Bevacizumab
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Vascular Endothelial Growth Factor (VEGF) inhibitors, Therapy Class:
Antineoplastic agent, Approved Countries
India, the United States, the United Kingdom, Australia, Germany, France, Canada, Japan, Brazil, China and Spain.
Bevacizumab is an antineoplastic agent belonging to the pharmacological class of Vascular Endothelial Growth Factor (VEGF) inhibitors.
The FDA approved bevacizumab for treating various cancers, including metastatic colorectal cancer, renal cell carcinoma, non-small cell lung cancer, glioblastoma, and ovarian cancer, among others, in combination with other therapies.
Bevacizumab reaches steady-state concentration in roughly 84 days. After a 10 mg/kg dose, it accumulates at a ratio of 2.8 and maintains a 20-day half-life.
The most common side effects of bevacizumab include rectal bleeding, taste change, and headache.
Bevacizumab is available in injectable solutions.
The molecule is available in India, the United States, the United Kingdom, Australia, Germany, France, Canada, Japan, Brazil, China and Spain.
Bevacizumab is an antineoplastic agent belonging to the pharmacological class of Vascular Endothelial Growth Factor (VEGF) inhibitors.
Vascular endothelial growth factor (VEGF) is actively bound by bevacizumab, which prevents it from interacting with Flt-1 and KDR receptors on the surface of endothelial cells. In angiogenesis models, this inhibition is essential because it stops endothelial cell proliferation and the creation of new blood vessels. When bevacizumab was given to mice with xenotransplanted colon cancer that were nude (athymic), it significantly inhibited the growth of microvascular growth and effectively stopped the spread of the disease. This demonstrated action indicates the function of bevacizumab in preventing tumour-associated angiogenesis and obstructing the spread of metastatic disease, providing possible therapeutic advantages in restraining the advancement of cancer.
Bevacizumab takes approximately 84 days to reach a steady-state concentration.
Bevacizumab is available in injectable solutions.
Injectable solutions: To be administered parenterally as applicable.
As the physician recommends, the medication can be taken with or without food as directed.
- Cancer of the colon and rectum
- Non-small cell lung cancer
- Kidney cancer
- Brain tumour
- Ovarian cancer
- Cervical cancer
- Glioblastoma
- Off-label indication for exudative age-related macular degeneration (ARMD)
- Cancer of the colon and rectum: Bevacizumab's anti-angiogenic effect prevents colorectal cancer (CRC) that starts in the colon or rectum from growing tumours. Additionally, there could be signs and symptoms like weariness, weight loss, diarrheal changes, and blood in the stool. Combined with chemotherapy, it prevents the growth of new blood vessels, stopping tumours from spreading. This treatment increases overall survival rates, prolongs progression-free survival, and increases the effectiveness of chemotherapy, especially in advanced stages, thereby improving its management of colorectal cancer.
- Non-small cell lung cancer: Bevacizumab Injection slows the growth of blood vessels surrounding the tumour, prevents tumour angiogenesis, and hinders the spread of non-small cell lung cancer. It can be taken either by itself or in conjunction with other drugs. This therapy increases overall survival rates, prolongs progression-free survival, and increases the efficacy of chemotherapy, especially in the later stages of the illness. Bevacizumab Injection provides substantial benefits to individuals with non-small cell lung cancer who smoke or do not smoke, indicating a significant advance in the treatment of the disease.
- Metastatic renal cell carcinoma (mRCC): Bevacizumab treats kidney cancer and related symptoms like blood in the urine, unexplained low back pain, weight loss, fatigue, and loss of appetite. It halts cancer growth and hinders the multiplication of cancer cells.
- Brain tumour: Bevacizumab inhibits the growth of cancer cells and prevents their multiplication in brain tumours, whether malignant or benign—an abnormal cell collection in the brain. It aids in reducing tumour size, decreasing swelling (oedema), and potentially improving associated symptoms.
- Ovarian cancer: Bevacizumab, in combination with chemotherapy, restrains tumour blood vessel formation, limiting ovarian cancer cell growth. This cancer, originating in the ovaries, often detected late, can spread to the pelvis and stomach, posing a high fatality risk. Bevacizumab halts cancer cell growth and prevents their multiplication, offering a vital treatment approach in combating this aggressive form of cancer.
- Cervical cancer: In cervical cancer, bevacizumab, an anti-cancer medication, kills cancerous cells by hindering blood vessel growth that sustains tumour development when administered alongside standard therapies. This action effectively restrains cancer progression in the cervix of females.
- Hepatocellular carcinoma (HCC): In hepatocellular carcinoma (HCC), cancer originates in the liver's primary cell type, hepatocytes. Chronic liver conditions like cirrhosis or hepatitis B or C infections commonly cause its development. When combined with other therapies, bevacizumab restrains the formation of blood vessels around tumours, limiting cancer progression.
- Glioblastoma: When combined with standard therapies, bevacizumab inhibits the growth of glioblastoma, a highly aggressive and malignant brain tumour derived from glial cells, specifically astrocytes. It may or may not be effective in shrinking tumour size, reducing swelling, and improving symptoms because it inhibits the growth of new blood vessels surrounding the tumour.
- Patients with metastatic colorectal cancer (mCRC) may receive bevacizumab as their first or second line of treatment when combined with intravenous fluorouracil-based chemotherapy.
Restrictions on Use: For colon cancer, bevacizumab is not recommended as an adjuvant treatment.
- As a first-line treatment in patients with non-small cell lung cancer (NSCLC) that is unresectable, locally advanced, recurrent, or metastatic, bevacizumab is indicated in combination with carboplatin and paclitaxel.
- For the treatment of metastatic renal cell carcinoma (mRCC), bevacizumab in combination with interferon alfa is indicated.
- Patients with cervical cancer that is metastatic, recurrent, or persistent should be treated with bevacizumab in combination with either paclitaxel and topotecan or paclitaxel and cisplatin.
- After initial surgical resection, patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer may be treated with bevacizumab alone, in combination with carboplatin and paclitaxel, or as a single agent.
- Bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan treats patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have undergone no more than two chemotherapy regimens.
- For patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, bevacizumab is indicated as a single agent or in combination with carboplatin and paclitaxel or carboplatin and gemcitabine.
- For the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not had systemic therapy previously, bevacizumab in combination with atezolizumab is indicated.
Parenterally: Patients are premedicated with antihistamines or corticosteroids before administering bevacizumab intravenously, which undergoes slow infusion lasting 30 to 90 minutes, contingent on the dosage. Healthcare providers dilute the infusion solution in sterile saline or dextrose solution. The dosage and frequency align with the specific cancer type and treatment regimen prescribed. The administration follows strict aseptic techniques and prioritizes caution against potential infusion reactions. Bevacizumab's intravenous infusion ensures controlled and monitored delivery, maximizing therapeutic efficacy while minimizing cancer-related adverse effects.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Injectable solutions: 25mg/mL (4-mL, 16-mL single-dose vials)
Bevacizumab is available as an injectable solution.
Dose Adjustment in Adult Patients:
- Metastatic Colorectal Cancer
When given as an infusion over 90 minutes for the first dose, the dosage can be increased to 5 mg/kg or 10 mg/kg once every two weeks, or 7.5 mg/kg or 15 mg/kg once every three weeks, depending on tolerability.
- Non-Small Cell Lung Cancer
7.5 mg/kg or 15 mg/kg once every three weeks by infusion over ninety minutes for the first dose; based on tolerance, subsequent infusions could occur over sixty or thirty minutes. Usually in conjunction with paclitaxel and carboplatin.
- Renal Cell Carcinoma
10 mg/kg once every two weeks by infusion over ninety minutes on the first dose; depending on tolerability, subsequent infusions may take sixty or thirty minutes. In combination with interferon alfa.
- Cervical Cancer
In combination with paclitaxel/cisplatin or paclitaxel/topotecan, at a doses of 15 mg per kg every three weeks, administered by infusion over ninety minutes on the first dose and sixty or thirty minutes on subsequent doses, depending on tolerability.
Platinum-resistant in ovarian, fallopian tube, or peritoneal cancer
Recommended when combined with topotecan, pegylated liposomal doxorubicin, or paclitaxel for adults with primary peritoneal, fallopian tube, or platinum-resistant recurrent epithelial ovarian cancer who have had no more than two chemotherapy treatments.
One of the following IV chemotherapy regimens: weekly topotecan, weekly pegylated liposomal doxorubicin, or paclitaxel combined with bevacizumab 10 mg/kg IV every two weeks OR bevacizumab 15 mg/kg IV every three weeks combined with topotecan.
platinum-sensitive
Recommended for women with primary peritoneal, fallopian tube, or platinum-sensitive recurrent epithelial ovarian, either when combined with carboplatin and paclitaxel or with carboplatin and gemcitabine chemotherapy, and then bevacizumab alone.
Adults are considered "platinum-sensitive" if a relapse happens more than six months after their last platinum-based chemotherapy treatment.
IV bevacizumab (15 mg/kg q3)weeks in conjunction with paclitaxel and carboplatin for six to eight cycles, OR bevacizumab 15 mg/kg IV every three weeks in conjunction with gemcitabine and carboplatin for six to ten cycles, then bevacizumab 15 mg/kg every three weeks before the disease progresses when using a single agent.
Treatment for stage III or IV illness after initial resection through surgery
For a maximum of 22 cycles or until the disease progresses, whichever comes first, bevacizumab 15 mg per kg IV every 3 Weeks in combination with carboplatin and paclitaxel for up to 6 cycles. Afterwards, bevacizumab 15 mg/kg IV q3Weeks as a single agent.
- Glioblastoma
10 mg/kg once every two weeks by infusion; the first dose is given over 90 minutes, and subsequent doses may be given over 60 or 30 minutes, depending on tolerability.
- Breast Cancer
In combination with paclitaxel, administer 10 mg/kg once every two weeks or 15 mg per kg once every three weeks by infusion over 90 minutes for the first dose, and then administer the subsequent doses over 60 or 30 minutes, depending on tolerability.
- ARMD exudative (off-label)
Off-label: once monthly intravitreal injection of 1.25 mg (in 0.05 mL of solution).
- Carcinoma Hepatocellular
Day 1 IV bevacizumab (15 mg/kg) (following atezolizumab administration), PLUS
Day 1 IV atezolizumab 1,200 mg/kg
Repeat three times a week.
Continue until the disease worsens or the toxicity becomes unacceptable.
There aren't specific dietary restrictions; ensure regular meals. Avoid grapefruit or its juice due to potential interactions affecting drug metabolism. Exercise caution with medications, supplements, or herbal products that might interact with bevacizumab. Maintaining adequate hydration is important for overall well-being during treatment.
The dietary restriction should be individualized as per patient requirements.
- Hypersensitivity or serious allergic reactions to bevacizumab or any of its components.
- Recent history or risk of severe bleeding.
- Severe proteinuria (protein in urine).
- Pregnancy or the potential for pregnancy due to the risk of fetal harm.
Discontinue bevacizumab upon fistula formation, as non-gastrointestinal fistulas necessitate immediate cessation.
For severe arterial thromboembolic events (ATE) like myocardial or cerebral infarctions, discontinue bevacizumab.
Monitor and manage hypertension, temporarily halting bevacizumab if blood pressure remains uncontrolled. Discontinue for hypertensive crisis or hypertensive encephalopathy.
Discontinue bevacizumab if reversible posterior leukoencephalopathy syndrome (RPLS) emerges.
Monitor urine protein levels; discontinue bevacizumab for nephrotic syndrome and suspend temporarily for moderate proteinuria.
Cease bevacizumab for severe infusion reactions.
Inform females of reproductive potential about the risk of ovarian failure associated with bevacizumab.
Alcohol Warning
It is unsafe to consume alcohol.
Breast Feeding Warning
Avoid breastfeeding while taking bevacizumab.
Pregnancy Warning
It is not recommended during pregnancy as it may harm the unborn baby.
Food Warning
Consume veggies, limit dairy, exercise, and avoid red meat.
The adverse reactions related to bevacizumab can be categorized as:
- Common Adverse Effects: Hypertension, proteinuria, increased risk of bleeding, gastrointestinal perforation, and infusion-related reactions.
- Less Common Adverse Effects: Fatigue, headache, gastrointestinal discomfort, and taste changes.
- Rare Adverse Effects: Arterial thromboembolic events, reversible posterior leukoencephalopathy syndrome (RPLS), and ovarian failure.
Reports on post-marketing
Body as a whole: Polyserositis reported in postmarketing observations.
Cardiovascular: Adverse events include pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (RPLS), arterial aneurysms, dissections, and rupture, alongside mesenteric venous occlusion.
Osteonecrosis of the jaw and non-mandibular osteonecrosis were reported.
Eye disorders from unapproved intravitreal use include severe complications like permanent vision loss, endophthalmitis, intraocular inflammation, and retinal detachment.
Gastrointestinal complications encompass ulcers, necrosis, and anastomotic ulceration.
Hemic and lymphatic issues involve pancytopenia.
Hepatobiliary disorders include gallbladder perforation.
Infections: Necrotizing fasciitis, often secondary to wound healing complications, gastrointestinal perforation, or fistula formation.
Musculoskeletal: Osteonecrosis of the jaw.
Renal: Renal thrombotic microangiopathy.
Respiratory: Nasal septum perforation, dysphonia.
Persistent, recurrent, or metastatic cervical carcinoma linked.
Systemic events from unapproved intravitreal use encompass arterial thromboembolic events, hypertension, gastrointestinal perforation, and bleeding.
Non-mandibular osteonecrosis and posterior reversible encephalopathy syndrome (PRES) were reported in postmarketing observations.
The clinically relevant drug interactions of bevacizumab are briefly summarized here.
Microangiopathic hemolytic anaemia risk may be elevated when using sunitinib. It may raise the chance of pancytopenia and agranulocytosis when combined with dipyrone. This could make taking clozapine more likely to cause agranulocytosis. This may increase the possibility of sorafenib-induced hand-foot skin reaction. Potentially raise the risk of jaw osteonecrosis when combined with derivatives of bisphosphonates.
The common side effects of bevacizumab include:
Rectal bleeding
Taste change
Headache
Urine containing protein
Nosebleeds
Back pain
Dry skin
High blood pressure
Nasal inflammation
- Pregnancy
Pregnancy Category C (FDA): Use caution if the benefits outweigh the risks.
Pregnant women may experience fetal harm from the drug due to its mechanism of action and results from animal studies.
A small number of postmarketing reports detail pregnancies in which bevacizumab was used, but these reports are insufficient to identify drug-associated risks.
Animal data
During organogenesis, bevacizumab was given intravenously (IV) to pregnant rabbits every three days at doses about 1 to 10 times the clinical dose of 10 mg per kg. This resulted in fetal resorptions, decreased weight gain in both the mother and the fetus, and several congenital malformations, including corneal opacities and abnormal ossification of the skull and skeleton, including defects in the limbs and phalangeal.
VEGF, VEGF Receptor 2 (VEGFR2), and angiogenesis are linked in animal models to essential aspects of female reproduction, embryofetal development, and postnatal development.
Contraception
Advise female patients who are capable of becoming pregnant to use an effective form of birth control during their treatment and for six months after their last bevacizumab dose.
Infertility
Before beginning, counsel women who may become pregnant about the possibility of ovarian failure; the long-term effects of bevacizumab exposure on fertility are unknown.
- Nursing MotherS
There is no information on bevacizumab's presence in human milk, how it affects breastfed infants, or how it affects milk production. Although there is human IgG in human milk, available information indicates that breast milk antibodies do not significantly enter the circulation of newborns and infants. It is advised that women refrain from breastfeeding while taking Avastin and for six months following the last dose due to the possibility of severe adverse reactions in breastfed infants.
- Pediatric Use
As per the FDA, Bevacizumab use in Pediatric patients has not been established.
- Geriatrics (> 65 years old) Use
The safety and efficacy of bevacizumab in the geriatric population have been studied. Caution is advised due to potential heightened sensitivity to medication in elderly individuals, necessitating close monitoring for adverse effects and adjusting doses based on individual health conditions.
Dose Adjustment in Kidney Impairment Patients:
Renal impairment: Dosage adjustment may be required.
Dose Adjustment in Hepatic Impairment Patients:
Mild to moderate: Dosage adjustment may be needed.
Severe: Contraindicated.
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of bevacizumab.
Signs and Symptoms
Overconsumption of Bevacizumab may lead to severe hypertension, proteinuria, thromboembolic events, gastrointestinal perforation, and potential complications associated with excessive vascular suppression and impaired wound healing.
Management
There is no specific antidote or treatment for overdosage of bevacizumab. If recent ingestion occurs, employ gastric lavage or administer activated charcoal. Monitor closely for severe adverse effects like hypertension, proteinuria, and thromboembolic events. Address these complications with interventions such as blood pressure control, renal function monitoring, and anticoagulation management. Surgical consultation is necessary for gastrointestinal perforation.
Maintain proper hydration, balance electrolytes, and manage symptoms like bleeding or wound complications. Vigilantly monitor potential delayed effects due to bevacizumab's long half-life. Mitigate adverse effects and ensure patient safety through close observation, supportive measures, and prompt intervention in cases of Bevacizumab overdosage.
Pharmacodynamics
By binding to circulating vascular endothelial-derived growth factor (VEGF) and preventing it from binding to related receptors, bevacizumab effectively reduces downstream signalling. Research has demonstrated that bevacizumab improves the delivery of chemotherapy drugs to the target area while also helping to restore normal vasculature at the tumour site, increasing the supply of nutrients and oxygen. On the contrary, VEGF signalling plays a crucial role in wound healing, coagulation, angiogenesis, lymphangiogenesis, blood pressure regulation, and renal filtration, among other processes. Because VEGF is involved in many different physiological processes, blocking it may have unintended effects even though it may slow the progression of metastatic disease.
Pharmacokinetics:
Absorption: The time required to achieve a steady-state concentration of this substance spans approximately 84 days. Following a 10 mg/kg dose, an observed accumulation ratio 2.8 is noted.
Distribution: This substance's volume of distribution (Vd) averages around 2.9 L, with gender-based variations: 3.2 L in males and 2.7 L in females.
Elimination: The clearance rate of this substance is approximately 0.23 L/day on average, with slight differences between genders: 0.26 L/day in males and 0.21 L/day in females. The half-life is about 20 days.
- Kurkjian C, Kim ES. Risks and benefits with bevacizumab: evidence and clinical implications. Ther Adv Drug Saf. 2012 Apr;3(2):59-69. doi: 10.1177/2042098611430109. PMID: 25083226; PMCID: PMC4110846.
- Pang J, Xu F, Aondio G, Li Y, Fumagalli A, Lu M, Valmadre G, Wei J, Bian Y, Canesi M, Damiani G, Zhang Y, Yu D, Chen J, Ji X, Sui W, Wang B, Wu S, Kovacs A, Revera M, Wang H, Jing X, Zhang Y, Chen Y, Cao Y. Efficacy and tolerability of bevacizumab in patients with severe Covid-19. Nat Commun. 2021 Feb 5;12(1):814. doi: 10.1038/s41467-021-21085-8. PMID: 33547300; PMCID: PMC7864918.
- Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun. 2005 Jul 29;333(2):328-35. doi: 10.1016/j.bbrc.2005.05.132. PMID: 15961063.
- Zhao T, Wang X, Xu T, Xu X, Liu Z. Bevacizumab significantly increases the risks of hypertension and proteinuria in cancer patients: A systematic review and comprehensive meta-analysis. Oncotarget. 2017 May 23;8(31):51492-51506. doi: 10.18632/oncotarget.18190. PMID: 28881662; PMCID: PMC5584263.
- Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther. 2006 Nov;28(11):1779-802. doi: 10.1016/j.clinthera.2006.11.015. PMID: 17212999.
- KD Tripathi. [link]. Seventh Edition. New Delhi, India: Jaypee Brothers Medical Publishers; 2013: Page No 871
- https://www.ncbi.nlm.nih.gov/books/NBK482126/
- https://www.ncbi.nlm.nih.gov/books/NBK548877/
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125085s225lbl.pdf
Published on: 10 Jan 2024 4:51 AM GMT