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Bevacizumab 100mg/4Ml (humanized anti-VEGF monoclonal antibody)

Bevacizumab 100mg/4Ml

Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineoplastic agents, other antineoplastic agents, monoclonal antibodies, ATC code: L01X C07

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. Neutralizing the biological activity of VEGF regresses the vascularization of tumours, normalizes remaining tumour vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour growth.

Bevacizumab Therapeutic Indications

Bevacizumab is indicated for the treatment of:

  1. In addition to platinum-based chemotherapy, indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology.
  2. Metastatic carcinoma of the colon or rectum in adult patients in combination with fluoropyrimidine-based chemotherapy.
  3. Advanced and/or metastatic renal cell cancer in adult patients as first line treatment in combination with Interferon alfa-2a.
  4. Advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in adult patients as the front-line treatment in combination with carboplatin and paclitaxel. For treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer and naive to VEGF receptor-targeted agents including Bevacizumab
  5. Platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in adult patients in combination with paclitaxel, topotecan or pegylated doxorubicin who received only up to two prior chemotherapy regimens and naive to VEGF receptor-targeted agents including bevacizumab.
  6. Persistent, recurrent, or metastatic carcinoma of the cervix in adult patients in combination with paclitaxel and cisplatin/topotecan who cannot receive platinum therapy.
  7. Glioblastoma with progressive disease in adult patients following prior therapy as a single agent.
  8. Metastatic breast cancer as first line treatment in combination with capecitabine in adult patients in whom treatment with other chemotherapy options including taxanesor anthracyclines is not considered appropriate. Metastatic breast cancer as first line treatment in adult patients in combination with paclitaxel.

Bevacizumab Posology and Method of Administration

Bevacizumab was administered at the dose level of 7.5mg/kg of body weight every 3 weeks as an IV infusion in addition to platinum-based chemotherapy during clinical trial in patients with unresectable or metastatic NSCLC.

Information provided below is based on the innovator data. Non-small cell lung cancer (NSCLC)

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy

Bevacizumab is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by Bevacizumab as a single agent until disease progression.

The recommended dose of Bevacizumab is 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks as an IV infusion. Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.

Metastatic carcinoma of the colon or rectum (mCRC): The recommended dose of Bevacizumab, administered as an IV infusion, is either 5 mg/kg or 10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.

Advanced and/or metastatic renal cell cancer (mRCC): The recommended dose of Bevacizumab is 10 mg/kg of body weight given once every 2weeks as an IV infusion. It is recommended that treatment be continued until progressionof the underlying disease or until unacceptable toxicity.

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Epithelial ovarian, fallopian tube and primary peritoneal cancer

Front-line treatment: Bevacizumab is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of bevacizumab as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier. The recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an IV infusion.

Treatment of platinum-sensitive recurrent disease: Bevacizumab is administered in combination with carboplatin and gemcitabine for 6 cycles and up to 10 cycles followed by continued use of bevacizumab as single agent until disease progression. The recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an IV infusion.

Treatment of platinum-resistant recurrent disease: Bevacizumab is administered in combination with one of the following agents – paclitaxel, topotecan (given weekly) or pegylated liposomal doxorubicin. The recommended dose of bevacizumab is 10 mg/kg of body weight given once every 2 weeks as an IV infusion. When bevacizumab is administered in combination with topotecan (given on days 1-5, every 3 weeks), the recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an IV infusion. It is recommended that treatment be continued until disease progression or unacceptable toxicity.

Cervical Cancer: Bevacizumab is administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin or paclitaxel and topotecan. The recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an IV infusion. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.

Glioblastoma: The recommended dose of Bevacizumab is 10 mg/kg every 2 weeks as an IV infusion.

Metastatic breast cancer (mBC): The recommended dose of Bevacizumab is 10 mg/kg of body weight given once every 2 weeks or 15mg/kg of body weight given once every 3 weeks as an IV infusion. It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.

Bevacizumab Special populations

Elderly patients: No dose adjustment is required in the elderly.

Patients with renal impairment: The safety and efficacy have not been studied in patients with renal impairment.

Patients with hepatic impairment: The safety and efficacy have not been studied in patients with hepatic impairment.

Paediatric population: The safety and efficacy of Bevacizumab in children less than 18 years old have not been established. There is no relevant use of Bevacizumab in the paediatric population in the indications for treatment of cancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with Bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Bevacizumab in children with glioblastoma.

Bevacizumab Method of administration

The initial dose should be delivered over 90 minutes as an IV infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. It should not be administered as an IV push or bolus.

Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended.

Bevacizumab infusions should not be administered or mixed with glucose solutions. This medicinal product must not be mixed with other medicinal products.

Bevacizumab Contraindications

  • Hypersensitivity to the active substance or to any of the excipients.
  • Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanized antibodies.
  • Pregnancy

Bevacizumab Special warnings and precautions for use

Gastrointestinal (GI) perforations and Fistulae: Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation when treated with bevacizumab. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with bevacizumab and all patients with GI perforation had a history of prior radiation. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation.

GI-vaginal Fistulae: Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumabare at increased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal- vaginal fistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and all patients with GI-vaginal fistulae had a history of prior radiation.

Recurrence of cancer within the field of prior radiation is an additional important risk factor for the development of GI-vaginal fistulae.

Non-GIFistulae: Patients may be at increased risk for the development of fistulae when treated withBevacizumab. Permanently discontinue Bevacizumab in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Limited information is available on the continued use of Bevacizumab in patients with other fistulae. In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of Bevacizumab should be considered.

Wound healing complications: Bevacizumab may adversely affect the wound healing process. Serious wound healingcomplications, including anastomotic complications, with a fatal outcome have beenreported. Therapy should not be initiated for at least 28 days following major surgery oruntil the surgical wound is fully healed. In patients who experienced wound healingcomplications during therapy, treatment should be withheld until the wound is fully healed.

Therapy should be withheld for elective surgery.

Hypertension: An increased incidence of hypertension was observed in bevacizumab-treated patients.Clinical safety data suggest that the incidence of hypertension is likely to be dose dependent.Pre-existing hypertension should be adequately controlled before startingbevacizumab treatment. There is no information on the effect of bevacizumab in patients with uncontrolled hypertension at the time of initiating therapy. Monitoring of blood pressure is generally recommended during therapy.

Posterior Reversible Encephalopathy Syndrome (PRES): There have been rare reports of Bevacizumab-treated patients developing signs andsymptoms that are consistent with PRES, a rare neurologic disorder, which can presentwith the following signs and symptoms among others: seizures, headache, altered mentalstatus, visual disturbance, or cortical blindness, with or without associated hypertension. Adiagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonanceimaging (MRI). In patients developing PRES, treatment of specific symptoms includingcontrol of hypertension is recommended along with discontinuation of bevacizumab.The safety of reinitiating Bevacizumab therapy in patients previously experiencingPRES is not known.

Proteinuria: Patients with a history of hypertension may be at increased risk for thedevelopment of Proteinuria when treated with Bevacizumab. There is evidence suggestingthat all Grade Proteinuria may be related to the dose. Monitoring of proteinuria by dipstickurinalysis is recommended prior to starting and during therapy. Grade 4 Proteinuria(nephrotic syndrome) was seen in up to 1.4% of patients treated with Bevacizumab.Therapy should be permanently discontinued in patients who develop nephrotic syndrome.

Arterial thromboembolism: In clinical trials, the incidence of arterial thromboembolic reactions includingcerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardialinfarctions (MIs) was higher in patients receiving Bevacizumab in combination with chemotherapy compared to those who received chemotherapy alone.

Venous thromboembolism: Patients may be at risk of developing venous thrombo embolic reactions, includingpulmonary embolism under Bevacizumab treatment.

Haemorrhage: Patients treated with Bevacizumab have an increased risk of haemorrhage, especially tumour- associated haemorrhage. Bevacizumab should be discontinued permanently in patients who experience Grade3 or 4bleedingduring Bevacizumab therapy.

Pulmonary haemorrhage/haemoptysis: Patients with non-small cell lung cancer treated with Bevacizumab may be at risk ofserious, and in some cases fatal, pulmonary haemorrhage/haemoptysis. Patients withrecent pulmonary haemorrhage/haemoptysis (>2.5 mL of red blood) should not be treatedwith Bevacizumab.

Congestive Heart Failure (CHF): Reactions consistent with CHF were reported in clinical trials. The findings ranged fromasymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiringtreatment or hospitalization. Caution should be exercised when treating patients with clinicallysignificant cardiovascular disease such as pre-existing coronary artery disease, orcongestive heart failure with bevacizumab.

Hypersensitivity reactions/infusion reactions: Patients may be at risk of developing infusion/hypersensitivity reactions. Closeobservation of the patient during and following the administration of Bevacizumab isrecommended as expected for any infusion of a therapeutic humanized monoclonalantibody. If a reaction occurs, the infusion should be discontinued and appropriatemedical therapies should be administered. A systematic premedication is not warranted.

Osteonecrosis of the jaw (ONJ): Cases of ONJ have been reported in cancer patients treated with Bevacizumab, themajority of whom had received prior or concomitant treatment with IV bisphosphonates,for which ONJ is an identified risk. Caution should be exercised when Bevacizumab andIV bisphosphonates are administered simultaneously or sequentially.

Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with Bevacizumab. In patients who have previously received or are receiving IV bisphosphonates invasive dental procedures should be avoided, if possible.

Intravitreal use: Bevacizumab is not formulated for intravitreal use.

Eye disorders: Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intravitreal use of Bevacizumab compounded from vials approved for IV administration in cancer patients. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and conjunctival haemorrhage. Some of these reactions have resulted in various degrees of visual loss, including permanent blindness.

Systemic effects following intravitreal use: A reduction of circulating VEGF concentration has been demonstrated following intravitrealanti-VEGF therapy. Systemic adverse reactions including non-ocular haemorrhages andarterial thrombo embolic reactions have been reported following intravitreal injection ofVEGF inhibitors.

Ovarian failure/fertility: Bevacizumab may impair female fertility. Therefore, fertility preservation strategies shouldbe discussed with women of child-bearing potential prior to starting treatment withbevacizumab.

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Bevacizumab Fertility, pregnancy and lactation

Pregnancy: There are no clinical trial data on the use of Bevacizumab in pregnant women. Studies inanimals have shown reproductive toxicity including malformations. IgGs are known tocross 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 embryo toxic chemotherapeutics have been observed. Bevacizumab is contraindicated in pregnancy.

Breast-feeding: It is not known whether Bevacizumab is excreted in human milk. As maternal IgG isexcreted in milk and bevacizumab could harm infant growth and development, womenmust discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of Bevacizumab.

Fertility: Repeat dose toxicity studies in animals have shown that bevacizumab may have anadverse effect on female fertility. In a phase III trial in the adjuvant treatment of patients withcolon cancer, a sub study with premenopausal women has shown a higher incidence of newcases 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.

Bevacizumab Effects on Ability to Drive and Use Machines

Information provided in this section is based on the innovator data. Bevacizumab has no or negligible influence on the ability to drive and use machines. However, somnolence and syncope have been reported with bevacizum abuse. If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate.

Bevacizumab Undesirable Effects

The most frequently reported AEs with incidence of more than 4% during the study were nausea, vomiting, hypertension, asthenia, anaemia, leukopenia, neutropenia, thrombocytopenia, tachycardia, constipation, diarrhoea, abdominal pain, hypochlorhydria, pyrexia, mucosalulceration, loss of appetite, pain, fatigue, respiratory distress, dizziness, alopecia, dyspnoea and cough, hypokalaemia, hyponatremia, headache and back pain. These were the expected AEs reported with the use of Bevacizumab and other chemotherapy agents used during the conduct of the study. Overall, Intas Bevacizumab drug product and AvastinTM were well tolerated in patients with NSCLC.

Bevacizumab Overdose

Information provided in this section is based on the innovator data. The highest dose tested in humans (20 mg/kg of bodyweight, IV every 2weeks) was associated with severe migraine in several patients.

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