Metastatic Colorectal Cancer (mCRC)

Avastin 400mg/16ml is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Avastin 400mg/16ml, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin 400mg/16ml-containing regimen.

Limitation of Use: Avastin 400mg/16ml is not indicated for adjuvant treatment of colon cancer.

Non-Squamous Non–Small Cell Lung Cancer (NSCLC)

Avastin 400mg/16ml is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Glioblastoma

Avastin 400mg/16ml is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin 400mg/16ml in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin 400mg/16ml.

Metastatic Renal Cell Carcinoma (mRCC)

Avastin 400mg/16ml is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Persistent, Recurrent, or Metastatic Carcinoma of the Cervix

Avastin 400mg/16ml in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix.

Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Avastin 400mg/16ml in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.

Avastin 400mg/16ml injection is given with other medicines to treat patients with metastatic (a cancer that has spread) carcinoma of the colon or rectum. Avastin 400mg/16ml is also used to treat a certain type of metastatic lung cancer called nonsquamous, non-small cell lung cancer, and a certain type of brain tumor called glioblastoma.

Avastin 400mg/16ml is a substance that helps the body fight cancer. It prevents the growth of certain types of blood vessels to cancer cells. This helps to decrease the growth of cancer cells by starving the cells of nutrients that are needed to grow.

Avastin 400mg/16ml injection is also used in combination with other medicines (eg, interferon alfa) to treat patients with cancer of the kidney that has spread to other areas of the body. It is also used in combination with other medicines (eg, paclitaxel and cisplatin, or paclitaxel and topotecan) to treat patients with cancer of the cervix that has spread to other areas of the body. Avastin 400mg/16ml is also used in combination with other medicines (eg, paclitaxel, pegylated liposomal doxorubicin, or topotecan) to treat patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Avastin 400mg/16ml is to be given only by or under the immediate supervision of your doctor.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, Avastin 400mg/16ml is used in certain patients with the following medical conditions:

• Diabetic macular edema (swelling of the back of the eye in diabetic patients).
• Glioblastoma multiforme, recurrent, after therapy with temozolomide (a type of brain cancer that is getting worse or not responding to therapy).
• Metastatic colorectal cancer, first-line therapy, in combination with capecitabine and oxaliplatin (cancer of the colon or rectum that has spread to other areas of the body).

General: Substitution by any other biological medicinal product requires the consent of the prescribing physician.

Avastin 400mg/16ml should be prepared by a healthcare professional using aseptic technique.

The initial Avastin 400mg/16ml dose should be delivered over 90 min as an IV infusion. If the 1st infusion is well-tolerated, the 2nd infusion may be administered over 60 min. If the 60-min infusion is well-tolerated, all subsequent infusions may be administered over 30 min.

Dose reduction of Avastin 400mg/16ml for adverse events is not recommended. If indicated, Avastin 400mg/16ml should either be permanently discontinued or temporarily suspended (Precautions).

Avastin 400mg/16ml is not formulated for intravitreal use.

Metastatic Colorectal Cancer (mCRC): The recommended dose of Avastin 400mg/16ml, administered as an IV infusion, is as follows: First-line Treatment: 5 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg of body weight given once every 3 weeks. Second-line Treatment: 10 mg/kg of body weight given every 2 weeks or 15 mg/kg of body weight given once every 3 weeks.

It is recommended that Avastin 400mg/16ml treatment be continued until progression of the underlying disease.

Locally Recurrent or Metastatic Breast Cancer (mBC): The recommended dose of Avastin 400mg/16ml is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kg of body weight given once every 3 weeks as an IV infusion. It is recommended that Avastin 400mg/16ml treatment be continued until progression of the underlying disease.

Advanced, Metastatic or Recurrent Non-Small Cell Lung Cancer (NSCLC): Avastin 400mg/16ml is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by Avastin 400mg/16ml as a single agent until disease progression.

The recommended dose of Avastin 400mg/16ml when used in addition to cisplatin-based chemotherapy is 7.5 mg/kg of body weight given once every 3 weeks as an IV infusion.

The recommended dose of Avastin 400mg/16ml when used in addition to carboplatin-based chemotherapy is 15 mg/kg of body weight given once every 3 weeks as an IV infusion.

Advanced and/or Metastatic Renal Cell Cancer (mRCC): The recommended dose of Avastin 400mg/16ml is 10 mg/kg of body weight given once every 2 weeks as an IV infusion.

It is recommended that Avastin 400mg/16ml treatment be continued until progression of the underlying disease.

Malignant Glioma (WHO Grade IV)-Glioblastoma: The recommended dose of Avastin 400mg/16ml is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kg of body weight given once every 3 weeks as an IV infusion.

It is recommended that Avastin 400mg/16ml treatment be continued until progression of the underlying disease.

Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer: Avastin 400mg/16ml is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Avastin 400mg/16ml as single agent for 15 months or until disease progression, whichever occurs earlier.

The recommended dose of Avastin 400mg/16ml is 15 mg/kg of body weight given once every 3 weeks as an IV infusion.

Special Dosage Instructions: Children and Adolescents: The safety and efficacy of Avastin 400mg/16ml in children and adolescents have not been studied.

See also:
What is the most important information I should know about Avastin 400mg/16ml?

Treatment with Avastin 400mg/16ml may cause you to have problems with wound healing, which could result in bleeding or infection. If you need to have any type of surgery, you will need to stop receiving Avastin 400mg/16ml at least 4 weeks ahead of time. Do not start using Avastin 400mg/16ml for at least 4 weeks after surgery, or until your surgical incision heals.

Before being treated with Avastin 400mg/16ml, tell your doctor if you have a bleeding or blood-clotting disorder, heart disease, congestive heart failure, high blood pressure, or a history of heart attack, stroke, blood clots, or stomach or intestinal bleeding (including perforation).

Some people receiving a Avastin 400mg/16ml injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, itchy, or have a fast heartbeat, chills, wheezing, or chest pain during the injection.

Call your doctor at once if you have: any unusual bleeding or bruising, blood in your urine or stools, coughing up blood, any bleeding that will not stop, severe stomach pain with fever and vomiting, sudden numbness or weakness, leg pain or swelling, chest pain, severe headache, problems with speech or balance, swelling or rapid weight gain, urinating less than usual, loss of bladder or bowel control, or missed menstrual periods.

Avastin 400mg/16ml can cause a rare but serious neurologic disorder affecting the brain. Symptoms include headache, confusion, vision problems, feeling very weak or tired, fainting, and seizure (blackout or convulsions). These rare symptoms may occur within hours of your first dose of Avastin 400mg/16ml, or they may not appear for up to a year after your treatment started. Call your doctor at once if you have any of these side effects.

To be sure this medication is not causing harmful effects, your blood pressure will need to be checked often. Your urine may also need to be tested. Visit your doctor regularly.

Avastin 400mg/16ml may cause a woman's ovaries to stop working correctly. Symptoms of ovarian failure include 3 or more missed menstrual periods in a row. This may affect your fertility (ability to have children). Talk to your doctor about your specific risks.

Use Avastin 400mg/16ml solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Avastin 400mg/16ml solution is given as an injection at your doctor's office, hospital, or clinic. Contact your health care provider if you have any questions.
• If you miss a dose of Avastin 400mg/16ml solution, contact your doctor immediately to establish a new dosing schedule.

Ask your health care provider any questions you may have about how to use Avastin 400mg/16ml solution.

Use: Labeled Indications

Cervical cancer, persistent/recurrent/metastatic (Avastin 400mg/16ml and Avastin 400mg/16ml biosimilars): Treatment of persistent, recurrent, or metastatic cervical cancer (in combination with paclitaxel and either cisplatin or topotecan).

Colorectal cancer, metastatic (Avastin 400mg/16ml and Avastin 400mg/16ml biosimilars): First- or second-line treatment of metastatic colorectal cancer (CRC) (in combination with fluorouracil-based chemotherapy); second-line treatment of metastatic CRC (in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy) after progression on a first-line treatment containing Avastin 400mg/16ml.

Limitations of use: Not indicated for the adjuvant treatment of colon cancer.

Glioblastoma, recurrent (Avastin 400mg/16ml and Avastin 400mg/16ml biosimilars): Treatment of recurrent glioblastoma in adults.

Non-small cell lung cancer, nonsquamous (Avastin 400mg/16ml and Avastin 400mg/16ml biosimilars):First-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non-small cell lung cancer (in combination with carboplatin and paclitaxel).

Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (Avastin 400mg/16ml only):

Stage III or IV disease, following initial surgical resection: Treatment of stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection (in combination with carboplatin and paclitaxel, followed by single-agent Avastin 400mg/16ml).

Platinum-resistant recurrent: Treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (in combination with paclitaxel, doxorubicin [liposomal], or topotecan) in patients who received no more than 2 prior chemotherapy regimens.

Platinum-sensitive recurrent: Treatment of platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (in combination with carboplatin and paclitaxel or with carboplatin and gemcitabine and then followed by single-agent Avastin 400mg/16ml).

Renal cell carcinoma, metastatic (Avastin 400mg/16ml and Avastin 400mg/16ml biosimilars): Treatment of metastatic renal cell carcinoma (in combination with interferon alfa).

Note: Mvasi (Avastin 400mg/16ml-awwb) and Avastin 400mg/16ml (Avastin 400mg/16ml-bvzr) are approved as biosimilars to Avastin 400mg/16ml (Avastin 400mg/16ml).

Off Label Uses

Age-related macular degeneration

Data from multicenter, randomized, controlled trials support the use of intravitreal Avastin 400mg/16ml in the management of age-related macular degeneration (AMD).

See also:
What other drugs will affect Avastin 400mg/16ml?

Effect of Antineoplastic Agents on Avastin 400mg/16ml Pharmacokinetics: No clinically relevant pharmacokinetic interaction of co-administered chemotherapy on Avastin 400mg/16ml pharmacokinetics has been observed based on the results of a population pharmacokinetics analysis. There was neither statistical significance nor clinically relevant difference in clearance of Avastin 400mg/16ml in patients receiving Avastin 400mg/16ml monotherapy compared to patients receiving Avastin 400mg/16ml in combination with interferon α-2a or other chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or cisplatin/gemcitabine).

Effect of Avastin 400mg/16ml on the Pharmacokinetics of other Antineoplastic Agents: Results from a drug-drug interaction study, AVF3135g demonstrated no significant effect of Avastin 400mg/16ml on the pharmacokinetics of irinotecan and its active metabolite SN38.

Results from NP18587 demonstrated no significant effect of Avastin 400mg/16ml on the pharmacokinetics of capecitabine and its metabolites, and on the pharmacokinetics of oxaliplatin, as determined by measurement of free and total platinum.

Results from BO17705 demonstrated no significant effect of Avastin 400mg/16ml on the pharmacokinetics of interferon α-2a.

Results from BO17704 demonstrated no significant effect of Avastin 400mg/16ml on the pharmacokinetics of cisplatin. Due to high inter-patient variability and limited sampling, the results from BO17704 do not allow firm conclusions on the impact of Avastin 400mg/16ml on gemcitabine pharmacokinetics to be drawn.

Combination of Avastin 400mg/16ml and Sunitinib Malate: In 2 clinical studies of metastatic renal cell carcinoma, microangiopathic hemolytic anemia (MAHA) was reported in 7 of 19 patients treated with Avastin 400mg/16ml (10 mg/kg every 2 weeks) and sunitinib malate (50 mg daily) combination.

Microangiopathic hemolytic anemia is a hemolytic disorder which can present with red cell fragmentation, anemia and thrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine and neurological symptoms were observed in some of these patients. All of these findings were reversible upon discontinuation of Avastin 400mg/16ml and sunitinib malate.

Radiotherapy: The safety and efficacy of concomitant administration of chemotherapy (temozolomide), radiotherapy and Avastin 400mg/16ml was evaluated in study BO21990, a phase III, randomised, double-blind, placebo-controlled study of 921 patients with newly diagnosed glioblastoma. No new adverse events associated with Avastin 400mg/16ml were reported in this study.

The safety and efficacy of concomitant administration of radiotherapy and Avastin 400mg/16ml has not been established in other indications.

Incompatibilities: No incompatibilities between Avastin 400mg/16ml and polyvinyl chloride or polyolefin bags have been observed. A concentration dependent degradation profile of Avastin 400mg/16ml was observed when diluted with dextrose solutions (5%).

See also:
What are the possible side effects of Avastin 400mg/16ml?

Clinical Trials: Clinical trials have been conducted in patients with various malignancies treated with Avastin 400mg/16ml, predominantly in combination with chemotherapy. The safety profile from a clinical trial population of approximately 5,200 patients is presented as follows. For post-marketing experience, see Post-Marketing as follows. See Clinical/Efficacy studies for details of major studies, including study designs and major efficacy results.

The most serious adverse drug reactions were: Gastrointestinal Perforations; haemorrhage including pulmonary haemorrhage/haemoptysis, which is more common in NSCLC patients; arterial thromboembolism.

Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with Avastin 400mg/16ml therapy are likely to be dose-dependent.

The most frequently observed adverse drug reactions across clinical trials in patients receiving Avastin 400mg/16ml were hypertension, fatigue or asthenia, diarrhea and abdominal pain.

Table 16 lists adverse drug reactions associated with the use of Avastin 400mg/16ml in combination with different chemotherapy regimens in multiple indications. These reactions had occurred either with at least a 2% difference compared to the control arm (NCI-CTC grade 3-5 reactions) or with at least a 10% difference compared to the control arm (NCI-CTC grade 1-5 reactions), in at least one of the major clinical trials. The adverse drug reactions listed in Table 16 fall into the following categories: Very common (≥10%) and common (≥1% to <10%). Adverse drug reactions are added to the appropriate category in Table 16 according to the highest incidence seen in any of the major clinical trials. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. Some of the adverse reactions are reactions commonly seen with chemotherapy however, Avastin 400mg/16ml may exacerbate these reactions when combined with chemotherapeutic agents. Examples includes palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with paclitaxel.

Further Information on Selected Serious Adverse Drug Reactions: The following adverse drug reactions, reported using common toxicity criteria (NCI-CTC) for assessment of toxicity, have been observed in patients treated with Avastin 400mg/16ml.

Gastrointestinal Perforation and Fistulae

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), gastrointestinal perforation (all grade) were reported in 3.2% of patients, all of whom had a history of prior pelvic radiation.

The occurrence of those events varied in type and severity, ranging from free air seen on the plain abdominal X-ray, which resolved without treatment, to intestinal perforation with abdominal abscess and fatal outcome. In some cases, underlying intra-abdominal inflammation was present, either from gastric ulcer disease, tumour necrosis, diverticulitis or chemotherapy-associated colitis. A causal association of intra-abdominal inflammatory process and gastrointestinal perforation to Avastin 400mg/16ml has not been established.

Fatal outcome was reported in approximately a 3rd of serious cases of gastrointestinal perforations, which represents between 0.2-1% of all Avastin 400mg/16ml-treated patients.

In Avastin 400mg/16ml clinical trials, gastrointestinal fistulae (all grade) have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported less commonly in patients with other types of cancer.

In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal fistulae was 8.3% in Avastin 400mg/16ml-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies.

Non-GI Fistulae : Avastin 400mg/16ml use has been associated with serious cases of fistulae including events resulting in death.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-240), 1.8% of Avastin 400mg/16ml-treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, vesical, or female genital tract fistulae.

Uncommon (≥0.1% to <1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract (eg, bronchopleural, biliary fistulae) were observed across various indications. Fistulae have also been reported in post-marketing experience.

Events were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of Avastin 400mg/16ml, with most events occurring within the first 6 months of therapy.

Hemorrhage: In clinical trials across all indications, the overall incidence of NCI-CTC grade 3-5 bleeding events ranged from 0.4-6.9% in Avastin 400mg/16ml-treated patients, compared to 0-4.5% of patients in the chemotherapy control group. The haemorrhagic events that have been observed in Avastin 400mg/16ml clinical studies were predominantly tumour-associated haemorrhage and minor mucocutaneous hemorrhage (eg, epistaxis).

Tumour-Associated Haemorrhage: Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in studies in patients with NSCLC. Possible risk factors include squamous cell histology, treatment with anti-rheumatic/anti-inflammatory drugs, treatment with anticoagulants, prior radiotherapy, Avastin 400mg/16ml therapy, previous medical history of atherosclerosis, central tumour location and cavitation of tumours prior to or during therapy. The only variables that showed statistically significant correlations with bleeding were Avastin 400mg/16ml therapy and squamous cell histology. Patients with NSCLC of known squamous cell histology or mixed cell type with predominant squamous cell histology were excluded from subsequent studies, while patients with unknown tumour histology were included.

In patients with NSCLC excluding predominant squamous histology, all Grade events were seen with a frequency of up to 9% when treated with Avastin 400mg/16ml plus chemotherapy compared with 5% in the patients treated with chemotherapy alone. Grade 3-5 events have been observed in up to 2.3% of patients treated with Avastin 400mg/16ml plus chemotherapy as compared with <1% with chemotherapy alone. Major or massive pulmonary haemorrhage/haemoptysis can occur suddenly and up to two thirds of the serious pulmonary haemorrhages resulted in a fatal outcome.

Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in colorectal patients, and have been assessed as tumour-associated haemorrhages.

Tumour-associated haemorrhages were also seen rarely in other tumour types and locations and included cases of CNS bleeding in patients with hepatoma with CNS metastases and in patients with glioblastoma.

The incidence of CNS bleeding in patients with untreated CNS metastases receiving Avastin 400mg/16ml has not been prospectively evaluated in randomised clinical studies. In an exploratory retrospective analysis of data from 13 completed randomised trials in patients with various tumour types, 3 patients out of 91 (3.3%) with brain metastases experienced CNS bleeding (all Grade 4) when treated with Avastin 400mg/16ml, compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to Avastin 400mg/16ml. In two subsequent studies in patients with treated brain metastases (which included around 800 patients), one case of Grade 2 CNS haemorrhage was reported.

Intracranial haemorrhage can occur in patients with relapsed glioblastoma. In study AVF3708g, CNS haemorrhage was reported in 2.4% (2/84) of patients in the Avastin 400mg/16ml alone arm (Grade 1); and in 3.8% (3/79) of patients treated with Avastin 400mg/16ml and irinotecan (Grades 1, 2 and 4).

Across all Avastin 400mg/16ml clinical trials, mucocutaneous haemorrhages were seen in up to 50% of patients treated with Avastin 400mg/16ml. These were most commonly NCI-CTC grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any change in the Avastin 400mg/16ml treatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneous haemorrhage (eg, epistaxis) may be dose-dependent.

There have also been less common events of minor mucocutaneous haemorrhage in other locations such as, gingival bleeding or vaginal bleeding.

Hypertension : An increased incidence of hypertension (all grades) of up to 42.1% has been observed in patients treated with Avastin 400mg/16ml compared with up to 14% in the comparator arm. In clinical trials across all indications, the overall incidence of NCI-CTC grade 3 and 4 hypertension in patients receiving Avastin 400mg/16ml ranged from 0.4 to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1% of patients treated with Avastin 400mg/16ml compared to up to 0.2% patients treated with the same chemotherapy alone.

Hypertension was generally adequately controlled with oral antihypertensives such as, angiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation of Avastin 400mg/16ml treatment or hospitalisation.

Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal. The risk of Avastin 400mg/16ml-associated hypertension did not correlate with the patients' baseline characteristics, underlying disease or concomitant therapy.

Posterior Reversible Encephalopathy Syndrome : Two confirmed cases (0.8%) of PRES have been reported in one clinical study. Symptoms usually resolve or improve within days, although some patients have experienced neurologic sequelae.

Thromboembolism: Arterial Thromboembolism: An increased incidence of arterial thromboembolic events was observed in patients treated with Avastin 400mg/16ml across indications including cerebrovascular accidents, myocardial infarction, transient ischemic attacks, and other arterial thromboembolic events.

In clinical trials, the overall incidence ranged up to 5.9% in the Avastin 400mg/16ml-containing arms compared up to 1.7% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving Avastin 400mg/16ml in combination with chemotherapy compared to 0.5% of patients receiving chemotherapy alone. Cerebrovascular accidents (including transient ischemic attacks) were reported in up to 2.3% of Avastin 400mg/16ml-treated patients versus 0.5% of patients in the control group. Myocardial infarction was reported in 1.4% of Avastin 400mg/16ml treated versus 0.7% of patients in the observed control group.

In one clinical trial, AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment with irinotecan, were included. In this trial, arterial thromboembolic events were observed in 11% (11/100) of Avastin 400mg/16ml patients compared to 5.8% (6/104) in the chemotherapy-control group. In an uncontrolled clinical trial, AVF3708g, in patients with relapsed glioblastoma, arterial thromboembolic events were observed in 6.3% (5/79) of patients who received Avastin 400mg/16ml in combination with irinotecan compared to 4.8% (4/84) of patients who received Avastin 400mg/16ml alone.

Venous Thromboembolism : In clinical trials across indications, the overall incidence of venous thromboembolic events ranged from 2.8 to 17.3% in the Avastin 400mg/16ml-containing arms compared to 3.2 to 15.6% in the chemotherapy-control arms. Venous thromboembolic events include deep venous thrombosis and pulmonary embolism.

Grade 3-5 venous thromboembolic events have been reported in up to 7.8% of patients treated with chemotherapy plus Avastin 400mg/16ml compared with up to 4.9% in patients with chemotherapy alone. Patients who have experienced a venous thromboembolic event may be at higher risk for a recurrence if they receive Avastin 400mg/16ml in combination with chemotherapy versus chemotherapy alone.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 venous thromboembolic events have been reported in up to 10.6% of patients treated with chemotherapy and Avastin 400mg/16ml compared with up to 5.4% in patients with chemotherapy alone.

In clinical trial BO21990, Grade 3-5 venous thromboembolic events were observed in 7.6% of patients with newly diagnosed glioblastoma treated with Avastin 400mg/16ml in combination with chemotherapy and radiotherapy, compared to 8% of patients treated with chemotherapy and radiotherapy alone.

Congestive Heart Failure (CHF): In clinical trials with Avastin 400mg/16ml, congestive heart failure (CHF) was observed in all cancer indications studied to date but occurred predominantly in patients with metastatic breast cancer. In 5 phase III studies (AVF2119g, E2100, BO17708 and AVF3694g and AVF3693g) in patients with metastatic breast cancer, CHF grade 3 or higher, was reported in up to 3.5% of patients treated with Avastin 400mg/16ml in combination with chemotherapy compared with up to 0.9% in the control arms. For patients in study AVF3694g who received anthracyclines concomitantly with Avastin 400mg/16ml, the incidences of grade 3 or higher CHF for the respective Avastin 400mg/16ml and control arms were similar to those in the other studies in metastatic breast cancer: 2.9% in the anthracycline+Avastin 400mg/16ml arm and 0% in the anthracycline+placebo arm. In addition, in study AVF3694g, the incidences of all grade CHF were similar between the anthracycline+Avastin 400mg/16ml (6.2%) and the anthracycline+placebo arms (6%).

Most patients who developed CHF during mBC trials showed improved symptoms and/or left ventricular function following appropriate medical therapy.

In most clinical trials of Avastin 400mg/16ml, patients with pre-existing CHF of NYHA II-IV were excluded, therefore, no information is available on the risk of CHF in this population.

Prior anthracyclines exposure and/or prior radiation to the chest wall may be possible risk factors for the development of CHF.

An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large B-cell lymphoma when receiving Avastin 400mg/16ml with a cumulative doxorubicin dose greater than 300 mg/m². This phase III clinical trial compared rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) + Avastin 400mg/16ml to R-CHOP without Avastin 400mg/16ml. While the incidence of CHF was, in both arms, above that previously observed for doxorubicin therapy, the rate was higher in the R-CHOP + Avastin 400mg/16ml arm.

Wound Healing : As Avastin 400mg/16ml may adversely impact wound healing, patients who had major surgery within the last 28 days prior to starting Avastin 400mg/16ml treatment were excluded from participation in phase III trials.

Across mCRC clinical trials, there was no increased risk of post-operative bleeding or wound healing complications observed in patients who underwent major surgery between 28-60 days prior to starting Avastin 400mg/16ml therapy. An increased incidence of post-operative bleeding or wound healing complications occurring within 60 days of major surgery was observed, if the patient was being treated with Avastin 400mg/16ml at the time of surgery. The incidence varied between 10% (4/40) and 20% (3/15).

Cases of serious wound healing complications have been reported during Avastin 400mg/16ml use, some of which had a fatal outcome.

In locally recurrent and metastatic breast cancer trials, Grade 3-5 wound healing complications were observed in up to 1.1% of patients receiving Avastin 400mg/16ml compared with up to 0.9% of patients in the control arms.

In a study of patients with relapsed glioblastoma (study AVF3708g), the incidence of postoperative wound healing complications (including craniotomy site wound dehiscence and cerebrospinal fluid leak) was 3.6% in patients treated with single-agent Avastin 400mg/16ml and 1.3% in patients treated with Avastin 400mg/16ml plus irinotecan.

In patients with newly diagnosed glioblastoma (study BO21990) the incidence of grade 3-5 postoperative wound healing complications (including complications following craniotomy) was 3.3% when treated with Avastin 400mg/16ml in combination with chemotherapy and radiotherapy, compared with 1.6% when treated with chemotherapy and radiotherapy alone.

Proteinuria : In clinical trials, proteinuria has been reported within the range of 0.7 to 38% of patients receiving Avastin 400mg/16ml. Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome. Grade 3 proteinuria was reported in up to 8.1% of treated patients, grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. The proteinuria seen in Avastin 400mg/16ml clinical trials was not associated with renal impairment and rarely required permanent discontinuation of Avastin 400mg/16ml therapy.

Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with Avastin 400mg/16ml. There is evidence suggesting that grade 1 proteinuria may be related to Avastin 400mg/16ml dose. Testing for proteinuria is recommended prior to start of Avastin 400mg/16ml therapy. In most clinical studies, urine protein levels of ≥2 g/24 hrs led to the holding of Avastin 400mg/16ml until recovery to <2 g/24 hrs.

Hypersensitivity and Infusion Reactions : In some clinical trials, anaphylactic and anaphylactoid-type reactions were reported more frequently in patients receiving Avastin 400mg/16ml in combination with chemotherapies than with chemotherapy alone. The incidence of these reactions in some clinical trials of Avastin 400mg/16ml is common (up to 5% in Avastin 400mg/16ml-treated patients).

Ovarian Failure/Fertility : The incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH level ≥30 mIU/mL and a negative serum β-HCG pregnancy test, has been evaluated. New cases of ovarian failure were reported more frequently in patients receiving Avastin 400mg/16ml. After discontinuation of Avastin 400mg/16ml treatment, ovarian function recovered in a majority of women. Long-term effects of the treatment with Avastin 400mg/16ml on fertility are unknown.

Infections : In clinical trial BO21990, a randomised, double-blind, placebo controlled, multicentre phase III study of Avastin 400mg/16ml in combination with chemotherapy plus radiotherapy for the treatment of patients with newly diagnosed glioblastoma, the incidence of all grade and grade 3-5 infections was 54.4% and 12.8% in the Avastin 400mg/16ml plus chemotherapy and radiotherapy arm versus 39.1% and 7.8% in the chemotherapy plus radiotherapy only arm, respectively.

Elderly Patients: In randomised clinical trials, >65 years was associated with an increased risk of developing arterial thromboembolic events including cerebrovascular accidents, transient ischemic attacks and myocardial infarction as compared to those ≤65 years when treated with Avastin 400mg/16ml.

Other reactions with a higher frequency seen in patients over 65 were Grade 3-4 leucopenia and thrombocytopenia, and all grade neutropenia, diarrhoea, nausea, headache and fatigue.

From a clinical trial in patients with metastatic colorectal cancer (study AVF2107), no increase in the incidences of other reactions, including gastrointestinal perforation, wound healing complications, congestive heart failure and haemorrhage, was observed in elderly patients (>65 years) receiving Avastin 400mg/16ml as compared to those ≤65 years treated with Avastin 400mg/16ml.

Laboratory Abnormalities: Decreased neutrophil count, decreased white blood count and presence of urine protein may be associated with Avastin 400mg/16ml treatment.

Across clinical trials, the following grade 3 and 4 laboratory abnormalities were seen with an increased (≥2%) incidence in patients treated with Avastin 400mg/16ml compared to those in the control groups: Hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, increased prothrombin time (PT), normalised ratio.

Post-Marketing: See Table 17.

Laboratory Abnormalities: No text.