Antineoplastic Agents

Bevacizumab

Bevacizumab 25 mg per ml. Each vial contains 100 mg of bevacizumab in 4 ml and 400 mg in 16 ml respectively. Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in Chinese Hamster ovary cells.

Concentrate for solution for infusion. Clear to slightly opalescent, colourless to pale brown liquid.

Avastin (bevacizumab) in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of patients with metastatic carcinoma of the colon or rectum. Avastin in combination with paclitaxel is indicated for first-line treatment of patients with metastatic breast cancer. Avastin, in addition to platinum-based chemotherapy, is indicated for first-line treatment of patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. Avastin in combination with interferon alfa-2a is indicated for first line treatment of patients with advanced and/or metastatic renal cell cancer.

General

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

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

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

Do not administer as an intravenous push or bolus.

Instructions for the preparation of Avastin infusions are described in section 6.6. Avastin infusions should not be administered or mixed with glucose solutions.

Metastatic carcinoma of the colon or rectum (mCRC)

The recommended dose of Avastin, administered as an intravenous infusion, is either 5 mg/kg or 10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks.

Dose reduction for adverse events is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended.

Metastatic breast cancer (mBC)

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

Non-small cell lung cancer (NSCLC)

Avastin is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed 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 every 3 weeks as an intravenous infusion.

Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses.

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 an intravenous infusion.

Special populations

Children and Adolescents: The safety and efficacy in children and adolescents have not been established. Avastin is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

Elderly: No dose adjustment is required in the elderly.

Renal impairment: The safety and efficacy have not been studied in patients with renal impairment.

Hepatic impairment: The safety and efficacy have not been studied in patients with hepatic impairment.

The safety and efficacy in children and adolescents have not been studied. Avastin is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

No dose adjustment is required in the elderly.

• Hypersensitivity to the active substance or to any of the excipients.

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

• Pregnancy

Gastrointestinal perforations

Patients may be at an increased risk for the development of gastrointestinal perforation when treated with Avastin. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation.

Fistulae

Patients may be at increased risk for the development of fistulae when treated with Avastin.

Permanently discontinue Avastin in patients with TE (tracheoesophageal) fistula or any grade 4 fistula. Limited information is available on the continued use of Avastin in patients with other fistulae.

In cases of internal fistula not arising in the GI tract, discontinuation of Avastin should be considered.

Wound healing complications 

Avastin may adversely affect the wound healing process. Therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experienced wound healing complications during therapy, treatment should be withheld until the wound is fully healed. Therapy should be withheld for elective surgery.

Hypertension

An increased incidence of hypertension was observed in Avastin-treated patients. Clinical safety data suggest that the incidence of hypertension is likely to be dose-dependent. Pre existing hypertension should be adequately controlled before starting Avastin treatment. There is no information on the effect 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 treatment appropriate for the individual situation of the affected patient. The use of diuretics to manage hypertension is not advised in patients who receive a cisplatin-based chemotherapy regimen. Avastin should be permanently discontinued, if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy.

Reversible posterior leukoencephalopathy syndrome (RPLS) 

There have been rare reports of Avastin-treated patients developing signs and symptoms that are consistent with Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a rare neurologic disorder, which can present with the following signs and symptoms among others: seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of RPLS requires confirmation by brain imaging. In patients developing RPLS, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of Avastin. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known.

Proteinuria

Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with Avastin. There is evidence suggesting that Grade 1 [US National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 2.0] proteinuria may be related to the dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Therapy should be permanently discontinued in patients who develop Grade 4 proteinuria (nephrotic syndrome).

Arterial thromboembolism

In five randomised clinical trials, the incidence of arterial thromboembolic events including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher in patients receiving Avastin in combination with chemotherapy compared to those who received chemotherapy alone.

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

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

Venous thromboembolism

Patients may be at risk of developing venous thromboembolic events, including pulmonary embolism under Avastin treatment. Avastin should be discontinued in patients with life-threatening (Grade 4) pulmonary embolism, patients with Grade 3 need to be closely monitored.

Haemorrhage

Patients treated with Avastin have an increased risk of haemorrhage, especially tumour-associated haemorrhage. Avastin should be discontinued permanently in patients who experience Grade 3 or 4 bleeding during Avastin therapy.

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 such patients has not been prospectively evaluated in randomised clinical trials. Patients should be monitored for signs and symptoms of CNS bleeding, and Avastin treatment discontinued in cases 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 of thromboembolism prior to starting Avastin treatment, as such patients were excluded from clinical trials. Therefore, caution should be exercised before initiating therapy in these patients. However, patients who developed venous thrombosis while receiving therapy did not appear to have an increased rate of grade 3 or above bleeding when treated with a full dose of warfarin and Avastin concomitantly.

Pulmonary haemorrhage/haemoptysis

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

Congestive heart failure (CHF)

Events consistent with CHF were reported in clinical trials. The symptoms ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation. Most of the patients who experienced CHF had metastatic breast cancer and had received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF, such as pre-existing coronary heart disease or concomitant cardiotoxic therapy.

Caution should be exercised when treating patients with clinically significant cardiovascular disease or pre-existing congestive heart failure with Avastin.

Neutropenia and infections

Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus Avastin in comparison to chemotherapy alone. This has mainly been seen in combination with platinum- or taxane-based therapies in the treatment of NSCLC and mBC.

Hypersensitivity reactions/infusion reactions

Patients may be at risk of developing infusion/hypersensitivity reaction. Close observation of the patient during and following the administration of bevacizumab is recommended as expected for any infusion of a therapeutic humanized monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered. A systematic premedication is not warranted.

Eye disorders

Adverse reactions have been reported from unapproved intravitreal use. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and conjunctival haemorrhage. Some of these appeared as serious adverse reactions.

Effect of antineoplastic agents on bevacizumab pharmacokinetics

No clinically relevant pharmacokinetic interaction of co-administered chemotherapy on Avastin disposition has been observed based on the results of a population PK analysis. There was no difference in clearance of Avastin in patients treated with single-agent Avastin compared to patients receiving Avastin in combination with the bolusIFL regimen. The effect of other co-administered chemotherapies on Avastin clearance is considered not clinically significant.

Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents

Results from a dedicated drug-drug interaction study, demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN38.

Results from one study in metastatic colorectal cancer patients demonstrated no significant effect of bevacizumab on the pharmacokinetics of capecitabine and its metabolites, and on the pharmacokinetics of oxaliplatin, as determined by measurement of free and total platinum.

Results from one study in renal cancer patients demonstrated no significant effect of bevacizumab on the pharmacokinetics of interferon alfa-2a.

The potential effect of bevacizumab on the pharmacokinetics of cisplatin and gemcitabine was investigated in non-squamous NSCLC patients. Study results demonstrated no significant effect of bevacizumab on the pharmacokinetics of cisplatin. Due to high inter-patient variability and limited sampling, the results from that study do not allow firm conclusions to be drawn on the impact of bevacizumab on gemcitabine pharmacokinetics.

Combination of bevacizumab and sunitinib malate

In two clinical studies of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia (MAHA) was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two weeks) and sunitinib malate (50 mg daily) combination.

MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, and thrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, and neurological symptoms were observed in some of these patients. All of these findings were reversible upon discontinuation of bevacizumab and sunitinib malate.

Radiotherapy

The safety and efficacy of concomitant administration of radiotherapy and Avastin has not been established.

The overall safety profile of Avastin is based on data from over 3,500 patients with various malignancies, predominantly treated with Avastin in combination with chemotherapy in clinical trials.

The most serious adverse drug reactions were:

• Gastrointestinal perforations.

• Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small cell lung cancer patients.

• Arterial thromboembolism.

The most frequently observed adverse drug reactions across clinical trials in patients receiving Avastin were hypertension, 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.

Table 1 lists adverse drug reactions associated with the use of Avastin in combination with different chemotherapy regimens in multiple indications. These reactions had occurred either with at least a 2% difference compared to the control arm (NCI-CTC grade 3-5 reactions) or with at least a 10% difference compared to the control arm (NCI-CTC grade 1-5 reactions), in at least one of the major clinical trials.

The adverse drug reactions listed in this table fall into the following categories: Very Common ( 10%) and Common ( 1% - < 10%). Adverse drug reactions are added to the appropriate category in the table below according to the highest incidence seen in any of the major clinical trials.

Within each frequency grouping adverse drug reactions are presented in the order of decreasing seriousness. Some of the adverse drug reactions are reactions commonly seen with chemotherapy, (e.g. palmar-plantar erythrodysaesthesia syndrome with capecitabine and peripheral sensory neuropathy with paclitaxel or oxaliplatin); however, an exacerbation by Avastin therapy can not be excluded.

Table 1: Very Common and Common Adverse Drug Reactions

* Pooled arterial thromboembolic events including cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic events.

Data are unadjusted for the differential time on treatment.

Further information on selected serious adverse drug reactions:

Gastrointestinal perforations:

Avastin has been associated with serious cases of gastrointestinal perforation or fistulae (see also under heading Fistulae).

Gastrointestinal perforation have been reported in clinical trials with an incidence of less than 1% in patients with metastatic breast cancer or non-squamous non-small cell lung cancer, and in up to 2.0% in metastatic colorectal cancer patients. 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.

The presentation of these events varied in type and severity, ranging from free air seen on the plain abdominal Xray, which resolved without treatment, to intestinal perforation with abdominal abscess and fatal outcome. In some cases underlying intraabdominal inflammation was present, either from gastric ulcer disease, tumour necrosis, diverticulitis, or chemotherapy-associated colitis.

Fistulae:

Avastin use has been associated with serious cases of fistulae including events resulting in death.

In clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer, but were also reported less commonly in patients with other types of cancers. Uncommon ( 0.1% to < 1%) reports of other types of fistulae that involve areas of the body other than the gastrointestinal tract (e.g. bronchopleural, urogenital and biliary fistulae) were observed across various indications. Fistulae have also been reported in post-marketing experience.

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

Wound healing:

As Avastin may adversely impact wound healing, patients who had major surgery within the last 28 days were excluded from participation in phase III clinical trials.

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

In locally recurrent and metastatic breast cancer, Grade 3-5 wound healing complications were observed in 1.1% of patients receiving Avastin + paclitaxel and in none of the patients receiving paclitaxel alone.

Hypertension:

An increased incidence of hypertension (all grades) of up to 34% has been observed in Avastin-treated patients in clinical trials compared with up to 14% in those treated with comparator. Grade 3 and 4 hypertension (requiring oral antihypertensive medication) in patients receiving Avastin ranged from 3.0% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with Avastin and chemotherapy compared to up to 0.2% of patients treated with the same chemotherapy alone.

Hypertension was generally adequately controlled with oral antihypertensives such as angiotensinconverting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation 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' baseline characteristics, underlying disease or concomitant therapy.

Proteinuria:

In clinical trials, proteinuria has been reported within the range of 0.7% to 38% of patients receiving Avastin.

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria. Grade 3 proteinuria was reported in < 3% of treated patients: however, in patients treated for advanced and/or metastatic renal cell carcinoma this was up to 7%. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. The proteinuria seen in clinical trials was not associated with renal dysfunction and rarely required permanent discontinuation of therapy. Testing for proteinuria is recommended prior to start of Avastin therapy. In most clinical studies urine protein levels of 2g /24 hrs led to the holding of Avastin until recovery to < 2g/24 hrs.

Haemorrhage:

In clinical trials across all indications the overall incidence of NCI-CTC Grade 3-5 bleeding events ranged from 0.4% to 5% in Avastin treated patients, compared with up to 2.9% of patients in chemotherapy control group.

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

Tumourassociated haemorrhage.

Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in studies in patients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cell histology, treatment with antirheumatic/anti-inflammatory drugs, treatment with anticoagulants, prior radiotherapy, Avastin therapy, previous medical history of atherosclerosis, central tumour location and cavitation of tumours prior to or during therapy. The only variables that showed statistically significant correlations with bleeding were Avastin therapy and squamous cell histology. Patients with NSCLC of known squamous cell histology or mixed cell type with predominant squamous cell histology were excluded from subsequent phase III studies, while patients with unknown tumour histology were included.

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

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

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

The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab has not been prospectively evaluated in randomised clinical studies. In an exploratory retrospective analysis of data from 13 completed randomised trials in patients with various tumour types, 3 patients out of 91 (3.3%) with brain metastases experienced CNS bleeding (all Grade 4) when treated with bevacizumab, compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to bevacizumab. In two ongoing studies in patients with treated brain metastases, one case of Grade 2 CNS haemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at the time of interim safety analysis.

Across all clinical trials, mucocutaneous haemorrhage has been seen in 20% - 40% of Avastin-treated patients. These were most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any changes in the Avastin treatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneous haemorrhage (e.g. epistaxis) may be dose-dependent.

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

Thromboembolism:

Arterial thromboembolism:

An increased incidence of arterial thromboembolic events was observed in patients treated with Avastin across indications, including cerebrovascular accidents, myocardial infarction, transient ischemic attacks, and other arterial thromboembolic events.

In clinical trials, the overall incidence of arterial thromboembolic events ranged up to 3.8% in the Avastin containing arms compared with up to 1.7% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving Avastin compared to 0.5% in patients receiving chemotherapy alone. Cerebrovascular accidents (including transient ischemic attacks) were reported in up to 2.3% of patients treated with Avastin in combination with chemotherapy compared to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was reported in 1.4% of patients treated with Avastin in combination with chemotherapy compared to 0.7% of patients treated with chemotherapy alone.

In one clinical trial, AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment with irinotecan were included. In this trial arterial thromboembolic events were observed in 11% (11/100) of patients compared to 5.8% (6/104) in the chemotherapy control group.

Venous thromboembolism:

The incidence of venous thromboembolic events in clinical trials was similar in patients receiving Avastin in combination with chemotherapy compared to those receiving the control chemotherapy alone. Venous thromboembolic events include deep venous thrombosis, pulmonary embolism and thrombophlebitis.

In clinical trials across indications, the overall incidence of venous thromboembolic events ranged from 2.8% to 17.3% of Avastin-treated patients compared with 3.2% to 15.6% in the control arms.

Grade 3-5 venous thromboembolic events have been reported in up to 7.8% of patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treated with chemotherapy alone.

Patients who have experienced a venous thromboembolic event may be at higher risk for a recurrence 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 indications studied to date, but occurred predominantly in patients with metastatic breast cancer. In two phase III studies (AVF2119g and E2100) in patients with metastatic breast cancer an increase of CHF Grade 3 or more with Avastin was seen. CHF was reported in up to 3.5% of patients treated with Avastin compared with up to 0.9% in the control arms. Most of these patients showed improved symptoms and/or left ventricular function following appropriate medical therapy.

In most clinical trials of Avastin, patients with pre-existing CHF of NYHA (New York Heart Association (NYHA) IIIV were excluded, therefore, no information is available on the risk of CHF in this population.

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

Elderly Patients

In randomised clinical trials, age> 65 years was associated with an increased risk of developing arterial thromboembolic events, including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs). Other reactions with a higher frequency seen in patients over 65 were grade 3-4 leucopenia and thrombocytopenia; and all grade neutropenia, diarrhoea, nausea, headache and fatigue as compared to those aged 65 years when treated with Avastin.

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

Laboratory Abnormalities:

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

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

Post-marketing experience:

Table 2: Adverse reactions reported in post-marketing setting

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

Roche

(POM)

10 September 2010