• Metastatic Colorectal Cancer

Vegzelma, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first-or second-line treatment of patients with metastatic colorectal cancer (mCRC).

Vegzelma, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen.

Limitations of Use: Vegzelma is not indicated for adjuvant treatment of colon cancer [see 5.1 Pharmacodynamic properties].

• First-Line Non-Squamous Non–Small Cell Lung Cancer

Vegzelma, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer (NSCLC).

• Recurrent Glioblastoma

Vegzelma is indicated for the treatment of recurrent glioblastoma (GBM) in adults.

• Metastatic Renal Cell Carcinoma

Vegzelma, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC).

• Persistent, Recurrent, or Metastatic Cervical Cancer

Vegzelma, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

• Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Vegzelma, in combination with carboplatin and paclitaxel, followed by Vegzelma as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.

Vegzelma, 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.

Vegzelma, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by Vegzelma as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

• Hepatocellular Carcinoma

Vegzelma, in combination with atezolizumab, is indicated for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.

Important Administration Information
Withhold for at least 28 days prior to elective surgery. Do not administer Vegzelma until at least 28 days following major surgery and until adequate wound healing.

Metastatic Colorectal Cancer
The recommended dosage when Vegzelma is administered in combination with intravenous fluorouracil-based chemotherapy is:

• 5 mg/kg intravenously every 2 weeks in combination with bolus-IFL.
• 10 mg/kg intravenously every 2 weeks in combination with FOLFOX4.
• 5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy in patients who have progressed on a first-line bevacizumab product-containing regimen.

 First-Line Non-Squamous Non-Small Cell Lung Cancer
The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel.

Recurrent Glioblastoma
The recommended dosage is 10 mg/kg intravenously every 2 weeks.

Metastatic Renal Cell Carcinoma
The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with interferon alfa.

Persistent, Recurrent, or Metastatic Cervical Cancer
The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin or in combination with paclitaxel and topotecan.

Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
Stage III or IV Disease Following Initial Surgical Resection
The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel for up to 6 cycles, followed by Vegzelma 15 mg/kg every 3 weeks as a single agent for a total of up to 22 cycles or until disease progression, whichever occurs earlier.

Recurrent Disease
Platinum Resistant
The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan (every week).

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with topotecan (every 3 weeks).

Platinum Sensitive
The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and paclitaxel for 6 to 8 cycles, followed by Vegzelma 15 mg/kg every 3 weeks as a single agent until disease progression.

The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and gemcitabine for 6 to 10 cycles, followed by Vegzelma 15 mg/kg every 3 weeks as a single agent until disease progression.

Hepatocellular Carcinoma
The recommended dosage is 15 mg/kg intravenously after administration of 1,200 mg of atezolizumab intravenously on the same day, every 3 weeks until disease progression or unacceptable toxicity.

Refer to the Prescribing Information for atezolizumab prior to initiation for recommended dosage information.

Dosage Modifications for Adverse Reactions
Table 1 describes dosage modifications for specific adverse reactions. No dose reductions for Vegzelma are recommended.

Table 1: Dosage modifications for adverse reactions

Adverse reaction	Severity	Dosage modification
Gastrointestinal Perforations and Fistulae.	Gastrointestinal perforation, any grade Tracheoesophageal fistula, any grade Fistula, Grade 4 Fistula formation involving any internal organ	Discontinue Vegzelma
Wound Healing Complications.	Any	Withhold Vegzelma until adequate wound healing.The safety of resumption of Vegzelma after resolution of wound healing complications has not been established.
	Necrotizing fasciitis	Discontinue Vegzelma
Hemorrhage.	Grade 3 or 4	Discontinue Vegzelma
	Recent history of hemoptysis of 1/2 teaspoon (2.5 ml) or more	Withhold Vegzelma
Thromboembolic Events.	Arterial thromboembolism, severe	Discontinue Vegzelma
	Venous thromboembolism, Grade 4	Discontinue Vegzelma
Hypertension.	Hypertensive crisis Hypertensive encephalopathy	Discontinue Vegzelma
	Hypertension, severe	Withhold Vegzelma if not controlled with medical management; resume once controlled
Posterior Reversible Encephalopathy Syndrome (PRES).	Any	Discontinue Vegzelma
Renal Injury and Proteinuria.	Nephrotic syndrome	Discontinue Vegzelma
	Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome	Withhold Vegzelma until proteinuria less than 2 grams per 24 hours
Infusion-Related Reactions.	Severe	Discontinue Vegzelma
	Clinically significant	Interrupt infusion; resume at a decreased rate of infusion after symptoms resolve
	Mild, clinically insignificant	Decrease infusion rate
Congestive Heart Failure.	Any	Discontinue Vegzelma

Preparation and Administration
Preparation

• Use appropriate aseptic technique.
• Use sterile needle and syringe to prepare Vegzelma.
• Visually inspect vial for particulate matter and discoloration prior to preparation for administration. Discard vial if solution is cloudy, discolored or contains particulate matter.
• Withdraw necessary amount of Vegzelma and dilute in a total volume of 100 ml of 0.9% Sodium Chloride Injection, USP. Do not administer or mix with dextrose solution.
• Discard any unused portion left in a vial, as the product contains no preservatives.
• Diluted Vegzelma solution may be stored at 2°C to 8°C (36°F to 46°F) for up to 8 hours, if not used immediately.
• No incompatibilities between Vegzelma and polyvinylchloride or polyolefin bags have been observed.

Administration

• Administer as an intravenous infusion.
• First infusion: Administer infusion over 90 minutes.
• Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated. Administer all subsequent infusions over 30 minutes if second infusion over 60 minutes is tolerated.

• 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 recombinant human or humanised antibodies. • Pregnancy (see section 4.6).

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

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. 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 (see section 4.8)
Patients may be at increased risk for the development of fistulae when treated with bevacizumab. Permanently discontinue Vegzelma 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 Vegzelma should be considered.

Wound healing complications (see section 4.8)
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. Vegzelma 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-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 Vegzelma 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. Vegzelma 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 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 Vegzelma. The safety of reinitiating bevacizumab 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. 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 (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 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 Vegzelma.

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 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.

Vegzelma 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. Vegzelma should be discontinued permanently in patients who experience Grade 3 or 4 bleeding during Vegzelma therapy (NCI-CTCAE v.3) (see section 4.8).

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 (see section 4.8). Patients should be monitored for signs and symptoms of CNS bleeding, and Vegzelma 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 bevacizumab concomitantly (NCI-CTCAE v.3).

Pulmonary haemorrhage/haemoptysis
Patients with NSCLC 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 Vegzelma, 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 CHF 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) (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 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 (see section 4.8)
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) (see section 4.8)
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 Vegzelma. In patients who have previously received or are receiving intravenous bisphosphonates invasive dental procedures should be avoided, if possible.

Intravitreal use
Vegzelma 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 (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 Vegzelma.

Vegzelma contains sodium and polysorbate 20
Vegzelma contains sodium. This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium free’.

Vegzelma contains polysorbate 20. Each ml of Vegzelma 100 mg/4 ml Concentrate for Solution for Infusion contains 0.4 mg polysorbate 20. Polysorbates may cause allergic reactions. To be considered by the doctor if the patient has any known allergies.

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 (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 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 progression-free survival (PFS) and/or overall survival (OS), and with increased toxicity compared with bevacizumab 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 in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). ImmunoglobulinGs (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 (see section 4.8). Bevacizumab is contraindicated in pregnancy (see section 4.3).

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 (see section 5.3), women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of bevacizumab.

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 trial in the adjuvant treatment of patients with colon cancer, a substudy with premenopausal women has shown a higher incidence of new cases of ovarian failure in the bevacizumab group compared to the control group. After discontinuation of bevacizumab treatment, ovarian function recovered in the majority of patients. Long term effects of the treatment with bevacizumab on fertility are unknown.

Bevacizumab has no or negligible influence on the ability to drive and use machines. However, somnolence and syncope have been reported with bevacizumab 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.

Summary of the safety profile
The overall safety profile of bevacizumab is based on data from over 5,700 patients with various malignancies, predominantly treated with bevacizumab in combination with chemotherapy in clinical trials.

The most serious adverse reactions were:

• Gastrointestinal perforations (see section 4.4).
• Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in NSCLC patients (see section 4.4).
• Arterial thromboembolism (see section 4.4).

The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab 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 therapy are likely to be dose-dependent.

Tabulated list of adverse reactions
The adverse reactions listed in this section fall into the following frequency categories: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Tables 1 and 2 list adverse reactions associated with the use of bevacizumab 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 through:

• 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,
• Post-authorisation safety studies,
• Spontaneous reporting,
• Epidemiological studies\non-interventional or observational studies,
• Or through an evaluation of individual case reports.

Table 2 provides 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 by the marketing authorisation holder (MAH) 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 are 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 commonly seen with chemotherapy; however, bevacizumab may 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, nail disorders or alopecia with paclitaxel, and paronychia with erlotinib.

Table 1 Adverse reactions by frequency

System organ class	Very common	Common	Uncommon	Rare	Very rare	Frequency not known
Infections and infestations		Sepsis, abscessb,d, cellulitis, infection, urinary tract infection		Necrotising fasciitisa
Blood and lymphatic system disorders	Febrile neutropenia, leucopenia, neutropeniab, thrombocyopenia	Anaemia, lymphopenia
Immune system disorders		Hypersensitivity, infusion reactionsa,b,d		Anaphylactic shock
Metabolism and nutrition disorders	Anorexia, hypomagnesaemia, hyponatraemia	Dehydration
Nervous system disorders	Peripheral sensory neuropathyb, dysarthria, headache, dysguesia	Cerebrovascular accident, syncope, somnolence		Posterior reversible encephalopathy syndromea,b,d	Hypertensive encephalopathya
Eye disorders	Eye disorder, lacrimation increased
Cardiac disorders		Congestive heart failureb,d, supraventricular tachycardia
Vascular disorders	Hypertensionb,d, thromboembolism (venous)b,d	Thromboembolism (arterial)b,d, haemorrhageb,d, deep vein thrombosis				Renal thrombotic microangiopathya,b, aneurysms and artery dissections
Respiratory, thoracic and mediastinal disorders	Dyspnoea, rhinitis, epistaxis, cough	Pulmonary haemorrhage/haemoptysisb,d, pulmonary embolism, hypoxia, dysphoniaa				Pulmonary hypertensiona, nasal septum perforationa
Gastrointestinal disorders	Rectal haemorrhage, stomatitis, constipation, diarrhoea, nausea, vomiting, abdominal pain	Gastrointestinal perforationb,d, intestinal perforation, ileus, intestinal obstruction, recto-vaginal fistulaed,e, gastrointestinal disorder, proctalgia				Gastrointestinal ulcera
Hepatobiliary disorders						Gallbladder perforationa,b
Skin and subcutaneous tissue disorders	Wound healing complicationsb,d, exfoliative dermatitis, dry skin, skin discoloration	Palmar-plantar erythrodysaesthesia syndrome
Musculoskeletal and connective tissue disorders	Arthralgia, myalgia	Fistulab,d, muscular weakness, back pain				Osteonecrosis of thejawa,b, nonmandibular osteonecrosisa,f
Renal and urinary disorders	Proteinuriab,d
Reproductive system and breast disorders	Ovarian failureb,c,d	Pelvic pain
Congenital, familial, and genetic disorder						Foetal abnormalitiesa,b
General disorders and administration site conditions	Asthenia, fatigue, pyrexia, pain, mucosal inflammation	Lethargy
Investigations	Weight decreased

When events were noted as both all grade and grade 3-5 adverse drug reactions in clinical trials, the highest frequency observed in patients has been reported. Data are unadjusted for the differential time on treatment.

^a For further information please refer to Table 3 'Adverse reactions reported in post-marketing setting.'

^b Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).

^c Based on a substudy from NSABP C-08 with 295 patients

^d For additional information refer below within section "Further information on selected serious adverse reactions."

^e Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.

^f Observed in paediatric population only

Table 2 Severe adverse reactions by frequency

System organ class	Very common	Common	Uncommon	Rare	Very rare	Frequency not known
Infections and infestations		Sepsis, cellulitis, abscessa,b, infection, urinary tract infection				Necrotising fasciitisc
Blood and lymphatic system disorders	Febrile neutropenia, leucopenia, neutropeniaa, thrombocytopenia	Anaemia, lymphopenia
Immune system disorders		Hypersensitivity, infusion reactionsa,b,c		Anaphylactic shock
Metabolism and nutrition disorders		Dehydration, hyponatraemia
Nervous system disorders	Peripheral sensory neuropathya	Cerebrovascular accident, syncope, somnolence, headache				Posterior reversible encephalopathy syndromea,b,c, hypertensive encephalopathyc
Cardiac disorders		Congestive heart failurea,b, supraventricular tachycardia
Vascular disorders	Hypertensiona,b	Thromboembolism arteriala,b, haemorrhagea,b, thromboembolism (venous)a,b, deep vein thrombosis				Renal thrombotic, microangiopathyb,c, aneurysms and artery dissections
Respiratory, thoracic and mediastinal disorders		Pulmonary haemorrhage/haemoptysisa,b, pulmonary embolism, epistaxis, dyspnoea, hypoxia				Pulmonary hypertensionc, nasal septum perforationc
Gastrointestinal disorders	Diarrhoea, nausea, vomiting, abdominal pain	Intestinal perforation, ileus, intestinal obstruction, recto-vaginal fistulaec,d, gastrointestinal disorder, stomatitis, proctalgia				Gastrointestinal perforationa,b, gastrointestinal ulcerc, rectal haemorrhage
Hepatobiliary disorders						Gallbladder perforationb,c
Skin and subcutaneous tissue disorders		Wound healing complicationsa,b, palmar-plantar erythrodysaesthesia syndrome
Musculoskeletal and connective tissue disorders		Fistulaa,b, myalgia, arthralgia, muscular weakness, back pain				Osteonecrosis of the jawb,c, non-mandibular osteonecrosisa,f
Renal and urinary disorders		Proteinuriaa,b
Reproductive system and breast disorders		Pelvic pain				Ovarian failurea,b
Congenital, familial, and genetic disorder						Foetal abnormalitiesa,c
General disorders and administration site conditions	Asthenia, fatigue	Pain, lethargy, mucosal inflammation

Table 2 provides 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 by the MAH to be clinically significant or severe. These clinically significant adverse reactions were reported in clinical trials but the grade 3-5 reactions did not meet the threshold of at least a 2% difference compared to the control arm. Table 2 also includes clinically significant adverse reactions that were observed only in the postmarketing setting, therefore, the frequency and NCI-CTCAE grade is not known. These clinically significant reactions have therefore been included in Table 2 within the column entitled “Frequency Not Known.”

^a Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).

^b For additional information refer below within section "Further information on selected serious adverse reactions"

^c For further information please refer to Table 3 'Adverse reactions reported in post-marketing setting.'

^d Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.

Description of selected serious adverse reactions
Gastrointestinal (GI) perforations and fistulae (see section 4.4)
Bevacizumab has been associated with serious cases of gastrointestinal perforation.

Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% in patients with non-squamous NSCLC, up to 1.3% in patients with metastatic breast cancer, up to 2.0% in patients with mRCC or in patients with ovarian cancer, and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG- 0240), GI perforations (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.

Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which represents between 0.2%-1% of all bevacizumab treated patients.

In bevacizumab 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.

GI-vaginal fistulae in study GOG-0240
In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal fistulae was 8.3% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with bevacizumab + chemotherapy was higher in patients with recurrence within the field of prior radiation (16.7%) compared with patients with no prior radiation and/ or no recurrence inside the field of prior radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies.

Non-GI fistulae (see section 4.4)
Bevacizumab use has been associated with serious cases of fistulae including reactions resulting in death.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-0240), 1.8% of bevacizumab-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 (e.g. bronchopleural and biliary fistulae) were observed across various indications. Fistulae have also been reported in post-marketing experience.

Reactions were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of bevacizumab, with most reactions occurring within the first 6 months of therapy.

Wound healing (see section 4.4)
As bevacizumab may adversely impact wound healing, patients who had major surgery within the last 28 days were excluded from participation in phase III clinical trials.

In clinical trials of metastatic carcinoma of the colon or rectum, there was no increased risk of post-operative bleeding or wound healing complications observed in patients who underwent major surgery 28-60 days prior to starting bevacizumab. An increased incidence of post-operative bleeding or wound healing complication occurring within 60 days of major surgery was observed if the patient was being treated with bevacizumab at the time of surgery. The incidence varied between 10% (4/40) and 20% (3/15).

Serious wound healing complications, including anastomotic complications, have been reported, 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 bevacizumab compared with up to 0.9% of patients in the control arms (NCI-CTCAE v.3).

In clinical trials of ovarian cancer, Grade 3-5 wound healing complications were observed in up to 1.8% of patients in the bevacizumab arm versus 0.1% in the control arm (NCI-CTCAE v.3).

Hypertension (see section 4.4)
In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (all grades) ranged up to 42.1% in the bevacizumab containing arms compared with up to 14% in the control arms. The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with bevacizumab and chemotherapy compared to up to 0.2% of patients treated with the same chemotherapy alone.

In study JO25567, all grade hypertension was observed in 77.3% of the patients who received bevacizumab in combination with erlotinib as first-line treatment for non-squamous NSCLC with EGFR activating mutations, compared to 14.3% of patients treated with erlotinib alone. Grade 3 hypertension was 60.0% in patients treated with bevacizumab in combination with erlotinib compared to 11.7% in patients treated with erlotinib alone. There were no grade 4 or 5 hypertension events.

Hypertension was generally adequately controlled with oral anti-hypertensives such as angiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation of bevacizumab treatment or hospitalisation.

Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal.

The risk of bevacizumab-associated hypertension did not correlate with the patients’ baseline characteristics, underlying disease or concomitant therapy.

Posterior reversible encephalopathy syndrome (see section 4.4)
There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are consistent with PRES, a rare neurological disorder. Presentation may include seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension.

The clinical presentation of PRES is often nonspecific, and therefore the diagnosis of PRES requires confirmation by brain imaging, preferably MRI. In patients developing PRES, early recognition of symptoms with prompt treatment of specific symptoms including control of hypertension (if associated with severe uncontrolled hypertension) is recommended in addition to discontinuation of bevacizumab therapy. Symptoms usually resolve or improve within days after treatment discontinuation, although some patients have experienced some neurologic sequelae. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known.

Across clinical trials, 8 cases of PRES have been reported. Two of the eight cases did not have radiological confirmation via MRI.

Proteinuria (see section 4.4)
In clinical trials, proteinuria has been reported within the range of 0.7% to 54.7% of patients receiving bevacizumab.

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was reported in up to 10.9% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of Vegzelma therapy.

In most clinical trials urine protein levels of ≥ 2g/24 hrs led to the holding of bevacizumab until recovery to < 2g/24 hrs.

Haemorrhage (see section 4.4)
In clinical trials across all indications the overall incidence of NCI-CTCAE v.3 Grade 3-5 bleeding reactions ranged from 0.4% to 6.9% in bevacizumab treated patients, compared with up to 4.5% of patients in the chemotherapy control group.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 bleeding reactions have been reported in up to 8.3% of patients treated with bevacizumab in combination with paclitaxel and topotecan compared with up to 4.6% of patients treated with paclitaxel and topotecan.

The haemorrhagic reactions that have been observed in clinical trials were predominantly tumour-associated haemorrhage (see below) and minor mucocutaneous haemorrhage (e.g. epistaxis).

Tumour-associated haemorrhage (see section 4.4)
Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in trials in patients with NSCLC. Possible risk factors include squamous cell histology, treatment with antirheumatic/anti-inflammatory substances, treatment with anticoagulants, prior radiotherapy, bevacizumab 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 bevacizumab 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 phase III trials, while patients with unknown tumour histology were included.

In patients with NSCLC excluding predominant squamous histology, all Grade reactions were seen with a frequency of up to 9.3% when treated with bevacizumab plus chemotherapy compared with up to 5% in the patients treated with chemotherapy alone. Grade 3-5 reactions have been observed in up to 2.3% of patients treated with bevacizumab plus chemotherapy as compared with < 1% with chemotherapy alone (NCI-CTCAE v.3). 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 cancer patients, and have been assessed as tumour-associated haemorrhages.

Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, including cases of central nervous system (CNS) bleeding in patients with CNS metastases (see section 4.4).

The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab has not been prospectively evaluated in randomised clinical trials. 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 bevacizumab, compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to bevacizumab. In two subsequent studies in patients with treated brain metastases (which included around 800 patients), one case of Grade 2 CNS haemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at the time of interim safety analysis (NCI-CTCAE v.3).

Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% of bevacizumab-treated patients. These were most commonly NCI-CTCAE v.3 Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any changes in the bevacizumab treatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneous haemorrhage (e.g. epistaxis) may be dose-dependent.

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

 

Thromboembolism (see section 4.4)

• Arterial thromboembolism: An increased incidence of arterial thromboembolic reactions was observed in patients treated with bevacizumab across indications, including cerebrovascular accidents, myocardial infarction, transient ischaemic attacks, and other arterial thromboembolic reactions.
  
  In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the bevacizumab containing arms compared with up to 2.1% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving bevacizumab compared to 0.5% in patients receiving chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) were reported in up to 2.7% of patients treated with bevacizumab in combination with chemotherapy compared to up to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was reported in up to 1.4% of patients treated with bevacizumab in combination with chemotherapy compared to up to 0.7% of patients treated with chemotherapy alone.
  
  In one clinical trial evaluating bevacizumab 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 trial arterial thromboembolic reactions were observed in 11% (11/100) of patients compared to 5.8% (6/104) in the chemotherapy control group.
   
• Venous thromboembolism: The incidence of venous thromboembolic reactions in clinical trials was similar in patients receiving bevacizumab in combination with chemotherapy compared to those receiving the control chemotherapy alone. Venous thromboembolic reactions include deep venous thrombosis, pulmonary embolism and thrombophlebitis.
  
  In clinical trials across indications, the overall incidence of venous thromboembolic reactions ranged from 2.8% to 17.3% of bevacizumab-treated patients compared with 3.2% to 15.6% in the control arms.
  
  Grade 3-5 (NCI-CTCAE v.3) venous thromboembolic reactions have been reported in up to 7.8% of patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treated with chemotherapy alone (across indications, excluding persistent, recurrent, or metastatic cervical cancer).
  
  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 15.6% of patients treated with bevacizumab in combination with paclitaxel and cisplatin compared with up to 7.0% of patients treated with paclitaxel and cisplatin.
  
  Patients who have experienced a venous thromboembolic reaction may be at higher risk for a recurrence if they receive bevacizumab in combination with chemotherapy versus chemotherapy alone.

Congestive heart failure (CHF)
In clinical trials with bevacizumab, CHF was observed in all cancer indications studied to date, but occurred predominantly in patients with metastatic breast cancer. In four phase III trials (AVF2119g, E2100, BO17708 and AVF3694g) in patients with metastatic breast cancer CHF Grade 3 (NCI-CTCAE v.3) or higher was reported in up to 3.5% of patients treated with bevacizumab in combination with chemotherapy compared with up to 0.9% in the control arms. For patients in study AVF3694g who received anthracyclines concomitantly with bevacizumab, the incidences of Grade 3 or higher CHF for the respective bevacizumab and control arms were similar to those in the other studies in metastatic breast cancer: 2.9% in the anthracycline + bevacizumab arm and 0% in the anthracycline + placebo arm. In addition, in study AVF3694g the incidences of all Grade CHF were similar between the anthracycline + bevacizumab (6.2%) and the anthracycline + placebo arms (6.0%).

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 bevacizumab, patients with pre-existing CHF of NYHA (New York Heart Association) 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 bevacizumab with a cumulative doxorubicin dose greater than 300 mg/m². This phase III clinical trial compared rituximab/cyclophosphamide/doxorubicin/ vincristine/prednisone (R-CHOP) plus bevacizumab to R-CHOP without bevacizumab. While the incidence of CHF was, in both arms, above that previously observed for doxorubicin therapy, the rate was higher in the R-CHOP plus bevacizumab arm. These results suggest that close clinical observation with appropriate cardiac assessments should be considered for patients exposed to cumulative doxorubicin doses greater than 300 mg/m² when combined with bevacizumab.

Hypersensitivity reactions (including anaphylactic shock)/infusion reactions (see section 4.4 and Post-marketing experience below)
In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently in patients receiving bevacizumab in combination with chemotherapy than with chemotherapy alone. The incidence of these reactions in some clinical trials of bevacizumab is common (up to 5% in bevacizumab-treated patients).

Infections
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 infections have been reported in up to 24% of patients treated with bevacizumab in combination with paclitaxel and topotecan compared with up to 13% of patients treated with paclitaxel and topotecan.

Ovarian failure/fertility (see sections 4.4 and 4.6)
In NSABP C-08, a phase III trial of bevacizumab in adjuvant treatment of patients with colon cancer, 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 in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% patients in the mFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluable women. Long term effects of the treatment with bevacizumab on fertility are unknown.

 Laboratory abnormalities
Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be associated with Vegzelma treatment.

Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities occurred in patients treated with bevacizumab with at least a 2% difference compared to the corresponding control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, increased international normalised ratio (INR).

Clinical trials have shown that transient increases in serum creatinine (ranging between 1.5-1.9 times baseline level), both with and without proteinuria, are associated with the use of bevacizumab. The observed increase in serum creatinine was not associated with a higher incidence of clinical manifestations of renal impairment in patients treated with bevacizumab.

Other special populations
Elderly patients
In randomised clinical trials, age > 65 years was associated with an increased risk of developing arterial thromboembolic reactions, including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions. Other reactions with a higher frequency seen in patients over 65 were Grade 3-4 leucopenia and thrombocytopenia (NCI-CTCAE v.3); and all Grade neutropenia, diarrhoea, nausea, headache and fatigue as compared to those aged ≤ 65 years when treated with bevacizumab (see sections 4.4 and 4.8 under Thromboembolism). In one clinical trial, the incidence of hypertension of grade ≥ 3 was two fold higher in patients aged > 65 years than in the younger age group (<65 years). In a study of platinum-resistant recurrent ovarian cancer patients, alopecia, mucosal inflammation, peripheral sensory neuropathy, proteinuria and hypertension were also reported and occurred at a rate at least 5% higher in the CT + BV arm for bevacizumab-treated patients ≥ 65 years of age compared with bevacizumab-treated patients aged < 65 years.

No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing complications, CHF, and haemorrhage was observed in elderly patients (> 65 years) receiving bevacizumab as compared to those aged ≤ 65 years treated with bevacizumab.

Paediatric population
The safety and efficacy of bevacizumab in children less than 18 years old have not been established.

In study BO25041 of bevacizumab added to postoperative radiation therapy (RT) with concomitant and adjuvant temozolomide in paediatric patients with newly diagnosed supratentorial, infratentorial, cerebellar, or peduncular high-grade glioma, the safety profile was comparable with that observed in other tumour types in adults treated with bevacizumab.

In study BO20924 of bevacizumab with current standard of care in rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma, the safety profile of bevacizumab treated children was comparable with that observed in adults treated with bevacizumab.

Vegzelma is not approved for use in patients under the age of 18 years. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years treated with bevacizumab.

Post-marketing experience
Table 3 Adverse reactions reported in post-marketing setting

System organ class (SOC)	Reactions (frequency*)
Infections and infestations	Necrotising fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation (rare) (see also section 4.4)
Immune system disorders	Hypersensitivity reactions and infusion reactions (common); with the following possible co-manifestations: dyspnoea/difficulty breathing, flushing/redness/rash, hypotension or hypertension, oxygen desaturation, chest pain, rigors and nausea/vomiting (see also section 4.4 and Hypersensitivity reactions/infusion reactions above) Anaphylactic shock (rare) (see also section 4.4)
Nervous system disorders	Hypertensive encephalopathy (very rare) (see also section 4.4 and Hypertension in section 4.8) ----------------------------------------------------------------------------------------------------------------------------------------------------------- Posterior reversible encephalopathy syndrome (PRES), (rare) (see also section 4.4)
Vascular disorders	Renal thrombotic microangiopathy, which may be clinically manifested as proteinuria (not known) with or without concomitant sunitinib use. For further information on proteinuria see section 4.4 and Proteinuria in section 4.8.
Respiratory, thoracic and mediastinal disorders	Nasal septum perforation (not known), pulmonary hypertension (not known), dysphonia (common)
Gastrointestinal disorders	Gastrointestinal ulcer (not known)
Hepatobiliary disorders	Gall bladder perforation (not known)
Musculoskeletal and connective tissue disorders	Cases of osteonecrosis of the jaw (ONJ) have been reported in patients treated with bevacizumab, most of which occurred in patients who had identified risk factors for ONJ, in particular exposure to intravenous bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also section 4.4)
	Cases of non-mandibular osteonecrosis have been observed in bevacizumab treated paediatric patients (see section 4.8, Paediatric population).
Congenital, familial, and genetic disorder	Cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see section 4.6)

* If specified, the frequency has been derived from clinical trial data

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

• Saudi Arabia

The National Pharmacovigilance Centre (NPC)
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa

•  Other GCC States

Please contact the relevant competent authority.

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

Bevacizumab is a vascular endothelial growth factor inhibitor. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that contains human framework regions and murine complementarity-determining regions. Bevacizumab has an approximate molecular weight of 149 kDa. Bevacizumab is produced in a mammalian cell (Chinese Hamster Ovary) expression system.

Mechanism of action
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

Clinical studies
Metastatic Colorectal Cancer
Study AVF2107g
The safety and efficacy of bevacizumab was evaluated in a double-blind, active-controlled study [AVF2107g (NCT00109070)] in 923 patients with previously untreated mCRC who were randomized (1:1:1) to placebo with bolus-IFL (irinotecan 125 mg/m², fluorouracil 500 mg/m², and leucovorin 20 mg/m² given once weekly for 4 weeks every 6 weeks), bevacizumab (5 mg/kg every 2 weeks) with bolus-IFL, or bevacizumab (5 mg/kg every 2 weeks) with fluorouracil and leucovorin. Enrollment to the bevacizumab with fluorouracil and leucovorin arm was discontinued after enrollment of 110 patients in accordance with the protocol-specified adaptive design. Bevacizumab was continued until disease progression or unacceptable toxicity or for a maximum of 96 weeks. The main outcome measure was overall survival (OS).

The median age was 60 years; 60% were male, 79% were White, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prior adjuvant chemotherapy. The dominant site of disease was extra-abdominal in 56% of patients and was the liver in 38% of patients.

The addition of bevacizumab improved survival across subgroups defined by age (< 65 years, ≥ 65 years) and sex. Results are presented in Table 4 and Figure 1.

Table 4: Efficacy results in study AVF2107g

Efficacy Parameter	Bevacizumab with bolus-IFL (N=402)	Placebo with bolus-IFL (N=411)
Overall Survival
Median, in months	20.3	15.6
Hazard ratio (95% CI)	0.66 (0.54, 0.81)
p-valuea	< 0.001
Progression-Free survival
Median, in months	10.6	6.2
Hazard ratio (95% CI)	0.54 (0.45, 0.66)
p-valuea	< 0.001
Overall response rate
Rate (%)	45%	35%
p-valueb	< 0.01
Duration of response
Median, in months	10.4	7.1

^a by stratified log-rank test.

^b by χ² test

Figure 1: Kaplan-Meier Curves for Duration of Survival in Metastatic Colorectal Cancer in Study

AVF2107g

Among the 110 patients randomized to bevacizumab with fluorouracil and leucovorin, median OS was 18.3 months, median progression-free survival (PFS) was 8.8 months, overall response rate (ORR) was 39%, and median duration of response was 8.5 months.

Study E3200
The safety and efficacy of bevacizumab were evaluated in a randomized, open-label, active-controlled study [E3200 (NCT00025337)] in 829 patients who were previously treated with irinotecan and fluorouracil for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized (1:1:1) to FOLFOX4 (Day 1: oxaliplatin 85 mg/m² and leucovorin 200 mg/m² concurrently, then fluorouracil 400 mg/m² bolus followed by 600 mg/m² continuously; Day 2: leucovorin 200 mg/m², then fluorouracil 400 mg/m² bolus followed by 600 mg/m² continuously; every 2 weeks), bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) with FOLFOX4, or bevacizumab alone (10 mg/kg every 2 weeks). Bevacizumab was continued until disease progression or unacceptable toxicity. The main outcome measure was OS.

The bevacizumab alone arm was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee based on evidence of decreased survival compared to FOLFOX4 alone.

The median age was 61 years; 60% were male, 87% were White, 49% had an ECOG performance status of 0, 26% received prior radiation therapy, and 80% received prior adjuvant chemotherapy, 99% received prior irinotecan with or without fluorouracil for metastatic disease, and 1% received prior irinotecan and fluorouracil as adjuvant therapy.

The addition of bevacizumab to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone; median OS was 13.0 months vs. 10.8 months [hazard ratio (HR) 0.75 (95% CI: 0.63, 0.89), p-value of 0.001 stratified log-rank test] with clinical benefit seen in subgroups defined by age (< 65 years, ≥ 65 years) and sex. PFS and ORR based on investigator assessment were higher in patients receiving bevacizumab with FOLFOX4.

Study TRC-0301
The activity of bevacizumab with fluorouracil (as bolus or infusion) and leucovorin was evaluated in a single arm study [TRC-0301 (NCT00066846)] enrolling 339 patients with mCRC with disease progression following both irinotecan- and oxaliplatin-based chemotherapy. Seventy-three percent of patients received concurrent bolus fluorouracil and leucovorin. One objective partial response was verified in the first 100 evaluable patients for an ORR of 1% (95% CI: 0%, 5.5%).

Study ML18147
The safety and efficacy of bevacizumab were evaluated in a prospective, randomized, open-label, multinational, controlled study [ML18147 (NCT00700102)] in 820 patients with histologically confirmed mCRC who had progressed on a first-line bevacizumab containing regimen. Patients were excluded if they progressed within 3 months of initiating first-line chemotherapy and if they received bevacizumab for less than 3 consecutive months in the first-line setting. Patients were randomized (1:1) within 3 months after discontinuing bevacizumab as first-line treatment to receive fluoropyrimidine-irinotecan-or fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks). The choice of second-line treatment was contingent upon first-line chemotherapy. Second-line treatment was administered until progressive disease or unacceptable toxicity. The main outcome measure was OS. A secondary outcome measure was ORR.

The median age was 63 years (21 to 84 years); 64% were male, 52% had an ECOG performance status of 1, 44% had an ECOG performance status of 0, 58% received irinotecan-based therapy as first-line treatment, 55% progressed on first-line treatment within 9 months, and 77% received their last dose of bevacizumab as first-line treatment within 42 days of being randomized. Second-line chemotherapy regimens were generally balanced between each arm.

The addition of bevacizumab to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of OS and PFS. There was no significant difference in ORR. Results are presented in Table 5 and Figure 2.

Table 5: Efficacy Results in Study ML18147

Efficacy Parameter	Bevacizumab with Chemotherapy (N=409)	Chemotherapy (N=411)
Overall Survivala
Median, in months	11.2	9.8
Hazard ratio (95% CI)	0.81 (0.69, 0.94)
Progression-Free Survivalb
Median, in months	5.7	4.0
Hazard ratio (95% CI)	0.68 (0.59, 0.78)

^a p=0.0057 by unstratified log-rank test.

^b p-value < 0.0001 by unstratified log-rank test.

Figure 2: Kaplan-Meier Curves for Duration of Survival in Metastatic Colorectal Cancer in Study ML18147

Lack of Efficacy in Adjuvant Treatment of Colon Cancer
Lack of efficacy of bevacizumab as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical studies.

The first study [BO17920 (NCT00112918)] was conducted in 3451 patients with high-risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent. Patients were randomized to receive bevacizumab at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule with FOLFOX4 (N=1155) or on a 3-weekly schedule with XELOX (N=1145) or FOLFOX4 alone (N=1151). The main outcome measure was disease free survival (DFS) in patients with stage III colon cancer.

The median age was 58 years; 54% were male, 84% were White and 29% were ≥ 65 years. Eighty-three percent had stage III disease.

The addition of bevacizumab to chemotherapy did not improve DFS. As compared to FOLFOX4 alone, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher for patients receiving bevacizumab with FOLFOX4 or with XELOX. The hazard ratios for DFS were 1.17 (95% CI: 0.98,1.39) for bevacizumab with FOLFOX4 versus FOLFOX4 alone and 1.07 (95% CI: 0.90, 1.28) for bevacizumab with XELOX versus FOLFOX4 alone. The hazard ratios for OS were 1.31 (95% CI: 1.03, 1.67)and 1.27 (95% CI: 1, 1.62) for the comparison of bevacizumab with FOLFOX4 versus FOLFOX4 alone and bevacizumab with XELOX versus FOLFOX4 alone, respectively. Similar lack of efficacy for DFS was observed in the bevacizumab -containing arms compared to FOLFOX4 alone in the high-risk stage II cohort.

In a second study [NSABP-C-08 (NCT00096278)], patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either bevacizumab administered at a dose equivalent to 2.5 mg/kg/week with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% White. Seventy-five percent had stage III disease. The main outcome was DFS among stage III patients. The HR for DFS was 0.92 (95% CI: 0.77, 1.10). OS was not significantly improved with the addition of bevacizumab to mFOLFOX6 [HR 0.96 (95% CI: 0.75,1.22)].

First-Line Non–Squamous Non–Small Cell Lung Cancer
Study E4599 The safety and efficacy of bevacizumab as first-line treatment of patients with locally advanced, metastatic, or recurrent non–squamous NSCLC was studied in a single, large, randomized, active-controlled, open-label, multicenter study [E4599 (NCT00021060)]. A total of 878 chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel (200 mg/m²) and carboplatin (AUC6) with or without bevacizumab 15 mg/kg. After completing or discontinuing chemotherapy, patients randomized to receive bevacizumab continued to receive bevacizumab alone until disease progression or until unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors only), CNS metastasis, gross hemoptysis (1/2 teaspoon or more of red blood), unstable angina, or receiving therapeutic anticoagulation. The main outcome measure was duration of survival.

The median age was 63 years; 54% were male, 43% were ≥ 65 years, and 28% had ≥5% weight loss at study entry. Eleven percent had recurrent disease. Of the 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease.

OS was statistically significantly longer for patients receiving bevacizumab with paclitaxel and carboplatin compared with those receiving chemotherapy alone. Median OS was 12.3 months vs. 10.3 months [HR 0.80 (95% CI: 0.68, 0.94), final p-value of 0.013, stratified log-rank test]. Based on investigator assessment which was not independently verified, patients were reported to have longer PFS with bevacizumab with paclitaxel and carboplatin compared to chemotherapy alone. Results are presented in Figure 3.

Figure 3: Kaplan-Meier Curves for Duration of Survival in First-Line Non-Squamous Non-Small Cell Lung Cancer in Study E4599

 In an exploratory analysis across patient subgroups, the impact of bevacizumab on OS was less robust in the following subgroups: women [HR0.99 (95% CI: 0.79, 1.25)], patients ≥ 65 years [HR0.91 (95% CI: 0.72, 1.14)] and patients with ≥5% weight loss at study entry [HR0.96 (95% CI: 0.73, 1.26)].

Study BO17704
The safety and efficacy of bevacizumab in patients with locally advanced, metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy was studied in another randomized, double-blind, placebo-controlled study [BO17704 (NCT00806923)]. A total of 1043 patients were randomized (1:1:1) to receive cisplatin and gemcitabine with placebo, bevacizumab 7.5 mg/kg or bevacizumab 15 mg/kg. The main outcome measure was PFS. Secondary outcome measure was OS.

The median age was 58 years; 36% were female and 29% were ≥ 65 years. Eight percent had recurrent disease and 77% had Stage IV disease.

PFS was significantly higher in both bevacizumab -containing arms compared to the placebo arm [HR 0.75 (95% CI: 0.62, 0.91), p-value of0.0026 for bevacizumab 7.5 mg/kg and HR 0.82 (95% CI: 0.68; 0.98), p-value of0.0301 for bevacizumab 15 mg/kg]. The addition of bevacizumab to cisplatin and gemcitabine failed to demonstrate an improvement in the duration of OS [HR 0.93 (95% CI: 0.78; 1.11), p-value of0.420 for bevacizumab 7.5 mg/kg and HR 1.03 (95% CI:0.86, 1.23), p-value of 0.761 for bevacizumab 15 mg/kg].

Recurrent Glioblastoma
Study EORTC 26101
The safety and efficacy of bevacizumab were evaluated in a multicenter, randomized (2:1), open-label study in patients with recurrent GBM (EORTC 26101, NCT01290939). Patients with first progression following radiotherapy and temozolomide were randomized (2:1) to receive bevacizumab (10 mg/kg every 2 weeks) with lomustine (90 mg/m² every 6 weeks) or lomustine (110 mg/m² every 6 weeks) alone until disease progression or unacceptable toxicity. Randomization was stratified by World Health Organization performance status (0 vs. >0), steroid use (yes vs. no), largest tumor diameter (≤ 40 vs. > 40 mm), and institution. The main outcome measure was OS. Secondary outcome measures were investigator-assessed PFS and ORR per the modified Response Assessment in Neuro-oncology (RANO) criteria, health related quality of life (HRQoL), cognitive function, and corticosteroid use.

A total of 432 patients were randomized to receive lomustine alone (N=149) or bevacizumab with lomustine (N=283). The median age was 57 years; 24.8% of patients were ≥ 65 years. The majority of patients with were male (61%); 66% had a WHO performance status score > 0; and in 56% the largest tumor diameter was ≤ 40 mm. Approximately 33% of patients randomized to receive lomustine received bevacizumab following documented progression.

No difference in OS (HR 0.91, p-value of 0.4578) was observed between arms; therefore, all secondary outcome measures are descriptive only. PFS was longer in the bevacizumab with lomustine arm [HR 0.52 (95% CI: 0.41, 0.64)] with a median PFS of 4.2 months in the bevacizumab with lomustine arm and 1.5 months in the lomustine arm. Among the 50% of patients receiving corticosteroids at the time of randomization, a higher percentage of patients in the bevacizumab with lomustine arm discontinued corticosteroids (23% vs. 12%).

Study AVF3708g and Study NCI 06-C-0064E
The efficacy and safety of bevacizumab 10 mg/kg every 2 weeks in patients with previously treated GBM were evaluated in one single arm single center study (NCI 06-C-0064E) and a randomized noncomparative multicenter study [AVF3708g (NCT00345163)]. Response rates in both studies were evaluated based on modified WHO criteria that considered corticosteroid use. In AVF3708g, the response rate was 25.9% (95% CI: 17%, 36.1%) with a median duration of response of 4.2 months (95% CI: 3, 5.7). In Study NCI 06-C-0064E, the response rate was 19.6% (95% CI: 10.9%, 31.3%) with a median duration of response of 3.9 months (95% CI: 2.4, 17.4).

Metastatic Renal Cell Carcinoma
Study BO17705
The safety and efficacy of bevacizumab were evaluated in patients with treatment-naïve mRCC in a multicenter, randomized, double-blind, international study [BO17705 (NCT00738530)] comparing interferon alfa and bevacizumab versus interferon alfa and placebo. A total of 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either bevacizumab (10 mg/kg every 2 weeks; N = 327) or placebo (every 2 weeks; N = 322) with interferon alfa (9 MIU subcutaneously three times weekly for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 60 years (18 to 82 years); 70% were male and 96% were White. The study population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate (1-2), 8% poor (3−5), and 7% missing.

PFS was statistically significantly prolonged among patients receiving bevacizumab compared to placebo; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95% CI: 0.49, 0.72), p-value < 0.0001, stratified log-rank test]. Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 12%, p-value < 0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the patients receiving bevacizumab with interferon alfa and 21 months in patients receiving interferon alone [HR 0.86, (95% CI: 0.72, 1.04)]. Results are presented in Figure 4.

Figure 4: Kaplan-Meier Curves for Progression-Free Survival in Metastatic Renal Cell Carcinoma in Study BO17705

Persistent, Recurrent, or Metastatic Cervical Cancer
Study GOG-0240
The safety and efficacy of bevacizumab were evaluated in patients with persistent, recurrent, or metastatic cervical cancer in a randomized, four-arm, multicenter study comparing bevacizumab with chemotherapy versus chemotherapy alone [GOG-0240 (NCT00803062)]. A total of 452 patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without bevacizumab, or paclitaxel and topotecan with or without bevacizumab.

The dosing regimens for bevacizumab, paclitaxel, cisplatin and topotecan were as follows:

• Day 1: Paclitaxel 135 mg/m² over 24 hours, Day 2: cisplatin 50 mg/m² with bevacizumab;
• Day 1: Paclitaxel 175 mg/m² over 3 hours, Day 2: cisplatin 50 mg/m² with bevacizumab;
• Day 1: Paclitaxel 175 mg/m² over 3 hours with cisplatin 50 mg/m² with bevacizumab;
• Day 1: Paclitaxel 175 mg/m² over 3 hours with bevacizumab, Days 1-3: topotecan IV 0.75 mg/m² over 30 minutes.

Patients were treated until disease progression or unacceptable adverse reactions. The main outcome measure was OS. Secondary outcome measures included ORR.

The median age was 48 years (20 to 85 years). Of the 452 patients randomized at baseline, 78% of patients were White, 80% had received prior radiation, 74% had received prior chemotherapy concurrent with radiation, and 32% had a platinum-free interval (PFI) of less than 6 months. Patients had a GOG performance status of 0 (58%) or 1 (42%). Demographic and disease characteristics were balanced across arms.

Results are presented in Figure 5 and Table 6.

Figure 5: Kaplan-Meier Curves for Overall Survival in Persistent, Recurrent, or Metastatic Cervical Cancer in Study GOG-0240

 Table 6: Efficacy results in Study GOG-0240

Efficacy Parameter	Bevacizumab with Chemotherapy (N=227)	Chemotherapy (N=225)
Overall Survival
Median, in monthsa	16.8	12.9
Hazard ratio (95% CI)	0.74 (0.58, 0.94)
p-valueb	0.0132

a Kaplan-Meier estimates.

b log-rank test (stratified).

The ORR was higher in patients who received bevacizumab with chemotherapy [45% (95% CI: 39, 52)] compared to patients who received chemotherapy alone [34% (95% CI: 28,40)].

Table 7: Efficacy Results in Study GOG-0240

Efficacy Parameter	Topotecan and Paclitaxel with or without bevacizumab (N=223)	Cisplatin and Paclitaxel with or without bevacizumab (N=229)
Overall Survival
Median, in monthsa	13.3	15.5
Hazard ratio (95% CI)	1.15 (0.91, 1.46)
p-value	0.23

a Kaplan-Meier estimates.

The HR for OS with bevacizumab with cisplatin and paclitaxel as compared to cisplatin and paclitaxel alone was 0.72 (95% CI: 0.51,1.02). The HR for OS with bevacizumab with topotecan and paclitaxel as compared to topotecan and paclitaxel alone was 0.76 (95% CI: 0.55, 1.06).

Stage III or IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Following Initial Surgical Resection
Study GOG-0218
The safety and efficacy of bevacizumab were evaluated in a multicenter, randomized, double-blind, placebo controlled, three arm study [Study GOG-0218 (NCT00262847)] evaluating the effect of adding bevacizumab to carboplatin and paclitaxel for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer (N=1873) following initial surgical resection. Patients were randomized (1:1:1) to one of the following arms:

 

• CPP: carboplatin (AUC 6) and paclitaxel (175 mg/m²) for six cycles, with concurrent placebo started at cycle 2, followed by placebo alone every three weeks for a total of up to 22 cycles of therapy (n=625) or
• CPB15: carboplatin (AUC 6) and paclitaxel (175 mg/m²) for six cycles, with concurrent bevacizumab started at cycle 2, followed by placebo alone every three weeks for a total of up to 22 cycles of therapy (n=625) or
• CPB15+: carboplatin (AUC 6) and paclitaxel (175 mg/m²) for six cycles, with concurrent bevacizumab started at cycle 2, followed by bevacizumab as a single agent every three weeks for a total of up to 22 cycles of therapy (n=623).

The main outcome measure was investigator-assessed PFS. OS was a secondary outcome measure.

The median age was 60 years (range 22-89 years) and 28% of patients were >65 years of age. Overall, approximately 50% of patients had a GOG PS of 0 at baseline, and 43% a GOG PS score of 1. Patients had either epithelial ovarian cancer (83%), primary peritoneal cancer (15%), or fallopian tube cancer (2%).

Serous adenocarcinoma was the most common histologic type (85% in CPP and CPB15 arms, 86% in CPB15+ arm). Overall, approximately 34% of patients had resected FIGO Stage III with residual disease < 1 cm, 40% had resected Stage III with residual disease >1 cm, and 26% had resected Stage IV disease.

The majority of patients in all three treatment arms received subsequent antineoplastic treatment, 78.1% in the CPP arm, 78.6% in the CPB15 arm, and 73.2% in the CPB15+ arm. A higher proportion of patients in the CPP arm (25.3%) and CPB15 arm (26.6%) received at least one anti-angiogenic (including bevacizumab) treatment after discontinuing from study compared with the CPB15+ arm (15.6%).

Study results are presented in Table 8 and Figure 6.

Table 8: Efficacy results in Study GOG-0218

Efficacy Parameter	Bevacizumab with carboplatin and paclitaxel followed by bevacizumab alone (N=623)	Bevacizumab with carboplatin and paclitaxel (N=625)	Carboplatin and paclitaxel (N= 625)
Progression-Free Survival per Investigator
Median, in months	18.2	12.8	12.0
Hazard ratio (95% CI)a	0.62 (0.52, 0.75)	0.83 (0.70, 0.98)
p –valueb	< 0.0001	NS
Overall Survivalc
Median, in months	43.8	38.8	40.6
Hazard ratio (95% CI)a	0.89 (0.76, 1.05)	1.06 (0.90, 1.24)

NS=not significant

^a Relative to the control arm; stratified hazard ratio

^b Two-sided p-value based on re-randomization test

^c Final overall survival analysis

Figure 6: Kaplan-Meier Curves for Investigator-Assessed Progression-Free Survival in Stage III or IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Following Initial Surgical Resection in Study GOG-0218

 Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Study MO22224
The safety and efficacy of bevacizumab were evaluated in a multicenter, open-label, randomized study [MO22224 (NCT00976911)] comparing bevacizumab with chemotherapy versus chemotherapy alone in patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within <6 months from the most recent platinum-based therapy (N=361). Patients had received no more than 2 prior chemotherapy regimens. Patients received one of the following chemotherapy regimens at the discretion of the investigator: paclitaxel (80 mg/m² on days 1, 8, 15 and 22 every 4 weeks; pegylated liposomal doxorubicin 40 mg/m² on day 1 every 4 weeks; or topotecan 4 mg/m² on days 1, 8 and 15 every 4 weeks or 1.25 mg/m² on days 1-5 every 3 weeks). Patients were treated until disease progression, unacceptable toxicity, or withdrawal. Forty percent of patients on the chemotherapy alone arm received bevacizumab alone upon progression. The main outcome measure was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 61 years (25 to 84 years) and 37% of patients were ≥65 years. Seventy-nine percent had measurable disease at baseline, 87% had baseline CA-125 levels ≥2 times ULN and 31% had ascites at baseline. Seventy-three percent had a PFI of 3 months to 6 months and 27% had PFI of <3 months. ECOG performance status was 0 for 59%, 1 for 34% and 2 for 7% of the patients.

The addition of bevacizumab to chemotherapy demonstrated a statistically significant improvement in investigator-assessed PFS, which was supported by a retrospective independent review analysis. Results for the ITT population are presented in Table 9 and Figure 7. Results for the separate chemotherapy cohorts are presented in Table 10.

Table 9: Efficacy results in Study MO22224

Efficacy Parameter	Bevacizumab with Chemotherapy (N=179)	Chemotherapy (N=182)
Progression-Free Survival per Investigator
Median (95% CI), in months	6.8 (5.6, 7.8)	3.4 (2.1, 3.8)
HR (95% CI)a	0.38 (0.30, 0.49)
p-value b	<0.0001
Overall Survival
Median (95% CI), in months	16.6 (13.7, 19.0)	13.3 (11.9, 16.4)
HR (95% CI)a	0.89 (0.69, 1.14)
Overall Response Rate
Number of Patients with Measurable Disease at Baseline	142	144
Rate, % (95% CI)	28% (21%, 36%)	13% (7%, 18%)
Duration of Response
Median, in months	9.4	5.4

^a per stratified Cox proportional hazards model

b per stratified log-rank test

Figure 7: Kaplan-Meier Curves for Investigator-Assessed Progression-Free Survival in Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study MO22224

 Table 10: Efficacy Results in Study MO22224 by Chemotherapy

Efficacy Parameter	Paclitaxel		Topotecan		Pegylated Liposomal Doxorubicin
	Bevacizumab with Chemotherapy (N=60)	Chemotherapy   (N=55)	Bevacizumab with Chemotherapy (N=57)	Chemotherapy   (N=63)	Bevacizumab with Chemotherapy (N=62)	Chemotherapy   (N=64)
Progression-Free Survival per Investigator
Median, in months (95% CI)	9.6 (7.8, 11.5)	3.9 (3.5, 5.5)	6.2 (5.3, 7.6)	2.1 (1.9, 2.3)	5.1 (3.9, 6.3)	3.5 (1.9, 3.9)
Hazard ratioa (95% CI)	0.47 (0.31, 0.72)		0.24 (0.15, 0.38)		0.47 (0.32, 0.71)
Overall Survival
Median, in months (95% CI)	22.4 (16.7, 26.7)	13.2 (8.2, 19.7)	13.8 (11.0, 18.3)	13.3 (10.4, 18.3)	13.7 (11.0, 18.3)	14.1 (9.9, 17.8)
Hazard ratio a (95% CI)	0.64 (0.41, 1.01)		1.12 (0.73, 1.73)		0.94 (0.63, 1.42)
Overall Response Rate
Number of patients with measurable disease at baseline	45	43	46	50	51	51
Rate, % (95% CI)	53 (39, 68)	30 (17, 44)	17 (6, 28)	2 (0, 6)	16 (6, 26)	8 (0, 15)
Duration of Response
Median, in months	11.6	6.8	5.2	NE	8.0	4.6

^a  per stratified Cox proportional hazards model

NE=Not Estimable

Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Study AVF4095g
The safety and efficacy of bevacizumab were evaluated in a randomized, double-blind, placebo-controlled study [AVF4095g (NCT00434642)] studying bevacizumab with chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment (N=484). Patients were randomized (1:1) to receive bevacizumab (15 mg/kg day 1) or placebo every 3 weeks with carboplatin (AUC 4, day 1) and gemcitabine (1000 mg/m² on days 1 and 8) a for 6 to 10 cycles followed by bevacizumab or placebo alone until disease progression or unacceptable toxicity. The main outcome measures were investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 61 years (28 to 87 years) and 37% of patients were ≥65 years. All patients had measurable disease at baseline, 74% had baseline CA-125 levels >ULN (35 U/ml). The platinum-free interval (PFI) was 6 months to 12 months in 42 % of patients and >12 months in 58% of patients. The ECOG performance status was 0 or 1 for 99.8% of patients.

 A statistically significant prolongation in PFS was demonstrated among patients receiving bevacizumab with chemotherapy compared to those receiving placebo with chemotherapy (Table 11 and Figure 8). Independent radiology review of PFS was consistent with investigator assessment [HR 0.45 (95% CI: 0.35, 0.58)]. OS was not significantly improved with the addition of bevacizumab to chemotherapy [HR 0.95 (95% CI: 0.77, 1.17)].

 Table 11: Efficacy results in study AVF4095g

Efficacy Parameter	Bevacizumab with Gemcitabine and Carboplatin (N=242)	Placebo with Gemcitabine and Carboplatin (N=242)
Progression-Free Survival
Median, in months	12.4	8.4
Hazard ratio (95% CI)	0.46 (0.37, 0.58)
p-value	< 0.0001
Overall Response Rate
% patients with overall response	78%	57%
p-value	< 0.0001

 Figure 8: Kaplan-Meier Curves for Progression-Free Survival in Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study AVF4095g

Study GOG-0213
The safety and efficacy of bevacizumab were evaluated in a randomized, controlled, open-label study [Study GOG­0213 (NCT00565851)] of bevacizumab with chemotherapy versus chemotherapy alone in the treatment of patientswith platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have notreceived more than one previous regimen of chemotherapy (N=673). Patients were randomized (1:1) to receive carboplatin (AUC 5) and paclitaxel (175 mg/m² IV over 3 hours) every 3 weeks for 6 to 8 cycles (N=336) or bevacizumab (15 mg/kg) every 3 weeks with carboplatin (AUC 5) and paclitaxel (175 mg/m² IV over 3 hours) for 6 to 8 cycles followed by bevacizumab (15 mg/kg every 3 weeks) as a single agent until disease progression orunacceptable toxicity. The main outcome measure was OS. Other outcome measures were investigator-assessed PFS, and ORR.

The median age was 60 years (23 to 85 years) and 33% of patients were ≥ 65 years. Eighty-three percent had measurable disease at baseline and 74% had abnormal CA-125 levels at baseline. Ten percent of patients had received prior bevacizumab. Twenty-six percent had a PFI of 6 months to 12 months and 74% had a PFI of >12 months. GOG performance status was 0 or 1 for 99% of patients.

Results are presented in Table 12 and Figure 9.

 Table 12: Efficacy Results in Study GOG-0213

Efficacy Parameter	Bevacizumab with Carboplatin and Paclitaxel (N=337)	Carboplatin and Paclitaxel (N=336)
Overall Survival
Median, in months	42.6	37.3
Hazard ratio (95% CI) (IVRS)a	0.84 (0.69, 1.01)
Hazard ratio (95% CI) (eCRF)b	0.82 (0.68, 0.996)
Progression-Free Survival
Median, in months	13.8	10.4
Hazard ratio (95% CI) (IVRS)a	0.61 (0.51, 0.72)
Overall Response Rate
Number of patients with measurable disease at baseline	274	286
Rate, %	213 (78%)	159 (56%)

^a HR was estimated from Cox proportional hazards models stratified by the duration of treatment free-interval prior to enrolling onto this study per IVRS (interactive voice response system) and secondary surgical debulking status.

^b HR was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status.

 Figure 9: Kaplan Meier Curves for Overall Survival in Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study GOG-0213

Hepatocellular Carcinoma
The efficacy of bevacizumab in combination with atezolizumab was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in patients with locally advanced unresectable and/or metastatic hepatocellular carcinoma who have not received prior systemic therapy. Randomization was stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), baseline AFP (<400 vs. ≥400 ng/ml), and by ECOG performance status (0 vs. 1).

A total of 501 patients were randomized (2:1) to receive either atezolizumab as an intravenous infusion of 1200 mg, followed by 15 mg/kg bevacizumab, on the same day every 3 weeks or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. Patients could discontinue either atezolizumab or bevacizumab (e.g., due to adverse events) and continue on single-agent therapy until disease progression or unacceptable toxicity associated with the single-agent.

The study enrolled patients who were ECOG performance score 0 or 1 and who had not received prior systemic treatment. Patients were required to be evaluated for the presence of varices within 6 months prior to treatment, and were excluded if they had variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding. Patients with Child-Pugh B or C cirrhosis, moderate or severe ascites; history of hepatic encephalopathy; a history of autoimmune disease; administration of a live, attenuated vaccine within 4 weeks prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization; or untreated or corticosteroid-dependent brain metastases were excluded. Tumor assessments were performed every 6 weeks for the first 54 weeks and every 9 weeks thereafter.

The demographics and baseline disease characteristics of the study population were balanced between the treatment arms. The median age was 65 years (range: 26 to 88) and 83% of patients were male. The majority of patients were Asian (57%) or White (35%); 40% were from Asia (excluding Japan). Approximately 75% of patients presented with macrovascular invasion and/or extrahepatic spread and 37% had a baseline AFP ≥400 ng/ml. Baseline ECOG performance status was 0 (62%) or 1 (38%). HCC risk factors were Hepatitis B in 48% of patients, Hepatitis C in 22% and 31% of patients had non-viral liver disease. The majority of patients had BCLC stage C (82%) disease at baseline, while 16% had stage B and 3% had stage A.

The major efficacy outcome measures were overall survival (OS) and independent review facility (IRF)-assessed progression free survival (PFS) per RECIST v1.1. Additional efficacy outcome measures were IRF-assessed overall response rate (ORR) per RECIST and mRECIST.

Efficacy results are presented in Table 13 and Figure 10.

 Table 13: Efficacy Results from IMbrave150

	Bevacizumab in combination with Atezolizumab (N= 336)	Sorafenib (N=165)
	Overall Survival
Number of deaths (%)	96 (29)	65 (39)
Median OS in months	NE	13.2
(95% CI)	(NE, NE)	(10.4, NE)
Hazard ratio1 (95% CI)	0.58 (0.42, 0.79)
p-value2	0.00062
	Progression-Free Survival3
Number of events(%)	197 (59)	109 (66)
Median PFS in months (95% CI)	6.8 (5.8, 8.3)	4.3 (4.0, 5.6)
Hazard ratio1 (95% CI)	0.59 (0.47, 0.76)
p-value	<0.0001
	Overall Response Rate3,5 (ORR), RECIST 1.1
Number of responders (%)	93 (28)	19 (12)
(95% CI)	(23, 33)	(7,17)
p-value4	<0.0001
Complete responses, n (%)	22 (7)	0
Partial responses, n (%)	71 (21)	19 (12)
	Duration of Response3,5 (DOR) RECIST 1.1
	(n=93)	(n=19)
Median DOR in months	NE	6.3
(95% CI)	(NE, NE)	(4.7, NE)
Range (months)	(1.3+, 13.4+)	(1.4+, 9.1+)
	Overall Response Rate3,5 (ORR), HCC mRECIST
Number of responders (%)	112 (33)	21 (13)
(95% CI)	(28, 39)	(8, 19)
p-value4	<0.0001
Complete responses, n (%)	37 (11)	3 (1.8)
Partial responses, n (%)	75 (22)	18 (11)
	Duration of Response3,5 (DOR) HCC mRECIST
	(n=112)	(n=21)
Median DOR in months (95% CI)	NE (NE, NE)	6.3 (4.9, NE)
Range (months)	(1.3+, 13.4+)	(1.4+, 9.1+)
1 Stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. ≥400 ng/ml) 2 Based on two-sided stratified log-rank test; as compared to significance level 0.004 (2-sided) based on 161/312=52% information using the OBF method 3 Per independent radiology review 4 Based on two-sided Cochran-Mantel-Haesnszel test 5 Confirmed responses + Denotes a censored value CI=confidence interval; HCC mRECIST= Modified RECIST Assessment for Hepatocellular Carcinoma; NE=not estimable; N/A=not applicable; RECIST 1.1= Response Evaluation Criteria in Solid Tumors v1.1

 Figure 10: Kaplan-Meier Plot of Overall Survival in IMbrave150

 

The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of bevacizumab every week, every 2 weeks, or every 3 weeks, bevacizumab pharmacokinetics are linear and the predicted time to reach more than 90% of steady state concentration is 84 days. The accumulation ratio following a dose of 10 mg/kg once every 2 weeks is 2.8.

Population simulations of bevacizumab exposures provide a median trough concentration of 80.3 mcg/ml on Day 84 (10^th, 90^th percentile: 45, 128) following a dose of 5 mg/kg once every two weeks.

Distribution
The mean (% coefficient of variation [CV%]) central volume of distribution is 2.9 (22%) L.

Elimination
The mean (CV%) clearance is 0.23 (33) L/day. The estimated half-life is 20 days (11 to 50 days).

Specific Populations
The clearance of bevacizumab varied by body weight, sex, and tumor burden. After correcting for body weight, males had a higher bevacizumab clearance (0.26 L/day vs. 0.21 L/day) and a larger central volume of distribution (3.2 L vs. 2.7 L) than females. Patients with higher tumor burden (at or above median value of tumor surface area) had a higher bevacizumab clearance (0.25 L/day vs. 0.20 L/day) than patients with tumor burdens below the median. In Study AVF2107g, there was no evidence of lesser efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated with bevacizumab as compared to females and patients with low tumor burden.

Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been conducted to assess potential of bevacizumab for carcinogenicity or mutagenicity.

Bevacizumab may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrested follicular development or absent corpora lutea, as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4-or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident.

Animal Toxicology and/or Pharmacology
Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.

• Di-Sodium hydrogen phosphate anhydrous
• Sodium dihydrogen phosphate monohydrate
• Trehalose dihydrate
• Polysorbate 20
• Water for injection

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

A concentration dependent degradation profile of bevacizumab was observed when diluted with glucose solutions (5%).

Unopened vial 36 months. Diluted medicinal product Chemical and physical in-use stability has been demonstrated for a period of up to 60 days at 2 to 8°C after dilution and a period of up to 7 days at temperatures not exceeding 30°C in sodium chloride 9 mg/ml (0.9%) solution for injection. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2-8°C).

Avoid freeze.

Protect from light.

Store in the original package.

Type I glass vials with chlorobutyl rubber stoppers.

Pack size: 1 Single-Dose Vial (4 ml).

Vegzelma should be prepared by a healthcare professional using aseptic technique to ensure the sterility of the prepared solution. A sterile needle and syringe should be used to prepare Vegzelma.

The necessary amount of bevacizumab should be withdrawn and diluted to the required administration volume with sodium chloride 9 mg/ml (0.9%) solution for injection. The concentration of the final bevacizumab solution should be kept within the range of 1.4 mg/ml to 16.5 mg/ml. In the majority of the occasions the necessary amount of Vegzelma can be diluted with 0.9 % sodium chloride solution for injection to a total volume of 100 ml.

Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration.

No incompatibilities between Vegzelma and polyolefine bags or infusion sets have been observed.

Vegzelma is for single-use only, as the product contains no preservatives. Any unused medicinal product or waste material should be disposed in accordance with local requirements.