Bevacizumab Kamada

/ Kamada

Metastatic carcinoma of the colon or rectum (mCRC)
The recommended dose is either 5 mg/kg or 10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks.
It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.
Metastatic breast cancer (mBC)
The recommended dose 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 intravenous infusion.
It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.
Non-small cell lung cancer (NSCLC)
– First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy : Bevacizumab is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by bevacizumab as a single agent until disease progression.
The recommended dose of bevacizumab is 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.
It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.
– First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination with erlotinib: EGFR mutation testing should be performed prior to initiation of treatment with the combination of bevacizumab and erlotinib. It is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.
The recommended dose of bevacizumab when used in addition to erlotinib is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.
It is recommended that the treatment with bevacizumab in addition to erlotinib is continued until disease progression.
– Advanced and/or metastatic renal cell cancer (mRCC)
The recommended dose is 10 mg/kg of body weight given once every 2 weeks as an intravenous infusion.
It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.
Malignant Glioma (WHO Grade IV)- Glioblastoma
The recommended dose is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kg of body weight given once every 3 weeks.
It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.
Epithelial ovarian, fallopian tube and primary peritoneal cancer
– Front-line treatment: Bevacizumab is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of bevacizumab as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier.
The recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.
– Treatment of platinum-sensitive recurrent disease: Bevacizumab is administered in combination with carboplatin and gemcitabine for 6 cycles and up to 10 cycles followed by continued use of bevacizumab as single agent until disease progression. The recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.
– Treatment of platinum-resistant recurrent disease: Bevacizumab is administered in combination with one of the following agents –topotecan (given weekly) or pegylated liposomal doxorubicin.
The recommended dose of bevacizumab is 10 mg/kg of body weight given once every 2 weeks as an intravenous infusion. When Bevacizumab is administered in combination with topotecan (given on days 1-5, every 3 weeks), the recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.
It is recommended that treatment be continued until disease progression or unacceptable toxicity.
Cervical Cancer
Bevacizumab is administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin or paclitaxel and topotecan.
The recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.
It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.
See prescribing information for full details.

• Bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of patients with metastatic carcinoma of the colon or rectum.
• Bevacizumab in addition to platinum – based chemotherapy, is indicated for first – line treatment of patients with unresectable advanced metastatic or recurrent non- small cell lung cancer other than predominantly squamous cell histology.
• Bevacizumab in combination with interferon alfa-2a is indicated for first line treatment of patients with advanced and /or metastatic renal cell cancer.
• Bevacizumab in combination with paclitaxel is indicated for first-line treatment of patients with metastatic breast cancer.
• Bevacizumab as asingle agent, is indicated for the treatment of glioblastoma in patients with progressive disease following prior therapy.
• Bevacizumab, in combination with carboplatin and paclitaxel, is indicated for the front-line treatment of advanced (FIGO stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are at high risk for recurrence (residual disease after debulking).
• Bevacizumab, in combination with carboplatin and gemcitabine, is indicated for the treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptortargeted agents.
• Bevacizumab in combination with topotecan, or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents.
• Bevacizumab in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for treatment of patients with persistent, recurrent, or metastatic carcinoma of the cervix.
• Bevacizumab in combination with erlotinib, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations.

• Hypersensitivity to the active substance or to any of the excipients.
• Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.
• Pregnancy.

Gastrointestinal (GI) perforations and Fistulae
Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation when treated with bevacizumab. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with bevacizumab and all patients with GI perforation had a history of prior radiation. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation.
GI-vaginal Fistulae in study GOG-0240
Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab are at increased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal fistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and all patients with GI-vaginal fistulae had a history of prior radiation. Recurrence of cancer within the field of prior radiation is an additional important risk factor for the development of GI-vaginal fistulae.
Non-GI Fistulae
Patients may be at increased risk for the development of fistulae when treated with bevacizumab.
Permanently discontinue bevacizumab in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula [US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3)]. Limited information is available on the continued use of bevacizumab in patients with other fistulae.
In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of bevacizumab should be considered.
Wound healing complications
Bevacizumab may adversely affect the wound healing process. Serious wound healing complications, including anastomotic complications, with a fatal outcome have been reported. Therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experienced wound healing complications during therapy, treatment should be withheld until the wound is fully healed. Therapy should be withheld for elective surgery.
Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with bevacizumab. This condition is usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Bevacizumab therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.
Hypertension
An increased incidence of hypertension was observed in bevacizumab-treated patients. Clinical safety data suggest that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertension should be adequately controlled before starting bevacizumab treatment. There is no information on the effect of bevacizumab in patients with uncontrolled hypertension at the time of initiating therapy.
Monitoring of blood pressure is generally recommended during therapy.
In most cases hypertension was controlled adequately using standard antihypertensive treatment appropriate for the individual situation of the affected patient. The use of diuretics to manage hypertension is not advised in patients who receive a cisplatin-based chemotherapy regimen. Bevacizumab should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy.
Posterior Reversible Encephalopathy Syndrome (PRES)
There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are consistent with PRES, a rare neurologic disorder, which can present with the following signs and symptoms among others: seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of bevacizumab. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known.
Proteinuria
Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with bevacizumab. There is evidence suggesting that all Grade (US National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE v.3]) proteinuria may be related to the dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of patients treated with bevacizumab. Therapy should be permanently discontinued in patients who develop nephrotic syndrome (NCI-CTCAE v.3).
Arterial thromboembolism
In clinical trials, the incidence of arterial thromboembolic reactions including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher in patients receiving bevacizumab in combination with chemotherapy compared to those who received chemotherapy alone.
Patients receiving bevacizumab plus chemotherapy, with a history of arterial thromboembolism, diabetes or age greater than 65 years have an increased risk of developing arterial thromboembolic reactions during therapy. Caution should be taken when treating these patients with bevacizumab.
Therapy should be permanently discontinued in patients who develop arterial thromboembolic reactions.
Venous thromboembolism
Patients may be at risk of developing venous thromboembolic reactions, including pulmonary embolism under bevacizumab treatment.
Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab in combination with paclitaxel and cisplatin may be at increased risk of venous thromboembolic events.
Bevacizumab should be discontinued in patients with life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism (NCI-CTCAE v.3). Patients with thromboembolic reactions ≤ Grade 3 need to be closely monitored (NCI-CTCAE v.3).
Haemorrhage
Patients treated with bevacizumab have an increased risk of haemorrhage, especially tumour-associated haemorrhage. Bevacizumab should be discontinued permanently in patients who experience Grade 3 or 4 bleeding during bevacizumab therapy (NCI-CTCAE v.3).
Patients with untreated CNS metastases were routinely excluded from clinical trials with bevacizumab, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patients has not been prospectively evaluated in randomised clinical trials. Patients should be monitored for signs and symptoms of CNS bleeding, and bevacizumab treatment discontinued in cases of intracranial bleeding.
There is no information on the safety profile of bevacizumab in patients with congenital bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting bevacizumab treatment, as such patients were excluded from clinical trials. Therefore, caution should be exercised before initiating therapy in these patients. However, patients who developed venous thrombosis while receiving therapy did not appear to have an increased rate of Grade 3 or above bleeding when treated with a full dose of warfarin and Bbevacizumab concomitantly (NCI-CTCAE v.3).
Pulmonary haemorrhage/haemoptysis
Patients with non-small cell lung cancer treated with bevacizumab may be at risk of serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/ haemoptysis (> 2.5 mL of red blood) should not be treated with bevacizumab.
Aneurysms and artery dissections
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating bevacizumab, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
Congestive heart failure (CHF)
Reactions consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation. Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with bevacizumab.
Most of the patients who experienced CHF had metastatic breast cancer and had received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF were present.
In patients in AVF3694g who received treatment with anthracyclines and who had not received anthracyclines before, no increased incidence of all Grade CHF was observed in the anthracycline + bevacizumab group compared to the treatment with anthracyclines only. CHF Grade 3 or higher reactions were somewhat more frequent among patients receiving bevacizumab in combination with chemotherapy than in patients receiving chemotherapy alone. This is consistent with results in patients in other studies of metastatic breast cancer who did not receive concurrent anthracycline treatment (NCI-CTCAE v.3).
Neutropenia and infections
Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy alone. This has mainly been seen in combination 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 (including anaphylactic shock) /infusion reactions
Patients may be at risk of developing infusion/hypersensitivity reactions (including anaphylactic shock). Close observation of the patient during and following the administration of bevacizumab is recommended as expected for any infusion of a therapeutic humanised monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered. A systematic premedication is not warranted.
Osteonecrosis of the jaw (ONJ)
Cases of ONJ have been reported in cancer patients treated with bevacizumab, the majority of whom had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when bevacizumab and intravenous bisphosphonates are administered simultaneously or sequentially.
Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with bevacizumab. In patients who have previously received or are receiving intravenous bisphosphonates invasive dental procedures should be avoided, if possible.
Intravitreal use
Bevacizumab is not formulated for intravitreal use.
Eye disorders
Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intravitreal use of bevacizumab compounded from vials approved for intravenous administration in cancer patients. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and conjunctival haemorrhage. Some of these reactions have resulted in various degrees of visual loss, including permanent blindness.
Systemic effects following intravitreal use
A reduction of circulating VEGF concentration has been demonstrated following intravitreal anti-VEGF therapy. Systemic adverse reactions including non-ocular haemorrhages and arterial thromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors.
Ovarian failure/fertility
Bevacizumab may impair female fertility. Therefore fertility preservation strategies should be discussed with women of child-bearing potential prior to starting treatment with bevacizumab.
See prescribing information for full details.

The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab were hypertension, fatigue or asthenia, diarrhoea and abdominal pain. See prescribing information for full details.

Effect of antineoplastic agents on bevacizumab pharmacokinetics
No clinically relevant interaction of co-administered chemotherapy on bevacizumab pharmacokinetics was observed based on the results of population pharmacokinetic analyses. There were neither statistically significant nor clinically relevant differences in bevacizumab clearance in patients receiving bevacizumab monotherapy compared to patients receiving bevacizumab in combination with interferon alfa-2a, erlotinib or chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or cisplatin/gemcitabine).
Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents
No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics of co-administered interferon alfa 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapies irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurement of free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabine pharmacokinetics cannot be drawn.
Combination of bevacizumab and sunitinib malate
In two clinical trials of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia (MAHA) was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two weeks) and sunitinib malate (50 mg daily) combination. MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, 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 bevacizumab and sunitinib malate.
Combination with platinum- or taxane-based therapies
Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) 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 bevacizumab has not been established.
EGFR monoclonal antibodies in combination with bevacizumab 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. Results from the randomised phase III studies, PACCE and CAIRO-2, in patients with mCRC suggest that the use of anti-EGFR monoclonal antibodies panitumumab and cetuximab, respectively, in combination with bevacizumab plus chemotherapy, is associated with decreased PFS and/or OS, and with increased toxicity compared with bevacizumab plus chemotherapy alone.

Pregnancy
There are no clinical trial data on the use of bevacizumab in pregnant women. Studies in animals have shown reproductive toxicity including malformations. IgGs are known to cross the placenta, and bevacizumab is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to cause serious birth defects when administered during pregnancy. In the post-marketing setting, cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed. Bevacizumab is contraindicated in pregnancy.
Breast-feeding
It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milk and bevacizumab could harm infant growth and development, women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of bevacizumab.

The highest dose tested in humans (20 mg/kg of body weight, intravenous every 2 weeks) was associated with severe migraine in several patients.

Do not shake the vial.
Store in a refrigerator (2°C-8°C). Do not freeze.
Keep the vial in the outer carton in order to protect from light.