Bevacizumab

Registered South African indications:

• Metastatic colorectal cancer
• Locally recurrent or metastatic breast cancer
• Advanced, metastatic or recurrent adenocarcinoma of the lung
• Advanced and/or metastatic renal cell cancer
• Epithelial ovarian, fallopian tube and primary peritoneal cancer
• Cervical cancer
• Malignant glioma (WHO Grade IV) - glioblastoma

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to Chinese Hamster Ovary cell products or other recombinant human or humanised antibodies
• Pregnancy

Cautions

• Breastfeeding
• Females of childbearing potential
• Renal impairment
• Hepatic impairment
• Elderly
• Intra-abdominal inflammatory process in patients with metastatic carcinoma of the colon or rectum
• History of prior radiation
• Persistent, recurrent or metastatic cervical cancer
• Patients requiring wound care therapy
• Pre-existing hypertension 
• History of aneurysms
• Risk factors for aneurysms and artery dissections
• Re-initiating bevacizumab therapy in patients previously experiencing Posterior reversible encephalopathy syndrome (PRES)
• History of arterial thromboembolism
• Diabetes mellitus
• Thromboembolic reactions ≤ Grade 3
• Untreated central nervous system metastases
• Congenital bleeding diathesis
• Acquired coagulopathy
• Patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting bevacizumab treatment
• Recent pulmonary haemorrhage or haemoptysis 
• Clinically significant cardiovascular disease
  - Pre-existing coronary artery disease
  - Congestive heart failure
• Risk factors for osteonecrosis of the jaw
  - History of dental disease requiring invasive dental procedures
  - Prior or concomitant treatment with intravenous bisphosphonates
• Intravitreal administration
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Metastatic colorectal cancer (additional agent required) 
• Locally recurrent or metastatic breast cancer (additional agent required)
  - In combination with paclitaxel is indicated for first-line treatment of metastatic breast cancer patients
  - In combination with capecitabine as first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment of bevacizumab in combination with capecitabine
• Unresectable advanced, metastatic or recurrent adenocarcinoma of the lung (additional agent required)
  - First-line treatment in addition to platinum-based chemotherapy for patients with unresectable advanced, metastatic or recurrent non-small lung cancer other than predominantly squamous cell histology
  - First-line treatment in combination with erlotinib for patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor activating mutations
• Advanced and/or metastatic renal cell cancer (additional agent required)
• Advanced epithelial ovarian, fallopian tube and primary peritoneal cancer (additional agent required)
  - Front-line treatment of patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer
  - In combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel for the first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents
  - In combination with topotecan or pegylated liposomal doxorubicin for platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received no more than two prior chemotherapeutic regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents
• Persistent, recurrent or metastatic carcinoma of the cervix (additional agent required)
  - In combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy
• Newly diagnosed malignant glioma (WHO Grade IV) - glioblastoma (additional agent required) 
  - In combination with radiotherapy and temozolomide for newly diagnosed glioblastoma
  - As a single agent, or in combination with irinotecan for patients with glioblastoma after relapse or disease progression

---

Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Contraindicated
• There are no clinical trial data on the use of bevacizumab in pregnant women. Studies in animals have shown reproductive toxicity including malformations
• IgGs are known to cross the placenta, and bevacizumab is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to cause serious birth defects when administered during pregnancy
• In the post-marketing setting, cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed
• Bevacizumab is contraindicated in pregnancy. Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment

Breastfeeding

• Caution; not recommended
• It is not known whether bevacizumab is excreted in human milk
• As maternal IgG is excreted in milk and bevacizumab could harm infant growth and development, women must discontinue breastfeeding during therapy and not breastfeed for at least six months following the last dose of bevacizumab

Fertility

• Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility
• In a phase III trial in the adjuvant treatment of patients with colon cancer, a substudy with premenopausal women has shown a higher incidence of new cases of ovarian failure in the bevacizumab group compared to the control group. After discontinuation of bevacizumab treatment, ovarian function recovered in the majority of patients
• Long term effects of the treatment with bevacizumab on fertility are unknown

Renal Impairment

• Caution; no information available
  Safety and efficacy have not been studied in patients with renal impairment since the kidneys are not a major organ for bevacizumab metabolism or excretion

Hepatic Impairment

• Caution; no information available
  Safety and efficacy have not been studied in patients with hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion

Elderly

• Caution; no dose adjustment recommended
  Patients >65 years have an increased risk of developing arterial thromboembolic reactions during therapy. Caution should be taken when treating these patients with bevacizumab

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Peripheral sensory neuropathy
• Dysarthria
• Headache
• Cerebrovascular accident
• Syncope
• Somnolence
• Posterior reversible encephalopathy syndrome
• Hypertensive encephalopathy
• Fatigue
• Stroke

Cardiovascular Disorders

• Congestive cardiac failure
• Supraventricular tachycardia
• Hypertension
• Thromboembolism (venous and arterial)
• Haemorrhage
• Deep vein thrombosis
• Aneurysms
• Artery dissections
• Renal thrombotic microangiopathy

Respiratory Disorders

• Dyspnoea
• Rhinitis
• Cough
• Pulmonary haemorrhage
• Haemoptysis
• Pulmonary embolism
• Epistaxis
• Hypoxia
• Dysphonia
• Pulmonary hypertension
• Nasal septum perforation

Gastrointestinal Disorders

• Rectal haemorrhage
• Stomatitis
• Constipation
• Diarrhoea
• Nausea and vomiting
• Gastrointestinal perforation
• Intestinal perforation
• Ileus
• Intestinal obstruction
• Recto-vaginal fistulae
• Proctalgia
• Gastrointestinal ulcer
• Abdominal pain

Hepatobiliary Disorders

• Gallbladder perforation

Genitourinary Disorders

• Urinary tract infection
• Proteinuria
• Ovarian failure
• Pelvic pain

Endocrine and Metabolic Disorders

• Anorexia
• Hypomagnesaemia
• Hyponatraemia
• Dehydration
• Decreased weight

Musculoskeletal Disorders

• Arthralgia
• Fistula
• Myalgia
• Muscular weakness
• Back pain
• Osteonecrosis of the jaw
• Non-mandibular osteonecrosis (paediatric population)

Skin and Subcutaneous Tissue Disorders

• Abscess
• Cellulitis
• Necrotising fasciitis
• Wound healing complications
• Exfoliative dermatitis
• Dry skin
• Skin discoloration
• Palmar-plantar erythro-dysaesthesia syndrome
• Mucosal inflammation

Immune, Blood and Lymphatic System Disorders

• Sepsis
• Infection
• Febrile neutropenia
• Leucopenia
• Neutropenia
• Thrombocytopenia
• Anaemia
• Lymphopenia
• Hypersensitivity
  - Dyspnoea/difficulty breathing
  - Flushing/redness/rash
  - Hypotension/hypertension
  - Oxygen desaturation
  - Chest pain
  - Rigors
  - Nausea and vomiting
• Infusion reactions
• Fever
• Fistula formation

Sensory Disorders

• Eye disorder
• Increased lacrimation
• Dysgeusia

Others

• Foetal abnormalities
• Pain 

• Anticoagulants
• EGFR monoclonal antibodies
• Panitumumab
• Cetuximab
• Platinum- or taxane-based therapies (non-small cell lung cancer and metastatic breast cancer)
• Sunitinib malate 
• Intravenous bisphosphonates
• Radiotherapy

• Blood pressure

None routine. Specific cases may require

• 24hr urine protein test
• Pregnancy test
• Ophthalmic examination 

Additional observations

• Evaluate for varices (within 6 months of treatment initiation)
• Signs and symptoms of:
  - Infusion reaction
  - GI perforation or fistula, bleeding, thromboembolism, wound healing complications, and heart failure
  - Infectious endophthalmitis

Traceability

• In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded in the patient file

Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF regresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour growth.

Injection (per 4ml) 100mg

• Avastin (Roche) originator

Injection (per 16ml) 400mg

• Avastin (Roche) originator