Please refer to the appropriate Summary of Product Characteristics (SmPC) before prescribing. This medicine is subject to additional monitoring. ▼Oyavas 25 mg/ml concentrate for solution for infusion. Each mL of concentrate contains 25 mg of bevacizumab. Each 4 mL vial contains 100 mg of bevacizumab. Each 16 mL vial contains 400 mg of bevacizumab.
Indication:
Oyavas in combination with fluoropyrimidine based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum. Oyavas in combination with paclitaxel is indicated for first line treatment of adult patients with metastatic breast cancer. Oyavas in combination with capecitabine is indicated for first line treatment of adult 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 with Oyavas incombination with capecitabine. Oyavas, in addition to platinum-based chemotherapy, is 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. Oyavas, in combination with erlotinib, is indicated for first line treatment of adult patients with unresectable advanced, metastatic, or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor activating mutations. Oyavas in combination with interferon alfa 2a is indicated for first line treatment of adult patients with advanced and/or metastatic renal cell cancer. Oyavas, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. Oyavas, in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel, is indicated for treatment of adult patients with 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. Oyavas, in combination with topotecan, or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with platinum resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor targeted agents. Oyavas, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix.
Dosage and administration:
Must only be administered under the supervision of a physician qualified in the use of antineoplastic medicinal products. Refer to Summary of Product Characteristics prior to dosing. 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 Oyavas, 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. Metastatic breast cancer (mBC). The recommended dose is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. Non-small cell lung cancer (NSCLC). First line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy. Oyavas is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by Oyavas as a single agent until disease progression. The recommended dose is 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks as an IV infusion. First line treatment of non-squamous NSCLC with EGFR activating mutations in combination with erlotinib. EGFR mutation testing should be performed prior to initiation of treatment with the combination of Oyavas and erlotinib. It is important that a well validated and robust methodology is chosen to avoid false negative or false positive determinations. The recommended dose when used in addition to erlotinib is 15 mg/kg of body weight given once every 3 weeks as an IV infusion. It is recommended that the treatment with Oyavas in addition to erlotinib is continued until disease progression. Advanced and/or metastatic renal cell cancer (mRCC). The recommended dose is 10 mg/kg of body weight given once every 2 weeks as an IV infusion. Epithelial ovarian, fallopian tube and primary peritoneal cancer. Oyavas is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Oyavas as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier. The recommended dose is 15 mg/kg of body weight given once every 3 weeks as an IV infusion. Treatment of platinum sensitive recurrent disease. Oyavas is administered in combination with either carboplatin and gemcitabine for 6 cycles and up to 10 cycles or in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by continued use of Oyavas as single agent until disease progression. The recommended dose is 15 mg/kg of body weight given once every 3 weeks as an IV infusion. Treatment of platinum resistant recurrent disease. Oyavas is administered in combination with one of the following – topotecan (given weekly) or pegylated liposomal doxorubicin. The recommended dose of Oyavas is 10 mg/kg of body weight given once every 2 weeks as an IV infusion. When administered in combination with topotecan (given on days 1 5, every 3 weeks), the recommended dose is 15 mg/kg of body weight given once every 3 weeks as an IV infusion. Cervical cancer. Oyavas is administered in combination with one of the following regimens: paclitaxel and cisplatin or paclitaxel and topotecan. The recommended dose is 15 mg/kg of body weight given once every 3 weeks as an IV infusion. No dose adjustment is required in patients ≥ 65 years of age. The safety and efficacy have not been studied in patients with renal or hepatic impairment. The safety and efficacy in children aged less than 18 years old has 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, ovary, fallopian tube, peritoneum, cervix and kidney. Oyavas is for intravenous use. The initial dose should be delivered over 90 minutes. 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 intravenous push or bolus. Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended. Oyavas infusions should not be administered or mixed with glucose solutions. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to Chinese Hamster Ovary cell products or other recombinant human or humanised antibodies. Pregnancy.
Warnings and Precautions:
In order to improve the traceability, the name and the batch number of the administered product should be recorded in the patient file. Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation. Intraabdominal 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. Patients treated for persistent, recurrent, or metastatic cervical cancer are 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. Patients may be at increased risk for the development of fistulae when treated with bevacizumab. Permanently discontinue Oyavas in patients with tracheoesophageal (TE) fistula or any grade 4 fistula [US National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.3)]. 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 Oyavas should be considered. Bevacizumab may adversely affect the wound healing process. Serious wound healing complications, including anastomotic complications, with a fatal outcome have been reported. Therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experienced wound healing complications during therapy, treatment should be withheld until the wound is fully healed. Therapy should be withheld for elective surgery. Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with bevacizumab. This condition is usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated. An increased incidence of hypertension was observed in bevacizumab treated patients. Data suggest that the incidence of hypertension is likely to be dose dependent. Pre-existing hypertension should be adequately controlled before starting 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 recommended during therapy. In most cases hypertension was controlled adequately using standard antihypertensive treatment appropriate for the individual situation. The use of diuretics to manage hypertension is not advised in patients who receive a cisplatin based chemotherapy regimen. Oyavas should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy. Reports of bevacizumab treated patients developing signs and symptoms that are consistent with posterior reversible encephalopathy syndrome (PRES), a rare neurologic disorder, which can present with the following signs and symptoms among others: seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. In patients developing PRES, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of Oyavas. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known. Patients with a history of hypertension may be at increased risk for the development of proteinuria. Evidence suggests that all grade (NCI CTCAE v.3) proteinuria may be related to the dose. Monitoring of proteinuria by dipstick urinalysis 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 (NCI CTCAE v.3). In clinical trials, the incidence of arterial thromboembolic reactions including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher in patients receiving bevacizumab in combination with chemotherapy compared to those who received chemotherapy alone. Patients receiving bevacizumab plus chemotherapy, with a history of arterial thromboembolism, diabetes or age greater than 65 years have an increased risk of developing arterial thromboembolic reactions during therapy. Caution should be taken when treating these patients. Therapy should be permanently discontinued in patients who develop arterial thromboembolic reactions. Patients may be at risk of developing venous thromboembolic reactions, including pulmonary embolism. Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab in combination with paclitaxel and cisplatin may be at increased risk of venous thromboembolic events. Oyavas should be discontinued in patients with life threatening (grade 4) thromboembolic reactions, including pulmonary embolism (NCI CTCAE v.3). Patients with thromboembolic reactions ≤ grade 3 need to be closely monitored (NCI CTCAE v.3). Patients treated with bevacizumab have an increased risk of haemorrhage, especially tumour associated haemorrhage. Oyavas should be discontinued permanently in patients who experience grade 3 or 4 bleeding during bevacizumab therapy (NCI CTCAE v.3). Patients with untreated CNS metastases were routinely excluded from clinical trials with bevacizumab, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patients has not been prospectively evaluated in randomised clinical trials. Patients should be monitored for signs and symptoms of CNS bleeding, and Oyavas treatment discontinued in cases of intracranial bleeding. There is no information on the safety profile of bevacizumab in patients with congenital bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting bevacizumab treatment, as such patients were excluded from clinical trials. Caution should be exercised before initiating therapy in these patients. Patients who developed venous thrombosis while receiving therapy did not appear to have an increased rate of grade 3 or above bleeding when treated with a full dose of warfarin and bevacizumab concomitantly (NCI CTCAE v.3). Patients with non-small cell lung cancer treated with bevacizumab may be at risk of serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/ haemoptysis (> 2.5 mL of red blood) should not be treated with Oyavas. The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Oyavas, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm. Reactions consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation. Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with Oyavas. Most of the patients who experienced CHF had metastatic breast cancer and had received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF were present. Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy alone. This has mainly been seen in combination with platinum or taxane based therapies in the treatment of NSCLC, mBC, and in combination with paclitaxel and topotecan in persistent, recurrent, or metastatic cervical cancer. Patients may be at risk of developing infusion/hypersensitivity reactions. Close observation of the patient during and following the administration is recommended. If a reaction occurs, the infusion should be discontinued, and appropriate medical therapies administered. A systematic premedication is not warranted. Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients treated with bevacizumab, the majority of whom had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when Oyavas and intravenous bisphosphonates are administered simultaneously or sequentially. Invasive dental procedures are a risk factor. A dental examination and appropriate preventive dentistry to be considered prior to starting treatment. In patients who have previously received or are receiving intravenous bisphosphonates invasive dental procedures should be avoided, if possible. Oyavas is not formulated for intravitreal use. Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intravitreal use of bevacizumab compounded from vials approved for intravenous 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. A reduction of circulating VEGF concentration has been demonstrated following intravitreal anti VEGF therapy. Systemic adverse reactions including non-ocular haemorrhages and arterial thromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors. Bevacizumab may impair female fertility. Therefore, fertility preservation strategies should be discussed with women of childbearing potential prior to starting treatment with bevacizumab. Contains less than 1 mmol sodium (23 mg) per vial, essentially ‘sodium free’.
Pregnancy and lactation:
Women of childbearing potential must use effective contraception during and up to 6 months after treatment. 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 is suspected to cause serious birth defects when administered during pregnancy. Cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed. Oyavas is contraindicated in pregnancy. 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 breast feeding during therapy and not breast feed for at least six months following the last dose of bevacizumab.
Undesirable effects:
For full list of side effects, consult SmPC. The most commonly reported undesirable effects are: febrile neutropenia, leukopenia, thrombocytopenia, anaemia, lymphopenia, hypersensitivity, infusion reactions, anorexia, hypomagnesaemia, hyponatraemia, dehydration, peripheral sensory neuropathy, dysarthria, headache, dysgeusia, cerebrovascular accident, syncope, somnolence, eye disorders, hypertension, thromboembolism (venous & arterial), DVT, dyspnoea, rhinitis, epistaxis, cough, pulmonary haemorrhage & embolism, haemoptysis, hypoxia, dysphonia, rectal haemorrhage, stomatitis, constipation, diarrhoea, nausea, vomiting, abdominal pain, gastrointestinal perforation and disorder, intestinal obstruction, recto-vaginal fistulae, proctalgia, would healing complications dermatitis, dry skin, skin discolouration, Palmar-plantar erythrodysesthesia syndrome, arthralgia, myalgia, fistula, muscular weakness, back pain, proteinuria, ovarian failure, pelvic pain, asthenia, fatigue, pyrexia, pain, mucosal inflammation, lethargy decreased weight. Serious undesirable effects include gastrointestinal perforations, haemorrhage, including pulmonary haemorrhage/haemoptosis, which is more common in non-small cell lung cancer, arterial thromboembolism.
Overdose:
The highest dose tested in humans (20 mg/kg of body weight, intravenous every 2 weeks) was associated with severe migraine in several patients.
Legal Category:
POM.
Pack size:
Each vial contains 25 mg/ml bevacizumab
Pack of 1 x 4 ml vial.
Pack of 1 x 16 ml vial.
Price:
1 x 4ml £230.00
1 x 16ml £877.80
MA Number:
PL GB 00240/0346.
MA Holder:
Thornton & Ross Ltd. (trading as ‘STADA’), Linthwaite, Huddersfield, HD7 5QH, UK.
Date of preparation:
July 2021.
Unique ID no:
OYA-001
Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to 01484 848164