Systemic Therapy Program
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Disease Group



Cancer Type

Document Type

Drug Monographs
Treatment Regimens
Scientific Name:
BEVACIZUMAB
Brand Name(s):
Avastin®

Drug Monograph

Pharmacology

Mechanism of Action

Bevacizumab is a humanized recombinant monoclonal antibody which binds to human vascular endothelial growth factor (VEGF) and prevents the interaction of VEGF with its receptors (Flt-1 and KDR) on endothelial cell surfaces.  Bevacizumab reduces microvascular growth by blocking angiogenesis normally stimulted by the VEGF pathway.  Thus, metastatic disease progression is inhibited.

Pharmacokinetics

Oral Absorption:  no information
Distribution:  no information
Metabolism:  no information
Excretion:
t½ = 20 days (range 11-50 days)
Cl = 0.262 L/day (males) and 0.207 L/day (females)
Clearance was slightly higher in patients with higher tumour burden

Side Effects

IMMEDIATE ONSET  (hours to days)

proteinuria: (14-21% of patients with renal cell carcinoma- nephrotic syndrome
   in 0.5%, with one fatality)
neutropenia (21% grade 3-4), leukopenia (37% grade 3-4)
   stomatitis (33%)
• infusion-related reactions: (< 3%- severe reactions rare).

EARLY ONSET  (days to weeks)

gastrointestinal perforations (2-4%- some fatal): presentation with abdominal 
   pain associated with constipation and vomiting
hemorrhage: pulmonary hemorrhage (4-31% of patients with lung cancer, some
   cases fatal, presenting as major/massive hemoptysis after cavitation and
   necrosis of the lung tumour), gastrointestinal hemorrhage, subarachnoid 
   hemorrhage, hemorrahgic stroke; some minor hemorrhage events/epistaxis
hypertension: (60-67%- 12% severe) may persist for months despite
   aggressive antihypertensive medications
asthenia (74%- 10% severe)
diarrhea (34% severe)
• pain (61%- 8% severe)
• anorexia (43%)
• constipation (40%- 4% severe)

Therapeutics

Approved Indications

• In combination with intravenous 5-fluorouracil-based chemotherapy for first line treatment of  metastatic cancer of the colon or rectum
• As monotherapy for treatment of malignant glioma or glioblastoma  (dose = 15 mg/Kg)
OTHER ONCOLOGY USES (Not Approved in Canada)
• In combination with chemotherapy for treatment of lung cancer cancer (dose = 10 mg/Kg)
• In combination with chemotherapy for persistent, recurrent or metastatic cervical cancer

Routes

Intravenous infusion (over 90 minutes).
Do NOT administer as IV push or bolus injection.

Administration

• Withdraw dose from vials of Bevacizumab and dilute to a total of 100 mL with 0.9% sodium chloride solution.
• May infuse at 0.5 mg/Kg/min rate- 10 min for 5 mg/Kg doses or 15 min for 7.5 mg/Kg doses
• If there is any concern about infusion reaction, administer through free-flowing IV- first dose over 90 minutes; if well tolerated, second and subsequent doses may be given over 60 minutes; if 60 minute dosing is well tolerated, third and subsequent doses may be given over 30 minutes.
• Observe for infusion-related symptoms.
• DO NOT give by IV push or bolus dose

IV Compatibility

sodium chloride 0.9%
NOT compatible with 5% dextrose solution

Dosing

Intravenous:
• 5 mg/Kg IV every 14 days
• Do not initiate within 28 days of surgery, to allow healing of incision

Pediatric:
• Safety & effectiveness not established

Dose Adjustment Criteria

No recommended dose reductions
Evidence of protienuria, severe hypertension:
Temporary suspension of bevacizumab until evaluation complete
Elective surgery:
Suspend bevacizumab for several week before surgery, and for at least 4 weeks after surgery

Antiemetic Risk

LOW RISK (Less than 10% of patients)
• No routine antiemetic pre-chemotherapy or post-chemotherapy

Contraindications

None known

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets and hemoglobin (CBC) before each cycle of treatment
• Blood pressure measurement every 2-3 weeks (or at each visit)
• Urine test for protein (dipstick) at each visit
• Clinical examination of any wounds, abdominal exam at each visit
• Observation for hypersensitivity reaction during and for 30 minutes after injection (emergency treatment readily available)

SUGGESTED CRITERIA
Hypersensitivity/Allergy
0. None
1. Transient rash, fever <38oC
2. Urticaria, fever > 38oC, mild bronchospasm
3. Serum sickness, bronchospasm, requires parenteral medications
4. Anaphylaxis
Rated In Response To Patient Reaction

Extravasation Hazard

None known

Significant Interactions

Suspected pharmacokinetic interaction with irinotecan (increased concentration of SN38, active metabolite of irinotecan, when bevacizumab given in combination). • no other interactions reported

Product Information

Commercial Product Description

Vials with 100mg/4mL or 400mg/16mL.

Pharmaceutical Considerations

Injection:
100 mg/4 mL and 400 mg/16 mL vials; each mL contains 25 mg bevacizumab in a buffered solution.
For single use only, unused portions must be discarded. Store in original carton under refrigeration.
Do not freeze. 
The solution should be clear and colourless to pale brown. Do not shake solution.

Compatibility:
It is recommended that rituximab not be mixed with other drugs.

Stability:
Diluted solution stable for 8 hours (if stored under refrigeration).  Discard after stability has expired.

Handling Risk Level

Pregnancy XKNOWN HAZARDOUS DRUG
FDA Pregnancy Risk Factor X

  • This drug must be handled using precautions outlined in CCNS Policies for Occupational Safety, Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:

HAZARD RISK LEVEL 3
FDA Pregnancy Risk Factor C
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

GUIDELINES:
NCDF Coverage Criteria:  Treatment of Advanced Colorectal Cancer:
Bevacizumab combination therapy in patients who have documented evidence of locally advanced or MCRC, with an ECOG performance status 0-2 for whom a combination would be recommended, choose to receive systemic chemotherapy and meet the following criteria:
• Bevacizumab in combination with first or second line combination chemotherapy including irinotecan/fluoropyrimidine-based regimens such as FOLFIRI or IFL or oxaliplatin/fluoropyrimidine-based regimens such as FOLFOX. The value of continuing bevacizumab in the second line (after receiving with first line chemotherapy) is not clear. In any one patient, only one option as first or second line combination therapy is approved at a maximum dose of 5 mg/kg every two weeks (or equivalent dose).
• Bevacizumab may be considered in combination with single agent fluoropyrimidine therapy such as 5-FU/LV or capecitabine in selected cases.
• Bevacizumab would not be used in combination in the third-line setting.
• Bevacizumab would not be used as a single agent therapy for patients where chemotherapy cannot be given or as maintenance therapy following combination chemotherapy discontinuation.
• Bevacizumab would not be used post curative resection of metastatic disease i.e.pseudo-adjuvant therapy.
• There is currently no data to support the use of Bevacizumab in the adjuvant setting.
pCODR Recommendation:  In combination with a fluoropyrimidine, for the first-line treatment of patients with advanced or metastatic colorectal cancer (mCRC) for whom combination chemotherapy with oxaliplatin or irinotecan is unsuitable, with ECOG performance status 0-2.    July 21, 2015

Cervical Cancer
pCODR Recommendation:  In combination with chemotherapy for patients with metastatic (Stage IVB), persistent, or recurrent carcinoma of the cervix of all subtypes (except small cell) and good performance status.   March 23, 2015

Ovarian Cancer
Bevacizumab in the front-line treatment of patients with advanced stage ovarian cancer at a high risk of progressionl. Bevacizumab given at a dose of 7.5 mg/kg in combination with carboplatin and paclitaxel in cycles 2-6, and as a maintenance treatment for up to 12 additional cycles or until disease progression, whichever occurs first. This patient population should include those with advanced stage, "high risk for progression" (stage III with >1 cm of residual disease, stage III unresectable, or stage IV) epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who have good performance status.  June 4, 2015

Visit the Pan-Canadian Oncology Drug Review website (www.pcodr.ca) for the guidelines on Bevacizumab for carcinoma of the cervix and ovarian cancer.
• Go to "Additional Information" tab (above) for links to pCODR Reviews

Availability & Funding

Administrative Information (Nova Scotia)

CCNS Provincial Formulary Status- Specialized Level Captial Health Only -- Not on Canadian Market. • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs Pharmacare Formulary Status- Non-Formulary NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety

New Cancer Drug Fund Status (Nova Scotia)

New Cancer Drug Fund (NCDF) funding approved for: Treatment of Advanced Colorectal Cancer- Bevacizumab combination therapy in patients who have documented evidence of locally advanced or MCRC, with an ECOG performance status 0-2 for whom a combination would be recommended, choose to receive systemic chemotherapy and meet the following criteria: 1. Bevacizumab in combination with first or second line combination chemotherapy including irinotecan/ fluoropyrimidine-based regimens such as FOLFIRI or IFL or oxaliplatin/fluoropyrimidine-based regimens such as FOLFOX. The value of continuing bevacizumab in the second line (after receiving with first line chemotherapy) is not clear. In any one patient, only one option as first or second line combination therapy is approved at a maximum dose of 5 mg/kg every two weeks (or equivalent dose). 2. Bevacizumab may be considered in combination with single agent fluoropyrimidine therapy such as 5-FU/LV or capecitabine in selected cases. 3. Bevacizumab would not be used in combination in the third-line setting. 4. Bevacizumab would not be used as a single agent therapy for patients where chemotherapy cannot be given or as maintenance therapy following combination chemotherapy discontinuation. 5. Bevacizumab would not be used post curative resection of metastatic disease i.e. pseudo-adjuvant therapy. 6. There is currently no data to support the use of Bevacizumab in the adjuvant setting. New Cancer Drug Fund (NCDF) funding approved for: First line treatment of patients with advanced stage ovarian cancer at a high risk of progression (stage III with > 1 cm residual disease, stage III unresectable or stage IV) epithelial ovarian, primary peritoneal or fallopian tube cancer and good performance status. This would include initial treatment in combination with chemotherapy and maintenance therapy for up to 12 additional cycles or until disease progression whichever occurs first. New Cancer Drug Fund (NCDF) funding approved for: In combination with chemotherapy for patients with metastatic (stage IVB), persistant or recurrent carcinoma of the cervix of all histologic subtypes (except small cell) and good performance status. Retreatment with bevacizumab plus chemotherapy may be offered to patients who have achieved a complete response (with previous bevacizumab and chemotherapy) and off treatment for at least 6 months.