Medicinal Products

AVASTIN 25 mg / ml concentrate for solution for infusion Box of 1 vial of 4 ml

Generic drug of the therapeutic class: Oncology and Hematology
active ingredients: Bevacizumab
Lab: Roche Registration Ltd

Soft capsule
All forms

Indication

Avastin (bevacizumab) is indicated for first-line treatment in patients with metastatic colorectal cancer in combination with intravenous 5-fluorouracil / folinic acid chemotherapy with or without irinotecan.

Dosage AVASTIN 25 mg / ml concentrate for solution for infusion Box of 1 vial of 4 ml

- Avastin should be administered under the supervision of a physician experienced in the use of antineoplastic agents.
It is recommended to continue treatment until the progression of the underlying disease.
- Avastin is recommended at a dosage of 5 mg / kg body weight given once every 14 days as an intravenous infusion. A dose reduction is not recommended if an adverse event occurs. In this case, the treatment must be either temporarily suspended or permanently stopped, as described in the section on warnings and precautions for use.
- The initial dose should be given by an intravenous infusion of 90 minutes. If the first infusion is well tolerated, the second infusion can be given within 60 minutes. If the infusion given in 60 minutes is well tolerated, all subsequent infusions can be administered within 30 minutes.
- The initial dose should be given after chemotherapy, all subsequent doses may be given before or after chemotherapy.
- Do not administer IV fast or bolus.
- Avastin infusions should not be administered or mixed with glucose solutions (see section on incompatibilities).
- Special populations:
. Children and adolescents : Tolerance and efficacy have not been studied in children and adolescents. Avastin should not be used in this population until additional data are available (see section Preclinical Safety Data).
. Elderly : No dose adjustment is needed in the elderly.
. Patients with renal impairment : Tolerance and efficacy have not been studied in patients with renal impairment.
. Hepatic impairment : Tolerance and efficacy have not been studied in patients with hepatic impairment.

Against indications

- Hypersensitivity to the active substance or to any of the excipients.
- Hypersensitivity to products of Chinese hamster ovary (CHO) cells or other recombinant human or humanized antibodies.
- Avastin is contraindicated in patients with untreated metastases of the central nervous system (CNS) (see sections cautionary and precautions for use and adverse effects).
- Pregnancy: There are no data on the use of Avastin in pregnant women. Animal studies have shown reproductive toxicity including malformations. It is known that IgG crosses the placental barrier and Avastin is likely to inhibit fetal angiogenesis. Avastin is contraindicated in pregnant women. Women of childbearing potential should use appropriate contraceptive measures during treatment with Avastin and for at least 6 months after the last dose of Avastin.
- Breast-feeding: It is not known if bevacizumab is excreted in human milk. Since maternal IgG passes into milk and bevacizumab could compromise infant growth and development, women should discontinue breastfeeding during treatment and should not breastfeed for at least 6 months after the last dose. Avastin.
Children and adolescents: Tolerance and efficacy have not been studied in children and adolescents. Avastin should not be used in this population until additional data become available.

Avastin side effects

- The safety profile of Avastin is based on data collected in clinical trials in 1132 patients with metastatic colorectal cancer, locally advanced or metastatic non-small cell lung cancer, metastatic breast cancer, or hormone-resistant prostate cancer who received Avastin monotherapy or chemotherapy.
- The most serious adverse events were:
. Gastrointestinal perforations (see section warnings and precautions for use).
. Haemorrhages (see section warnings and precautions for use).
. Arterial thromboembolism (see section warnings and precautions for use).
- The most commonly observed adverse events in all clinical studies in patients receiving Avastin with or without chemotherapy were: asthenia, diarrhea, nausea, and SAP pain (Without Other Precision).
- Analyzes of clinical safety data suggest that arterial hypertension and proteinuria during treatment with Avastin are likely dose-dependent.
- In a randomized, double-blind, controlled Phase III clinical study in the treatment of metastatic colorectal cancer (Study MAJ AVF2107g), 396 patients were treated with IFL + placebo (Group 1), 392 patients with IFL + Avastin (Group 2), and 109 patients with 5-fluorouracil / folinic acid (5-FU / AF) + Avastin (Group 3). In a Phase II, randomized, double-blind, controlled study (Study AVF2192g), the safety of Avastin was studied in 204 patients with metastatic colorectal cancer, who were not optimal candidates for a first-line treatment. league with irinotecan. Of these patients, 104 were treated with 5-FU / AF + placebo (Group 1) and 100 patients with 5-FU / AF + Avastin (Group 2). The overall tolerance in these two studies is presented in data 1 below:
Data 1: Overall Tolerance in Studies AVF2107g and AVF2192g :
AVF2107g: IFL + placebo N = 396 / IFL + Avastin N = 392 // AVF2192g: 5-FU / AF + placebo N = 104/5-FU / AF + Avastin N = 100 .
. Death within 60 days of randomization: 4.9% / 3.0% // 13.5% / 5.0%.
. Median duration of tolerance monitoring (weeks): 28/40 // 23/31.
. Serious adverse events (SAEs) leading to death: 2.8% / 2.6% // 6.7% / 4.0%.
. Adverse events (AEs) leading to discontinuation of treatment: 7.1% / 8.4% // 11.5% / 10.0%.
Unadjusted data for different treatment times .
- Grade 3 and 4 adverse events (regardless of causality) observed in> = 10% and between> = 1% - <10% of patients treated with Avastin compared to control groups, in Phase III and II in metastatic colorectal cancer (AVF2107g, AVF2192g) are described in data 2 .
Data 2: Grade 3 and 4 adverse events (regardless of place of causation and occurring at an incidence> = 2% in the Avastin group compared to the control group) observed in> = 10% and> = 1% - <10% of patients treated with Avastin: AVF2107g and AVF2192g .
AVF2107g: IFL + Avastin / AVF2192g: 5-FU / AF + Avastin .
> = 10% :
Cardiac disorders: - / Hypertension / -.
> = 1% and <10% :
. Cardiac disorders: Hypertension / -.
. Hematological and lymphatic system disorders: Leukopenia / -.
. General disorders and administration site conditions: Pain / Asthenia. Pain.
. Gastrointestinal disorders: Diarrhea. Abdominal pain / -.
. Infections and infestations: - / Septicemia. Abscess.
. Nervous system disorders: - / Cerebral ischemia. Syncope.
. Vascular disorders: Deep vein thrombosis. Thromboembolism (arterial) * / Thromboembolism (arterial) *.
* Pooled arterial thromboembolic events including stroke, myocardial infarction, transient ischemic attacks and other arterial thromboembolic events .
Unadjusted data for different treatment times .
- Adverse events of any grade (regardless of causality) observed in> = 10% and> = 1% - <10% of patients treated with Avastin compared to controls in Phase III studies and II in metastatic colorectal cancer (AVF2107g, AVF2192g) are described in Data 3 .
Data 3: Adverse events of all grades (regardless of causality and occurring at an incidence> = 10% in the Avastin group compared to the control group) seen in> = 10% and> = 1% - <10 % of patients treated with Avastin: AVF2107g and AVF2192g studies .
AVF2107g: IFL + Avastin / AVF2192g: 5-FU / AF + Avastin .
> = 10% :
. Cardiac disorders: Hypertension / Hypertension.
. Gastrointestinal disorders: Rectal hemorrhage. Stomatitis. Constipation / Stomatitis.
. General disorders and administration site conditions: Pain / Asthenia. Pain. Fever.
. Metabolism and nutrition disorders: Anorexia / -.
> = 1% and <10% :
. Eye disorders: Eye disorders / -.
. Disorders of the nervous system: dysgeusia.
. Respiratory, thoracic and mediastinal disorders: Epistaxis. Dyspnea. Rhinitis / -.
. Skin and subcutaneous tissue disorders: Exfoliative dermatitis. Depigmentation of the skin. Dryness / -.
Unadjusted data on the different treatment times .
- The following adverse events have been observed in patients treated with Avastin and may possibly be related to treatment with Avastin :
. Gastrointestinal perforations (see section warnings and precautions for use):
Avastin has been associated with severe cases of gastrointestinal perforation in patients with metastatic colorectal cancer.
In clinical trials in metastatic colorectal cancer, gastrointestinal perforation was observed in 1.4% to 2.0% of Avastin-treated patients, 0.4% to 1% of whom experienced a fatal outcome. The clinical picture of these events varied in nature and severity, ranging from the presence of free air observed on unintentional abdominal radiography (ASP), with spontaneous resolution without treatment, to perforation of the colon with abdominal abscess, and fatal outcome. The common feature of these observations was the presence of intra-abdominal inflammation due to gastric ulcer, tumor necrosis, diverticulitis or colitis associated with chemotherapy.
. Wound healing (see warnings and precautions section):
Since Avastin may impair wound healing, patients who had undergone major surgery in the last 28 days were excluded from clinical trial participation in metastatic colorectal cancer.
In clinical trials in metastatic colorectal cancer in patients operated on for their cancer within 28 to 60 days prior to initiation of treatment, there was no increased risk of postoperative bleeding or complications at wound healing, during treatment with Avastin, compared to the control group. Adverse events consistent with postoperative bleeding or complications of wound healing have been observed in 10% to 20% of patients treated with Avastin who underwent major surgery while undergoing treatment.
. Hypertension (see section warnings and precautions for use):
An increase in the incidence of high blood pressure has been observed in patients treated with Avastin. High blood pressure has generally been treated with oral antihypertensives such as angiotensin converting enzyme inhibitors, diuretics and calcium channel blockers. It rarely led to discontinuation of treatment (0.7% of all Avastin-treated patients) or hospitalization, and resulted in hypertensive encephalopathy in one case (0.1%).
There was no correlation between the risk of hypertension associated with the use of Avastin and baseline patient characteristics, underlying disease or concomitant treatment.
In clinical trials in metastatic colorectal cancer, all grades of hypertension occurred in 22.4% to 32.0% of patients treated with Avastin. Grade 3 hypertension (justifying oral antihypertensive therapy) has been reported in 11.0% to 16.0% of patients treated with Avastin. No hypertensive crisis (Grade 4) has been reported.
In treated patients, at the 24th week of treatment, the mean change in blood pressure from baseline was + 4.1 to + 5.4 mmHg for diastolic blood pressure and + 5.5 at + 8.4 mmHg for systolic blood pressure.
. Proteinuria (see section warnings and precautions for use):
Proteinuria, reported as an adverse event, was observed in 23.3% of all patients treated with Avastin. Proteinuria ranged in severity from chick-free, transient, trace-like to nephrotic syndrome; this proteinuria is Grade 1 in the majority of cases. Proteinuria observed in clinical trials has not been associated with renal dysfunction and has rarely justified definitive discontinuation of treatment.
In clinical trials in metastatic colorectal cancer, proteinuria was reported as an adverse event in 21.7% to 38.0% of patients treated with Avastin. Grade 4 proteinuria has not been reported.
. Haemorrhages (see section warnings and precautions for use):
Overall, 4.0% of NCI-CTC Grade 3 and 4 bleeding events were observed in all patients treated with Avastin. In clinical trials in metastatic colorectal cancer, there was no significant difference in the incidence of Grade 3 and 4 bleeding events between patients treated with Avastin (3.1% to 5.1%) and the control group (2.5% to 2.9%).
The bleeding events observed in clinical trials were mainly tumor-associated haemorrhages (see below) and minor mucocutaneous bleeding.
Tumor-associated haemorrhage was observed in the Phase I and Phase II studies. In patients with non-small cell lung cancer treated with Avastin, severe bleeding was observed in 9% (6% of whom were fatal) of patients. These events occurred abruptly in the form of major or massive haemoptysis in patients with squamous cell histology and / or central thoracic tumors near large vessels. In some cases, these haemorrhages were preceded by cavitation and / or necrosis of the tumor.
In rare cases, tumor-associated haemorrhage has also been observed in other types of tumors and in other localities including central nervous system (CNS) hemorrhages in a patient with occult metastatic hepatoma CNS (see section contraindications) and continuous blood oozing from sarcoma of the thigh with necrosis.
In clinical trials in metastatic colorectal cancer, tumor-associated haemorrhagic events were observed in 1% to 3% of patients treated with Avastin. The addition of Avastin did not result in a significant increase in the incidence or severity of Grade 3 or 4 bleeding events.
In all clinical trials, mucocutaneous haemorrhage was noted in 20% to 40% of patients treated with Avastin. These were mostly Grade 1 epistaxis according to the NCI-CTC criteria of less than 5 minutes duration, disappearing without treatment and not justifying changes to the regimen. In clinical trials in metastatic colorectal cancer, epistaxis was reported in 22.0% to 34.3% of patients treated with Avastin.
Less frequent minor cutaneomucous bleeding events have also been reported in other locations such as gingival or vaginal bleeding.
. Thromboembolism (see section warnings and precautions for use):
In clinical trials in metastatic colorectal cancer, the overall incidence of thromboembolic events was comparable in the Avastin-treated group (18.0% to 19.4%) and the control group (16.0%). 2% to 18.3%).
. Arterial thromboembolism :
In clinical trials in metastatic colorectal cancer, the incidence of arterial thromboembolic events including stroke, MI, TIA, and other arterial thromboembolic events was higher in the Avastin group (3.3 % to 10.0%) compared to the control group (1.3% to 4.8%).
In five randomized trials including metastatic colorectal cancer (N = 1745) arterial thromboembolic events including stroke, MI, TIA and other arterial thromboembolic events occurred in 4.5% (45 / 1004) compared with 2.0% (15/741) of patients treated with chemotherapy alone. In patients treated with Avastin in combination with chemotherapy, arterial thromboembolic events had a fatal outcome in 0.8% (8/1004) of cases. In patients treated with chemotherapy alone, a fatal outcome due to arterial thromboembolic events was reported in 0.4% (3/741) of the cases. Stroke (including TIA) occurred in 2.2% of patients treated with Avastin combined with chemotherapy and in 0.5% of patients treated with chemotherapy alone. MIs occurred in 1.9% of patients treated with Avastin combined with chemotherapy compared to 1.1% of patients treated with chemotherapy alone.
. Venous thromboembolism :
In clinical trials in metastatic colorectal cancer, venous thromboembolic events including deep venous thrombosis, pulmonary embolism and thrombophlebitis occurred in 9.0% to 16.6% of Avastin-treated patients compared with 13, 5% to 15.2% in the controls. It was not possible to determine whether these events were due to the underlying cancer of patients, cytotoxic chemotherapy, Avastin or other risk factors.
. Congestive Heart Failure (CHF) / Cardiomyopathy :
In the phase III clinical trial in metastatic breast cancer, ICC / cardiomyopathy was reported in 3% of patients treated with Avastin compared to 1% in the control group. These events varied in severity from an asymptomatic decline in left ventricular ejection fraction to symptomatic CHF justifying hospitalization and treatment. All patients treated with Avastin had been previously treated with anthracyclines (cumulative doses of doxorubicin ranging from 240 to 360 mg / m²). Many of these patients had previously undergone radiotherapy of the left chest wall. Most of these patients experienced improvement in their symptoms and / or left ventricular function following appropriate medical treatment.
There was no information on patients with pre-existing CHF (grade II-IV NYHA classification) at the time of initiation of treatment because these patients were excluded from the studies. There has been no increase in the incidence of CHF in patients with metastatic colorectal cancer treated with Avastin.
. Elderly patients :
Data from 5 randomized clinical trials show that age> 65 years was associated with an increased risk of development of arterial thromboembolic events including stroke, TIA, and MI during treatment with Avastin (see section 4.2). caution and precautions for use and adverse effects in Thromboembolism ). No increase in the incidence of events related to Avastin administration, including gastrointestinal perforation, complications of wound healing, hypertension, proteinuria, hemorrhage and congestive heart failure / cardiomyopathy, have been observed in elderly patients (> 65 years) with metastatic colorectal cancer treated with Avastin compared to those <= 65 years treated with Avastin.
In the Phase III clinical study in metastatic colorectal cancer (AVF2107g), 114 of the 392 patients who received Avastin were older than 65 years. Only Grade 3/4 leukopenia occurred with> = 5% incidence in elderly patients (> 65 years) compared to patients <= 65 years of age.
In a phase II study in metastatic colorectal cancer (AVF2192g), the majority of patients treated with Avastin were over 65 years of age (83%). The overall safety profile of Avastin from this study was comparable to the overall safety profile observed in the AVF2107g study.
. Anomalies of biological parameters :
A decrease in the number of neutrophils, a decrease in the number of white blood cells and the presence of urinary protein can be associated with Avastin.
In all clinical trials, decreased neutrophil counts and decreased white blood cell counts were the most frequently observed abnormalities in Grade 3 and 4 laboratory findings in patients treated with Avastin. In all clinical trials, Grade 3 and 4 laboratory abnormalities occurring in> = 5% of patients treated with Avastin alone or in combination with chemotherapy included decreased neutrophils, decreased white blood cell counts, presence of protein in the urine, a decrease in serum potassium and phosphoremia, an increase in blood glucose and alkaline blood phosphatases.
The higher incidence of decreased neutrophils and decreased white blood cell counts in the IFL + Avastin group may be related to an increase in the concentration of SN38, the active metabolite of irinotecan (see interactions section). ).

Popular Posts

Category Medicinal Products, Next Article