Bevacizumab - Uses, Dosage, Side Effects, Precautions, Precautions, and Interactions

Overview:

Bevacizumab injections are given with other medicines to treat patients with colon or rectum metastatic cancer. The medicine helps to decrease the growth of cancer cells. Bevacizumab is (Food and Drug Administration) FDA-approved to be used in combination with chemotherapy for ovarian cancer.

Bevacizumab belongs to the class of medications called antiangiogenic agents, which interfere with the formation of the blood vessels, bringing oxygen to the tumor cells. Bevacizumab acts as a steroid-sparing agent during immunotherapy.

How Does Bevacizumab Work?

Bevacizumab acts as a vascular endothelial growth factor (VEGF) inhibitor and blocks it from binding to its associated receptors. The drug helps to establish normal vasculature at the tumor site resulting in increased nutrient and oxygen supply. It also helps to improve the delivery of chemotherapy drugs to the target area.

The metabolism of Bevacizumab is through proteolytic catabolism throughout the body. The clearance of the drug is faster in males than females at 0.207 L/day. The half-life is estimated to be 20 days. Bevacizumab can stay in the body for about four months.

Uses of Bevacizumab:

Bevacizumab is Food and Drug Administration (FDA)-approved for treating colorectal cancer (cancer of the colon and rectum), lung cancer, kidney cancer, and glioblastoma (aggressive cancer that occurs in the brain or spinal cord). The anti-cancer drug is also used to treat cervical cancer and hepatocellular carcinoma (HCC) that has metastasized or cannot be removed by surgery. Bevacizumab is used with other chemotherapy drugs, like Carboplatin and Paclitaxel as a first-line therapy to treat locally advanced non-small cell lung cancer. The drug helps to treat renal cell cancer in combination with interferon alfa (an immunomodulator).

Limitations:

• Bevacizumab comes with a black box warning. The drug can cause infusion-related reactions which may be life-threatening and require immediate medical attention.

• Bevacizumab is not indicated for adjuvant treatment of colon cancer.

• Bevacizumab is associated with an increased risk of toxicity, resulting in black box warning for gastrointestinal perforation, wound healing complications, and hemorrhage.

• In November 2011, FDA withdrew Bevacizumab, concluding that it was unsafe and ineffective for the treatment of breast cancer.

Route of Administration:

• Intravenous.

• Subcutaneous.

• Intramuscular.

Dosage Forms and Strengths

Injectable Solution - 25 mg/ml.

Bevacizumab is available in two vial sizes: a 3 ml vial that holds 100 mg of the drug and a 16 ml vial that holds 400 mg of the drug.

Typical Dosage:

The maximum tolerated dose of Bevacizumab is 20 mg/kg.

Special Considerations

Bevacizumab therapy is associated with increased toxicities and has a black box warning.

• Allergy - Bevacizumab can cause severe allergic reactions with symptoms such as skin rash, itching, flushing, swelling of lips, hands, or feet, and trouble breathing and should be avoided in patients who have had an allergy to the drug.

• Pregnancy and Breastfeeding - Bevacizumab can cause harmful effects on the fetus and should be avoided. Intravenous Bevacizumab should be administered with caution while breastfeeding. Breastfeeding should be avoided for at least six months following the last dose.

• Elderly - Long exposure to the treatment of Bevacizumab can cause severe side effects and should be administered with caution.

• Children - The safety and effectiveness of Bevacizumab in the pediatric population have not been established.

• Mind Alertness - Therapy with Bevacizumab causes tiredness, fatigue, and headache. It is advised to avoid any chores requiring alertness.

Warnings and Contraindications:

Contraindications:

• Fistula Formation - Therapy with Bevacizumab may cause a fatal fistula involving transesophageal, vaginal, renal, and bladder sites. The drug should be avoided in patients with fistula involving an internal organ.

• Gastrointestinal Perforation - Bevacizumab should be avoided in patients with bowel obstruction or recto-sigmoid involvement. Inhibitors of vascular endothelial growth factor receptors may cause gastrointestinal perforation and fistulae and should be avoided.

• Bleeding - Bevacizumab affects wound healing and increases the incidences of healing complications that may require surgical intervention. The drug should not be given for at least 28 days before elective surgery and post-surgery until the wound has completely healed. Bevacizumab should not be administered to patients with a recent history of hemoptysis or hemorrhage.

• Posterior Reversible Encephalopathy Syndrome (PRES) - Bevacizumab can cause a neurological disorder PRES with symptoms like headache, seizures, lethargy, confusion, and blindness. The drug should be avoided in patients previously affected by this neurological disorder.

• Immunization - Avoid immunization with live vaccines, like rubella, mumps, measles, or yellow fever while undergoing Bevacizumab treatment for up to 12 months after the completion of treatment.

Warnings and Precautions:

• Hypertension - Bevacizumab should be administered cautiously in patients with preexisting hypertension as the drug may aggravate the condition. Blood pressure should be assessed before the initiation of the treatment and during the treatment regularly.

• Proteinuria - Therapy with Bevacizumab should be administered with caution in patients with renal dysfunction as there can be an increased incidence and severity of proteinuria.

• Thromboembolic Disorders - Bevacizumab should be avoided in patients with a history of venous and arterial thromboembolic venous (VTE ) or arterial (ATE) as it increases the incidences of ATE or VTE be fatal.

For Patients

What Is Cancer?

Cancer is a disease in which some of the body’s cells grow uncontrollably and spread to other parts of the body. It starts when a gene mutates (changes its form) and creates cancer cells. Cancer can involve any part of the body and may develop for years without developing symptoms. Some of the risk factors that increase the chances of cancer are smoking, high-sugar and fat diets, environment (exposure to toxins), and radiation exposure. And hormone therapy.

Symptoms of Cancer:

Some of the early symptoms of cancer include

• Unexplained weight loss.

• Chronic tiredness.

• Persistent pain.

• Fever may occur at night.

• Changes in skin, particularly change in shape and size or new moles.

Untreated cancer may cause abdominal symptoms including

• Easy bruising or bleeding.

• Lumps under the skin.

• Difficulty breathing and swallowing.

Why Is Bevacizumab Prescribed to Treat Cancer?

Bevacizumab is an antiangiogenic agent (a tumor-starving therapy). It is used with chemotherapy drugs as it hits cancer from a different angle and prevents the growth of new blood vessels, including normal and those feeding tumors. Bevacizumab targets a cancer cell protein called vascular endothelial growth factor which helps cancer to grow and get oxygen and food from the blood. Because of this benefit, Bevacizumab is used for the treatment of patients with advanced (stage III or IV) cancer following initial therapy.

Facts One Should Know About Bevacizumab:

• Bevacizumab is a targeted therapy used to treat different types of cancer.

• It is given every two to three weeks.

• Bevacizumab begins to work as soon as one takes the first dose. However, one may not feel any different as it does not treat the symptoms caused by cancer. The drug kills and slows down the growth of cancer cells.

• Drink plenty of fluids while taking Bevacizumab.

• Wash hands often to avoid infections. Avoid sun exposure while taking Bevacizumab.

• The effect of Bevacizumab will last up to three to four months in the body. However, it may depend on the dose and duration of the treatment.

How Should One Take Bevacizumab?

Bevacizumab injections are available as a solution that should be administered slowly over 90 minutes into the vein. The second infusion is over 60 minutes if the first infusion is well tolerated. The subsequent infusions are over 30 minutes if the second infusion is well tolerated.

• A trained doctor or nurse should administer the drug in a medical facility. Bevacizumab is usually given once every two or three weeks and is continued for as long as it controls cancer.

• Bevacizumab is given through a drip into the arm or hand which is connected to a cannula. A central line (a long plastic tube used to give drugs into large veins) that stays while one is getting their treatment (a few months).

• The dosing schedule depends on the condition one has, other medications that the person may be taking, and the body's response to the treatment.

• Some people can have serious reactions to Bevacizumab. In such cases, the doctor may slow down the infusion, delay, or stop the treatment.

• Blood tests are required to be done before and after the treatment to check the level of blood cells and other substances in the blood. It is also done to check liver and kidney functions.

• In case of a missed dose, take it soon after one remembers. However, do not take two tablets together at once, as it may cause adverse reactions.

• Avoid taking this medicine after it expires. Check for the expiry on the back of the medicine pack.

Information to Be Given to the Doctor Before Taking Bevacizumab:

• Medical History - It is advised to inform the doctor of one’s prescription and nonprescription medications, vitamins, supplements, and herbal products that one may be taking. Also, mention if one is taking Anthracycline (a type of chemotherapy used to treat breast cancer and some types of leukemia).

• Allergy - Inform the doctor if one has had an allergic reaction to Bevacizumab or any of its ingredients. Check the drug composition for the ingredients.

• Radiation Therapy - It is important to inform the doctor if one has been treated with radiation therapy of the chest or pelvis.

• Pregnancy and Breastfeeding - Inform the doctor if one is planning a pregnancy or is pregnant, or is breastfeeding. It is advised to avoid getting pregnant while taking Bevacizumab injections as it can harm the fetus. Use birth control to avoid pregnancy during the treatment and at least six months after the final dose. Breastfeeding should be avoided with Bevacizumab injection for at least six months after the final dose.

• Surgery - Inform the doctor if one has had surgery recently or is planning a surgery, including dental surgery. The doctor may stop the Bevacizumab injection for at least 28 days before the surgery. Also, one should not receive a Bevacizumab injection until at least 28 days after surgery, until the area has completely healed.

Safety of Bevacizumab:

Bevacizumab can cause toxicities including bleeding, hypertension, wound-healing complications, and gastrointestinal perforation. However, the drug is well-tolerated and the toxicities are not usually overlapping with those of cytotoxic chemotherapy.

Effectiveness of Bevacizumab:

Bevacizumab blocks cancer from growing blood vessels, resulting in the starvation of cancer cells followed by cell death. The drug is effective in treating patients with advanced or stage III and IV cancers.

Side Effects Expected With Bevacizumab:

Mild side effects may include,

• Changes in taste.

• Dry skin.

• Loss of appetite.

• Diarrhea.

• Trouble sleeping.

• Bleeding such as nosebleeds or rectal bleeding.

• Headache.

• Change in voice.

• High blood pressure.

• Runny or stuffy nose.

Serious side effects can include,

Thromboembolic Events - It can cause

• Episodes of heart attack (blood flow to the heart is blocked).

• Stroke (poor blood flow to the brain causing cell death).

• Angina (type of chest pain).

• Pulmonary embolism (blood clot lodged in an artery in the lung).

• Deep vein thrombosis (blood clot in a deep vein in the leg).

Gastrointestinal Perforation - It can cause symptoms including,

• Blindness.

• Headache.

• Seizures.

• Increased blood pressure.

• Confusion.

Kidney Damage - It may cause proteinuria (high levels of proteins in the urine) that may cause symptoms including,

• Bloating.

• Weight gain.

• High blood pressure.

• Swelling in hands and feet.

• Foamy urine.

Severe Infusion Reaction - It may cause symptoms such as

• Headache.

• Chest pain.

• Wheezing.

• Hypertension.

• Excessive sweating.

Heart Failure - It causes symptoms that include,

• Bloating.

• Tiredness.

• Wheezing.

• Fatigue.

• Shortness of breath.

• Long-lasting cough.

Early Menopause - The women will have symptoms such as

• Lack of periods.

• Vaginal dryness.

• Trouble sleeping.

• Change in the mood.

Can One Stop Taking Bevacizumab Suddenly Without the Doctor's Approval?

• Bevacizumab must be administered under doctor or nurse supervision.

• Never stop taking medicines without talking to the doctor. The doctor will decrease the dose gradually.

• Do not take the drug more than advised by the doctor.

Dietary Restrictions to Consider When Taking Bevacizumab:

• Alcohol - Consumption of alcohol should be avoided while taking Bevacizumab as the drug might worsen the side effects such as headache and should therefore be avoided.

Storage of Bevacizumab:

• Keep the medicine in their original packaging.

• Once a vial is opened, use it immediately. Store unused vials of Bevacizumab in the refrigerator at two to eight degrees. The diluted solutions may be refrigerated at two to eight degrees for up to eight hours.

• Store at room temperature between 2 to -8 degrees centigrade.

• Direct contact with heat, air, and light may damage the medicines. Therefore, keep the medicines away from direct light and heat.

• Keep all medicines out of reach of children and pets. Always lock the safety caps of the medication to protect small children from poisoning themselves.

Disposal of Bevacizumab:

• Do not keep outdated medicines or medicines that are no longer needed. Discard any unused portion of the reconstituted vial.

• If a spill occurs, restrict access to the affected area, and adequate protection including gloves and safety spectacles should be worn. The spill may be treated with five percent sodium hypochlorite after cleaning with absorbent paper.

• The contaminated material may be placed in a leakproof disposal bag for cytotoxics and incinerated at 1100 degrees centigrade.

• In case the medicine passes its expiry date or the treatment is stopped by the doctor, return the syringes to the pharmacist. Do not flush them down the toilet or throw them away in the trash.

Overdose:

• In case of an overdose, call the poison control helpline.

• Call the emergency services if the person has collapsed or has trouble breathing.

For Doctors,

Indications

Bevacizumab is approved to be used alone or with other drugs to treat

• Cervical Cancer - Bevacizumab can be used to treat cervical cancer that has not responded well to other treatments and has spread to other parts of the body or has come back.

• Colorectal Cancer - The drug is approved to treat colorectal cancer that has spread to other parts of the body. Bevacizumab can be used with Fluorouracil as the first or second treatment.

• Glioblastoma - Bevacizumab is indicated to treat glioblastoma that has come back.

• Hepatocellular Carcinoma - Bevacizumab is approved to be used to treat hepatocellular carcinoma in patients where the liver cancer has spread or cannot be removed by surgery.

• Nonsquamous Non-small Cell Lung Cancer - The drug is approved as the first therapy for nonsquamous non-small cell lung cancer that cannot be removed by surgery or has come back.

• Ovarian Epithelial or Primary Peritoneal Cancer - Bevacizumab can be combined with Carboplatin and Paclitaxel to treat ovarian epithelial or primary peritoneal cancer in patients whose cancer has come back.

• Renal Carcinoma - It is approved to treat kidney cancer that has spread to other parts of the body along with interferon-alpha.

Pharmacology of Bevacizumab

Description

Bevacizumab is a monoclonal anti-vascular endothelial growth factor antibody. The recombinant humanized monoclonal IgG1 antibody contains human framework regions and murine complementarity-determining regions. Bevacizumab is a clear, colorless, sterile, pH 6.2 solution for intravenous infusion supplied in 100 mg and 400 mg single-dose vials to deliver 4 ml or 16 ml of Bevacizumab.

Components

Active Ingredients - Bevacizumab.

Inactive Ingredients

• 51 mM sodium phosphate.

• Trehalose dihydrate.

• 0.04% polysorbate 20.

The drug is to be diluted in 0.9% sodium chloride solution prior to administration.

Clinical Pharmacology

Mechanism of Action - Cancer cells promote tumor angiogenesis by releasing VEGF, resulting in the creation of an immature and disorganized vascular network. The hypoxic microenvironment promoted by these cells favors the survival of more aggressive tumor cells. Bevacizumab binds and inactivates serum VEGF inhibiting proangiogenic signals. This prevents the formation of new blood vessels and decreases tumor vasculature and blood supply to the tumor.

Pharmacodynamics

Bevacizumab binds circulating vascular endothelial-derived growth factors and prevents its binding to associated receptors. The effect of Bevacizumab re-establishes normal vasculature at the tumor site resulting in an increased oxygen supply. It also improves the delivery of the chemotherapeutic drug to the target area.

Pharmacokinetics

• The Mean Cmax- 17.38 ug ml.

• Median Tmax- 2.50 hours.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose]

Pharmacokinetic Changes

Monoclonal antibodies are large in size and do not readily cross the cell membrane. They are not able to withstand proteolysis in the gastrointestinal tract. Due to these characteristics, the drug is poorly absorbed via the oral route and is administered either intravenously, intramuscularly, or subcutaneously.

Distribution

• Steady-state Plasma Levels - 84 days.

• Mean Half-Life - 20 days.

• Protein Bound - More than 97%.

• Time to Approach Steady-state Levels - 100 days.

• Mean Volume of Distribution - 3.29 L for males and 2.39 L for females.

Metabolism

• Metabolic Processes - The metabolism of Bevacizumab is primarily via proteolytic catabolism throughout the body, involving non-specific elimination pathways, such as neonatal Fc receptor and target-mediated elimination.

Elimination -

Due to their large size, monoclonal antibodies are not renally eliminated under normal physiological conditions. Metabolism or excretion is the primary process of elimination.

Drug Interactions:

• Clozapine - Using Clozapine (used to treat schizophrenia) together with Bevacizumab is not recommended. Clozapine can lower white blood cell count, and combining it with Bevacizumab affects bone marrow function.

• Deferiprone - The use of Deferiprone (used to remove excess iron from the body in patients with anemia, thalassemia, or sickle cell disease) can lower white blood cell count. Combining it with Bevacizumab can further affect white blood cells or bone marrow function.

• Panitumumab - Combining Bevacizumab with other chemotherapy drugs is not recommended and can lead to worsening of the treatment outcome. The patients will experience aggravated side effects with increased frequency.

• Thalidomide - Using Thalidomide with Bevacizumab can increase the risk of dangerous blood clots, especially in patients with high blood pressure, and high cholesterol, or those who smoke.

What Have Clinical Trials Shown About Bevacizumab?

Trial 1:

Objective - To determine whether sequential scheduling of Bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with metastatic colorectal cancer.

• A open-label, randomized clinical phase three trial was conducted in patients aged 18 to 75 years with unresectable, previously untreated, or single-line-treated metastatic colorectal cancer.

Primary Endpoint Outcome - Response rate.

Secondary Endpoint Outcome - Overall survival.

Result - Response rate did not differ between the sequential and concomitant schedule of Bevacizumab administration in combination with a standard Oxaliplatin-based regimen. However, the sequential schedule of Bevacizumab administration was associated with longer overall survival, fewer adverse effects, and better quality of life.

Trial 2:

Objective - To study the overall survival of patients receiving Bevacizumab as primary treatment for ovarian cancer.

• A phase III, randomized trial of Bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma.

• A total of 1873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous Carboplatin and Paclitaxel in comparison with chemotherapy plus concurrent and maintenance Bevacizumab.

Primary Outcome Measure - Disease-specific survival.

Result - No survival advantage was observed with no disease-specific survival observed for patients who received Bevacizumab compared with chemotherapy alone.

Complications or Side Effects of Bevacizumab:

• High Blood Pressure - It is the most common adverse event associated with Bevacizumab. Blood pressure should be measured before each Bevacizumab administration. The treatment should be permanently discontinued if the hypertension is not adequately controlled with appropriate therapy.

• Proteinuria - It is dose-dependent and common when Bevacizumab is given for a longer duration. It is important to assess urinary protein excretion before every administration of Bevacizumab. The treatment is not recommended in cases of nephrotic syndrome (24-hour urine protein is more than 3.5 g)

• Hemorrhage - Bleeding, especially epistaxis (nosebleed) is a frequent complication of Bevacizumab treatment. Data on the occurrence of hemorrhage in patients with brain tumors have been reported. It is recommended to accurately select patients and evaluate potential risk factors before starting Bevacizumab treatment.

• Thromboembolism - This is relatively common in patients with brain tumors. Anticoagulant therapy with low-molecular-weight heparin (LMWH) is preferred as a therapeutic option for patients treated with Bevacizumab.

• Arterial Thromboembolic Events - These include incidences of cerebral infarction, unstable angina, and transient ischemic attacks in Bevacizumab-treated patients. Caution is recommended when prescribing the drug to patients above 65 or with a history of vascular diseases.