Bevacizumab 100 & 400 Equity Injection

u2022 Metastatic Colorectal Cancer: Bevacizumab Equity in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of patients with metastatic adenocarcinoma of the colon or rectum.

u2022 Locally recurrent or metastatic Breast Cancer: Bevacizumab Equity in combination with paclitaxel is indicated for first-line treatment of patients with locally recurrent or metastatic adenocarcinoma of the breast.

u2022 Advanced, metastatic or recurrent adenocarcinoma of the lung: Bevacizumab Equity, in addition to platinum-based chemotherapy, is indicated for first-line treatment of patients with unresectable advanced, metastatic or recurrent adenocarcinoma of the lung.

u2022 Advanced and/or metastatic Renal Cell Cancer (mRCC): Bevacizumab Equity in combination with interferon alfa-2a is indicated for first-line treatment of patients with advanced and/or metastatic renal cell cancer.

Bevacizumab Equity must be prepared and administered under the supervision of a healthcare provider experienced in the use of antineoplastic medicines.

Posology

Metastatic carcinoma of the colon or rectum (mCRC)

The recommended dose of Bevacizumab Equity, administered as an intravenous 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 treatment be continued until progression of the underlying disease or until unacceptable toxicity.

Metastatic Breast Cancer (mBC)

The recommended dose of Bevacizumab Equity 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.

Adenocarcinoma of the lung

Bevacizumab Equity is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by Bevacizumab Equity as a single agent until disease progression. The recommended dose of Bevacizumab Equity when used in addition to cisplatin-based chemotherapy is 7,5 mg/kg of body weight given once every 3 weeks as an intravenous infusion. The recommended dose of Bevacizumab Equity when used in addition to carboplatin-based chemotherapy 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.

Advanced and/or metastatic Renal Cell Cancer (mRCC)

The recommended dose of Bevacizumab Equity 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.

Special populations

Analyses of demographic data suggest that no dose adjustments are necessary for age or sex.

Elderly: No close adjustment for Bevacizumab Equity is required in the patients u2265 65 years of age.

Renal impairment: The safety and efficacy of Bevacizumab Equity have not been studied in patients with renal impairment (see section 5.2).

Hepatic impairment: The safety and efficacy of Bevacizumab Equity has not been studied in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Bevacizumab Equity in children and adolescents aged less than 18 years old have not been established.

Method of administration

The initial dose should be delivered over 90 minutes as an intravenous infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. The initial dose of Bevacizumab Equity should be administered following chemotherapy, all subsequent doses can be given before or after chemotherapy.

Bevacizumab Equity should not be administered as an intravenous push or bolus. Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended as described in section 4.4.

Precautions to be taken before handling or administering the medicine

For instructions on dilution of the medicine before administration, see section 6.6. Bevacizumab Equity infusions should not be administered or mixed with glucose solutions. This medicine must not be mixed with other medicines except those mentioned in section 6.6.

u2022 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

u2022 Hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanised antibodies.

u2022 Pregnancy and lactation (see section 4.6)

u2022 Patients with untreated Central Nervous System (CNS) metastases (see section 4.4).

u2022 Concomitant use with sunitinib (see section 4.5).

u2022 Intravitreal use.

Traceability

In order to improve the traceability of biological medicines, the name and the batch number of the administered product should be clearly recorded.

Gastrointestinal (GI) perforations and Fistulae (see section 4.8)

Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation when treated with Bevacizumab Equity. 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 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

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 (see section 4.8)

Patients may be at increased risk for the development of fistulae when treated with Bevacizumab Equity. Permanently discontinue Bevacizumab Equity 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 Equity in patients with other fistulae. In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of Bevacizumab Equity should be considered.

Wound healing complications (see section 4.8)

Bevacizumab Equity 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 less frequently been reported in patients treated with Bevacizumab Equity. This condition is usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Bevacizumab Equity therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.

Hypertension (see section 4.8)

An increased incidence of hypertension was observed in Bevacizumab Equity-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 Equity treatment.

There is no information on the effect of Bevacizumab Equity 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 Equity 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) (see section 4.8)

There have been reports of Bevacizumab Equity-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 Equity. The safety of reinitiating Bevacizumab Equity therapy in patients previously experiencing PRES is not known.

Proteinuria (see section 4.8)

Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with Bevacizumab Equity. 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 Equity. Therapy should be permanently discontinued in patients who develop nephrotic syndrome (NCI-CTCAE v.3).

Arterial thromboembolism (see section 4.8)

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 Equity in combination with chemotherapy compared to those who received chemotherapy alone. Patients receiving Bevacizumab Equity 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 Equity.

Therapy should be permanently discontinued in patients who develop arterial thromboembolic reactions.

Venous thromboembolism (see section 4.8)

Patients may be at risk of developing venous thromboembolic reactions, including pulmonary embolism under Bevacizumab Equity treatment.

Patients treated with Bevacizumab Equity in combination with paclitaxel and cisplatin may be at increased risk of venous thromboembolic events. Bevacizumab Equity should be discontinued in patients with life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism (NCI-CTCAE v.3). Patients with thromboembolic reactions u2264 Grade 3 need to be closely monitored (NCI-CTCAE v.3).

Haemorrhage

Patients treated with Bevacizumab Equity have an increased risk of haemorrhage, especially tumour-associated haemorrhage. Bevacizumab Equity should be discontinued permanently in patients who experience Grade 3 or 4 bleeding during Bevacizumab Equity therapy (NCI-CTCAE v.3) (see section 4.8). Patients with untreated CNS metastases were routinely excluded from clinical trials with Bevacizumab Equity, 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 (see section 4.8). Patients should be monitored for signs and symptoms of CNS bleeding, and Bevacizumab Equity treatment discontinued in cases of intracranial bleeding.

There is no information on the safety profile of Bevacizumab Equity 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 Equity 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 Bevacizumab Equity concomitantly (NCI-CTCAE v.3).

Pulmonary haemorrhage/haemoptysis

Patients with non-small cell lung cancer treated with Bevacizumab Equity 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 Equity.

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 Equity, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Congestive heart failure (CHF) (see section 4.8)

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 Equity.

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 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 Equity 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) (see section 4.8).

Neutropenia and infections (see section 4.8)

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 Equity in comparison to chemotherapy alone.

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 following the administration of Bevacizumab Equity 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) (see section 4.8)

Cases of ONJ have been reported in cancer patients treated with Bevacizumab Equity, 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 Equity 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 Equity. In patients who have previously received or are receiving intravenous bisphosphonates invasive dental procedures should be avoided, if possible.

Intravitreal use

Bevacizumab Equity 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 Equity 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.

Ovarian failure/fertility

Bevacizumab Equity may impair female fertility (see sections 4.6 and 4.8). Therefore, fertility preservation strategies should be discussed with women of child-bearing potential prior to starting treatment with Bevacizumab Equity.

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 Equity monotherapy compared to patients receiving Bevacizumab Equity 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 medicines

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 clinical studies of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia (MAHA) was reported in patients treated with Bevacizumab Equity (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 Equity and sunitinib malate (see Hypertension, Proteinuria, PRES in section 4.4).

Combination with platinum- or taxane-based therapies (see sections 4.4 and 4.8)

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 Equity 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 clinical studies in patients with mCRC suggest that the use of anti-EGFR monoclonal antibodies panitumumab and cetuximab, respectively, in combination with Bevacizumab Equity plus chemotherapy, is associated with decreased progression free survival (PFS) and/or overall survival (OS), and with increased toxicity compared with Bevacizumab Equity plus chemotherapy alone.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment.

Pregnancy

There are no clinical trial data on the use of Bevacizumab Equity in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). IgGs are known to cross the placenta, and Bevacizumab Equity 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 (see section 4.8). Bevacizumab Equity is contraindicated in pregnancy (see section 4.3).

Breastfeeding

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 (see section 5.3), women must discontinue breastfeeding during therapy and not breastfeed for at least six months following the last dose of Bevacizumab Equity (see section 4.3).

Fertility

Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility (see section 5.3). In the adjuvant treatment of patients with colon cancer, premenopausal women have shown a higher incidence of new cases of ovarian failure in the Bevacizumab Equity group compared to the control group. After discontinuation of Bevacizumab Equity treatment, ovarian function recovered in the majority of patients. Long term effects of the treatment with Bevacizumab Equity on fertility are unknown.

Bevacizumab Equity has no or negligible influence on the ability to drive and use machines. However, somnolence and syncope have been reported with Bevacizumab Equity use (see Table 1 in section 4.8). If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate.

The overall safety profile of Bevacizumab Equity is based on data from patients with various malignancies, predominantly treated with Bevacizumab Equity in combination with chemotherapy in clinical trials.

Summary of the safety profile

The most serious adverse reactions were:

u2022 Gastrointestinal perforations (see section 4.4).

u2022 Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small cell lung cancer patients (see section 4.4).

u2022 Arterial thromboembolism (see section 4.4).

The most frequently observed adverse reactions across clinical trials in patients receiving Bevacizumab Equity were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.

Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with Bevacizumab Equity therapy are likely to be dose-dependent.

Tables 1 and 2 list adverse reactions associated with the use of Bevacizumab Equity in combination with different chemotherapy regimens in multiple indications, by MedDRA system organ class. Table 1 provides all adverse reactions by frequency that were determined to have a causal relationship with Bevacizumab Equity through:

u2022 comparative incidences noted between clinical trial treatment arms (with at least a 10 % difference compared to the control arm for NCI-CTCAE Grade 1-5 reactions or at least a 2 % difference compared to the control arm for NCI-CTCAE Grade 3-5 reactions),

u2022 post-authorisation safety studies,

u2022 spontaneous reporting,

u2022 epidemiological studies on-interventional or observational studies,

u2022 or through an evaluation of individual case reports.

Table 2 includes the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2 % difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 reactions. Table 2 also includes adverse reactions which are considered to be clinically significant or severe.

Post-marketing adverse reactions are included in both Tables 1 and 2, where applicable. Detailed information about these post-marketing reactions is provided in Table 3.

Adverse reactions are added to the appropriate frequency category in the tables below according to the highest incidence seen in any indication. Within each frequency category, adverse reactions are presented in the order of decreasing seriousness.

Some of the adverse reactions are reactions frequently seen with chemotherapy; however, Bevacizumab Equity may exacerbate these reactions when combined with chemotherapeutic medicines. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail disorders or alopecia with paclitaxel, and paronychia with erlotinib.

Table 1: Adverse Reactions by Frequency

System organ class Frequent Less frequent Frequency Not Known Infections and infestations Sepsis, abscess b,d , cellulitis, infection, urinary tract infection Necrotising fasciitis a Blood and lymphatic system disorders Febrile neutropenia, leukopenia, neutropenia b , thrombocytopenia, anaemia, lymphopenia Immune system disorders Hypersensitivity, infusion reactions a,b,d Metabolism and nutrition disorders Anorexia, hypomagnesaemia, hyponatraemia, dehydration Nervous system disorders Peripheral sensory neuropathy b , dysarthria, headache, dysguesia, cerebrovascular accident, syncope, somnolence Posterior reversible encephalopathy syndrome a,b,d , hypertensive encephalopathy a Eye disorders Eye disorder, increased lacrimation Cardiac disorders Congestive heart failure b,d , supraventricular tachycardia Vascular disorders Hypertension b,d , thromboembolism (venous) b,d , thromboembolis m Renal thrombotic microangio- pathy a,b , aneurysms and artery dissections Respiratory, thoracic and mediastinal disorders Dyspnoea, rhinitis, epistaxis, cough, pulmonary haemorrhage/ haemoptysis b,d , pulmonary embolism, hypoxia, dysphonia a Pulmonary hypertension a , nasal septum perforation a Gastrointestinal disorders Rectal haemorrhage, stomatitis, constipation, diarrhoea, nausea, vomiting, abdominal pain, gastrointestinal perforation b,d , intestinal perforation, ileus, intestinal obstruction, recto- vaginal fistulae d,e , gastrointestinal disorder, proctalgia Gastrointes- tinal ulcer a Hepato - biliary Gallbladder perforation a , b Skin and subcutaneous tissue disorders Wound healing complications b,d , exfoliative dermatitis, dry skin, skin discoloration, palmar- plantar erythrodysaesthesia syndrome Musculoskeletal and connective tissue disorders Arthralgia, myalgia, fistula b,d, muscular weakness, back pain Osteonecrosis of the jaw a,b , non-mandibular osteonecrosis a,f Renal and urinary disorders Proteinuria b,d Reproductive system and breast disorders Ovarian failure b,c,d , pelvic pain Congenital, familial, and genetic disorder Foetal abnormalities a,b General disorders and administration site conditions Asthenia, fatigue, pyrexia, pain, mucosal inflammation, lethargy Investigations Weight decreased a For further information please refer to Table 3 'Adverse reactions reported in post-marketing setting.'

Table 2: Severe Adverse Reactions by Frequency

System organ class Frequent Less frequent Frequency Not Known Infections and infestations Sepsis, cellulitis, abscess a,b , infection, urinary tract, infection Necrotising fasciitis c Blood and lymphatic system disorders F ebrile neutropenia, leukopenia, neutropenia a , thrombocytopenia, anaemia, lymphopenia Immune system disorders Hypersensitivity, infusion reactions a,b,c Metabolism and nutrition disorders D ehydration , hyponatraemia Nervous system disorders P eripheral sensory neuropathy a , cerebrovascular accident, syncope, somnolence, headache Posterior reversible encephalopathy syndrome a,b,c , hypertensive encephalopathy c Cardiac disorders Congestive heart failure a,b , supraventricular tachycardia Vascular disorders H ypertension a,b , thromboembolism arterial a,b , haemorrhage a,b , thromboembolism (venous) a,b , deep vein thrombosis Renal thrombotic microangiopathy b , c , aneurysms and artery dissections Respiratory, thoracic and mediastinal disorders P ulmonary haemorrhage/ haemoptysis a,b , pulmonary embolism, epistaxis, dyspnoea, hypoxia Pulmonary hypertension c , nasal septum perforation c Gastrointestinal disorders D iarrhoea, nausea, vomiting, abdominal pain, intestinal perforation, ileus, intestinal obstruction, recto-vaginal fistulae c,d , gastrointestinal disorder, stomatitis, proctalgia Gastrointestinal perforation a,b , gastrointestinal ulcer c , rectal haemorrhage Hepatobiliary disorders Gallbladder perforation b,c Skin and subcutaneous tissue disorders Wound healing complications a,b , Palmar-plantar erythrodysaesthesia syndrome Musculoskeletal and connective tissue disorders F istula a,b , myalgia, arthralgia, muscular weakness, back pain Osteonecrosis of the jaw b,c Renal and urinary disorders P roteinuria a,b Reproductive system and breast disorders P elvic pain O varian failure a,b Congenital, familial, and genetic disorder F oetal abnormalities a,c General disorders and administration site conditions A sthenia, fatigue, pain, lethargy, mucosal inflammation

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