AVASTIN 25mg / ml perfusive solution concentrate medication leaflet

Avastin 25 mg/ml concentrate for solution for infusion

Each ml of concentrate contains 25 mg of bevacizumab*.

Each 4 ml vial contains 100 mg of bevacizumab.

Each 16 ml vial contains 400 mg of bevacizumab.

For dilution and other handling recommendations, see section 6.6.

*Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in

Chinese Hamster Ovary cells.

Each 4 ml vial contains 1.6 mg of polysorbate 20.

Each 16 ml vial contains 6.4 mg of polysorbate 20.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear to slightly opalescent, colourless to pale brown liquid.

Bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment ofadult patients with metastatic carcinoma of the colon or rectum.

Bevacizumab in combination with paclitaxel is indicated for first-line treatment of adult patients withmetastatic breast cancer. For further information as to human epidermal growth factor receptor 2(HER2) status, please refer to section 5.1.

Bevacizumab in combination with capecitabine is indicated for first-line treatment of adult patientswith metastatic breast cancer in whom treatment with other chemotherapy options including taxanes oranthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded fromtreatment with Avastin in combination with capecitabine. For further information as to HER2 status,please refer to section 5.1.

Bevacizumab, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adultpatients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other thanpredominantly squamous cell histology.

Bevacizumab, in combination with erlotinib, is indicated for first-line treatment of adult patients withunresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with

Epidermal Growth Factor Receptor (EGFR) activating mutations (see section 5.1).

Bevacizumab in combination with interferon alfa-2a is indicated for first line treatment of adultpatients with advanced and/or metastatic renal cell cancer.

Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatmentof adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages

III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. (See section 5.1).

Bevacizumab, in combination with carboplatin and gemcitabine or in combination with carboplatinand paclitaxel, is indicated for treatment of adult patients with first recurrence of platinum-sensitiveepithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapywith bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.

Bevacizumab in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin isindicated for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian,fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapyregimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or

VEGF receptor-targeted agents (see section 5.1).

Bevacizumab, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecanin patients who cannot receive platinum therapy, is indicated for the treatment of adult patients withpersistent, recurrent, or metastatic carcinoma of the cervix (see section 5.1).

Do not shake the vial.

Avastin must be administered under the supervision of a physician experienced in the use ofantineoplastic medicinal products.

Metastatic carcinoma of the colon or rectum (mCRC)

The recommended dose of Avastin, administered as an intravenous infusion, is either 5 mg/kg or10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight givenonce every 3 weeks.

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity.

Metastatic breast cancer (mBC)

The recommended dose of Avastin is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kgof body weight given once every 3 weeks as an intravenous infusion.

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity.

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy

Avastin is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatmentfollowed by Avastin as a single agent until disease progression.

The recommended dose of Avastin is 7.5 mg/kg or 15 mg/kg of body weight given once every3 weeks as an intravenous infusion.

Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses(see section 5.1).

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity.

First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination witherlotinib

EGFR mutation testing should be performed prior to initiation of treatment with the combination of

Avastin and erlotinib. It is important that a well-validated and robust methodology is chosen to avoidfalse negative or false positive determinations.

The recommended dose of Avastin when used in addition to erlotinib is 15 mg/kg of body weightgiven once every 3 weeks as an intravenous infusion.

It is recommended that the treatment with Avastin in addition to erlotinib is continued until diseaseprogression.

For the posology and method of administration of erlotinib, please refer to the full erlotinib prescribinginformation.

Advanced and/or metastatic renal cell cancer (mRCC)

The recommended dose of Avastin is 10 mg/kg of body weight given once every 2 weeks as anintravenous infusion.

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity.

Epithelial ovarian, fallopian tube and primary peritoneal cancer

Front-line treatment: Avastin is administered in addition to carboplatin and paclitaxel for up to 6cycles of treatment followed by continued use of Avastin as single agent until disease progression orfor a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier.

The recommended dose of Avastin is 15 mg/kg of body weight given once every 3 weeks as anintravenous infusion.

Treatment of platinum-sensitive recurrent disease: Avastin is administered in combination with eithercarboplatin and gemcitabine for 6 cycles and up to 10 cycles or in combination with carboplatin andpaclitaxel for 6 cycles and up to 8 cycles, followed by continued use of Avastin as single agent untildisease progression. The recommended dose of Avastin is 15 mg/kg of body weight given once every3 weeks as an intravenous infusion.

Treatment of platinum-resistant recurrent disease: Avastin is administered in combination with one ofthe following agents - paclitaxel, topotecan (given weekly) or pegylated liposomal doxorubicin. Therecommended dose of Avastin is 10 mg/kg of body weight given once every 2 weeks as anintravenous infusion. When Avastin is administered in combination with topotecan (given on days 1-5,every 3 weeks), the recommended dose of Avastin is 15 mg/kg of body weight given once every3 weeks as an intravenous infusion. It is recommended that treatment be continued until diseaseprogression or unacceptable toxicity (see section 5.1, study MO22224).

Cervical cancer

Avastin is administered in combination with one of the following chemotherapy regimens: paclitaxeland cisplatin or paclitaxel and topotecan.

The recommended dose of Avastin is 15 mg/kg of body weight given once every 3 weeks as anintravenous infusion.

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity (see section 5.1).

Elderly patients: No dose adjustment is required in the patients ≥ 65 years of age.

Patients with renal impairment: The safety and efficacy have not been studied in patients with renalimpairment (see section 5.2).

Patients with hepatic impairment: The safety and efficacy have not been studied in patients withhepatic impairment (see section 5.2).

The safety and efficacy of bevacizumab in children aged less than 18 years old have not beenestablished. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendationon a posology can be made.

There is no relevant use of bevacizumab in the paediatric population in the indications for treatment ofcancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney.

The initial dose should be delivered over 90 minutes as an intravenous infusion. If the first infusion iswell tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion iswell tolerated, all subsequent infusions may be administered over 30 minutes.

It should not be administered as an intravenous push or bolus.

Dose reduction for adverse reactions is not recommended. If indicated, therapy should either bepermanently discontinued or temporarily suspended as described in section 4.4.

For instructions on dilution of the medicinal product before administration, see section 6.6. Avastininfusions should not be administered or mixed with glucose solutions. This medicinal product mustnot be mixed with other medicinal products except those mentioned in section 6.6.

- 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 orhumanised antibodies.

- Pregnancy (see section 4.6).

In order to improve the traceability of biological medicinal products, the name and the batch numberof 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 gallbladder perforation when treated with Avastin. Intra-abdominal inflammatory process may be a riskfactor 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 Avastinand all patients with GI perforation had a history of prior radiation. Therapy should be permanentlydiscontinued in patients who develop gastrointestinal perforation.

GI-vaginal Fistulae in study GOG-0240

Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin are at increasedrisk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal fistulae). Priorradiation 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 radiationis 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 Avastin.

Permanently discontinue Avastin 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 Avastin in patients with other fistulae.

In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of Avastin should beconsidered.

Wound healing complications (see section 4.8)

Avastin may adversely affect the wound healing process. Serious wound healing complications,including anastomotic complications, with a fatal outcome have been reported. Therapy should not beinitiated for at least 28 days following major surgery or until the surgical wound is fully healed. Inpatients who experienced wound healing complications during therapy, treatment should be withhelduntil 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 Avastin.

This condition is usually secondary to wound healing complications, gastrointestinal perforation orfistula formation. Avastin 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 Avastin-treated patients. Clinical safety datasuggest that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertensionshould be adequately controlled before starting Avastin treatment. There is no information on theeffect of Avastin 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 treatmentappropriate for the individual situation of the affected patient. The use of diuretics to managehypertension is not advised in patients who receive a cisplatin-based chemotherapy regimen. Avastinshould be permanently discontinued if medically significant hypertension cannot be adequatelycontrolled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensiveencephalopathy.

Posterior Reversible Encephalopathy Syndrome (PRES) (see section 4.8)

There have been rare reports of Avastin-treated patients developing signs and symptoms that areconsistent with PRES, a rare neurologic disorder, which can present with the following signs andsymptoms among others: seizures, headache, altered mental status, visual disturbance, or corticalblindness, with or without associated hypertension. A diagnosis of PRES requires confirmation bybrain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, treatmentof specific symptoms including control of hypertension is recommended along with discontinuation of

Avastin. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is notknown.

Proteinuria (see section 4.8)

Patients with a history of hypertension may be at increased risk for the development of proteinuriawhen treated with Avastin. 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 tothe dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and duringtherapy. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of patients treated with

Avastin. 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 cerebrovascularaccidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher inpatients receiving Avastin in combination with chemotherapy compared to those who receivedchemotherapy alone.

Patients receiving Avastin plus chemotherapy, with a history of arterial thromboembolism, diabetes orage greater than 65 years have an increased risk of developing arterial thromboembolic reactionsduring therapy. Caution should be taken when treating these patients with Avastin.

Therapy should be permanently discontinued in patients who develop arterial thromboembolicreactions.

Venous thromboembolism (see section 4.8)

Patients may be at risk of developing venous thromboembolic reactions, including pulmonaryembolism under Avastin treatment.

Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin in combinationwith paclitaxel and cisplatin may be at increased risk of venous thromboembolic events.

Avastin should be discontinued in patients with life-threatening (Grade 4) thromboembolic reactions,including pulmonary embolism (NCI-CTCAE v.3). Patients with thromboembolic reactions ≤ Grade 3need to be closely monitored (NCI-CTCAE v.3).

Patients treated with Avastin have an increased risk of haemorrhage, especially tumour-associatedhaemorrhage. Avastin should be discontinued permanently in patients who experience Grade 3 or 4bleeding during Avastin therapy (NCI-CTCAE v.3) (see section 4.8).

Patients with untreated CNS metastases were routinely excluded from clinical trials with Avastin,based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in suchpatients has not been prospectively evaluated in randomised clinical trials (see section 4.8). Patientsshould be monitored for signs and symptoms of CNS bleeding, and Avastin treatment discontinued incases of intracranial bleeding.

There is no information on the safety profile of Avastin in patients with congenital bleeding diathesis,acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment ofthromboembolism prior to starting Avastin treatment, as such patients were excluded from clinicaltrials. 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 anincreased rate of Grade 3 or above bleeding when treated with a full dose of warfarin and Avastinconcomitantly (NCI-CTCAE v.3).

Pulmonary haemorrhage/haemoptysis

Patients with non-small cell lung cancer treated with Avastin may be at risk of serious, and in somecases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/haemoptysis (> 2.5 ml of red blood) should not be treated with Avastin.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating Avastin, this risk should becarefully 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 fromasymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment orhospitalisation. Caution should be exercised when treating patients with clinically significantcardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with

Avastin.

Most of the patients who experienced CHF had metastatic breast cancer and had received previoustreatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHFwere present.

In patients in AVF3694g who received treatment with anthracyclines and who had not receivedanthracyclines before, no increased incidence of all Grade CHF was observed in theanthracycline + bevacizumab group compared to the treatment with anthracyclines only. CHF Grade 3or higher reactions were somewhat more frequent among patients receiving bevacizumab incombination with chemotherapy than in patients receiving chemotherapy alone. This is consistent withresults in patients in other studies of metastatic breast cancer who did not receive concurrentanthracycline 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 severeneutropenia (including some fatalities) have been observed in patients treated with some myelotoxicchemotherapy regimens plus Avastin in comparison to chemotherapy alone. This has mainly been seenin combination with platinum- or taxane-based therapies in the treatment of NSCLC, mBC, and incombination 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 anaphylacticshock). Close observation of the patient during and following the administration of bevacizumab isrecommended as expected for any infusion of a therapeutic humanised monoclonal antibody. If areaction occurs, the infusion should be discontinued and appropriate medical therapies should beadministered. 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 Avastin, the majority of whom hadreceived prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is anidentified risk. Caution should be exercised when Avastin and intravenous bisphosphonates areadministered simultaneously or sequentially.

Invasive dental procedures are also an identified risk factor. A dental examination and appropriatepreventive dentistry should be considered prior to starting the treatment with Avastin. In patients whohave previously received or are receiving intravenous bisphosphonates invasive dental proceduresshould be avoided, if possible.

Intravitreal use

Avastin is not formulated for intravitreal use.

Individual cases and clusters of serious ocular adverse reactions have been reported followingunapproved intravitreal use of Avastin compounded from vials approved for intravenousadministration in cancer patients. These reactions included infectious endophthalmitis, intraocularinflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigmentepithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhageor retinal haemorrhage and conjunctival haemorrhage. Some of these reactions have resulted invarious 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 arterialthromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors.

Ovarian failure/fertility

Avastin may impair female fertility (see sections 4.6 and 4.8). Therefore fertility preservationstrategies should be discussed with women of childbearing potential prior to starting treatment with

Avastin.

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

This medicine contains 1.6 mg of polysorbate 20 in each 100 mg/4 ml vial and 6.4 mg in each400 mg/16 ml vial which is equivalent to 0.4 mg/ml. Polysorbates may cause allergic reactions.

Effect of antineoplastic agents on bevacizumab pharmacokinetics

No clinically relevant interaction of co-administered chemotherapy on bevacizumab pharmacokineticswas observed based on the results of population pharmacokinetic analyses. There were neitherstatistically significant nor clinically relevant differences in bevacizumab clearance in patientsreceiving Avastin monotherapy compared to patients receiving Avastin in combination with interferonalfa-2a, erlotinib or chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicinor 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 chemotherapiesirinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurementof free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabinepharmacokinetics 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) andsunitinib malate (50 mg daily) combination.

MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, andthrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, andneurological symptoms were observed in some of these patients. All of these findings were reversibleupon discontinuation of bevacizumab and sunitinib malate (see Hypertension, Proteinuria, PRES insection 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 severeneutropenia (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 Avastin has not beenestablished.

EGFR monoclonal antibodies in combination with bevacizumab chemotherapy regimens

No interaction studies have been performed. EGFR monoclonal antibodies should not be administeredfor the treatment of mCRC in combination with bevacizumab-containing chemotherapy. Results fromthe randomised phase III studies, PACCE and CAIRO-2, in patients with mCRC suggest that the useof anti-EGFR monoclonal antibodies panitumumab and cetuximab, respectively, in combination withbevacizumab plus chemotherapy, is associated with decreased PFS and/or OS, and with increasedtoxicity compared with bevacizumab plus chemotherapy alone.

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

There are no clinical trial data on the use of Avastin in pregnant women. Studies in animals haveshown reproductive toxicity including malformations (see section 5.3). IgGs are known to cross theplacenta, and Avastin is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to causeserious birth defects when administered during pregnancy. In the post-marketing setting, cases offoetal abnormalities in women treated with bevacizumab alone or in combination with knownembryotoxic chemotherapeutics have been observed (see section 4.8). Avastin is contraindicated inpregnancy (see section 4.3).

It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milkand bevacizumab could harm infant growth and development (see section 5.3), women mustdiscontinue breast-feeding during therapy and not breast-feed for at least six months following the lastdose of Avastin.

Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect onfemale fertility (see section 5.3). In a phase III trial in the adjuvant treatment of patients with coloncancer, a substudy with premenopausal women has shown a higher incidence of new cases of ovarianfailure in the bevacizumab group compared to the control group. After discontinuation of bevacizumabtreatment, ovarian function recovered in the majority of patients. Long term effects of the treatmentwith bevacizumab on fertility are unknown.

Avastin has no or negligible influence on the ability to drive and use machines. However, somnolenceand syncope have been reported with Avastin use (see table 1 in section 4.8). If patients areexperiencing symptoms that affect their vision or concentration, or their ability to react, they should beadvised not to drive and use machines until symptoms abate.

The overall safety profile of Avastin is based on data from over 5 700 patients with variousmalignancies, predominantly treated with Avastin 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 innon-small cell lung cancer patients (see section 4.4).

- Arterial thromboembolism (see section 4.4).

The most frequently observed adverse reactions across clinical trials in patients receiving Avastin werehypertension, fatigue or asthenia, diarrhoea and abdominal pain.

Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with

Avastin therapy are likely to be dose-dependent.

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 Avastin in combination with differentchemotherapy regimens in multiple indications, by MedDRA system organ class.

Table 1 provides all adverse reactions by frequency that were determined to have a causal relationshipwith Avastin 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 on-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 adverseevents 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 beclinically significant or severe.

Post-marketing adverse reactions are included in both Tables 1 and 2, where applicable. Detailedinformation 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 thehighest incidence seen in any indication.

Within each frequency category, adverse reactions are presented in the order of decreasingseriousness.

Some of the adverse reactions are reactions commonly seen with chemotherapy; however, Avastinmay exacerbate these reactions when combined with chemotherapeutic agents. Examples includepalmar-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 Very common Common Uncommon Rare Very rare Frequency notclass known

Infections and Sepsis, Necrotisinginfestations Abscessb,d, fasciitis a

Cellulitis,

Infection,

Urinary tractinfection

Blood and Febrile Anaemia,lymphatic neutropenia, Lymphopeniasystem Leucopenia,disorders Neutropeniab,

Thrombo-cytopenia

Immune system Hypersensitivity, Anaphylacticdisorders infusion shockreactionsa,b,d

System organ Very common Common Uncommon Rare Very rare Frequency notclass known

Metabolism and Anorexia, Dehydrationnutrition Hypomagnesaemia,disorders Hyponatraemia

Nervous system Peripheral sensory Cerebrovascular Posterior Hypertensivedisorders neuropathyb, accident, reversible encephalo-

Dysarthria, Syncope, encephalo- pathya

Headache, Somnolence pathy

Dysguesia syndromea,b,d

Eye disorders Eye disorder,

Lacrimationincreased

Cardiac Congestive heartdisorders failureb,d,

Supraventriculartachycardia

Vascular Hypertensionb,d, Thrombo- Renaldisorders Thrombo- embolism thromboticembolism (arterial)b,d, microangiopathya,b,(venous)b,d Haemorrhageb,d, Aneurysms and

Deep vein artery dissectionsthrombosis

Respiratory, Dyspnoea, Pulmonary Pulmonarythoracic and Rhinitis, haemorrhage/ hypertensiona,mediastinal Epistaxis, Haemoptysisb,d, Nasal septumdisorders Cough Pulmonary perforationaembolism,

Hypoxia,

Dysphoniaa

Gastrointestinal Rectal Gastrointestinal Gastrointestinaldisorders haemorrhage, perforationb,d, ulcera

Stomatitis, Intestinal

Constipation, perforation,

Diarrhoea, Ileus,

Nausea, Intestinal

Vomiting, obstruction,

Abdominal pain Recto-vaginalfistulaed,e,

Gastrointestinaldisorder,

Proctalgia

Hepatobiliary Gallbladderdisorders perforationa,b

Skin and Wound healing Palmar-plantarsubcutaneous complicationsb,d, erythro-tissue disorders Exfoliative dysaesthesiadermatitis, syndrome

Dry skin,

Skin discolouration

Musculoskeletal Arthralgia, Fistulab,d, Osteonecrosis ofand connective Myalgia Muscular the jawa,btissue disorders weakness, Non-mandibular

Back pain osteonecrosisa,f

Renal and Proteinuriab,durinarydisorders

Reproductive Ovarian Pelvic painsystem and failureb,c,dbreast disorders

Congenital, Foetalfamilial, and abnormalitiesa,bgenetic disorder

General Asthenia, Lethargydisorders and Fatigue,

Pyrexia,

System organ Very common Common Uncommon Rare Very rare Frequency notclass knownadministration Pain,site conditions Mucosalinflammation

Investigations Weight decreased

When events were noted as both all grade and grade 3-5 adverse drug reactions in clinical trials, the highestfrequency 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 sameunderlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardialinfarction, transient ischaemic attack and other arterial thromboembolic reactions).c Based on a substudy from NSABP C-08 with 295 patientsd 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 Very common Common Uncommon Rare Very Frequency notclass rare known

Infections and Sepsis, Necrotisinginfestations Cellulitis, fasciitisc

Abscessa,b,

Infection,

Blood and Febrile Anaemia,lymphatic system neutropenia, Lymphopeniadisorders Leucopenia,

Neutropeniaa,

Thrombo-cytopenia

Immune system Hypersensitivity, Anaphylacticdisorders infusion reactions a,b,c shock

Metabolism and Dehydration,nutrition disorders Hyponatraemia

Nervous system Peripheral Cerebrovascular Posteriordisorders sensory accident, reversibleneuropathya Syncope, encephalo-

Somnolence, pathy

Headache syndrome a,b,c,

Hypertensiveencephalo-pathyc

Cardiac disorders Congestive heartfailurea,b,

Supraventriculartachycardia

Vascular Hypertensiona,b Thromboembolism Renaldisorders arteriala,b, thrombotic

Haemorrhagea,b, microangiopathyb,c,

Thromboembolism Aneurysms and(venous)a,b, artery dissections

Deep veinthrombosis

System organ Very common Common Uncommon Rare Very Frequency notclass rare known

Respiratory, Pulmonary Pulmonarythoracic and haemorrhage/ hypertensionc,mediastinal Haemoptysisa,b, Nasal septumdisorders Pulmonary perforationcembolism,

Epistaxis,

Dyspnoea,

Hypoxia

Gastrointestinal Diarrhoea, Intestinal Gastrointestinaldisorders Nausea, perforation, perforationa,b,

Vomiting, Ileus, Gastrointestinal

Abdominal pain Intestinal ulcerc,obstruction, Rectal haemorrhage

Recto-vaginalfistulaec,d,

Gastrointestinaldisorder,

Stomatitis,

Proctalgia

Hepatobiliary Gallbladderdisorders perforation b,c

Skin and Wound healingsubcutaneous complicationsa,b,tissue disorders Palmar-plantarerythrodysaesthesiasyndrome

Musculoskeletal Fistulaa,b, Osteonecrosis of theand connective Myalgia, jawb,ctissue disorders Arthralgia,

Muscular weakness,

Back pain

Renal and urinary Proteinuriaa,bdisorders

Reproductive Pelvic pain Ovarian failurea,bsystem and breastdisorders

Congenital, Foetalfamilial, and abnormalitiesa,cgenetic disorder

General disorders Asthenia, Pain,and Fatigue, Lethargy,administration site Mucosalconditions inflammation

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events withat 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 notmeet the threshold of at least a 2% difference compared to the control arm. Table 2 also includes clinicallysignificant 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 2within 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 thesame 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 adversereactions'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)

Avastin has been associated with serious cases of gastrointestinal perforation.

Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% inpatients with non-squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breastcancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer, andup 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 priorpelvic radiation.

The occurrence of those events varied in type and severity, ranging from free air seen on the plainabdominal X-ray, which resolved without treatment, to intestinal perforation with abdominal abscessand fatal outcome. In some cases underlying intra-abdominal inflammation was present, either fromgastric 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 Avastin treated patients.

In Avastin clinical trials, gastrointestinal fistulae (all grade) have been reported with an incidence ofup to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported lesscommonly 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-vaginalfistulae was 8.3% in Avastin-treated patients and 0.9% in control patients, all of whom had a history ofprior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with

Avastin + 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 priorradiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alonewere 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowelobstructions and require surgical intervention as well as diverting ostomies.

Non-GI Fistulae (see section 4.4)

Avastin 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-240),1.8% of Avastin-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 thegastrointestinal tract (e.g. bronchopleural and biliary fistulae) were observed across variousindications. Fistulae have also been reported in post-marketing experience.

Reactions were reported at various time points during treatment ranging from one week to greater than1 year from initiation of Avastin, with most reactions occurring within the first 6 months of therapy.

Wound healing (see section 4.4)

As Avastin may adversely impact wound healing, patients who had major surgery within the last28 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 surgery28-60 days prior to starting Avastin. An increased incidence of post-operative bleeding or woundhealing complication occurring within 60 days of major surgery was observed if the patient was beingtreated with Avastin 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, someof which had a fatal outcome.

In locally recurrent and metastatic breast cancer trials, Grade 3-5 wound healing complications wereobserved in up to 1.1% of patients receiving Avastin compared with up to 0.9% of patients in thecontrol arms (NCI-CTCAE v.3).

In clinical trials of ovarian cancer, Grade 3-5 wound healing complications were observed in up to1.8% 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 (allgrades) ranged up to 42.1% in the Avastin containing arms compared with up to 14% in the controlarms. The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving Avastinranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% ofpatients treated with Avastin and chemotherapy compared to up to 0.2% of patients treated with thesame chemotherapy alone.

In study JO25567, all grade hypertension was observed in 77.3% of the patients who received Avastinin combination with erlotinib as first-line treatment for non-squamous NSCLC with EGFR activatingmutations, compared to 14.3% of patients treated with erlotinib alone. Grade 3 hypertension was60.0% in patients treated with Avastin in combination with erlotinib compared to 11.7% in patientstreated with erlotinib alone. There were no grade 4 or 5 hypertension events.

Hypertension was generally adequately controlled with oral anti-hypertensives such asangiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted indiscontinuation of Avastin treatment or hospitalisation.

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

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

Posterior Reversible Encephalopathy Syndrome (see section 4.4)

There have been rare reports of Avastin-treated patients developing signs and symptoms that areconsistent with PRES, a rare neurological disorder. Presentation may include seizures, headache,altered mental status, visual disturbance, or cortical blindness, with or without associatedhypertension. 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 specificsymptoms including control of hypertension (if associated with severe uncontrolled hypertension) isrecommended in addition to discontinuation of bevacizumab therapy. Symptoms usually resolve orimprove within days after treatment discontinuation, although some patients have experienced someneurologic sequelae. The safety of reinitiating Avastin 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 haveradiological 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

Avastin.

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephroticsyndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria wasreported in up to 10.9% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in upto 1.4% of treated patients. Testing for proteinuria is recommended prior to start of Avastin therapy. Inmost clinical trials urine protein levels of ≥ 2g/24 hrs led to the holding of Avastin 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 bleedingreactions ranged from 0.4% to 6.9% in Avastin treated patients, compared with up to 4.5% of patientsin 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 Avastinin combination with paclitaxel and topotecan compared with up to 4.6% of patients treated withpaclitaxel 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 inpatients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cellhistology, treatment with antirheumatic/anti-inflammatory substances, treatment with anticoagulants,prior radiotherapy, Avastin therapy, previous medical history of atherosclerosis, central tumourlocation and cavitation of tumours prior to or during therapy. The only variables that showedstatistically significant correlations with bleeding were Avastin therapy and squamous cell histology.

Patients with NSCLC of known squamous cell histology or mixed cell type with predominantsquamous cell histology were excluded from subsequent phase III trials, while patients with unknowntumour histology were included.

In patients with NSCLC excluding predominant squamous histology, all Grade reactions were seenwith a frequency of up to 9.3% when treated with Avastin 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 Avastin plus chemotherapy as compared with < 1% with chemotherapy alone(NCI-CTCAE v.3). Major or massive pulmonary haemorrhage/haemoptysis can occur suddenly andup to two thirds of the serious pulmonary haemorrhages resulted in a fatal outcome.

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

Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, includingcases 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 hasnot been prospectively evaluated in randomised clinical trials. In an exploratory retrospective analysisof 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 twosubsequent studies in patients with treated brain metastases (which included around 800 patients), onecase of Grade 2 CNS haemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at thetime of interim safety analysis (NCI-CTCAE v.3).

Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% of Avastin-treatedpatients. These were most commonly NCI-CTCAE v.3 Grade 1 epistaxis that lasted less than5 minutes, resolved without medical intervention and did not require any changes in the Avastintreatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneoushaemorrhage (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 observedin patients treated with Avastin across indications, including cerebrovascular accidents, myocardialinfarction, 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

Avastin containing arms compared with up to 2.1% in the chemotherapy control arms. Fatal outcomewas reported in 0.8% of patients receiving Avastin compared to 0.5% in patients receivingchemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) were reportedin up to 2.7% of patients treated with Avastin in combination with chemotherapy compared to up to0.5% of patients treated with chemotherapy alone. Myocardial infarction was reported in up to 1.4% ofpatients treated with Avastin in combination with chemotherapy compared to up to 0.7% of patientstreated with chemotherapy alone.

In one clinical trial evaluating Avastin in combination with 5-fluorouracil/folinic acid, AVF2192g,patients with metastatic colorectal cancer who were not candidates for treatment with irinotecan wereincluded. In this trial arterial thromboembolic reactions were observed in 11% (11/100) of patientscompared to 5.8% (6/104) in the chemotherapy control group.

Venous thromboembolism: The incidence of venous thromboembolic reactions in clinical trials wassimilar in patients receiving Avastin in combination with chemotherapy compared to those receivingthe 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 rangedfrom 2.8% to 17.3% of Avastin-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% ofpatients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treatedwith chemotherapy alone (across indications, excluding persistent, recurrent, or metastatic cervicalcancer).

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 treatedwith Avastin in combination with paclitaxel and cisplatin compared with up to 7.0% of patients treatedwith paclitaxel and cisplatin.

Patients who have experienced a venous thromboembolic reaction may be at higher risk for arecurrence if they receive Avastin in combination with chemotherapy versus chemotherapy alone.

Congestive heart failure (CHF)

In clinical trials with Avastin, congestive heart failure (CHF) was observed in all cancer indicationsstudied to date, but occurred predominantly in patients with metastatic breast cancer. In four phase IIItrials (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 Avastin incombination 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 3or higher CHF for the respective bevacizumab and control arms were similar to those in the otherstudies in metastatic breast cancer: 2.9% in the anthracycline + bevacizumab arm and 0% in theanthracycline + placebo arm. In addition, in study AVF3694g the incidences of all Grade CHF weresimilar between the anthracycline + Avastin (6.2%) and the anthracycline + placebo arms (6.0%).

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

In most clinical trials of Avastin, 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 thispopulation.

Prior anthracyclines exposure and/or prior radiation to the chest wall may be possible risk factors forthe 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 than300 mg/m2. This phase III clinical trial comparedrituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) plus bevacizumab to R-

CHOP without bevacizumab. While the incidence of CHF was, in both arms, above that previouslyobserved for doxorubicin therapy, the rate was higher in the R-CHOP plus bevacizumab arm. Theseresults suggest that close clinical observation with appropriate cardiac assessments should beconsidered for patients exposed to cumulative doxorubicin doses greater than 300 mg/m2 whencombined 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 inpatients receiving Avastin in combination with chemotherapy than with chemotherapy alone. Theincidence of these reactions in some clinical trials of Avastin is common (up to 5% in bevacizumab-treated patients).

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 Avastin incombination with paclitaxel and topotecan compared with up to 13% of patients treated with paclitaxeland topotecan.

Ovarian failure/fertility (see sections 4.4 and 4.6)

In NSABP C-08, a phase III trial of Avastin in adjuvant treatment of patients with colon cancer, theincidence 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 premenopausalwomen. New cases of ovarian failure were reported in 2.6% patients in the mFOLFOX-6 groupcompared to 39% in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumabtreatment, ovarian function recovered in 86.2% of these evaluable women. Long term effects of thetreatment with bevacizumab on fertility are unknown.

Decreased neutrophil count, decreased white blood cell count and presence of urine protein may beassociated with Avastin treatment.

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

Clinical trials have shown that transient increases in serum creatinine (ranging between 1.5-1.9 timesbaseline level), both with and without proteinuria, are associated with the use of Avastin. Theobserved increase in serum creatinine was not associated with a higher incidence of clinicalmanifestations of renal impairment in patients treated with Avastin.

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

No increase in the incidence of other reactions, including gastrointestinal perforation, wound healingcomplications, congestive heart failure, and haemorrhage was observed in elderly patients (> 65 years)receiving Avastin as compared to those aged ≤ 65 years treated with Avastin.

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

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

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

Avastin 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 yearstreated with Avastin.

Table 3 Adverse reactions reported in post-marketing setting

System organ class Reactions (frequency*)(SOC)

Infections and Necrotising fasciitis, usually secondary to wound healinginfestations complications, gastrointestinal perforation or fistula formation (rare)(see also section 4.4)

Immune system Hypersensitivity reactions and infusion reactions (common); with thedisorders following possible co-manifestations: dyspnoea/difficulty breathing,flushing/redness/rash, hypotension or hypertension, oxygendesaturation, chest pain, rigors and nausea/vomiting (see also section4.4 and Hypersensitivity reactions (including anaphylacticshock)/infusion reactions above).

Anaphylactic shock (rare) (see also section 4.4).

System organ class Reactions (frequency*)(SOC)

Nervous system Hypertensive encephalopathy (very rare) (see also section 4.4 anddisorders Hypertension in section 4.8)

Posterior Reversible Encephalopathy Syndrome (PRES), (rare) (seealso section 4.4)

Vascular disorders Renal thrombotic microangiopathy, which may be clinicallymanifested as proteinuria (not known) with or without concomitantsunitinib use. For further information on proteinuria see section 4.4and Proteinuria in section 4.8.

Respiratory, thoracic Nasal septum perforation (not known)and mediastinaldisorders Pulmonary hypertension (not known)

Dysphonia (common)

Gastrointestinal Gastrointestinal ulcer (not known)disorders

Hepatobiliary Gall bladder perforation (not known)disorders

Musculoskeletal and Cases of Osteonecrosis of the Jaw (ONJ) have been reported inconnective tissue patients treated with Avastin, most of which occurred in patients whodisorders had identified risk factors for ONJ, in particular exposure tointravenous bisphosphonates and/or a history of dental diseaserequiring invasive dental procedures (see also section 4.4)

Cases of non-mandibular osteonecrosis have been observed in Avastintreated paediatric patients (see section 4.8, Paediatric population).

Congenital, familial, Cases of foetal abnormalities in women treated with bevacizumaband genetic disorder alone or in combination with known embryotoxic chemotherapeuticshave been observed (see section 4.6)

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineoplastic agents,monoclonal antibodies and antibody drug conjugates, ATC code: L01F G01

Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesisand angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and

KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGFregresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits theformation of new tumour vasculature, thereby inhibiting tumour growth.

Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer innude mice resulted in extensive anti-tumour activity in human cancers, including colon, breast,pancreas and prostate. Metastatic disease progression was inhibited and microvascular permeabilitywas reduced.

Metastatic carcinoma of the colon or rectum (mCRC)

The safety and efficacy of the recommended dose (5 mg/kg of body weight every two weeks) inmetastatic carcinoma of the colon or rectum were studied in three randomised, active-controlledclinical trials in combination with fluoropyrimidine-based first-line chemotherapy. Avastin wascombined with two chemotherapy regimens:

- AVF2107g: A weekly schedule of irinotecan/bolus 5-fluorouracil/folinic acid (IFL) for a total of4 weeks of each 6 week-cycle (Saltz regimen).

- AVF0780g: In combination with bolus 5-fluorouracil/folinic acid (5-FU/FA) for a total of6 weeks of each 8 week-cycle (Roswell Park regimen).

- AVF2192g: In combination with bolus 5-FU/FA for a total of 6 weeks of each 8 week-cycle(Roswell Park regimen) in patients who were not optimal candidates for first-line irinotecantreatment.

Three additional studies with bevacizumab have been conducted in mCRC patients: first-line(NO16966), second-line with no previous bevacizumab treatment (E3200), and second-line withprevious bevacizumab treatment following disease progression in first-line (ML18147). In thesestudies, bevacizumab was administered at the following dosing regimens in combination with

FOLFOX-4 (5-FU/LV/oxaliplatin), XELOX (capecitabine/oxaliplatin), andfluoropyrimidine/irinotecan and fluoropyrimidine/oxaliplatin:

- NO16966: Avastin 7.5 mg/kg of body weight every 3 weeks in combination with oralcapecitabine and intravenous oxaliplatin (XELOX) or Avastin 5 mg/kg every 2 weeks incombination with leucovorin plus 5-fluorouracil bolus, followed by 5-fluorouracil infusion, withintravenous oxaliplatin (FOLFOX-4).

- E3200: Avastin 10 mg/kg of body weight every 2 weeks in combination with leucovorin and5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin(FOLFOX-4) in bevacizumab-naïve patients.

- ML18147: Avastin 5.0 mg/kg of body weight every 2 weeks or Avastin 7.5 mg/kg of bodyweight every 3 weeks in combination with fluoropyrimidine/irinotecan orfluoropyrimidine/oxaliplatin in patients with disease progression following first-line treatmentwith bevacizumab. Use of irinotecan- or oxaliplatin-containing regimen was switcheddepending on first-line usage of either oxaliplatin or irinotecan.

This was a phase III randomised, double-blind, active-controlled clinical trial evaluating Avastin incombination with IFL as first-line treatment for metastatic carcinoma of the colon or rectum.

Eight hundred and thirteen patients were randomised to receive IFL + placebo (Arm 1) or

IFL + Avastin (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus5-FU/FA + Avastin (Arm 3). Enrolment in Arm 3 was discontinued, as pre-specified, once safety of

Avastin with the IFL regimen was established and considered acceptable. All treatments werecontinued until disease progression. The overall mean age was 59.4 years; 56.6% of patients had an

ECOG performance status of 0, 43% had a value of 1 and 0.4% had a value of 2. 15.5% had receivedprior radiotherapy and 28.4% prior chemotherapy.

The primary efficacy variable of the trial was overall survival. The addition of Avastin to IFL resultedin statistically significant increases in overall survival, progression-free survival and overall responserate (see Table 4). The clinical benefit, as measured by overall survival, was seen in all pre-specifiedpatient subgroups, including those defined by age, sex, performance status, location of primarytumour, number of organs involved and duration of metastatic disease.

The efficacy results of Avastin in combination with IFL-chemotherapy are displayed in Table 4.

Table 4 Efficacy results for trial AVF2107g

Arm 1 Arm 2

IFL + placebo IFL + Avastina

Number of patients 411 402

Overall survival

Median time (months) 15.6 20.395% CI 14.29-16.99 18.46-24.18

Hazard ratiob 0.660(p-value = 0.00004)

Progression-free survival

Median time (months) 6.2 10.6

Hazard ratio 0.54(p-value < 0.0001)

Overall response rate

Rate (%) 34.8 44.8(p-value = 0.0036)a 5 mg/kg every 2 weeks.b Relative to control arm.

Among the 110 patients randomised to Arm 3 (5-FU/FA + Avastin) prior to discontinuation of thisarm, the median overall survival was 18.3 months and the median progression free survival was8.8 months.

This was a phase II randomised, double-blind, active-controlled clinical trial evaluating the efficacyand safety of Avastin in combination with 5-FU/FA as first-line treatment for metastatic colorectalcancer in patients who were not optimal candidates for first-line irinotecan treatment. One hundred andfive patients were randomised to 5-FU/FA + placebo arm and 104 patients to 5-FU/FA + Avastin(5 mg/kg every 2 weeks) arm. All treatments were continued until disease progression.

The addition of Avastin 5 mg/kg every two weeks to 5-FU/FA resulted in higher objective responserates, significantly longer progression-free survival, and a trend in longer survival as compared to5-FU/FA chemotherapy alone.

This was a phase II randomised, active-controlled, open-labelled clinical trial investigating Avastin incombination with 5-FU/FA as first-line treatment of metastatic colorectal cancer. The median age was64 years. 19% of the patients had received prior chemotherapy and 14% prior radiotherapy.

Seventy-one patients were randomised to receive bolus 5-FU/FA or 5-FU/FA + Avastin (5 mg/kgevery 2 weeks). A third group of 33 patients received bolus 5-FU/FA + Avastin (10 mg/kg every2 weeks). Patients were treated until disease progression. The primary endpoints of the trial wereobjective response rate and progression-free survival. The addition of Avastin 5 mg/kg every twoweeks to 5-FU/FA resulted in higher objective response rates, longer progression-free survival, and atrend in longer survival, compared with 5-FU/FA chemotherapy alone (see Table 5). These efficacydata are consistent with the results from trial AVF2107g.

The efficacy data from trials AVF0780g and AVF2192g investigating Avastin in combination with5-FU/FA-chemotherapy are summarised in Table 5.

Table 5 Efficacy results for trials AVF0780g and AVF2192g

AVF0780g AVF2192g5-FU/FA 5-FU/FA + 5-FU/FA + 5-FU/FA + 5-FU/FA +

Avastina Avastinb placebo Avastin

Number of patients 36 35 33 105 104

Overall survival

Median time (months) 13.6 17.7 15.2 12.9 16.695% CI 10.35-16.95 13.63-19.32

Hazard ratioc - 0.52 1.01 0.79p-value 0.073 0.978 0.16

Progression-free survival

Median time (months) 5.2 9.0 7.2 5.5 9.2

Hazard ratio 0.44 0.69 0.5p-value - 0.0049 0.217 0.0002

Overall response rate

Rate (percent) 16.7 40.0 24.2 15.2 2695% CI 7.0-33.5 24.4-57.8 11.7-42.6 9.2-23.9 18.1-35.6p-value 0.029 0.43 0.055

Duration of response

Median time (months) NR 9.3 5.0 6.8 9.225-75 percentile (months) 5.5-NR 6.1-NR 3.8-7.8 5.59-9.17 5.88-13.01a 5 mg/kg every 2 weeks.b 10 mg/kg every 2 weeks.c Relative to control arm.

NR = not reached.

This was a phase III randomised, double-blind (for bevacizumab), clinical trial investigating Avastin7.5 mg/kg in combination with oral capecitabine and intravenous oxaliplatin (XELOX), administeredon a 3-weekly schedule; or Avastin 5 mg/kg in combination with leucovorin with 5-fluorouracil bolus,followed by 5-fluorouracil infusional, with intravenous oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule. The trial contained two parts: an initial unblinded 2-arm part (Part I) in whichpatients were randomised to two different treatment groups (XELOX and FOLFOX-4) and asubsequent 2 × 2 factorial 4-arm part (Part II) in which patients were randomised to four treatmentgroups (XELOX + placebo, FOLFOX-4 + placebo, XELOX + Avastin, FOLFOX-4 + Avastin). In

Part II, treatment assignment was double-blind with respect to Avastin.

Approximately 350 patients were randomised into each of the 4 trial arms in the Part II of the trial.

Table 6 Treatment regimens in trial NO16966 (mCRC)

Treatment Starting dose Schedule

FOLFOX-4 Oxaliplatin 85 mg/m2 IV 2 h Oxaliplatin on day 1or Leucovorin 200 mg/m2 IV 2 h Leucovorin on day 1 and 2

FOLFOX-4 +

Avastin 5-Fluorouracil 400 mg/m2 IV bolus, 5-fluorouracil IV bolus/infusion,600 mg/m2 IV 22 h each on days 1 and 2

Placebo or 5 mg/kg IV Day 1, prior to FOLFOX-4,

Avastin 30-90 min every 2 weeks

XELOX Oxaliplatin 130 mg/m2 IV 2 h Oxaliplatin on day 1or Capecitabine 1000 mg/m2 oral bid Capecitabine oral bid for

XELOX + 2 weeks (followed by 1 week

Avastin off treatment)

Placebo or 7.5 mg/kg IV Day 1, prior to XELOX, q

Avastin 30-90 min 3 weeks5-Fluorouracil: IV bolus injection immediately after leucovorin

The primary efficacy parameter of the trial was the duration of progression-free survival. In this trial,there were two primary objectives: to show that XELOX was non-inferior to FOLFOX-4 and to showthat Avastin in combination with FOLFOX-4 or XELOX chemotherapy was superior to chemotherapyalone. Both co-primary objectives were met:

- Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing armsin the overall comparison was demonstrated in terms of progression-free survival and overallsurvival in the eligible per-protocol population.

- Superiority of the Avastin-containing arms versus the chemotherapy alone arms in the overallcomparison was demonstrated in terms of progression-free survival in the ITT population (Table7).

Secondary PFS analyses, based on ‘on-treatment’-based response assessments, confirmed thesignificantly superior clinical benefit for patients treated with Avastin (analyses shown in Table 7),consistent with the statistically significant benefit observed in the pooled analysis.

Table 7 Key efficacy results for the superiority analysis (ITT population, trial NO16966)

Endpoint (months) FOLFOX-4 FOLFOX-4 P-valueor XELOX or XELOX+ placebo + bevacizumab(n = 701) (n = 699)

Primary endpoint

Median PFS** 8.0 9.4 0.0023

Hazard ratio (97.5% CI) a 0.83 (0.72-0.95)

Secondary endpoints

Median PFS (on treatment)** 7.9 10.4 < 0.0001

Hazard ratio (97.5% CI) 0.63 (0.52-0.75)

Overall response rate 49.2% 46.5%(invest. assessment)**

Median overall survival* 19.9 21.2 0.0769

Hazard ratio (97.5% CI) 0.89 (0.76-1.03)

* Overall survival analysis at clinical cut-off 31 January 2007

** Primary analysis at clinical cut-off 31 January 2006a Relative to control arm

In the FOLFOX treatment subgroup, the median PFS was 8.6 months in placebo and 9.4 months inbevacizumab treated patients, HR = 0.89, 97.5% CI = [0.73; 1.08]; p-value = 0.1871, the correspondingresults in the XELOX treatment subgroup being 7.4 vs. 9.3 months, HR = 0.77, 97.5% CI = [0.63;0.94]; p-value = 0.0026.

The median overall survival was 20.3 months in placebo and 21.2 months in bevacizumab treatedpatients in the FOLFOX treatment subgroup, HR = 0.94, 97.5% CI = [0.75; 1.16]; p-value = 0.4937,the corresponding results in the XELOX, treatment subgroup being 19.2 vs. 21.4 months, HR = 0.84,97.5% CI = [0.68; 1.04]; p-value = 0.0698.

This was a phase III randomised, active-controlled, open-label trial investigating Avastin 10 mg/kg incombination with leucovorin with 5-fluorouracil bolus and then 5-fluorouracil infusional, withintravenous oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule in previously-treatedpatients (second line) with advanced colorectal cancer. In the chemotherapy arms, the FOLFOX-4regimen used the same doses and schedule as shown in Table 6 for trial NO16966.

The primary efficacy parameter of the trial was overall survival, defined as the time fromrandomisation to death from any cause. Eight hundred and twenty-nine patients were randomised (292

FOLFOX-4, 293 Avastin + FOLFOX-4 and 244 Avastin monotherapy).

The addition of Avastin to FOLFOX-4 resulted in a statistically significant prolongation of survival.

Statistically significant improvements in progression-free survival and objective response rate werealso observed (see Table 8).

Table 8 Efficacy results for trial E3200

E3200

FOLFOX-4 FOLFOX-4 + Avastina

Number of patients 292 293

Overall survival

Median (months) 10.8 13.095% CI 10.12-11.86 12.09-14.03

Hazard ratiob 0.751(p-value = 0.0012)

Progression-free survival

Median (months) 4.5 7.5

Hazard ratio 0.518(p-value < 0.0001)

Objective response rate

Rate 8.6% 22.2%(p-value < 0.0001)a 10 mg/kg every 2 weeksb Relative to control arm

No significant difference was observed in the duration of overall survival between patients whoreceived Avastin monotherapy compared to patients treated with FOLFOX-4. Progression-freesurvival and objective response rate were inferior in the Avastin monotherapy arm compared to the

FOLFOX-4 arm.

This was a phase III randomised, controlled, open-label trial investigating Avastin 5.0 mg/kg every2 weeks or 7.5 mg/kg every 3 weeks in combination with fluoropyrimidine-based chemotherapyversus fluoropyrimidine-based chemotherapy alone in patients with mCRC who have progressed on afirst-line bevacizumab-containing regimen.

Patients with histologically confirmed mCRC and disease progression were randomised 1:1 within3 months after discontinuation of bevacizumab first-line therapy to receivefluoropyrimidine/oxaliplatin- or fluoropyrimidine/irinotecan-based chemotherapy (chemotherapyswitched depending on first-line chemotherapy) with or without bevacizumab. Treatment was givenuntil progressive disease or unacceptable toxicity. The primary outcome measure was overall survivaldefined as the time from randomisation until death from any cause.

A total of 820 patients were randomised. The addition of bevacizumab to fluoropyrimidine-basedchemotherapy resulted in a statistically significant prolongation of survival in patients with mCRCwho have progressed on a first-line bevacizumab-containing regimen (ITT = 819) (see Table 9).

Table 9 Efficacy results for study ML18147 (ITT population)

ML18147fluoropyrimidine/irinotecan fluoropyrimidine/irinotecanor orfluoropyrimidine/oxaliplatin fluoropyrimidine/oxaliplatinbased chemotherapy based chemotherapy+ Avastina

Number of patients 410 409

Overall survival

Median (months) 9.8 11.2

Hazard ratio (95% confidence 0.81 (0.69, 0.94)interval) (p-value = 0.0062)

Progression-free survival

Median (months) 4.1 5.7

Hazard ratio (95% confidence 0.68 (0.59, 0.78)interval) (p-value < 0.0001)

Objective response rate (ORR)

Patients included in analysis 406 404

Rate 3.9% 5.4%(p-value = 0.3113)a 5.0 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks

Statistically significant improvements in progression-free survival were also observed. Objectiveresponse rate was low in both treatment arms and the difference was not significant.

Study E3200 used a 5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-naïve patients,while study ML18147 used a 2.5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-pretreated patients. A cross-trial comparison of the efficacy and safety data is limited by differencesbetween these studies, most notably in patient populations, previous bevacizumab exposure andchemotherapy regimens.

Both the 5 mg/kg/week and 2.5 mg/kg/week equivalent doses of bevacizumab provided a statisticallysignificant benefit with regards to OS (HR 0.751 in study E3200; HR 0.81 in study ML18147) and

PFS (HR 0.518 in study E3200; HR 0.68 in study ML18147). In terms of safety, there was a higheroverall incidence of Grade 3-5 AEs in study E3200 relative to study ML18147.

Metastatic breast cancer (mBC)

Two large phase III trials were designed to investigate the treatment effect of Avastin in combinationwith two individual chemotherapy agents, as measured by the primary endpoint of PFS. A clinicallymeaningful and statistically significant improvement in PFS was observed in both trials.

Summarised below are PFS results for the individual chemotherapy agents included in the indication:

- Study E2100 (paclitaxel)

- Median PFS increase 5.6 months, HR 0.421 (p < 0.0001, 95% CI 0.343; 0.516)

- Study AVF3694g (capecitabine)

- Median PFS increase 2.9 months, HR 0.69 (p = 0.0002, 95% CI 0.56; 0.84)

Further details of each study and the results are provided below.

Trial E2100 was an open-label, randomised, active controlled, multicentre clinical trial evaluating

Avastin in combination with paclitaxel for locally recurrent or metastatic breast cancer in patients whohad not previously received chemotherapy for locally recurrent and metastatic disease. Patients wererandomised to paclitaxel alone (90 mg/m2 intravenously over 1 hour once weekly for three out of fourweeks) or in combination with Avastin (10 mg/kg intravenous infusion every two weeks). Priorhormonal therapy for the treatment of metastatic disease was allowed. Adjuvant taxane therapy wasallowed only if it was completed at least 12 months prior to trial entry. Of the 722 patients in the trial,the majority of patients had HER2-negative disease (90%), with a small number of patients withunknown (8%) or confirmed HER2-positive status (2%), who had previously been treated with orwere considered unsuitable for trastuzumab therapy. Furthermore, 65% of patients had receivedadjuvant chemotherapy including 19% prior taxanes and 49% prior anthracyclines. Patients withcentral nervous system metastases, including previously treated or resected brain lesions, wereexcluded.

In trial E2100, patients were treated until disease progression. In situations where earlydiscontinuation of chemotherapy was required, treatment with Avastin as a single agent continueduntil disease progression. The patient characteristics were similar across the trial arms. The primaryendpoint of this trial was progression free survival (PFS), based on trial investigators’ assessment ofdisease progression. In addition, an independent review of the primary endpoint was also conducted.

The results of this trial are presented in Table 10.

Table 10 Trial E2100 efficacy results

Progression-free survival

Investigator assessment* IRF assessment

Paclitaxel Paclitaxel/ Paclitaxel Paclitaxel/

Avastin Avastin(n = 354) (n = 368) (n = 354) (n = 368)

Median PFS (months) 5.8 11.4 5.8 11.3

HR 0.421 0.483(95% CI) (0.343; 0.516) (0.385; 0.607)p-value < 0.0001 < 0.0001

Response rates (for patients with measurable disease)

Investigator assessment IRF assessment

Paclitaxel Paclitaxel/ Paclitaxel Paclitaxel/

Avastin Avastin(n = 273) (n = 252) (n = 243) (n = 229)% pts with objective 23.4 48.0 22.2 49.8responsep-value < 0.0001 < 0.0001

* primary analysis

Overall survival

Paclitaxel Paclitaxel/

Avastin(n = 354) (n = 368)

Median OS (months) 24.8 26.5

HR 0.869(95% CI) (0.722; 1.046)p-value 0.1374

The clinical benefit of Avastin as measured by PFS was seen in all pre-specified subgroups tested(including disease-free interval, number of metastatic sites, prior receipt of adjuvant chemotherapyand oestrogen receptor (ER) status).

Study AVF3694g was a phase III, multicentre, randomised, placebo-controlled trial designed toevaluate the efficacy and safety of Avastin in combination with chemotherapy compared tochemotherapy plus placebo as first-line treatment for patients with HER2-negative metastatic orlocally recurrent breast cancer.

Chemotherapy was chosen at the investigator's discretion prior to randomisation in a 2:1 ratio toreceive either chemotherapy plus Avastin or chemotherapy plus placebo. The choices of chemotherapyincluded capecitabine, taxane (protein-bound paclitaxel, docetaxel), and anthracycline-based agents(doxorubicin/ cyclophosphamide, epirubicin/ cyclophosphamide, 5-fluorouracil/ doxorubicin/cyclophosphamide, 5-fluorouracil/epirubicin/cyclophosphamide) given every three weeks (q3w).

Avastin or placebo was administered at a dose of 15 mg/kg q3w.

This study included a blinded treatment phase, an optional open-label post-progression phase, and asurvival follow-up phase. During the blinded treatment phase, patients received chemotherapy andmedicinal product (Avastin or placebo) every 3 weeks until disease progression, treatment-limitingtoxicity, or death. On documented disease progression, patients who entered the optional open-labelphase could receive open-label Avastin together with a wide-range of second line therapies.

Statistical analyses were performed independently for 1) patients who received capecitabine incombination with Avastin or placebo; 2) patients who received taxane-based or anthracycline-basedchemotherapy in combination with Avastin or placebo. The primary endpoint of the study was PFS byinvestigator assessment. In addition, the primary endpoint was also assessed by an independent reviewcommittee (IRC).

The results of this study from the final protocol defined analyses for progression free survival andresponse rates for the independently powered capecitabine cohort of Study AVF3694g are presented in

Table 11 Results from an exploratory overall survival analysis which include an additional 7 monthsof follow-up (approximately 46% of patients had died) are also presented. The percentage of patientswho received Avastin in the open-label phase was 62.1% in the capecitabine + placebo arm and 49.9%in the capecitabine + Avastin arm.

Table 11 Efficacy results for study AVF3694g: - Capecitabinea and Avastin/Placebo(Cap + Avastin/Pl)

Progression-free survivalb

Investigator Assessment IRC Assessment

Cap + Pl Cap + Avastin Cap + Pl Cap + Avastin(n = 206) (n = 409) (n = 206) (n = 409)

Median PFS (months) 5.7 8.6 6.2 9.8

Hazard ratio vs placebo 0.69 (0.56; 0.84) 0.68 (0.54; 0.86)arm (95% CI)p-value 0.0002 0.0011

Response rate (for patients with measurable disease)b

Cap + Pl (n = 161) Cap + Avastin (n = 325)% pts with objective 23.6 35.4responsep-value 0.0097

Overall survivalb

HR0.88 (0.69; 1.13)(95% CI)p-value (exploratory) 0.33a1 000 mg/m2 oral twice daily for 14 days administered every 3 weeksbStratified analysis included all progression and death events except those where non-protocol therapy (NPT)was initiated prior to documented progression; data from those patients were censored at the last tumourassessment prior to starting NPT.

An unstratified analysis of PFS (investigator assessed) was performed that did not censor for non-protocol therapy prior to disease progression. The results of these analyses were very similar to theprimary PFS results.

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy

The safety and efficacy of Avastin, in addition to platinum-based chemotherapy, in the first-linetreatment of patients with non-squamous non-small cell lung cancer (NSCLC), was investigated intrials E4599 and BO17704. An overall survival benefit has been demonstrated in trial E4599 with a15 mg/kg/q3wk dose of bevacizumab. Trial BO17704 has demonstrated that both 7.5 mg/kg/q3wk and15 mg/kg/q3wk bevacizumab doses increase progression free survival and response rate.

E4599 was an open-label, randomised, active-controlled, multicentre clinical trial evaluating Avastinas first-line treatment of patients with locally advanced (stage IIIb with malignant pleural effusion),metastatic or recurrent NSCLC other than predominantly squamous cell histology.

Patients were randomised to platinum-based chemotherapy (paclitaxel 200 mg/m2) and carboplatin

AUC = 6.0, both by intravenous infusion (PC) on day 1 of every 3-week cycle for up to 6 cycles or PCin combination with Avastin at a dose of 15 mg/kg intravenous infusion day 1 of every 3-week cycle.

After completion of six cycles of carboplatin-paclitaxel chemotherapy or upon prematurediscontinuation of chemotherapy, patients on the Avastin + carboplatin-paclitaxel arm continued toreceive Avastin as a single agent every 3 weeks until disease progression. 878 patients wererandomised to the two arms.

During the trial, of the patients who received trial treatment, 32.2% (136/422) of patients received7-12 administrations of Avastin and 21.1% (89/422) of patients received 13 or more administrations of

Avastin.

The primary endpoint was duration of survival. Results are presented in Table 12.

Table 12 Efficacy results for trial E4599

Arm 1 Arm 2

Carboplatin/ Carboplatin/

Paclitaxel Paclitaxel +

Avastin15 mg/kg q 3 weeks

Number of patients 444 434

Overall survival

Median (months) 10.3 12.3

Hazard ratio 0.80 (p = 0.003)95% CI (0.69; 0.93)

Progression-free survival

Median (months) 4.8 6.4

Hazard ratio 0.65 (p < 0.0001)95% CI (0.56; 0.76)

Overall response rate

Rate (percent) 12.9 29.0 (p < 0.0001)

In an exploratory analysis, the extent of Avastin benefit on overall survival was less pronounced in thesubgroup of patients who did not have adenocarcinoma histology.

Trial BO17704 was a randomised, double-blind phase III trial of Avastin in addition to cisplatin andgemcitabine versus placebo, cisplatin and gemcitabine in patients with locally advanced (stage IIIbwith supraclavicular lymph node metastases or with malignant pleural or pericardial effusion),metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy. The primaryendpoint was progression free survival, secondary endpoints for the trial included the duration ofoverall survival.

Patients were randomised to platinum-based chemotherapy, cisplatin 80 mg/m2 intravenous infusionon day 1 and gemcitabine 1250 mg/m2 intravenous infusion on days 1 and 8 of every 3-week cycle forup to 6 cycles (CG) with placebo or CG with Avastin at a dose of 7.5 or 15 mg/kg intravenousinfusion day 1 of every 3-week cycle. In the Avastin-containing arms, patients could receive Avastinas a single-agent every 3 weeks until disease progression or unacceptable toxicity. Trial results showthat 94% (277/296) of eligible patients went on to receive single agent bevacizumab at cycle 7. A highproportion of patients (approximately 62%) went on to receive a variety of non-protocol specified anti-cancer therapies, which may have impacted the analysis of overall survival.

The efficacy results are presented in Table 13.

Table 13 Efficacy results for trial BO17704

Cisplatin/Gemcitabine Cisplatin/Gemcitabine

Cisplatin/Gemcitabine + Avastin + Avastin+ placebo 7.5 mg/kg q 3 weeks 15 mg/kg q 3 weeks

Number of patients 347 345 351

Progression-freesurvival

Median (months) 6.1 6.7 6.5(p = 0.0026) (p = 0.0301)

Hazard ratio 0.75 0.82[0.62; 0.91] [0.68; 0.98]

Best overallresponse ratea20.1% 34.1% 30.4%(p < 0.0001) (p = 0.0023)

Overall survival13.6 13.4

Median (months) 13.1 (p = 0.4203) (p = 0.7613)

Hazard ratio 0.93 1.03[0.78; 1.11] [0.86, 1.23]a patients with measurable disease at baseline

First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination witherlotinib

Study JO25567 was a randomised, open-label, multi-centre phase II study conducted in Japan toevaluate the efficacy and safety of Avastin used in addition to erlotinib in patients with non-squamous

NSCLC with EGFR activating mutations (exon 19 deletion or exon 21 L858R mutation) who had notreceived prior systemic therapy for stage IIIB/IV or recurrent disease.

The primary endpoint was progression-free survival (PFS) based on independent review assessment.

Secondary endpoints included overall survival, response rate, disease control rate, duration ofresponse, and safety.

EGFR mutation status was determined for each patient prior to patient screening and 154 patients wererandomised to receive either erlotinib + Avastin (erlotinib 150 mg oral daily + Avastin [15 mg/kgintravenously every 3 weeks]) or erlotinib monotherapy (150 mg oral daily) until disease progression(PD) or unacceptable toxicity. In the absence of PD, discontinuation of one component of studytreatment in the erlotinib + Avastin arm did not lead to discontinuation of the other component ofstudy treatment as specified in the study protocol.

The efficacy results of the study are presented in Table 14.

Table 14 Efficacy results for study JO25567

Erlotinib Erlotinib +

N = 77# Avastin

N = 75#

PFS^ (months)

Median 9.7 16.0

HR (95% CI) 0.54 (0.36; 0.79)p-value 0.0015

Overall response rate

Rate (n) 63.6% (49) 69.3% (52)p-value 0.4951

Overall survival* (months)

Median 47.4 47.0

HR (95% CI) 0.81 (0.53; 1.23)p-value 0.3267# A total of 154 patients (ECOG Performance Status 0 or 1) were randomised. However two of the randomisedpatients discontinued the study before receiving any study treatment^ Blinded independent review (protocol-defined primary analysis)

* Exploratory analysis: final OS analysis at clinical cut off on 31 October 2017, approx. 59% of patients haddied.

CI, confidence interval; HR, Hazard ratio from unstratified Cox regression analysis; NR, not reached.

Advanced and/or metastatic renal cell cancer (mRCC)

Avastin in combination with interferon alfa-2a for the first-line treatment of advanced and/ ormetastatic renal cell cancer (BO17705)

This was a phase III randomised double-blind trial conducted to evaluate the efficacy and safety of

Avastin in combination with interferon (IFN) alfa-2a versus IFN alfa-2a alone as first-line treatment inmRCC. The 649 randomised patients (641 treated) had Karnofsky Performance Status (KPS) of≥ 70%, no CNS metastases and adequate organ function. Patients were nephrectomised for primaryrenal cell carcinoma. Avastin 10 mg/kg was given every 2 weeks until disease progression. IFN alfa-2a was given up to 52 weeks or until disease progression at a recommended starting dose of 9 MIUthree times a week, allowing a dose reduction to 3 MIU three times a week in 2 steps. Patients werestratified according to country and Motzer score and the treatment arms were shown to be wellbalanced for the prognostic factors.

The primary endpoint was overall survival, with secondary endpoints for the trial includingprogression-free survival. The addition of Avastin to IFN-alpha-2a significantly increased PFS andobjective tumour response rate. These results have been confirmed through an independentradiological review. However, the increase in the primary endpoint of overall survival by 2 monthswas not significant (HR = 0.91). A high proportion of patients (approximately 63% IFN/placebo; 55%

Avastin/IFN) received a variety of non-specified post-trial anti-cancer therapies, includingantineoplastic agents, which may have impacted the analysis of overall survival.

The efficacy results are presented in Table 15

Table 15 Efficacy results for trial BO17705

BO17705

Placebo + IFNa Bvb + IFNa

Number of patients 322 327

Progression-free survival

Median (months) 5.4 10.2

Hazard ratio 0.6395% CI 0.52, 0.75(p-value < 0.0001)

Objective response rate (%) in Patientswith measurable disease

N 289 306

Response rate 12.8% 31.4%(p-value < 0.0001)

Overall survival

Median (months) 21.3 23.3

Hazard ratio 0.9195% CI 0.76, 1.10(p-value 0.3360)a Interferon alfa-2a 9 MIU 3×/weekb Bevacizumab 10 mg/kg q 2 wk

An exploratory multivariate Cox regression model using backward selection indicated that thefollowing baseline prognostic factors were strongly associated with survival independent of treatment:gender, white blood cell count, platelets, body weight loss in the 6 months prior to trial entry, numberof metastatic sites, sum of longest diameter of target lesions, Motzer score. Adjustment for thesebaseline factors resulted in a treatment hazard ratio of 0.78 (95% CI [0.63; 0.96], p = 0.0219),indicating a 22% reduction in the risk of death for patients in the Avastin + IFN alfa-2a arm comparedto IFN alfa-2a arm.

Ninety-seven patients in the IFN alfa-2a arm and 131 patients in the Avastin arm reduced the dose of

IFN alfa-2a from 9 MIU to either 6 or 3 MIU three times a week as pre-specified in the protocol.

Dose-reduction of IFN alfa-2a did not appear to affect the efficacy of the combination of Avastin and

IFN alfa-2a based on PFS event free rates over time, as shown by a sub-group analysis. The131 patients in the Avastin + IFN alfa-2a arm who reduced and maintained the IFN alfa-2a dose at 6or 3 MIU during the trial, exhibited at 6, 12 and 18 months PFS event free rates of 73, 52 and 21%respectively, as compared to 61, 43 and 17% in the total population of patients receiving

Avastin + IFN alfa-2a.

This was a randomised, double-blind, phase II clinical trial investigating Avastin 10 mg/kg in a 2weekly schedule with the same dose of Avastin in combination with 150 mg daily erlotinib, in patientswith metastatic clear cell RCC. A total of 104 patients were randomised to treatment in this trial, 53 to

Avastin 10 mg/kg every 2 weeks plus placebo and 51 to Avastin 10 mg/kg every 2 weeks pluserlotinib 150 mg daily. The analysis of the primary endpoint showed no difference between the

Avastin + Placebo arm and the Avastin + Erlotinib arm (median PFS 8.5 versus 9.9 months). Sevenpatients in each arm had an objective response. The addition of erlotinib to bevacizumab did not resultin an improvement in OS (HR = 1.764; p = 0.1789), duration of objective response (6.7 vs 9.1 months)or time to symptom progression (HR = 1.172; p = 0.5076).

This was a randomised phase II trial conducted to compare the efficacy and safety of bevacizumabversus placebo. A total of 116 patients were randomised to receive bevacizumab 3 mg/kg every2 weeks (n = 39), 10 mg/kg every 2 weeks; (n = 37), or placebo (n = 40).

An interim analysis showed there was a significant prolongation of the time to progression of diseasein the 10 mg/kg group as compared with the placebo group (hazard ratio, 2.55; p < 0.001). There was asmall difference, of borderline significance, between the time to progression of disease in the 3 mg/kggroup and that in the placebo group (hazard ratio, 1.26; p = 0.053). Four patients had objective(partial) response, and all of these had received the 10 mg/kg dose bevacizumab; the ORR for the10 mg/kg dose was 10%.

Epithelial ovarian, fallopian tube and primary peritoneal cancer

Front-line treatment of ovarian cancer

The safety and efficacy of Avastin in the front-line treatment of patients with epithelial ovarian,fallopian tube or primary peritoneal cancer were studied in two phase III trials (GOG-0218 and

BO17707) that evaluated the effect of the addition of Avastin to carboplatin and paclitaxel comparedto the chemotherapy regimen alone.

The GOG-0218 study was a phase III multicentre, randomised, double-blind, placebo-controlled, threearm study evaluating the effect of adding Avastin to an approved chemotherapy regimen (carboplatinand paclitaxel) in patients with advanced (stages IIIB, IIIC and IV according to FIGO staging versiondated 1988) epithelial ovarian, fallopian tube or primary peritoneal cancer.

Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy forovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, orhormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study.

A total of 1873 patients were randomised in equal proportions to the following three arms:

- CPP arm: Five cycles of placebo (started cycle 2) in combination with carboplatin (AUC 6) andpaclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of up to 15 months oftherapy

- CPB15 arm: Five cycles of Avastin (15 mg/kg q3w started cycle 2) in combination withcarboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for atotal of up to 15 months of therapy

- CPB15+ arm: Five cycles of Avastin (15 mg/kg q3w started cycle 2) in combination withcarboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by continued use of

Avastin (15 mg/kg q3w) as single agent for a total of up to 15 months of therapy.

The majority of patients included in the study were White (87% in all three arms); the median age was60 years in CPP and CPB15 arms and 59 years in CPB15+ arm; and 29% of patients in CPP or CPB15and 26% in CPB15+ were over 65 years of age. Overall approximately 50% of patients had a GOG PSof 0 at baseline, 43% a GOG PS score of 1, and 7% a GOG PS score of 2. Most patients had EOC(82% in CPP and CPB15, 85% in CPB15+) followed by PPC (16% in CPP, 15% in CPB15, 13% in

CPB15+) and FTC (1% in CPP, 3% in CPB15, 2% in CPB15+). The majority of patients had serousadenocarcinoma histologic type (85% in CPP and CPB15, 86% in CPB15+). Overall approximately34% of patients were FIGO stage III optimally debulked with gross residual disease, 40% stage IIIsub-optimally debulked, and 26% were stage IV patients.

The primary endpoint was PFS based on investigator’s assessment of disease progression based onradiological scans or CA 125 levels, or symptomatic deterioration per protocol. In addition, aprespecified analysis of the data censoring for CA-125 progression events was conducted, as well asan independent review of PFS as determined by radiological scans.

The trial met its primary objective of PFS improvement. Compared to patients treated withchemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who receivedbevacizumab at a dose of 15 mg/kg q3w in combination with chemotherapy and continued to receivebevacizumab alone (CPB15+), had a clinically meaningful and statistically significant improvement in

PFS.

In patients who only received bevacizumab in combination with chemotherapy and did not continue toreceive bevacizumab alone (CPB15), no clinically meaningful benefit in PFS was observed.

The results of this study are summarised in Table 16.

Table 16 Efficacy results from study GOG-0218

Progression-free survival 1

CPP CPB15 CPB15+(n = 625) (n = 625) (n = 623)

Median PFS (months) 10.6 11.6 14.7

Hazard ratio (95% CI) 2 0.89 0.70(0.78, 1.02) (0.61, 0.81)p-value 3, 4 0.0437 < 0.0001

Objective response rate 5

CPP CPB15 CPB15+(n = 396) (n = 393) (n = 403)% pts with objective response 63.4 66.2 66.0p-value 0.2341 0.2041

Overall survival 6

CPP CPB15 CPB15+(n = 625) (n = 625) (n = 623)

Median OS (months) 40.6 38.8 43.8

Hazard ratio (95% CI) 2 1.07 (0.91, 1.25) 0.88 (0.75, 1.04)p-value 3 0.2197 0.06411 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions norcensored for NPT prior to disease progression) with data cut-off date of 25 February, 2010.

2 Relative to the control arm; stratified hazard ratio.3 One-sided log-rank p-value4 Subject to a p-value boundary of 0.0116.5 Patients with measurable disease at baseline.6 Final overall survival analysis performed when 46.9% of the patients had died.

Prespecified PFS analyses were conducted, all with a cut-off date of 29 September 2009. The resultsof these prespecified analyses are as follows:

- The protocol specified analysis of investigator-assessed PFS (without censoring for CA-125progression or non-protocol therapy [NPT]) shows a stratified hazard ratio of 0.71 (95% CI:0.61-0.83, 1-sided log-rank p-value < 0.0001) when CPB15+ is compared with CPP, with amedian PFS of 10.4 months in the CPP arm and 14.1 months in the CPB15+ arm.

- The primary analysis of investigator-assessed PFS (censoring for CA-125 progressions and

NPT) shows a stratified hazard ratio of 0.62 (95% CI: 0.52-0.75, 1-sided log-rank p-value< 0.0001) when CPB15+ is compared with CPP, with a median PFS of 12.0 months in the CPParm and 18.2 months in the CPB15+ arm.

- The analysis of PFS as determined by the independent review committee (censoring for NPT)shows a stratified hazard ratio of 0.62 (95% CI: 0.50-0.77, 1-sided log-rank p-value < 0.0001)when CPB15+ is compared with CPP, with a median PFS of 13.1 in the CPP arm and19.1 months in the CPB15+ arm.

PFS subgroup analyses by disease stage and debulking status are summarised in Table 17. Theseresults demonstrate robustness of the analysis of PFS as shown in Table 16.

Table 17 PFS1 results by disease stage and debulking status from study GOG-0218

Randomised patients stage III optimally debulked disease 2,3

CPP CPB15 CPB15+(n = 219) (n = 204) (n = 216)

Median PFS (months) 12.4 14.3 17.5

Hazard ratio (95% CI)4 0.81 0.66(0.62, 1.05) (0.50, 0.86)

Randomised patients with stage III suboptimally debulked disease3

CPP CPB15 CPB15+(n = 253) (n = 256) (n = 242)

Median PFS (months) 10.1 10.9 13.9

Hazard ratio (95% CI)4 0.93 0.78(0.77, 1.14) (0.63, 0.96)

Randomised patients with stage IV disease

CPP CPB15 CPB15+(n = 153) (n = 165) (n = 165)

Median PFS (months) 9.5 10.4 12.8

Hazard Ratio (95% CI)4 0.90 0.64(0.70, 1.16) (0.49, 0.82)1 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions norcensored for NPT prior to disease progression) with data cut-off date of 25 February, 20102 With gross residual disease.3 3.7% of the overall randomised patient population had stage IIIB disease.4 Relative to the control arm.

BO17707 was a phase III, two arm, multicentre, randomised, controlled, open-label study comparingthe effect of adding Avastin to carboplatin plus paclitaxel in patients with FIGO stage I or IIA (Grade3 or clear cell histology only; n = 142), or FIGO stage IIB - IV (all Grades and all histological types,n = 1386) epithelial ovarian, fallopian tube or primary peritoneal cancer following surgery (NCI-

CTCAE v.3). FIGO staging version dated 1988 was used in this trial.

Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy forovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, orhormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study.

A total of 1528 patients were randomised in equal proportions to the following two arms:

- CP arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks duration

- CPB7.5+ arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks plus

Avastin (7.5 mg/kg q3w) for up to 12 months (Avastin was started at cycle 2 of chemotherapy iftreatment was initiated within 4 weeks of surgery or at cycle 1 if treatment was initiated morethan 4 weeks after surgery).

The majority of patients included in the study were White (96%), the median age was 57 years in bothtreatment arms, 25% of patients in each treatment arm were 65 years of age or over, andapproximately 50% of patients had an ECOG PS of 1; 7% of patients in each treatment arm had an

ECOG PS of 2. The majority of patients had EOC (87.7%) followed by PPC (6.9%) and FTC (3.7%)or a mixture of the three origins (1.7%). Most patients were FIGO stage III (both 68%) followed by

FIGO stage IV (13% and 14%), FIGO stage II (10% and 11%) and FIGO stage I (9% and 7%). Themajority of the patients in each treatment arm (74% and 71%) had poorly differentiated (Grade 3)primary tumours at baseline. The incidence of each histologic sub-type of EOC was similar betweenthe treatment arms; 69% of patients in each treatment arm had serous adenocarcinoma histologic type.

The primary endpoint was PFS as assessed by the investigator using RECIST.

The trial met its primary objective of PFS improvement. Compared to patients treated withchemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who receivedbevacizumab at a dose of 7.5 mg/kg q3w in combination with chemotherapy and continued to receivebevacizumab for up to 18 cycles had a statistically significant improvement in PFS.

The results of this study are summarised in Table 18.

Table 18 Efficacy results from study BO17707 (ICON7)

Progression-free survival

CP CPB7.5+(n = 764) (n = 764)

Median PFS (months) 2 16.9 19.3

Hazard ratio [95% CI] 2 0.86 [0.75; 0.98](p-value = 0.0185)

Objective response rate 1

CP CPB7.5+(n = 277) (n = 272)

Response rate 54.9% 64.7%(p-value = 0.0188)

Overall survival 3

CP CPB7.5+(n = 764) (n = 764)

Median (months) 58.0 57.4

Hazard ratio [95% CI] 0.99 [0. 85; 1. 15](p-value = 0. 8910)1 In patients with measurable disease at baseline.2 Investigator assessed PFS analysis with data cut-off date of 30 November 2010.3 Final overall survival analysis performed when 46.7% of the patients had died with data cut-off date of 31

March 2013.

The primary analysis of investigator-assessed PFS with a data cut-off date of 28 February 2010 showsan unstratified hazard ratio of 0.79 (95% CI: 0.68-0.91, 2-sided log-rank p-value 0.0010) with amedian PFS of 16.0 months in the CP arm and 18.3 months in the CPB7.5+ arm.

PFS subgroup analyses by disease stage and debulking status are summarised in Table 19. Theseresults demonstrate robustness of the primary analysis of PFS as shown in Table 18.

Table 19 PFS1 results by disease stage and debulking status from study BO17707 (ICON7)

Randomised patients with stage III optimally debulked disease 2,3

CP CPB7.5+(n = 368) (n = 383)

Median PFS (months) 17.7 19.3

Hazard ratio (95% CI) 4 0.89(0.74, 1.07)

Randomised patients with stage III suboptimally debulked disease3

CP CPB7.5+(n = 154) (n = 140)

Median PFS (months) 10.1 16.9

Hazard ratio (95% CI)4 0.67(0.52, 0.87)

Randomised patients with stage IV disease

CP CPB7.5+(n = 97) (n = 104)

Median PFS (months) 10.1 13.5

Hazard ratio (95% CI)4 0.74(0.55, 1.01)1 Investigator assessed PFS analysis with data cut-off date of 30 November 2010.2 With or without gross residual disease.3 5.8% of the overall randomised patient population had stage IIIB disease.4 Relative to the control arm.

Recurrent ovarian cancer

The safety and efficacy of Avastin in the treatment of recurrent epithelial ovarian, fallopian tube orprimary peritoneal cancer was studied in three phase III trials (AVF4095g , MO22224 and GOG-0213) with different patient populations and chemotherapy regimens.

- AVF4095g evaluated the efficacy and safety of bevacizumab in combination with carboplatinand gemcitabine, followed by bevacizumab as a single agent in patients with platinum-sensitiverecurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

- GOG-0213 evaluated the efficacy and safety of bevacizumab in combination with carboplatinand paclitaxel, followed by bevacizumab as a single agent in patients with platinum-sensitiverecurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

- MO22224 evaluated the efficacy and safety of bevacizumab in combination with paclitaxel,topotecan, or pegylated liposomal doxorubicin in patients with platinum-resistant recurrentepithelial ovarian, fallopian tube or primary peritoneal cancer.

The safety and efficacy of Avastin in the treatment of patients with platinum-sensitive, recurrentepithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received priorchemotherapy in the recurrent setting or prior bevacizumab treatment, was studied in a phase IIIrandomised, double-blind, placebo-controlled trial (AVF4095g). The study compared the effect ofadding Avastin to carboplatin and gemcitabine chemotherapy and continuing Avastin as a single agentto progression, to carboplatin and gemcitabine alone.

Only patients with histologically documented ovarian, primary peritoneal, or fallopian tube carcinomathat had recurred > 6 months after platinum-based chemotherapy and who had not receivedchemotherapy in the recurrent setting and who have not received prior therapy with bevacizumab orother VEGF inhibitors or VEGF receptor-targeted agents were included in the study.

A total of 484 patients with measurable disease were randomised 1:1 to either:

- Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrentplacebo every 3 weeks for 6 and up to 10 cycles followed by placebo (every 3 weeks) aloneuntil disease progression or unacceptable toxicity

- Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent

Avastin (15 mg/kg Day 1) every 3 weeks for 6 and up to 10 cycles followed by Avastin(15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity

The primary endpoint was progression-free survival based on investigator assessment using modified

RECIST 1.0. Additional endpoints included objective response, duration of response, overall survivaland safety. An independent review of the primary endpoint was also conducted.

The results of this study are summarised in Table 20.

Table 20 Efficacy results from study AVF4095g

Progression-free survival

Investigator Assessment IRC Assessment

Placebo + C/G Avastin + C/G Placebo + C/G Avastin + C/G(n = 242) (n = 242) (n = 242) (n = 242)

Not censored for NPT

Median PFS (months) 8.4 12.4 8.6 12.3

Hazard ratio(95% CI) 0.524 [0.425, 0.645] 0.480 [0.377, 0.613]p -value < 0.0001 < 0.0001

Censored for NPT

Median PFS (months) 8.4 12.4 8.6 12.3

Hazard ratio(95% CI) 0.484 [0.388, 0.605] 0.451 [0.351, 0.580]p-value < 0.0001 < 0.0001

Objective response rate

Investigator Assessment IRC Assessment

Placebo + C/G Avastin + C/G Placebo + C/G Avastin + C/G(n = 242) (n = 242) (n = 242) (n = 242)% pts with objectiveresponse 57.4% 78.5% 53.7% 74.8%p -value < 0.0001 < 0.0001

Overall survival

Placebo + C/G Avastin + C/G(n = 242) (n = 242)

Median OS (months) 32.9 33.6

Hazard ratio(95% CI) 0.952 [0.771, 1.176]p-value 0.6479

PFS subgroup analyses depending on recurrence since last platinum therapy are summarised in

Table 21.

Table 21 Progression-free survival by time from last platinum therapy to recurrence

Investigator Assessment

Time from last platinum Placebo + C/G Avastin + C/Gtherapy to recurrence (n = 242) (n = 242)6-12 months (n = 202)

Median 8.0 11.9

Hazard ratio (95% CI) 0.41 (0.29-0.58)> 12 months (n = 282)

Median 9.7 12.4

Hazard ratio (95% CI) 0.55 (0.41-0.73)

GOG-0213, a phase III randomised controlled open label trial, studied the safety and efficacy of

Avastin in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tubeor primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting. Therewas no exclusion criterion for prior anti-angiogenic therapy. The study evaluated the effect of adding

Avastin to carboplatin + paclitaxel and continuing Avastin as a single agent until disease progressionor unacceptable toxicity compared to carboplatin + paclitaxel alone.

A total of 673 patients were randomised in equal proportions to the following two treatment arms:

- CP arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 intravenously) every 3 weeks for 6 andup to 8 cycles.

- CPB arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 intravenously) and concurrent

Avastin (15 mg/kg) every 3 weeks for 6 and up to 8 cycles, followed by Avastin (15 mg/kgevery 3 weeks) alone until disease progression or unacceptable toxicity.

Most patients in both the CP arm (80.4%) and the CPB arm (78.9%) were White. The median age was60.0 years in the CP arm and 59.0 years in the CPB arm. The majority of patients (CP: 64.6%; CPB:68.8%) were in the age category < 65 years. At baseline, most patients in both treatment arms had a

GOG PS of 0 (CP: 82.4%: CPB; 80.7%) or 1 (CP: 16.7%: CPB; 18.1%). A GOG PS of 2 at baselinewas reported in 0.9% of patients in the CP arm and in 1.2% of patients in the CPB arm.“

The primary efficacy endpoint was overall survival (OS). The main secondary efficacy endpoint wasprogression-free survival (PFS). Results are presented in Table 22.

Table 22 Efficacy results1,2 from study GOG-0213

Primary endpoint

Overall survival (OS) CP CPB(n = 336) (n = 337)

Median OS (months) 37.3 42.6

Hazard ratio (95% CI) (eCRF)a 0.823 [CI: 0.680, 0.996]p-Value 0.0447

Hazard ratio (95% CI) (registration form)b 0.838 [CI: 0.693, 1.014]p-Value 0.0683

Secondary endpoint

Progression-free survival (PFS) CP CPB(n = 336) (n = 337)

Median PFS (months) 10.2 13.8

Hazard ratio (95% CI) 0.613 [CI: 0.521, 0.721]p-value < 0.00011 Final Analysis 2 Tumour assessments and response evaluations were determined by the investigators using the GOG

RECIST criteria (Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228Y247).

a Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval priorto enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status Yes/No(Yes=randomised to undergo cytoreduction or randomised to not undergo cytoreduction; No= not a candidate or did notconsent to cytoreduction). b stratified by the duration of treatment free-interval prior to enrolling onto this study per theregistration form, and secondary surgical debulking status Yes/No.

The trial met its primary objective of OS improvement. Treatment with Avastin at 15 mg/kg every3 weeks in combination with chemotherapy (carboplatin and paclitaxel) for 6 and up to 8 cycles,followed by Avastin until disease progression or unacceptable toxicity resulted, when data werederived from eCRF, in a clinically meaningful and statistically significant improvement in OScompared to treatment with carboplatin and paclitaxel alone.

Study MO22224 evaluated the efficacy and safety of bevacizumab in combination with chemotherapyfor platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Thisstudy was designed as an open-label, randomised, two-arm phase III evaluation of bevacizumab pluschemotherapy (CT + BV) versus chemotherapy alone (CT).

A total of 361 patients were enrolled into this study and administered either chemotherapy (paclitaxel,topotecan, or pegylated liposomal doxorubicin (PLD) alone or in combination with bevacizumab:

- CT Arm (chemotherapy alone):

- Paclitaxel 80 mg/m2 as a 1-hour intravenous infusion on Days 1, 8, 15, and 22 every4 weeks.

- Topotecan 4 mg/m2 as a 30-minute intravenous infusion on Days 1, 8, and 15 every4 weeks. Alternatively, a 1.25 mg/m2 dose could be administered over 30 minutes on

Days 1-5 every 3 weeks.

- PLD 40 mg/m2 as a 1 mg/min intravenous infusion on Day 1 only every 4 weeks. After

Cycle 1, the medicinal product could be delivered as a 1-hour infusion.

- CT + BV Arm (chemotherapy plus bevacizumab):

- The chosen chemotherapy was combined with bevacizumab 10 mg/kg intravenouslyevery 2 weeks (or bevacizumab 15 mg/kg every 3 weeks if used in combination withtopotecan 1.25 mg/m2 on Days 1-5 every 3 weeks).

Eligible patients had epithelial ovarian, fallopian tube or primary peritoneal cancer that progressedwithin <6 months of previous platinum therapy consisting of a minimum of 4 platinum therapy cycles.

Patients should have had a life expectancy of ≥ 12 weeks and no prior radiotherapy to the pelvis orabdomen. Most patients were FIGO stage IIIC or stage IV. The majority of patients in both arms hadan ECOG Performance Status (PS) of 0 (CT: 56.4% vs. CT + BV: 61.2%). The percentage of patientswith an ECOG PS of 1 or ≥ 2 was 38.7% and 5.0% in the CT arm, and 29.8% and 9.0% in the

CT + BV arm. Information on race exists for 29.3% of patients and nearly all patients were white. Themedian age of patients was 61.0 (range: 2584) years. A total of 16 patients (4.4%) were > 75 yearsold. The overall rates of discontinuation due to adverse events were 8.8% in the CT arm and 43.6% inthe CT + BV arm (mostly due to Grade 2-3 adverse events) and the median time to discontinuation inthe CT + BV arm was 5.2 months compared with 2.4 months in the CT arm. The rates ofdiscontinuation due to adverse events in the subgroup of patients > 65 years old were 8.8% in the CTarm and 50.0% in the CT + BV arm. The HR for PFS was 0.47 (95% CI: 0.35, 0.62) and 0.45 (95%

CI: 0.31, 0.67) for the < 65 and ≥ 65 subgroups, respectively.

The primary endpoint was progression-free-survival, with secondary endpoints including objectiveresponse rate and overall survival. Results are presented in Table 23.

Table 23 Efficacy Results from Study MO22224

Primary endpoint

Progression-free survival*

CT CT + BV(n = 182) (n = 179)

Median (months) 3.4 6.7

Hazard ratio(95% CI) 0.379 [0.296, 0.485]p-value < 0.0001

Secondary Endpoints

Objective response rate**

CT CT + BV(n = 144) (n = 142)% patients with objective response 18 (12.5%) 40 (28.2%)p -value 0.0007

Overall survival (final analysis)***

CT CT + BV(n = 182) (n = 179)

Median OS (months) 13.3 16.6

Hazard ratio(95% CI) 0.870 [0.678, 1.116]p-value 0.2711

All analyses presented in this table are stratified analyses.

* Primary analysis was performed with a data cut-off date of 14 November 2011.

**Randomised Patients with Measurable Disease at Baseline.

***The final analysis of overall survival was performed when 266 deaths, which account for 73.7% of enrolledpatients, were observed.

The trial met its primary objective of PFS improvement. Compared to patients treated withchemotherapy (paclitaxel, topotecan or PLD) alone in the recurrent platinum-resistant setting, patientswho received bevacizumab at a dose of 10 mg/kg every 2 weeks (or 15 mg/kg every 3 weeks if used incombination with 1.25 mg/m2 topotecan on Days 1-5 every 3 weeks) in combination withchemotherapy and continued to receive bevacizumab until disease progression or unacceptabletoxicity, had a statistically significant improvement in PFS. The exploratory PFS and OS analyses bychemotherapy cohort (paclitaxel, topotecan and PLD) are summarised in Table 24.

Table 24: Exploratory PFS and OS analyses by chemotherapy cohort

CT CT+BV

Paclitaxel n = 115

Median PFS (months) 3.9 9.2

Hazard ratio (95% CI) 0.47 [0.31, 0.72]

Median OS (months) 13.2 22.4

Hazard ratio (95% CI) 0.64 [0.41, 0.99]

Topotecan n = 120

Median PFS (months) 2.1 6.2

Hazard ratio (95% CI) 0.28 [0.18, 0.44]

Median OS (months) 13.3 13.8

Hazard ratio (95% CI) 1.07 [0.70, 1.63]

PLD n = 126

Median PFS (months) 3.5 5.1

Hazard ratio (95% CI) 0.53 [0.36, 0.77]

Median OS (months) 14.1 13.7

Hazard ratio (95% CI) 0.91 [0.61, 1.35]

Cervical Cancer

The efficacy and safety of Avastin in combination with chemotherapy (paclitaxel and cisplatin orpaclitaxel and topotecan) in the treatment for patients with persistent, recurrent or metastaticcarcinoma of the cervix was evaluated in study GOG-0240, a randomised, four-arm, open label, multi-centre phase III trial.

A total of 452 patients were randomised to receive either:

- Paclitaxel 135 mg/m2 intravenously over 24 hours on Day 1 and cisplatin 50 mg/m2intravenously on Day 2, every 3 weeks (q3w); or

Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenouslyon Day 2 (q3w); or

Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenouslyon Day 1 (q3w)

- Paclitaxel 135 mg/m2 intravenously over 24 hours on Day 1 and cisplatin 50 mg/m2intravenously on Day 2 plus bevacizumab 15 mg/kg intravenously on Day 2 (q3w); or

Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenouslyon Day 2 plus bevacizumab 15 mg/kg intravenously on Day 2 (q3w); or

Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenouslyon Day 1 plus bevacizumab 15 mg/kg intravenously on Day 1 (q3w)

- Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and topotecan 0.75 mg/m2intravenously over 30 minutes on days 1-3 (q3w)

- Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and topotecan 0.75 mg/m2intravenously over 30 minutes on Days 1-3 plus bevacizumab 15 mg/kg intravenously on Day 1(q3w)

Eligible patients had persistent, recurrent or metastatic squamous cell carcinoma, adenosquamouscarcinoma, or adenocarcinoma of the cervix which was not amenable to curative treatment withsurgery and/or radiation therapy and who have not received prior therapy with bevacizumab or other

VEGF inhibitors or VEGF receptor-targeted agents.

The median age was 46.0 years (range: 20-83) in the Chemo alone group and 48.0 years(range: 22-85) in the Chemo + Avastin group; with 9.3% of patients in the Chemo alone group and7.5% of patients in the Chemo + Avastin group over the age of 65 years.

Of the 452 patients randomised at baseline, the majority of patients were white (80.0% in the Chemoalone group and 75.3% in the Chemo + Avastin group), had squamous cell carcinoma (67.1% in the

Chemo alone group and 69.6% in the Chemo + Avastin group), had persistent/recurrent disease(83.6% in the Chemo alone group and 82.8% in the Chemo + Avastin group), had 1-2 metastatic sites(72.0% in the Chemo alone group and 76.2% in the Chemo + Avastin group), had lymph nodeinvolvement (50.2% in the Chemo alone group and 56.4% in the Chemo + Avastin group), and had aplatinum free interval≥ 6 months (72.5% in the Chemo alone group and 64.4% in the

Chemo + Avastin group).

The primary efficacy endpoint was overall survival. Secondary efficacy endpoints includedprogression-free survival and objective response rate.

Results from the primary analysis and the follow-up analysis are presented by Avastin Treatment andby Trial Treatment in Table 25 and Table 26, respectively.

Table 25 Efficacy results from study GOG-0240 by Avastin treatment

Chemotherapy Chemotherapy + Avastin(n = 225) (n = 227)

Primary endpoint

Overall survival - Primary analysis6

Median (months)1 12.9 16.8

Hazard ratio [95% CI] 0.74 [0.58, 0.94](p-value5 = 0.0132)

Overall survival - Follow-up analysis7

Median (months)1 13.3 16.8

Hazard ratio [95% CI] 0.76 [0.62, 0.94](p-value5,8 = 0.0126)

Secondary endpoints

Progression-free survival - Primary analysis6

Median PFS (months)1 6.0 8.3

Hazard ratio [95% CI] 0.66 [0.54, 0.81](p-value5 < 0.0001)

Best overall response - Primary analysis6

Responders (response rate2) 76 (33.8%) 103 (45.4%)95% CI for response rates3 [27.6%, 40.4%] [38.8%, 52.1%]

Difference in response rates 11.60%95% CI for difference in response rates4 [2.4%, 20.8%]p-value (chi-squared test) 0.01171 Kaplan-Meier estimates2 Patients and percentage of patients with best overall response of confirmed CR or PR; percentage calculated on patientswith measurable disease at baseline3 95% CI for one sample binomial using Pearson-Clopper method4 Approximate 95% CI for difference of two rates using Hauck-Anderson method5 log-rank test (stratified)6 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final analysis7 Follow-up analysis was performed with a data cut-off date of 07 March 20148 p-value displayed for descriptive purpose only

Table 26 Overall survival results from study GOG-0240 by Trial Treatment

Overall survival - Follow-up

Treatment Other Overall survival - Primary analysis1 analysis2

Comparison Factor Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Avastin vs. Cisplatin+ 0.72 (0.51, 1.02) 0.75 (0.55, 1.01)

No Avastin Paclitaxel (17.5 vs.14.3 months; p = 0.0609) (17.5 vs.15.0 months; p = 0.0584)

Topotecan+ 0.76 (0.55, 1.06) 0.79 (0.59, 1.07)

Paclitaxel (14.9 vs. 11.9 months; p = 0.1061) (16.2 vs. 12.0 months; p = 0.1342)

Topotecan+ Avastin 1.15 (0.82, 1.61) 1.15 (0.85, 1.56)

Paclitaxel (14.9 vs. 17.5 months; p = 0.4146) (16.2 vs 17.5 months; p = 0.3769)vs.

Cisplatin+ No Avastin 1.13 (0.81, 1.57) 1.08 (0.80, 1.45)

Paclitaxel (11.9 vs.14.3 months; p = 0.4825) (12.0 vs 15.0 months; p = 0.6267)1 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the finalanalysis2 Follow-up analysis was performed with a data cut-off date of 07 March 2014; all p-values are displayed fordescriptive purpose only

The European Medicines Agency has waived the obligation to submit the results of studies, in allsubsets of the paediatric population, in breast carcinoma, adenocarcinoma of the colon and rectum,lung carcinoma (small cell and non-small cell carcinoma), kidney and renal pelvis carcinoma(excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renalmedullary carcinoma and rhabdoid tumour of the kidney), ovarian carcinoma (excludingrhabdomyosarcoma and germ cell tumours), fallopian tube carcinoma (excluding rhabdomyosarcomaand germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) and cervix andcorpus uteri carcinoma.

High-grade glioma

Anti-tumour activity was not observed in two earlier studies among a total of 30 children aged> 3 years old with relapsed or progressive high-grade glioma when treated with bevacizumab andirinotecan (CPT-11). There is insufficient information to determine the safety and efficacy ofbevacizumab in children with newly-diagnosed high-grade glioma.

- In a single-arm study (PBTC-022), 18 children with recurrent or progressive non-pontine high-grade glioma (including 8 with glioblastoma [WHO Grade IV], 9 with anaplastic astrocytoma[Grade III] and 1 with anaplastic oligodendroglioma [Grade III]) were treated with bevacizumab(10 mg/kg) two weeks apart and then with bevacizumab in combination with CPT-11(125-350 mg/m²) once every two weeks until progression. There were no objective (partial orcomplete) radiological responses (MacDonald criteria). Toxicity and adverse reactions includedarterial hypertension and fatigue as well as CNS ischaemia with acute neurological deficit.

- In a retrospective single institution series, 12 consecutive (2005 to 2008) children with relapsedor progressive high-grade glioma (3 with WHO Grade IV, 9 with Grade III) were treated withbevacizumab (10 mg/kg) and irinotecan (125 mg/m²) every 2 weeks. There were no completeresponses and 2 partial responses (MacDonald criteria).

In a randomised phase II study (BO25041) a total of 121 patients aged ≥ 3 years to < 18 years withnewly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG)were treated with post operative radiation therapy (RT) and adjuvant temozolomide (T) with andwithout bevacizumab: 10 mg/kg every 2 weeks intravenously.

The study did not meet its primary endpoint of demonstrating a significant improvement of EFS(Central Radiology Review Committee (CRRC)-assessed) when bevacizumab was added to the RT/Tarm compared with RT/T alone (HR = 1.44; 95% CI: 0.90, 2.30). These results were consistent withthose from various sensitivity analyses and in clinically relevant subgroups. The results for allsecondary endpoints (investigator assessed EFS, and ORR and OS) were consistent in showing noimprovement associated with the addition of bevacizumab to the RT/T arm compared with the RT/Tarm alone.

Addition of Avastin to RT/T did not demonstrate clinical benefit in study BO25041 in 60 evaluablechildren patients with newly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG) (See section 4.2 for information on paediatric use).

Soft tissue sarcoma

In a randomised phase II study (BO20924) a total of 154 patients aged ≥ 6 months to < 18 years withnewly diagnosed metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma weretreated with standard of care (Induction IVADO/IVA+/- local therapy followed by Maintenance

Vinorelbine and cyclophosphamide) with or without bevacizumab (2.5 mg/kg/week) for a totalduration of treatment of approximately 18 months. At the time of the final primary analysis, theprimary endpoint of EFS by independent central review did not show a statistically significantdifference between the two treatment arms, with HR of 0.93 (95% CI: 0.61, 1.41; p-value = 0.72). Thedifference in ORR per independent central review was 18% (CI: 0.6%, 35.3%) between the twotreatment arms in the few patients who had evaluable tumour at baseline and had a confirmed responseprior to receiving any local therapy : 27/75 patients (36.0%, 95% CI: 25.2%, 47.9%) in the Chemo armand 34/63 patients (54.0%, 95% CI: 40.9%, 66.6%) in the Bv + Chemo arm. The final Overall

Survival (OS) analyses showed no significant clinical benefit from addition of bevacizumab tochemotherapy in this patient population.

Addition of Avastin to standard of care did not demonstrate clinical benefit in clinical trial BO20924,in 71 evaluable children (from age 6 months to less than 18 years old) patients with metastatic

Rhabdomyosarcoma and non-Rhabdomyosarcoma Soft Tissue Sarcoma.(See section 4.2 for information on paediatric use).

The incidence of AEs, including Grade ≥ 3 AEs and SAEs, was similar between the two treatmentarms. No AEs leading to death occurred in either treatment arm; all deaths were attributed to diseaseprogression. Bevacizumab addition to multimodal standard of care treatment seemed to be tolerated inthis paediatric population.

The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients with solidtumours. In all clinical trials, bevacizumab was administered as an intravenous infusion. The rate ofinfusion was based on tolerability, with an initial infusion duration of 90 minutes. Thepharmacokinetics of bevacizumab was linear at doses ranging from 1 to 10 mg/kg.

The typical value for central volume (Vc) was 2.73 l and 3.28 l for female and male patientsrespectively, which is in the range that has been described for IgGs and other monoclonal antibodies.

The typical value for peripheral volume (Vp) was 1.69 l and 2.35 l for female and male patientsrespectively, when bevacizumab is co-administered with anti-neoplastic agents. After correcting forbody weight, male patients had a larger Vc (+ 20%) than female patients.

Assessment of bevacizumab metabolism in rabbits following a single intravenous dose of 125I-bevacizumab indicated that its metabolic profile was similar to that expected for a native IgG moleculewhich does not bind VEGF. The metabolism and elimination of bevacizumab is similar to endogenous

IgG i.e. primarily via proteolytic catabolism throughout the body, including endothelial cells, and doesnot rely primarily on elimination through the kidneys and liver. Binding of the IgG to the FcRnreceptor results in protection from cellular metabolism and the long terminal half-life.

The value for clearance is, on average, equal to 0.188 and 0.220 l/day for female and male patients,respectively. After correcting for body weight, male patients had a higher bevacizumab clearance(+ 17%) than females. According to the two-compartmental model, the elimination half-life is 18 daysfor a typical female patient and 20 days for a typical male patient.

Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumabclearance was approximately 30% faster in patients with low levels of serum albumin and 7% faster insubjects with higher tumour burden when compared with a typical patient with median values ofalbumin and tumour burden.

The population pharmacokinetics were analysed in adult and paediatric patients to evaluate the effectsof demographic characteristics. In adults, the results showed no significant difference in thepharmacokinetics of bevacizumab in relation to age.

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in renally impairedpatients since the kidneys are not a major organ for bevacizumab metabolism or excretion.

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in patients withhepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion.

The pharmacokinetics of bevacizumab were evaluated in 152 children, adolescents and young adults(7 months to 21 years, 5.9 to 125 kg) across 4 clinical studies using a population pharmacokineticmodel. The pharmacokinetic results show that the clearance and volume of distribution ofbevacizumab were comparable between paediatric and young adult patients when normalised by bodyweight, with exposure trending lower as body weight decreased. Age was not associated with thepharmacokinetics of bevacizumab when body weight was taken into account.

The pharmacokinetics of bevacizumab was well characterised by the paediatric population PK modelfor 70 patients in Study BO20924 ((1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in Study

BO25041 (1 to 17 years; 11.2 to 82.3 kg). In Study BO20924, bevacizumab exposure was generallylower compared to a typical adult patient at the same dose. In Study BO25041, bevacizumab exposurewas similar compared to a typical adult at the same dose. In both studies, bevacizumab exposuretrended lower as body weight decreased.

In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed inyoung animals with open growth plates, at bevacizumab average serum concentrations below theexpected human therapeutic average serum concentrations. In rabbits, bevacizumab was shown toinhibit wound healing at doses below the proposed clinical dose. Effects on wound healing wereshown to be fully reversible.

Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not beenperformed.

No specific studies in animals have been conducted to evaluate the effect on fertility. An adverseeffect on female fertility can however be expected as repeat dose toxicity studies in animals haveshown inhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea andassociated decrease in ovarian and uterus weight as well as a decrease in the number of menstrualcycles.

Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits.

Observed effects included decreases in maternal and foetal body weights, an increased number offoetal resorptions and an increased incidence of specific gross and skeletal foetal malformations.

Adverse foetal outcomes were observed at all tested doses, of which the lowest dose resulted inaverage serum concentrations approximately 3 times larger than in humans receiving 5 mg/kg every2 weeks. Information on foetal malformations observed in the post marketing setting are provided insection 4.6 Fertility, Pregnancy and Lactation and 4.8 Undesirable Effects.

Trehalose dihydrate

Sodium phosphate

Polysorbate 20 (E 432)

Water for injections

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

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

Vial (unopened)3 years.

Chemical and physical in-use stability has been demonstrated for 30 days at 2 °C to 8 °C plus anadditional 48 hours at 2 °C to 30 °C in sodium chloride 9 mg/ml (0.9%) solution for injection. From amicrobiological 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 longerthan 24 hours at 2 °C to 8 °C, unless dilution has taken place in controlled and validated asepticconditions.

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

4 ml solution in a vial (Type I glass) with a stopper (butyl rubber) containing 100 mg of bevacizumab.16 ml solution in a vial (Type I glass) with a stopper (butyl rubber) containing 400 mg ofbevacizumab.

Pack of 1 vial.

Do not shake the vial.

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

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

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

No incompatibilities between Avastin and polyvinyl chloride or polyolefine bags or infusion sets havebeen observed.

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

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/04/300/001 - 100 mg/4 ml vial

EU/1/04/300/002 - 400 mg/16 ml vial

Date of first authorisation: 12 January 2005

Date of latest renewal: 17 November 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMA): https://www.ema.europa.eu.