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A - Regimen Name

BEVA Regimen
Bevacizumab


Disease Site
Central Nervous System

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

Single agent treatment of patients with glioblastoma (WHO Grade IV) after relapse or disease progression, following prior therapy.

 
B - Drug Regimen

bevacizumab
10 mg /kg IV Day 1
(This drug is not currently publicly funded for this regimen and intent)
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C - Cycle Frequency

REPEAT EVERY 14 DAYS

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated.

Bevacizumab should not be initiated in patients with recurrent hemoptysis, uncontrolled hypertension or wounds that require healing.

Prior to treatment, a dental evaluation should be performed and major dental procedures completed.

May consider prophylaxis for patients who have had prior mild hypersensitivity reactions and who are continuing on treatment.

Dosage with toxicity

Dose reductions are not recommended. Bevacizumab should be held or discontinued based on toxicity.

 

Bevacizumab action

Toxicity

Any grade

Grade 3

Grade 4

Hold:

Uncontrolled hypertension

 

 

Delayed wound healing

 

 

Proteinuria ≥ 2g/ 24 hours*

 

 

Surgery**

 

 

Discontinue:

 

Hypertension not controlled with medical management

Hypertension

Wound dehiscence, poor healing requiring medical intervention; necrotizing fasciitis

   

Nephrotic syndrome;
non- recovery of proteinuria ≥ 2g/24 hours

 

 

Severe hypersensitivity reaction

 

 

Tracheo-esophageal fistula, other non-GI fistulae

 

 

Fistula

GI Perforation or fistula

 

 

PRES, hypertensive encephalopathy

 

 

Arterial thromboembolism

 Pulmonary embolism

 Venous thromboembolism (including pulmonary embolism)

Symptomatic cardiac failure

 

 

Hemoptysis > 2.5 mL

Bleeding

Bleeding

Intracranial bleeding

 

 

* may restart when < 2g/24hrs

** for 28 days PRIOR (if surgery elective) and AFTER major surgery, or until wound healed



Hepatic Impairment

Has not been studied. Not a major route of bevacizumab metabolism or excretion.


Renal Impairment

Has not been studied. Not a major route of bevacizumab metabolism or excretion.


Dosage in the Elderly

Use with caution; patients > 65 years old have an increased risk of arterial thrombotic events as well as myelosuppression, fatigue, proteinuria, hypertension, dizziness, dysphonia, anorexia and GI effects (except gastrointestinal perforation).

 


 
F - Adverse Effects

Refer to bevacizumab drug monograph(s) for additional details of adverse effects. The adverse effects below were reported with and without concurrent chemotherapy use.


Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Bleeding
  • Fatigue
  • Hypertension (may be severe)
  • Proteinuria (may be severe)
  • Headache

 

  • Diarrhea
  • Venous thromboembolism (may be severe)
  • Nausea, vomiting 
  • Constipation 
  • Insomnia
  • Musculoskeletal pain
  • Cough, dyspnea
  • Rash (may be severe)
  • Anorexia
  • Infection
  • Dysphonia
  • Cardiotoxicity (may be severe)
  • Arterial thromboembolism
  • Hemorrhage (severe)
  • Myelosuppression
  • Arrhythmia
  • Pulmonary hypertension
  • Hypersensitivity
  • GI obstruction/perforation
  • Fistulas
  • Necrotizing fasciitis
  • Osteonecrosis (jaw, other)
  • RPLS/PRES
  • Thrombotic microangiopathy
  • Delayed wound healing
 
G - Interactions

Refer to bevacizumab drug monograph(s) for additional details


  • Avoid use with sunitinib as hemolytic anemia has been reported
 
H - Drug Administration and Special Precautions

Refer to bevacizumab drug monograph(s) for additional details


Different bevacizumab products are not interchangeable

Administration:

  • DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.

  • Bevacizumab infusions should NOT be administered or mixed with dextrose or glucose solutions due to potential for drug degradation.

  • Mix in 100 mL bag NS. (Final concentration should be 1.4 -16.5 mg/mL). 

  • Compatible with PVC or polyolefin bags.

  • Do not shake. Should not be mixed or diluted with other drugs.

  • Infuse over 90 minutes as loading dose, if well tolerated next infusion can be given over 60 minutes; if well tolerated, can thereafter be given over 30 minutes as maintenance dose.

  • Alternative infusion rates (for 5 mg/kg or 7.5 mg/kg dosing) have been described by Mahfoud et al and Reidy et al, but these have not been approved by Health Canada.

  • Refrigerate unopened vials and protect from light; do not freeze.

 

Contraindications:

  • Patients with known hypersensitivity to bevacizumab or its components

  • Patients with known hypersensitivity to Chinese hamster ovary cell product or to other recombinant human or humanized antibodies

  • Patients with untreated CNS metastases

 

Other Warnings/Precautions:

  • Elderly patients

  • Patients with a history of arterial thromboembolism or significant cardiovascular disease or cardiac failure

  • Patients with coagulopathies (congenital, acquired or therapeutic)

  • Patients with recurrent hemoptysis (>2.5ml), serious hemorrhage, or with squamous NSCLC

  • Patients with colorectal cancer and colorectal stents; increased risk of GI perforation has been reported; use with caution.

  • Hypertension should be controlled prior to starting treatment

  • Bevacizumab should not be initiated for at least 28 days following major surgery or until wound healing has occurred; hold for 28 days prior to major elective surgery

  • Use caution if given with bisphosphonates or other anti-angiogenic agents; increased risk of ONJ

  • The safety and efficacy of concurrent radiotherapy and bevacizumab has not been established.

 

Pregnancy/Lactation:

  • Bevacizumab is not recommended for use in pregnancy. Cases of fetal abnormalities have been reported. Adequate contraception (including at least 2 contraceptive methods) should be used by both sexes during treatment, and for at least 6 months after the last dose.

  • Breastfeeding is not recommended during treatment and for at least 6 months following the last dose. 

  • Fertility effects: Long-term effects unknown. Discuss fertility preservation with women of reproductive potential prior to starting treatment.

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • Blood pressure; baseline and every 2-3 weeks during therapy and more frequently in patients who develop hypertension

  • CBC; baseline and at each visit

  • Dental evaluation; baseline

  • Urine dipstick, 24 hour urine collection is recommended for patients with a 2+ or greater urine dipstick; baseline and at each visit

  • Clinical assessment of hypersensitivity, perforation, fistula, GI symptoms, ONJ, hemorrhage, thromboembolism, wound healing, hypertension, neurologic and cardiac effects; at each visit

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Cardiac function tests (Echo, RNA and/or MUGA scans) especially in patients who are close to the lifetime cumulative dose of anthracyclines/anthracenediones; baseline and as clinically indicated

  • Liver and renal function tests; baseline and at each visit


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J - Administrative Information

Approximate Patient Visit
First dose: 1.5 hours; Second dose: 1 hour; Subsequent: 0.5 hour
Pharmacy Workload (average time per visit)
17.013 minutes
Nursing Workload (average time per visit)
42.5 minutes
 
K - References
Bevacizumab drug monograph, Cancer Care Ontario.
 
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma. J Clin Oncol 2009; 27(28): 4733-40.
 
Kreisl TN, Kim L, Moore K, et al. Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma. J Clin Oncol 2009; 27(5): 740-5.
 
Reidy DL, Chung KY, Timoney JP, et al. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. Journal of Clinical Oncology 2007; 25: 2691-5.

August 2019 Updated adverse effects and drug administration / precautions sections


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.